Article

Effect of Moderate Alcohol Consumption on Adiponectin, Tumor Necrosis Factor- , and Insulin Sensitivity

February 2004
Diabetes Care 27(1):184-9

February 2004
27(1):184-9

DOI:10.2337/diacare.27.1.184

Source
PubMed

Authors:

Epidemiological studies suggest that moderate alcohol consumers have enhanced insulin sensitivity and a reduced risk of type 2 diabetes. Adiponectin, an adipocyte-derived plasma protein, has been found to be negatively associated with adiposity and positively associated with insulin sensitivity. Moderate alcohol consumption may increase adiponectin, which in turn causes a decrease of tumor necrosis factor (TNF)-alpha. A decreased TNF-alpha level may consequently increase insulin sensitivity. To test this hypothesis, we performed a randomized crossover partially diet-controlled study. A total of 23 healthy middle-aged male subjects consumed daily four glasses of whisky (40 g ethanol) or tap water with dinner during two successive periods of 17 days. Moderate alcohol consumption increased plasma adiponectin level (11%; P = 0.0002) but did not affect plasma TNF-alpha level. An increase in insulin sensitivity index was observed in an insulin-resistant subgroup (21%; P = 0.11), which positively correlated with the relative alcohol-induced increase in plasma adiponectin level (r = 0.73, P = 0.02). The experimental results are in agreement with observational data. Moderate alcohol consumption improved insulin sensitivity in relatively insulin-resistant middle-aged men, an effect that may be mediated through alcohol-induced increases in adiponectin.

Novel paradigms for the gut–brain axis during alcohol withdrawal, withdrawal-associated depression, and craving in patients with alcohol use disorder

Article

Full-text available

Sep 2023

Introduction Patients with alcohol use disorder (AUD) exhibit symptoms such as alcohol withdrawal, depression, and cravings. The gut-immune response may play a significant role in manifesting these specific symptoms associated with AUD. This study examined the role of gut dysfunction, proinflammatory cytokines, and hormones in characterizing AUD symptoms. Methods Forty-eight AUD patients [men (n = 34) and women (n = 14)] aged 23–63 years were grouped using the Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA) as clinically significant (CS-CIWA [score > 10] [n = 22]) and a clinically not-significant group (NCS-CIWA [score ≤ 10] [n = 26]). Clinical data (CIWA, 90-day timeline followback [TLFB90], and lifetime drinking history [LTDH]) and blood samples (for testing proinflammatory cytokines, hormones, and markers of intestinal permeability) were analyzed. A subset of 16 AUD patients was assessed upon admission for their craving tendencies related to drug-seeking behavior using the Penn-Alcohol Craving Score (PACS). Results CS-CIWA group patients exhibited unique and significantly higher levels of adiponectin and interleukin (IL)-6 compared to NCS-CIWA. In the CS group, there were significant and high effects of association for the withdrawal score with gut-immune markers (lipopolysaccharide [LPS], adiponectin, IL-6, and IL-8) and for withdrawal-associated depression with gut-immune markers (scored using MADRS with LPS, soluble cells of differentiation type 14 [sCD14], IL-6, and IL-8). Craving (assessed by PACS, the Penn-Alcohol Craving Scale) was significantly characterized by what could be described as gut dysregulation (LBP [lipopolysaccharide binding protein] and leptin) and candidate proinflammatory (IL-1β and TNF-α) markers. Such a pathway model describes the heavy drinking phenotype, HDD90 (heavy drinking days past 90 days), with even higher effects (R² = 0.955, p = 0.006) in the AUD patients, who had higher ratings for cravings (PACS > 5). Discussion The interaction of gut dysfunction cytokines involved in both inflammation and mediating activity constitutes a novel pathophysiological gut–brain axis for withdrawal symptoms and withdrawal-associated depression and craving symptoms in AUD. AUD patients with reported cravings show a significant characterization of the gut–brain axis response to heavy drinking. Trial registration ClinicalTrials.gov, identifier: NCT# 00106106.

Moderate alcohol drinking with meals is related to lower incidence of type 2 diabetes

Article

Oct 2022
AM J CLIN NUTR

Background: Previous studies on alcohol drinking and health largely have ignored the potential impact of the timing of drinking. Objectives: We aimed to investigate the joint associations of the timing of alcohol intake with respect to meals (i.e., with meals or outside of meals) and the amount of alcohol consumed with the risk of type 2 diabetes (T2D). Methods: A total of 312,388 current drinkers from the UK Biobank without T2D at baseline were included. Cox proportional hazards models were used to examine the association between the timing of alcohol intake with respect to meals and the risk of T2D. Results: During a median of 10.9 y of follow-up, 8598 incident cases of T2D were documented. After adjustment for covariates and the amount of alcohol consumed, consuming alcohol with meals was significantly associated with a 12% lower risk of T2D (HR: 0.88; 95% CI: 0.83, 0.93) than was consuming alcohol outside of meals. In addition, we found that the timing of alcohol intake with respect to meals significantly modified the relations between the amount of alcohol consumed and risk of T2D (P-interaction = 0.017); the beneficial association of moderate drinking with T2D risk was only observed in participants who consumed alcohol with meals, but not in others. Further analyses on various types of alcoholic beverages indicated that the beneficial associations between alcohol drinking with meals and T2D were mainly driven by wine consumption. Moreover, we found that when consumed together with meals, drinking more wine, rather than other alcoholic beverages, was related to lower concentrations of C-reactive protein. Conclusions: In current drinkers, moderate drinking of alcohol, especially wine, with meals is associated with a lower risk of T2D.

Cigarette smoking is a risk factor for the onset of fatty liver disease in nondrinkers: A longitudinal cohort study

Article

Full-text available

Apr 2018
PLOS ONE

Background The effect of cigarette smoking on the onset of nonalcoholic fatty liver disease (NAFLD) is unclear, especially that associated with drinking small amounts of alcohol. We conducted a longitudinal study to investigate the relationship between cigarette smoking and NAFLD onset, which was stratified according to the amount of alcohol consumed. Methods We enrolled 7,905 Japanese subjects who had received annual health checkups more than twice between April 2003 and August 2013, 4,045 of whom met at least one of the following exclusion criteria and were excluded: (a) fatty liver at baseline; (b) hepatitis B or hepatitis C; (c) alcohol consumption (men: ≥210 g/wk; women: ≥140 g/wk); (d) change in alcohol drinking status between baseline and the study’s endpoint; (e) change in cigarette smoking habits between baseline and the study’s endpoint; or (f) current treatment with antidiabetic agents, antihypertensive agents, and/or lipid-lowering agents. The remaining 3,860 subjects (1,512 men, 2,348 women) were divided into two groups based on average alcohol consumption. Results After adjusting for the variables associated with metabolic disease, smoking was associated with fatty liver disease onset compared with nonsmokers in nondrinkers (adjusted hazard ratio = 1.988, 95% confidence interval 1.057–3.595; p = 0.034). No association was found between smoking and fatty liver disease onset in the low alcohol consumption group (men: <210 g alcohol/week; women: <140 g alcohol/week). The fatty liver disease incidence increased significantly among the nondrinkers as the number of cigarettes smoked increased (p = 0.001). Conclusions Cigarette smoking may be a significant risk factor associated with NAFLD onset in nondrinkers. These results may help clinicians to identify patients who are at a high risk of developing NAFLD and to prevent the progression of NAFLD by promoting earlier interventions that help people discontinue unhealthy lifestyle habits.

Alcohol consumption and its association with long-term prognosis among cardiovascular disease patients

Thesis

Apr 2022

Chengyi Ding

Moderate alcohol consumption has been reported to be cardio-protective among apparently healthy individuals, but it remains unclear if this association is also present in those with cardiovascular disease (CVD). Inconsistency exists across guidelines regarding the recommended drinking limits for CVD patients. This thesis consists of three studies aiming to better understand alcohol consumption in this patient population and its association with long-term prognosis. By pooling the results from de novo analyses of three cohorts and 12 published studies identified through a systematic review, meta-analyses of 48423 CVD patients (Study 1) found lower risk of mortality and subsequent cardiovascular events for an alcohol consumption up to 105 grams per week compared to current non-drinking. These effects, however, were significantly attenuated or absent after distinguishing former drinkers from non-drinkers. Meanwhile, little is known about the longitudinal dynamics of alcohol consumption in CVD patients and the associated health risks. With repeated-measures data from two cohorts (n=12502), Study 2 plotted CVD patients’ mean trajectory of weekly alcohol consumption as a function of time, centred on the date of diagnosis and spanning up to 30 years before and after the diagnosis. For male patients, mean consumption increased over time, peaked at eight years before diagnosis at 95 grams per week, and declined afterwards. A flatter trajectory was seen in female patients, which remained stable at around 30 grams per week and started to decline after diagnosis. In Study 3, alcohol consumption trajectory was further differentiated into six distinct groups in an inception cohort of 1306 patients with incident CVD and related to their subsequent mortality risk from all causes. Patients who consistently drank moderately (within 112 grams per week) had a similar risk of mortality as those who were continuous non-drinkers. While increases in risk were found among patients who stopped drinking compared to continuous moderate drinkers, former drinkers also had the worst self-rated health. Temporal variability in alcohol consumption highlights the importance of taking a longitudinal approach to examine alcohol health relations. Findings indicating protective effects of baseline moderate drinking in CVD patients may be largely explained by a referent group contaminated by less healthy former drinkers and are not seen when considering long-term drinking trajectories. This thesis provides novel knowledge about alcohol’s relation to cardiovascular health, which could be used to inform CVD patient care and low-risk drinking guidelines.

Drinking Frequency but not Years may be Associated with Lower Urinary Tract Symptoms: Result from a Large Cross-Sectional Survey in Chinese Men

Article

Full-text available

Jun 2020

Objective: To evaluate the effect of the drinking frequency and years on lower urinary tract symptoms (LUTS) in a large Chinese male population. Methods: The current data were obtained from a consecutive series of 3,229 men aged 18-79 who participated in a routine physical examination in Fangchenggang First People's Hospital, Guangxi, China. During a face-to-face interview, the detailed demographic variables about alcohol consumption, potential confounding factors were collected. LUTS were assessed by International Prostate Symptom Score (IPSS) and defined as total LUTS, irritative (IRR) and obstructive (OBS) symptoms, respectively. Multivariate logistic regression analysis was used to evaluate the risk of total LUTS, IRR and OBS symptoms affected by alcohol consumption. Results: The prevalence of moderate to severe LUTS was 8.3% and apparently increased with age (P<0.001). A significant distribution presented in age, alcohol consumption, BMI, cigarette smoking, education attainment and hypertension among different strata of LUTS severity (P<0.05). Men who drank 1-2 times per week were less likely to have OBS symptoms (OR=0.45, 95%CI=0.29-0.70) regardless of age (OR=0.52, 95%CI=0.33-0.82) or multivariate adjusted (OR=0.52, 95%CI=0.33-0.83). Nevertheless, we did not observe a significant negative or positive association presented between drinking years and the risk of total LUTS, OBS and IRR symptoms. Conclusion: The current results imply that moderate drinking frequency may be protective against LUTS, and drinking years did not relate to worsening or improving LUTS.

Alcohol and Human Health: What Is the Evidence?

Article

Mar 2020

Henk Hendriks

Alcohol consumption has long been a part of human culture. However, alcohol consumption levels and alcohol consumption patterns are associated with chronic diseases. Overall, light and moderate alcohol consumption (up to 14 g per day for women and up to 28 g per day for men) may be associated with reduced mortality risk, mainly due to reduced risks for cardiovascular disease and type-2 diabetes. However, chronic heavy alcohol consumption and alcohol abuse lead to alcohol-use disorder, which results in physical and mental diseases such as liver disease, pancreatitis, dementia, and various types of cancer. Risk factors for alcohol-use disorder are largely unknown. Alcohol-use disorder and frequent heavy drinking have detrimental effects on personal health.

Compared to non-drinkers, individuals who drink alcohol have a more favorable multisystem physiologic risk score as measured by allostatic load

Article

Full-text available

Sep 2019
PLOS ONE

Aims: Alcohol use is associated with both positive and negative effects on individual cardiovascular risk factors, depending upon which risk factor is assessed. The present analysis uses a summative multisystem index of biologic risk, known as allostatic load (AL), to evaluate whether the overall balance of alcohol-associated positive and negative cardiovascular risk factors may be favorable or unfavorable. Methods: This analysis included 1255 adults from the Midlife in the United States (MIDUS) biomarker substudy. Participants, average age 54.5 (±11) years, were divided into 6 alcohol-use categories based on self-reported drinking habits. Current non-drinkers were classified as lifelong abstainers and former light drinkers, former moderate drinkers, or former heavy drinkers. Current alcohol users were classified as light, moderate, or heavy drinkers. A total AL score was calculated using 24 biomarkers grouped into 7 physiologic systems including cardiovascular, inflammation, glucose metabolism, lipid metabolism, sympathetic and parasympathetic nervous systems, and the hypothalamic-pituitary-adrenal axis. Mixed-effects regression models were fit to determine the relationship between alcohol use categories and AL with controls for covariates that may influence the relationship between alcohol use and AL. Results: 468 (37.6%) individuals were current non-drinkers while 776 (62.4%) were current drinkers. In adjusted mixed-effects regression models, all 3 groups of current drinkers had significantly lower average AL scores than the lifelong abstainer/former light drinker group (light: -0.23, 95% CI -0.40, -0.07, p < 0.01; moderate: -0.20, 95% CI -0.38, -0.02, p < 0.05; heavy: -0.30, 95% CI -0.57, -0.04, p < 0.05), while the average AL scores of former moderate and former heavy drinkers did not differ from the lifelong abstainer/former light drinker group. Conclusions: Current alcohol use is associated cross-sectionally with a favorable multisystem physiologic score known to be associated with better long-term health outcomes, providing evidence in support of long-term health benefits related to alcohol consumption.

Comparison of the effect of light alcohol consumption on Japanese men with and without fatty liver

Article

Full-text available

Sep 2019

Light and moderate drinking is associated with lower risk of metabolic syndrome (Mets)-related diseases in the general population. Non-alcoholic fatty liver disease (NAFLD) is considered to be a phenotype of Mets in the liver. Although there have been some reports of the association between NAFLD and light alcohol consumption (LAC), the association between Mets-related diseases and LAC in the subjects with and without fatty liver is unclear. Therefore, this study aimed to determine the influence of LAC on Mets-related diseases in individuals with and those without fatty liver. This study included 1,190 men who underwent regular health check-ups and consumed <20 g/day of alcohol. The subjects were divided into two groups, the non-fatty liver group and fatty liver group, and investigated the association between Mets-related diseases and LAC. Fatty liver was diagnosed by abdominal ultrasound. The effect of LAC was different between the non-fatty liver and fatty liver groups. In the non-fatty liver group, the odds ratio (OR) for hypertension was 1.73 (1.04-2.88;2 P=0.035). In the fatty liver group, the OR for each Mets-related diseases were as follows: Dyslipidemia, 0.64 (0.44-0.95, P=0.028); impaired glucose tolerance 0.57 (0.37-0.88; P=0.012); chronic kidney disease, 0.58 (0.36-0.94; P=0.029); and Mets by Japanese criteria, 0.63 (0.44-0.92; P=0.016). The influence of LAC on Mets-related diseases differs based on the presence of fatty liver. In individuals without fatty liver, light drinking is an independent risk factor for hypertension.

Effects of Moderate Ethanol Consumption on Lipid Metabolism and Inflammation Through Regulation of Gene Expression in Rats

Article

Jan 2019
ALCOHOL ALCOHOLISM

Aims: Epidemiological studies and experimental data from rodent models have reported a non-linear relationship between consumption of alcohol and cardiovascular disease (CVD) risk that suggests that light-to-moderate drinking as opposed to excessive consumption may provide some cardiovascular benefits. The present study examined potential mechanisms by which moderate alcohol consumption may provide a protective effect against CVD. Short summary: Wistar rats exposed for 3 months to a 20% ethanol intermittent-access voluntary drinking paradigm displayed a reduction in epididymal fat, blood glucose and non-HDL and total cholesterol. These effects were accompanied by decreased expression of Hmgcr, Srebp-2, Cox-2 and RelA, indicating downregulation of genes involved in cholesterol synthesis and inflammation. Methods: Twenty-four male Wistar rats voluntarily consumed a 20% v/v ethanol solution on alternate days for 13 weeks (ethanol-treated) or were given access to water alone (non-ethanol-exposed control). Results: There was no difference in body weight gain between the two groups, however, epididymal fat weight was lower in ethanol-fed rats (P = 0.030). Blood glucose, total cholesterol, non-high-density lipoprotein (HDL) and oxidized low-density lipoprotein (LDL) levels were lower in the ethanol group compared to controls (P < 0.05). There was a significant reduction in the expression of hydroxymethylglutaryl-coenzyme A reductase and sterol regulatory element-binding protein-2 in ethanol-treated rats (P < 0.05), suggesting that ethanol may have lowered cholesterol levels via downregulation of genes involved in cholesterol synthesis. Paraoxonase-1, which is associated with inhibition of LDL cholesterol oxidation, was upregulated in the ethanol group (P = 0.029). Ethanol-treated rats exhibited significantly lower levels of high-mobility box group protein 1 (P ≤ 0.05). Cyclooxygenase-2 and RelA gene expression were significantly lower in ethanol-treated rats (P < 0.05), indicating possible anti-inflammatory effects. Conclusions: These findings suggest that moderate ethanol consumption may potentially contribute to improved cardiovascular outcomes by reducing body fat, improving blood cholesterol and blood glucose, and modulation of gene expression involved in inflammation and/or cholesterol synthesis.

Effects of dietary resveratrol supplementation on digestive enzymes activities and serum biochemistry of rainbow trout (Oncorhynchus mykiss)

Article

Full-text available

Nov 2023

Article history: The effects of resveratrol as an anti-oxidant in improving growth and health have been shown in several experiments. This study aimed to evaluate the effects of different dietary resveratrol inclusion levels on digestive enzymes activity and serum biochemistry of rainbow trout (Oncorhynchus mykiss). Accordingly, 225 juvenile rainbow trout with an average body weight of 10.00 ± 1.50 g were stocked in nine experimental units. The study was performed as a completely randomized design including three dietary levels of resveratrol as follows: 0.00, 400 and 800 mg kg-1 feed. During the experiment, fish were fed based on their respective body weight using standard feeding tables at three feeding times for 8 weeks. Nine fish were randomly selected from each treatment at the end of the 4 th and 8 th weeks of the experiment. Results revealed that supplementing 800 mg kg-1 feed resveratrol significantly increased lipase activity (31.40 ± 0.32 U mg-1 protein) compared to the control group (29.92 ± 0.52 U mg-1 protein) at the end of week eight. Also, at the same time, it increased serum high-density lipoprotein (123.04 ± 1.57 mg dL-1) compared to the control group (97.055 ± 1.463 mg dL-1). In addition, dietary supplementation of 800 mg kg-1 feed resveratrol effectively reduced serum alanine aminotransferase, alkaline phosphatase and aspartate aminotransferase activities along with glucose, cortisol and cholesterol. In conclusion, resveratrol can be used as a suitable food supplement to improve fish health by increasing digestive enzymes activities.

Moderate and heavy alcohol drinking were positively associated with severe coronary artery calcification in Chinese men, while smoking was not.

Preprint

Full-text available

Mar 2023

Background: Previous studies reached inconsistent conclusions about the relationship between alcohol or cigarette consumption and coronary artery calcification (CAC). We aim to explore the association between drinking and smoking with CAC in men. Methods: Male patients who underwent coronary angiography (CAG) and intravascular ultrasound (IVUS) and diagnosed with coronary heart disease (CHD) were retrospectively included. Maximum angle of calcified plaque (Arc) and calcium length were measured by IVUS to evaluate CAC severity. Drinking and smoking details were collected. Drinking and smoking were stratified to 4 layers according to weekly alcohol intake(g) and total smoking(package*years), respectively. Uni- and multivariable analysis were performed to explore the association between drinking and smoking with severe coronary artery calcification (SCAC). Results: Totally, 359 men with CHD were included, of whom 151 were regular drinkers and 275 were smokers. Compared with non-drinkers, calcium length in light drinkers decreased (P<0.05), both Arc and calcium length in moderate and heavy drinkers increased (all P<0.05). Weekly alcohol intake was positively correlated with Arc and calcium length (r=0.490, P<0.001; r=0.381, P<0.001). A negative association was found between light drinking and SCAC (OR: 0.492, 95%CI: 0.177-1.372, P=0.175), while moderate (OR: 5.244, 95%CI: 2.245-12.252, P＜0.001) and heavy drinking (OR: 15.238, 95%CI: 5.695-40.767, P＜0.001) were positively associated with SCAC. No associations were found between smoking and SCAC (P>0.05). Conclusions: Light drinking showed a slight negative association with SCAC, whereas moderate and heavy drinking were positively associated with SCAC in Chinese men. No associations were found between smoking and SCAC.

Prospective Association of Circulating Adipokines with Cardiometabolic Risk Profile Among Women: The Rape Impact Cohort Evaluation Study

Article

Full-text available

Oct 2022

Background: Sexual violence is associated with poor cardiometabolic outcomes, yet the etiopathogenic pathways remain unclear. Adipokines may contribute to pathways in the development of cardiometabolic disease (CMD), including in vulnerable populations. Further investigation of adipokines among sexually traumatized individuals may inform cardiometabolic screening. This study aimed to investigate the association between circulating adipokines, metabolic syndrome (MetS), and longitudinal change in MetS components (namely abdominal obesity, blood pressure, lipid profile, and glycemic status) over a 1-year period in a cohort of rape exposed (RE) and rape unexposed (RUE) females. Materials and methods: Seven hundred seventy-eight RE and 617 RUE black South African women aged 18-40 years were recruited for the Rape Impact Cohort Evaluation study. Nonfasting blood samples were analyzed for cardiometabolic variables and adipokine levels using enzyme-linked immunosorbent assay. Serum adiponectin was measured in both RE and RUE and resistin, leptin, and leptin/adiponectin (L/A) ratio in RE only. Associations between baseline serum adipokines, MetS, and its components were assessed at baseline and follow-up using adjusted linear and logistic regressions. Results: In the RE group, adiponectin, leptin, and L/A ratio were significantly associated with MetS prevalence cross-sectionally (all p ≤ 0.001). No adipokine marker was related to incident MetS at 12-month follow-up. In the RE group, significant longitudinal associations with high-density lipoprotein cholesterol were shown for adiponectin (β = 0.146 [0.064], p = 0.022) and leptin (β = 0.001 [0.002], p = 0.012). Conclusions: Findings suggest that adipokines may have a potential role as biomarkers to identify RE individuals at high risk for CMD.

Prevalence of metabolic syndrome and its related factors among Vietnamese people: A systematic review and meta-analysis

Article

Apr 2022

Background and aims Metabolic risk factors are the leading causes of mortality and morbidity in recent decades, yet the burden of metabolic syndrome (MetS) has not been carefully assessed in Vietnam. This review thus aims to examine the prevalence of MetS and its related factors in Vietnam. Methods A systematic review was conducted using literature retrieved from PubMed/Medline, Web of Science, Embase, Scopus, and Google Scholar up until July 2021. We selected descriptive and analytical studies which reported the prevalence of MetS and related factors among healthy people aged less than 65 years old rather than morbid people in Vietnam. A meta-analysis with a random-effects model was applied to estimate the pooled prevalence from the included studies. Results Eighteen studies with 35421 participants were included in the final analysis. The pooled MetS prevalence among the adult population in Vietnam was 16.1% (95% Confidence Interval (CI): 14.1%–18.1%). Higher prevalence was seen among females (17.3%, 95% CI: 13.8%–20.8%). Low level of High Density Lipoprotein-Cholesterol (HDL-C) was the most prevalent component (34.1%), followed by high triglycerides (33.3%). Being female, living in urban areas, having obesity, and having a higher body mass index or body fat percentage were associated with an increased likelihood of having MetS. Conclusions MetS was common in the Vietnamese population. Low HDL-C should be considered as an early detectable indicator for MetS screening programs at the population level. Appropriate interventions should be conducted for high-risk groups such as females, those living in urban areas, and obesity.

A review of the role of ethanol-induced adipose tissue dysfunction in alcohol-associated liver disease

Article

Sep 2021
ALCOHOL CLIN EXP RES

Alcohol-associated liver disease (AALD) encompasses a spectrum of liver diseases that includes simple steatosis, steatohepatitis, fibrosis, and cirrhosis. The adverse effects of alcohol in liver and the mechanisms by which ethanol (EtOH) promotes liver injury are well studied. Although liver is known to be the primary organ affected by EtOH exposure, alcohol's effects on other organs are also known to contribute significantly to the development of liver injury. It is becoming increasingly evident that adipose tissue (AT) is an important site of EtOH action. Both AT storage and secretory functions are altered by EtOH. For example, AT lipolysis, stimulated by EtOH, contributes to chronic alcohol-induced hepatic steatosis. Adipocytes secrete a wide variety of biologically active molecules known as adipokines. EtOH alters the secretion of these adipokines from AT, which include cytokines and chemokines that exert paracrine effects in liver. In addition, the level of EtOH-metabolizing enzymes, in particular, CYP2E1, rises in the AT of EtOH-fed mice, which promotes oxidative stress and/or inflammation in AT. Thus, AT dysfunction characterized by increased AT lipolysis and free fatty acid mobilization and altered secretion of adipokines can contribute to the severity of AALD. Of note, moderate EtOH exposure results in AT browning and activation of brown adipose tissue which, in turn, can promote thermogenesis. In this review article, we discuss the direct effects of EtOH consumption in AT and the mechanisms by which EtOH impacts the functions of AT, which, in turn, increases the severity of AALD in animal models and humans.

Alcohol and Metabolic-associated Fatty Liver Disease

Article

Full-text available

Jul 2021

The diagnosis of metabolic-associated fatty liver disease is based on the detection of liver steatosis together with the presence of metabolic dysfunction. According to this new definition, the diagnosis of metabolic-associated fatty liver disease is independent of the amount of alcohol consumed. Actually, alcohol and its metabolites have various effects on metabolic-associated abnormalities during the process of alcohol metabolism. Studies have shown improved metabolic function in light to moderate alcohol drinkers. There are several studies focusing on the role of light to moderate alcohol intake on metabolic dysfunction. However, the results from studies are diverse, and the conclusions are often controversial. This review systematically discusses the effects of alcohol consumption, focusing on light to moderate alcohol consumption, obesity, lipid and glucose metabolism, and blood pressure.

Insulin Resistance as a Common Link Between Current Alzheimer’s Disease Hypotheses

Article

May 2021
J ALZHEIMERS DIS

Almost 115 years ago, Alois Alzheimer described Alzheimer’s disease (AD) for the first time. Since then, many hypotheses have been proposed. However, AD remains a severe health public problem. The current medical approaches for AD are limited to symptomatic interventions and the complexity of this disease has led to a failure rate of approximately 99.6%in AD clinical trials. In fact, no new drug has been approved for AD treatment since 2003. These failures indicate that we are failing in mimicking this disease in experimental models. Although most studies have focused on the amyloid cascade hypothesis of AD, the literature has made clear that AD is rather a multifactorial disorder. Therefore, the persistence in a single theory has resulted in lost opportunities. In this review, we aim to present the striking points of the long scientific path followed since the description of the first AD case and the main AD hypotheses discussed over the last decades. We also propose insulin resistance as a common link between many other hypotheses.

Modest alcohol consumption and risk of advanced liver fibrosis in nonalcoholic fatty liver disease: a systematic review and meta-analysis

Article

Full-text available

Jul 2021

Karn Wijarnpreecha

Background: Recent studies have suggested an association between modest alcohol consumption and a decreased risk of advanced liver fibrosis among patients with nonalcoholic fatty liver disease (NAFLD) although the results are inconsistent. The current systematic review and meta-analysis was conducted to comprehensively investigate this possible association by identifying all the relevant studies and combining their results. Methods: A comprehensive literature review was conducted utilizing the MEDLINE and EMBASE databases through February 2019 to identify all cross-sectional studies that compared the prevalence of advanced liver fibrosis among NAFLD patients who were modest alcohol drinkers to NAFLD patients who were non-drinkers. Effect estimates from each study were extracted and combined together using the random-effect, generic inverse variance method of DerSimonian and Laird. Results: A total of 6 studies with 8,936 participants fulfilled the eligibility criteria and were included in the meta-analysis. The risk of advanced liver fibrosis among patients with NAFLD who were modest alcohol drinkers was significantly lower compared to patients with NAFLD who were non-drinkers with a pooled odds ratio of 0.51 (95% confidence interval [CI] 0.35-0.75; I2 47%). The funnel plot was symmetric and was not suggestive of publication bias. Conclusion: A significantly lower risk of advanced liver fibrosis was observed among NAFLD patients who were modest alcohol drinkers compared to non-drinkers in this meta-analysis.

Genetic ablation of C-reactive protein gene confers resistance to obesity and insulin resistance in rats

Article

Full-text available

May 2021
DIABETOLOGIA

Aims/hypothesis Besides serving as a traditional inflammatory marker, C-reactive protein (CRP) is closely associated with the development of obesity, diabetes and cardiovascular diseases as a metabolic and inflammatory marker. We hypothesise that CRP protein directly participates in the regulation of energy and glucose metabolism rather than just being a surrogate marker, and that genetic deficiency of CRP will lead to resistance to obesity and insulin resistance. Methods Crp gene deletion was achieved by transcription activator-like effector nuclease (TALEN) technology in rats. The Crp knockout animals were placed on either a standard chow diet or a high-fat diet. Phenotypic changes in body weight, glucose metabolism, insulin sensitivity, energy expenditure and inflammation condition were examined. The central impact of CRP deficiency on leptin and insulin hypothalamic signalling, as well as glucose homeostasis, were examined via intracerebral ventricular delivery of leptin and CRP plus glucose clamp studies in the wild-type and Crp knockout rats. Results CRP deficiency led to a significant reduction in weight gain and food intake, elevated energy expenditure and improved insulin sensitivity after exposure to high-fat diet. Glucose clamp studies revealed enhanced hepatic insulin signalling and actions. Deficiency of CRP enhanced and prolonged the weight-reducing effect of central injected leptin and promoted the central and peripheral roles of leptin. By contrast, reinstatement of CRP into the hypothalamus of the knockout rats attenuated the effects of central leptin signalling on insulin sensitivity and peripheral glucose metabolism. Conclusions/interpretation This study represents the first line of genetic evidence that CRP is not merely a surrogate blood marker for inflammation and metabolic syndromes but directly regulates energy balance, body weight, insulin sensitivity and glucose homeostasis through direct regulation of leptin’s central effect and hypothalamic signalling. Graphical abstract

Moderate alcohol consumption is associated with impaired insulin secretion and fasting glucose in non-obese non-diabetic men

Article

Full-text available

Oct 2020

Aims: A low insulin secretion capacity has been implicated in the high prevalence of non-obese diabetes in East Asians. Since alcohol consumption alters insulin and glucose metabolism, we tested the hypothesis that alcohol consumption contributes to impaired insulin secretion and glucose intolerance in lean/normal-weight non-diabetic Japanese men. Methods: This cross-sectional study was undertaken among the residents of Shika town, Japan between 2011 and 2017. A total of 402 non-diabetic men, including participants with normal fasting plasma glucose (FPG) and impaired FPG (FPG 5.6 - 6.9 mmol/l) and aged ≥40 years old, were examined. FPG, the homeostasis model assessment of insulin secretion capacity (HOMA-B), and alcohol consumption were evaluated and compared between the BMI <25 and BMI ≥25 groups. Results: HOMA-B levels were lower in the BMI <25-group than in the BMI ≥25-group. Alcohol consumption correlated with a low HOMA-B level regardless of BMI, and, thus, the HOMA-B levels of alcohol drinkers were significantly lower in the BMI <25-group. A multivariable logistic regression analysis showed that alcohol consumption, even light to moderate consumption (1 - 25 g/day), was associated with significantly low levels of HOMA-B and impaired FPG in the BMI <25-group. Among participants with impaired FPG, a low level of HOMA-B was observed in alcohol drinkers, but not in non-drinkers. In contrast, light to moderate alcohol consumption was not related to HOMA-B or FPG in the BMI ≥25-group. Conclusion: Alcohol consumption, even a small amount, may contribute to reductions in HOMA-B levels and impaired FPG in lean/normal-weight Japanese men.

The effects of wine consumption on cardiovascular disease and associated risk factors: a narrative review

Article

Full-text available

Mar 2018

Accumulating evidence suggests that regular moderate consumption of wine can positively influence risk factors associated with cardiovascular health. These effects are often attributed to grape and wine-derived phenolic compounds and their effects on risk factors such as atherosclerosis, for which mechanisms have been clearly identified, such as a decrease in the oxidation of LDL-cholesterol and reduction of oxidative stress, and an increase in nitric oxide and related restoration of endothelial function. In addition, the ethanol component of wine increases HDL-cholesterol, inhibits platelet aggregation, promotes fibrinolysis and reduces systemic inflammation. Scientific research needs to be conducted, however, before we can begin to provide science-based dietary recommendations, although there is sufficient evidence to generally recommend consuming food sources rich in bioactive compounds such as wine in moderation. This narrative review examines published evidence on the cardioprotective effects associated with wine-derived compounds, with a primary focus on the development and progression of atherosclerosis and thrombosis.

Dietary Habits and Nutrition in Rheumatoid Arthritis: Can Diet Influence Disease Development and Clinical Manifestations?

Article

Full-text available

May 2020

Rheumatoid arthritis (RA) is a systemic, autoimmune disease characterized by joint involvement, with progressive cartilage and bone destruction. Genetic and environmental factors determine RA susceptibility. In recent years, an increasing number of studies suggested that diet has a central role in disease risk and progression. Several nutrients, such as polyunsaturated fatty acids, present anti-inflammatory and antioxidant properties, featuring a protective role for RA development, while others such as red meat and salt have a harmful effect. Gut microbiota alteration and body composition modifications are indirect mechanisms of how diet influences RA onset and progression. Possible protective effects of some dietary patterns and supplements, such as the Mediterranean Diet (MD), vitamin D and probiotics, could be a possible future adjunctive therapy to standard RA treatment. Therefore, a healthy lifestyle and nutrition have to be encouraged in patients with RA.

Prospective Associations of Serum Adiponectin, Leptin, and Leptin-Adiponectin Ratio with Incidence of Metabolic Syndrome: The Korean Genome and Epidemiology Study

Article

Full-text available

May 2020
Int J Environ Res Publ Health

Although the role of adiponectin and leptin in the etiology of metabolic syndrome (MetS) has been explored in various populations, limited knowledge is available on the prospective association of adiponectin and leptin with the risk of MetS development. The present study aimed to evaluate the associations of adiponectin, leptin, and the leptin-adiponectin (LA) ratio with the future risk of MetS in middle-aged and older Korean adults. Using a prospective, population-based Ansan-Ansung cohort of the Korean Genome and Epidemiology Study (KoGES), 2691 Korean adults (1317 men and 1374 women) were included in the present study. Serum adiponectin and leptin concentrations were measured using commonly available enzyme-linked immunosorbent assay kits. Multivariable Cox proportional hazard models were used to investigate the relationships of the different adiponectin and leptin concentrations and LA ratio with the incident MetS. During a mean follow-up of 6.75 years, a total of 359 (27.26%) men and 385 (28.02%) women were identified as developing new-onset MetS. After controlling for covariates, higher adiponectin levels were associated with lower incidence of MetS (hazard ratio (HR) for third vs. first tertile: 0.53, 95% confidence interval (CI): 0.40–0.70 for men and HR: 0.54, 95% CI: 0.42–0.71 for women), while higher leptin levels (HR for third vs. first tertile: 2.88, 95% CI: 2.01–4.13 for men and HR: 1.55, 95% CI: 1.13–2.13 for women) and LA ratio (HR for third vs. first tertile: 3.07, 95% CI: 2.13–4.44 for men and HR: 1.94, 95% CI: 1.41–2.66 for women) were associated with an increased incidence of MetS. Among men, in the fully adjusted models an increase by one standard deviation (SD) in adiponectin levels was associated with a 10% decrease in MetS risk (HR per SD: 0.90, 95% CI: 0.85–0.95) while leptin and LA ratio was associated with a 5% (HR per SD: 1.05, 95% CI: 1.01–1.08) and 40% (HR per SD: 1.40, 95% CI: 1.22–1.62) increase in MetS risk, respectively. Among women, a significant association with MetS risk was observed only in adiponectin levels (HR per SD: 0.91, 95% CI: 0.88–0.95). We found that higher adiponectin level was associated with a lower risk of MetS, while higher leptin level and LA ratio were associated with elevated MetS incidence, irrespective of body mass index at baseline in both Korean men and women. Adiponectin and leptin levels and LA ratio could play a role as a useful biomarker in the prediction of future MetS development among middle-aged and older Koreans.

Alcohol-induced impaired insulin secretion in a Japanese population: Five-year follow-up in the Gifu Diabetes Study

Article

Full-text available

May 2020

Aims/Introduction While moderate alcohol consumption lowers the risk of type 2 diabetes in European populations, the same cannot be assumed for Japanese patients with diabetes related to low insulin secretion rather than resistance. We aimed to evaluate the effects of daily alcohol consumption on glucose tolerance and diabetes development risk in Japanese populations. Materials and Methods This retrospective study randomly enrolled 452 men and 659 women aged 40–78 years in 2005 (Gifu, Japan). The participants completed a 75‐g oral glucose tolerance test and medical questionnaire. The homeostasis model assessment of insulin resistance (HOMA‐R), β‐cell function (HOMA‐β), and insulinogenic index were used to estimate insulin sensitivity and secretion. The relationships between alcohol consumption and these parameters were analyzed using logistic regression after adjusting for potential confounders. The 5‐year changes in hemoglobin A1c (HbA1c) levels were also evaluated. Results The adjusted odds ratios for elevated HOMA‐β values (<40%) in the 0–19.9 g/day, 20.0–39.9 g/day, and ≥40 g/day alcohol consumption groups were 0.98, 1.46, and 2.68, respectively. Alcohol consumption induced a significant decrease in the insulin secretion level among the ≥40 g/day drinkers, especially in men. However, there was no risk of increased insulin resistance based on the HOMA‐R (<2.5) results. The 5‐year risk of elevated HbA1c levels (≥ 6.5%) was increased according to increase in alcohol consumption in both men and women. Conclusions Daily alcohol consumption was associated with reduced insulin secretion and an increased diabetes development risk in Japanese populations.

Ethnopharmacological Applications Targeting Alcohol Abuse: Overview and Outlook

Article

Full-text available

Feb 2020

Excessive alcohol consumption is the cause of several diseases and thus is of a major concern for society. Worldwide alcohol consumption has increased by many folds over the past decades. This urgently calls for intervention and relapse counteract measures. Modern pharmacological solutions induce complete alcohol self-restraint and prevent relapse, but they have many side effects. Natural products are most promising as they cause fewer adverse effects. Here we discuss in detail the medicinal plants used in various traditional/folklore medicine systems for targeting alcohol abuse. We also comprehensively describe preclinical and clinical studies done on some of these plants along with the possible mechanisms of action.

Interaction Between Alcohol Use and Metabolic Risk Factors for Liver Disease: A Critical Review of Epidemiological Studies

Article

Dec 2019

Co-existence of alcohol use and metabolic risk - the two commonest population risk factors for non-viral chronic liver disease - is a growing concern. Clinical and mechanistic evidence point to considerable supra-additive interaction effects for the development and progression of chronic liver disease between hazardous alcohol use and metabolic abnormalities including obesity, diabetes, and the metabolic syndrome. Intermittent binge drinking once monthly or more often seems to be associated with progression of liver disease even when average alcohol intake is within the currently allowed limits for a diagnosis of non-alcoholic fatty liver disease (NAFLD), and supra-additive interaction between binge drinking and the metabolic syndrome has been reported. There are contradictory findings regarding the association between low alcohol use and liver steatosis, but, clearly, the mechanisms of alcoholic hepatotoxicity extend beyond simple fat accumulation. The presence of liver steatosis seems to amplify alcoholic hepatotoxicity. Recent longitudinal studies of NAFLD subjects report low alcohol use associated with both increased fibrosis progression and an elevated risk for liver cancer and severe liver disease. There is no clear safe limit of alcohol intake in the presence of NAFLD or metabolic risk. The interaction effects between alcohol and metabolic dysfunction merit increased attention in public health policy, individual counseling, and risk stratification. Based on current evidence, a strict dichotomization of liver disease into either pure alcoholic or non-alcoholic may be inappropriate.

Wine, alcohol, polyphenols and cardiovascular disease

Article

Jan 2014

Role of Mechanistic Target of Rapamycin and Autophagy in Alcohol-Induced Adipose Atrophy and Liver Injury

Article

Nov 2019

Chronic alcohol consumption induces adipose tissue atrophy. However, the mechanisms for how alcohol induces lipodystrophy and its impact on liver steatosis and injury are not fully elucidated. Autophagy is a highly conserved lysosomal degradation pathway, which regulates cellular homeostasis. Mice with autophagy-deficiency in adipose tissue have impaired adipogenesis. However, whether autophagy plays a role in alcohol-induced adipose atrophy and how altered adipocyte autophagy contributes to alcohol-induced liver remains unclear. To determine the role of adipose autophagy and mTOR in alcohol-induced adipose and liver pathogenesis, we generated adipocyte-specific Atg5 knockout (A-Atg5 KO), A- mTOR (mechanistic target of rapamycin) KO, A-Raptor KO, and A-TSC1 (tuberous sclerosis complex 1) KO mice by crossing floxed mice with Adipoq-Cre. The KO mice and their matched wild-type (WT) mice were challenged with chronic-plus-binge (Gao-binge) alcohol mouse model. Gao-binge alcohol induced adipose atrophy with increased autophagy and decreased Akt/mTOR signaling in epididymal adipose tissue in WT mice. A-Raptor KO mice experienced exacerbated alcohol-induced steatosis, but neither A-mTOR nor A-TSC1 KO mice exhibited similar detrimental effects. A-Atg5 KO mice had increased circulating levels of fibroblast growth factor 21 (FGF21) and adiponectin, which were resistant to alcohol-induced adipose atrophy and liver injury. In conclusion, autophagy deficiency in adipose tissue leads to reduced sensitivity to alcohol-induced adipose atrophy, which ameliorates alcohol-induced liver injury in mice.

Relationship between Plasma Adiponectin Level and Peptic Ulcer Disease

Article

Full-text available

Jun 2019

Obesity in acute alcoholic hepatitis increases morbidity and mortality

Article

Full-text available

Jul 2019

Background: Alcohol and obesity synergise to increase the risk of liver-related mortality. We examined the influence of adiposity on clinical outcomes in alcoholic hepatitis (AH) and the underlying inflammatory crosstalk between adipose tissue (AT) and the liver. Methods: A cohort of 233 patients with AH from the UK and USA provided data to analyse the effects of obesity in AH. Body mass index was corrected for the severity of ascites, termed cBMI. Inflammatory and metabolic profiling was undertaken by proteome analysis of human serum samples. The effect of alcohol on adipose tissue and CXCL11 expression was studied in 3 T3-derived adipocytes and in mice using the high-fat diet-plus-binge ethanol model. Findings: Obesity was common amongst patients with AH, seen in 19% of individuals. Obesity (HR 2.22, 95%CI 1.1-4.3, p = .022) and underweight (HR 2.38, 1.00-5.6, p = .049) were independently associated with mortality at 3 months. Proteome analysis demonstrated multiple metabolic and inflammatory factors differentially expressed in obese AH verse lean AH, with CXCL11 being the most elevated factor in obese AH. In vitro analysis of cultured adipocytes and in vivo analysis of mouse models showed that alcohol induced CXCL11 expression in AT, but not in liver. Interpretation: Obesity is common in AH and associated with a greater than two-fold increase in short-term mortality. Obese AH is associated with a different inflammatory phenotype, with the greatest elevation in CXCL11. These data confirm that adiposity is clinically important in acute alcohol-related liver disease and illustrate the adipose-liver inflammatory axis in AH. FUND: This work was supported in part by an EASL Sheila Sherlock Physician Scientist Fellowship. The funder played no role in gathering or analysing data or writing the manuscript. This paper presents independent research supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

The 2015 Dutch Food-Based Dietary Guidelines on Alcohol Consumption - A Critical Review

Article

Sep 2018

Early vascular damage from smoking and alcohol in teenage years: The ALSPAC study

Article

Full-text available

Aug 2018

Aims: To determine the impact of smoking and alcohol exposure during adolescence on arterial stiffness at 17 years. Methods and results: Smoking and alcohol use were assessed by questionnaires at 13, 15, and 17 years in 1266 participants (425 males and 841 females) from the ALSPAC study. Smoking status (smokers and non-smoker) and intensity (‘high’ >_100, ‘moderate’ 20–99, and ‘low or never’ <20 cigarettes in lifetime) were ascertained. Participants were classified by frequency (low or high) and intensity of drinking [light (LI <2), medium (MI 3–9), and heavy (HI >10 drinks on a typical drinking day)]. Carotid to femoral pulse wave velocity (PWV) was assessed at 17 years [mean ± standard deviation and/or mean difference (95% confidence intervals)]. Current smokers had higher PWV compared with non-smokers (P = 0.003). Higher smoking exposure was associated with higher PWV compared with non-smokers [5.81 ± 0.725 vs. 5.71 ± 0.677 m/s, mean adjusted difference 0.211 (0.087–0.334) m/s, P = 0.001]. Participants who stopped smoking had similar PWV to never smokers (P = 0.160). High-intensity drinkers had increased PWV [HI 5.85 ± 0.8 vs. LI 5.67 ± 0.604 m/s, mean adjusted difference 0.266 (0.055–0.476) m/s, P = 0.013]. There was an additive effect of smoking intensity and alcohol intensity, so that ‘high’ smokers who were also HI drinkers had higher PWV compared with never-smokers and LI drinkers [mean adjusted increase 0.603 (0.229–0.978) m/s, P = 0.002]. Conclusion: Smoking exposure even at low levels and intensity of alcohol use were associated individually and together with increased arterial stiffness. Public health strategies need to prevent adoption of these habits in adolescence to preserve or restore arterial health.

Effect of Alcohol Consumption on Survival in Nonalcoholic Fatty Liver Disease: A National Prospective Cohort Study

Article

Aug 2018

Nonalcoholic fatty liver disease (NAFLD) comprises more than two thirds of patients with chronic liver disease in the United States. The effect of alcohol consumption on survival in patients with NAFLD is not clear. We gathered data on National Health and Nutrition Examination Survey (NHANES) participants from 1988 to 2010, and linked them to National Death Index (NDI) for follow up of their survival. We diagnosed NAFLD based on a previously validated biochemical model (Hepatic Steatosis Index). We built multivariate Cox proportional hazards models to evaluate the effect of alcohol consumption on survival of patients with NAFLD. After excluding participants with significant alcohol use, viral hepatitis, or increased transferrin Saturation 4568 participants with NAFLD were included in the analysis. In a Cox model adjusted for age, sex, and smoking history, drinking 0.5‐1.5 drinks per day decreased the risk of overall mortality by 41% (HR=0.59, 95%CI 0.40‐0.85, p value=0.005) compared to not drinking. Drinking > 1.5 drinks per day showed a trend towards harm (HR=1.16, 95% CI 0.99‐1.36, p value=0.119). After further adjustment for race, physical activity, educational level, diabetes, and fiber and polyunsaturated fatty acid intake, drinking 0.5‐1.5 drinks per day continued to show a significant protective effect (HR=0.64, 95% CI 0.42‐0.97, p value=0.035), and drinking > 1.5 drinks per day showed a significant harmful effect on mortality (HR=1.45, 95% CI 1.01‐2.10, p value=0.047). Among patients with NAFLD modest alcohol consumption is associated with a significant decrease in all‐cause mortality, while drinking >1.5 drinks per day is associated with an increase in mortality. These results help to inform the discussion of potential risks and benefits of alcohol use in patients with NAFLD. This article is protected by copyright. All rights reserved.

RED WINE, GRAPE JUICE OR RESVERATROL CONSUMPTION EFFECTS ON LIPID AND GLYCEMIC PROFILE AND HEPATIC MORPHOLOGY OF WISTAR RATS SUBMITTED TO HIGH FAT DIET AND PHYSICAL TRAINING

Article

Full-text available

Dec 2017

When an enemy becomes a friend. On the benefits of alcohol consumption

Article

Full-text available

Apr 2018

While use of high doses of alcohol is a proven risk factor for various organs and systems, use of small and moderate doses bears evidence of the opposite data. Thus, regularly drinking a small amount of alcoholic drinks could reduce a person’s chances of developing coronary heart disease, stroke, type 2 diabetes, non-alcoholic fatty liver disease, osteoporosis and some other diseases, and also reduce overall mortality. Small doses of alcohol suppress the inflammation and peroxidation, normalize hemocoagulation, improve the lipid profile, favourably affect blood vessel tone and the insulin-signaling pathways. Positive effects of wine are the most studied, which is usually explained by the fact that it contains polyphenols, while positive effects of beer are studied to a lesser extent; however, it should be borne in mind that the studies were aimed at different types of alcoholic beverages. Thus, it can be considered inappropriate to completely prohibit the use of alcohol to persons without dependence and specific organ damage.

"Non-Alcoholic Fatty Liver Disease - Molecular Bases, Prevention and Treatment "

Book

Full-text available

Mar 2018

Ian J Martins

Nutritional diets are essential to prevent nonalcoholic fatty liver disease (NAFLD) in the global obesity and diabetes epidemic. The ingestion of palmitic acid-rich diets induces NAFLD in animal and human studies. The beneficial properties of olive oil (oleic acid) may be superseded by ingestion of palmitic acid-rich diets. Hepatic caffeine metabolism is regulated by palmitic and oleic acid with effects of these fats on amyloid beta metabolism. Healthy fats such as olive oil may facilitate rapid amyloid beta clearance in the periphery to maintain drug therapy in diabetes and various neurological diseases. Repression of the anti-aging gene sirtuin 1 (Sirt 1) prevents the beneficial properties of olive oil. Brain disorders induce NAFLD and supersede caffeine’s therapeutic effects in the prevention of NAFLD. Delayed hepatic caffeine metabolism in NAFLD and increased caffeine transport to the brain with aging-induced mitophagy in neurons with induction of type 3 diabetes and neurodegenerative disease.

Is There a Safe Alcohol Consumption Limit for the General Population and in Patients with Liver Disease?

Article

Apr 2024

Excessive alcohol consumption represents an important burden for health systems worldwide and is a major cause of liver- and cancer-related deaths. Alcohol consumption is mostly assessed by self-report that often underestimates the amount of drinking. While alcohol use disorders identification test - version C is the most widely used test for alcohol use screening, in patients with liver disease the use of alcohol biomarker could help an objective assessment. The amount of alcohol that leads to significant liver disease depends on gender, genetic background, and coexistence of comorbidities (i.e., metabolic syndrome factors). All patients with alcohol-associated liver disease are recommended to follow complete abstinence and they should be treated within multidisciplinary teams. Abstinence slows down and even reverses the progression of liver fibrosis and can help recompensate patients with complicated cirrhosis. Whether there is a safe amount of alcohol in the general population is a matter of intense debate. Large epidemiological studies showed that the safe amount of alcohol to avoid overall health-related risks is lower than expected even in the general population. Even one drink per day can increase cancer-related death. In patients with any kind of chronic liver disease, especially in those with metabolic-associated steatotic liver disease, no alcohol intake is recommended. This review article discusses the current evidence supporting the deleterious effects of small-to-moderate amounts of alcohol in the general population and in patients with underlying chronic liver disease.

Plain water intake in the prevention and management of type 2 diabetes mellitus (T2DM) – A study of biomarkers associated with insulin resistance in a black African population

Article

Mar 2024

You are What You Drink? How Associations Between Profiles of Beverage Consumption and Type 2 Diabetes Risk are Mediated by Biomarker Networks

Article

Apr 2023
AM J CLIN NUTR

Background: Multiple studies have independently investigated associations between the consumption of individual beverage types and specific plasma biomarkers, with type 2 diabetes (T2D) risk. However, as individuals do not consume single beverage types exclusively, and plasma biomarkers do not act in isolation, it remains unclear how patterns of beverage consumption and plasma biomarker networks associate both with each other, and T2D risk. Objective: To elucidate potential dietary determinants of T2D risk by defining a model that describes habitual beverage consumption profiles in relation to identified networks of circulating plasma biomarkers. Methods: This study included 1,461 case and 1,568 control participants from case-control studies of T2D nested within the Nurses' Health Study. Participants completed validated semi-quantitative food frequency questionnaires that assessed habitual beverage consumption, and provided blood samples from which 27 plasma biomarkers of cardiometabolic risk were identified. Common exploratory factor analysis (EFA) identified factors that separately described beverage consumption profiles and biomarker networks. Multivariable-adjusted regression elucidated the relationships between beverage and biomarker factors, and T2D risk. Results: EFA revealed five factors describing unique beverage consumption profiles and seven factors describing biomarker networks. The factor describing alcoholic beverage consumption was associated with a reduced risk of T2D [Odds Ratio (OR): 0.50 (0.40, 0.64), P<0.001] mediated, in part, by the factor describing increased concentrations of adiponectin biomarkers [19.9% (12.0, 31.1) P=0.004]. The factor describing low-calorie sweetened beverage (LCSBs) consumption was associated with an increased risk of T2D [OR: 1.33 (1.03, 1.72), P=0.021], and the factor describing lower concentrations of insulin-like growth factor binding proteins 1 and 2, and soluble leptin receptor, and increased leptin concentrations [P=0.005]. Conclusions: Moderate alcohol consumption was associated with reduced T2D risk, mediated in part by increased circulating adiponectin. LCSB consumption was associated with both increased T2D risk, and perturbed insulin-like growth factor and leptin signaling.

Associations between alcohol and cigarette use and type 1 and 2 myocardial infarction among people with HIV

Article

Feb 2023
HIV MED

Objectives: People with HIV have a higher risk of myocardial infarction (MI) than the general population, with a greater proportion of type 2 MI (T2MI) due to oxygen demand-supply mismatch compared with type 1 (T1MI) resulting from atherothrombotic plaque disruption. People living with HIV report a greater prevalence of cigarette and alcohol use than do the general population. Alcohol use and smoking as risk factors for MI by type are not well studied among people living with HIV. We examined longitudinal associations between smoking and alcohol use patterns and MI by type among people living with HIV. Design and methods: Using longitudinal data from the Centers for AIDS Research Network of Integrated Clinical Systems cohort, we conducted time-updated Cox proportional hazards models to determine the impact of smoking and alcohol consumption on adjudicated T1MI and T2MI. Results: Among 13 506 people living with HIV, with a median 4 years of follow-up, we observed 177 T1MI and 141 T2MI. Current smoking was associated with a 60% increase in risk of both T1MI and T2MI. In addition, every cigarette smoked per day was associated with a 4% increase in risk of T1MI, with a suggestive, but not significant, 2% increase for T2MI. Cigarette use had a greater impact on T1MI for men than for women and on T2MI for women than for men. Increasing alcohol use was associated with a lower risk of T1MI but not T2MI. Frequency of heavy episodic alcohol use was not associated with MI. Conclusions: Our findings reinforce the prioritization of smoking reduction, even without cessation, and cessation among people living with HIV for MI prevention and highlight the different impacts on MI type by gender.

Effects of different levels of resveratrol antioxidant on digestive enzymes, liver enzymes, and blood biochemical parameters of rainbow trout (Oncorhynchus mykiss)

Thesis

Sep 2021

The use of various antioxidants to improve fish growth and health has increased in recent years. This study aimed to evaluate the effects of resveratrol antioxidant on improving rainbow trout health by investigating its effects on digestive enzymes, liver enzymes, and biochemical parameters of rainbow trout blood.

Gut Microbiota: Target for Modulation of Gut-Liver-Adipose Tissue Axis in Ethanol-Induced Liver Disease

Article

Full-text available

May 2022
MEDIAT INFLAMM

Consumption of alcohol (ethanol) in various forms has been an integral part of human civilization. Since ages, it also has been an important cause of death and health impairment across the globe. Ethanol-mediated liver injury, known as alcoholic liver disease (ALD), is caused by surplus intake of alcohol. Several studies have proposed the different pathways that may be lead to ALD. One of the factors that may affect the cytochrome P450 (CYP2E1) metabolic pathway is gut dysbiosis. The gut microbiota produces various compounds that play an important role in regulating healthy functions of distal organs such as the adipose tissue and liver. Dysbiosis causes bacteremia, hepatic encephalopathy, and increased intestinal permeability. Recent clinical studies have found better understanding of the gut and liver axis. Another factor that may affect the ALD pathway is dysfunction of adipose tissue metabolism. Moreover, dysfunction of adipose tissue leads to ectopic fat deposition within the liver and disturbs lipid metabolism by increasing lipolysis/decreasing lipogenesis and impaired glucose tolerance of adipose tissue which leads to ectopic fat deposition within the liver. Adipokine secretion of resistin, leptin, and adiponectin is adversely modified upon prolonged alcohol consumption. In the combination of these two factors, a proinflammatory state is developed within the patient leading to the progression of ALD. Thus, the therapeutic approach for treatments and prevention for liver cirrhosis patients must be focused on the gut-liver-adipose tissue network modification with the use of probiotics, synbiotics, and prebiotics. This review is aimed at the effect of ethanol on gut and adipose tissue in both rodent and human alcoholic models.

Association of alcohol drinking with incident type 2 diabetes and pre‐diabetes: The Guangzhou Biobank Cohort Study

Article

May 2022

Aims: We examined associations of baseline alcohol drinking with incident type 2 diabetes (T2D) or impaired fasting glucose (IFG), and explore whether the associations were modified by genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2) and alcohol dehydrogenase-1B (ADH1B). Materials and methods: All participants aged 50+ (mean =60.45; standard deviation =6.88) years. Information of alcohol consumption was collected at baseline from 2003 to 2008. Incident T2D was defined as fasting glucose ≥7.0 mmol/l or post-load glucose ≥11.1 mmol/l at follow-up examination (2008-2012), self-reported T2D and/or initiation of hypoglycemia medication or insulin during follow-up. IFG was defined as fasting glucose ≥5.6 mmol/l and <7 mmol/l. Results: Of 15,716 participants without diabetes and 11,232 participants without diabetes and impaired fasting glucose at baseline, 1,624 (10.33%) developed incident T2D and 1,004 (8.94%) developed incident IFG during average 4 years of follow-up. After multivariable adjustments, compared with never drinking, occasional or moderate alcohol drinking was not associated with risk of incident hyperglycemia (T2D+IFG) (odds ratio (OR) =1.10, 95% confidence interval (CI) 0.95-1.27, and 0.90 (0.69-1.18), respectively), whereas heavy alcohol drinking was associated with a higher risk of incident hyperglycemia (T2D+IFG) (OR =1.82, 95% CI 1.24-2.68). No interactions of sex, overweight/obesity and genetic polymorphisms of ADH1B/ALDH2 genes with alcohol drinking on incident T2D and/or IFG were found (P for interaction from 0.12 to 0.85). Conclusions: Our results support a detrimental effect of heavy alcohol use on IFG and T2D. No protective effect was found for those carrying lower risk alleles for ADH1B/ALDH2 genes. (246 words) This article is protected by copyright. All rights reserved.

PROSIDING-SEMNAS-PSKM-FK-ULM 2nd

Experiment Findings

Full-text available

Nov 2019

Low-dose alcohol ameliorated high fat diet-induced anxiety-related behavior via enhancing adiponectin expression and activating the Nrf2 pathway

Article

Jan 2021

Long-term high-fat-diet (HFD)-induced obesity is associated with many comorbidities, such as cognitive impairment and anxiety, which are increasing public health burdens that have gained prevalence in adolescents. Although low-dose alcohol could attenuate the risk of cardiovascular disease, its mechanism on HFD-induced anxiety-related behavior remains not clear. The mice were divided into 4 groups, Control (Con), Alcohol (Alc), HFD and HFD + Alc groups. To verify the effects of low-dose alcohol on HFD-induced anxiety-related behavior, the mice were fed with HFD for 16 weeks. At the beginning of week 13, the HFD-fed mice were administered intragastrically with low-dose alcohol (0.8 g kg⁻¹) for 4 weeks. After 4 weeks of oral administration, low-dose alcohol decreased body weight and Lee's index in HFD-induced obese mice. Moreover, low-dose alcohol alleviated the anxiety-related behaviors of obese mice in the open field test and the elevated plus maze test. The HFD-induced damage to the hippocampus was improved in hematoxylin–eosin staining assay in mice. In addition, low-dose alcohol also suppressed HFD-induced oxidative stress and increased HFD-suppressed adiponectin (APN) expression and nuclear factor erythroid 2-related factor 2 (Nrf2) activation in the hippocampus. Taken together, low-dose alcohol significantly ameliorates HFD-induced obesity, oxidative stress and anxiety-related behavior in mice, which might be related to APN upregulation, Nrf2 activation and related antioxidase expression including SOD1, HO-1, and catalase.

Régimes méditerranéens et prévention du diabète : à l’heure des preuves

Article

Aug 2020

Résumé Les régimes de type méditerranéen (RM) ont été promus en santé publique comme un modèle alimentaire équilibré, diversifié et vertueux, caractérisé par un apport restreint en graisses saturées, important en acides gras monoinsaturés, et une forte densité nutritionnelle. Plusieurs études épidémiologiques prospectives ont mis en évidence un effet bénéfique des RM sur le risque de diabète de type 2 (DT2), le syndrome métabolique et les complications cardiovasculaires. L’adhésion aux RM est également associée à une diminution du risque de diabète gestationnel. Quelques études randomisées, dont l’étude PREDIMED, ont suggéré que l’adhésion à un RM réduisait le risque de DT2 d’environ 30 %. La pratique d’un RM est également associée à une amélioration du contrôle métabolique du DT2 avéré. Les mécanismes en cause sont encore discutés, mais tiennent vraisemblablement à la haute teneur des RM en composés antioxydants et/ou en acides gras monoinsaturés, et à un effet bénéfique sur le microbiote intestinal. À ce jour, et sous toutes les latitudes, les RM apparaissent comme la seule approche diététique de la prévention et du traitement du DT2 et de ses complications fondées sur des preuves.

Effetti chemiopreventivi in vitro di diverse tipologie di birre su cellule umane

Thesis

Full-text available

May 2020

Andrea Adelmo Della Penna

I tumori rappresentano una condizione patologica di tipo cronico-degenerativa la cui incidenza e prevalenza sono in continua crescita all’interno della popolazione umana. Il prolungamento dell’aspettativa di vita e l’invecchiamento della popolazione rappresentano due delle principali motivazioni di tale andamento, avendo, tali malattie, necessità di un tempo di latenza molto lungo per potersi sviluppare. Non è escluso che altri fattori di rischio intervengano, interagendo e combinandosi tra loro, nel determinare l’insorgenza e lo sviluppo dei tumori come, ad esempio, l’inquinamento ambientale, le scarse condizioni igieniche (nel caso di paesi in via di sviluppo), l’inadeguata attività fisica, la scorretta alimentazione e l’obesità. L’alimentazione riveste un ruolo molto importante nell’insorgenza dei tumori e gli alimenti, in virtù delle molteplici proprietà chimico-fisiche-microbiologiche che li contraddistinguono l’uno con l’altro, possono avere sia effetti benefici, che effetti negativi, nei confronti della salute dei consumatori. Le diverse tipologie di alimenti e la natura delle loro interazioni con l’organismo, permettono di avere una risposta completamente differente, in termini di effetti preventivi o dannosi. In questo lavoro di tesi, sono stati valutati alcuni effetti chemiopreventivi in vitro di sei diversi tipi di birra in termini sia di prevenzione del danno ossidativo al DNA (alla base dell’iniziazione tumorale) che di riduzione della proliferazione di cellule tumorali (caratteristica correlata con la promozione e progressione tumorale). Questi effetti chemiopreventivi potrebbero essere correlati alle caratteristiche chimiche delle birre, le quali a loro volta dipendono dalla ricetta impiegata per la produzione della birra stessa. Non è da escludere, tuttavia, che le birre possano incrementare il danno al DNA e la proliferazione delle cellule tumorali, agendo così come fattore di rischio tumorale. I risultati hanno mostrato che tutte le sei birre testate erano in grado di prevenire il danno al DNA indotto dall’H2O2 sui PBMC isolati di fresco dal sangue periferico umano. Dall’altro canto non si è evidenziato un evidente e statisticamente significativo incremento di danno al DNA basale (in assenza di H2O2) dopo il trattamento dei PBMC con le diverse birre.La separazione dei componenti ad alto e basso peso molecolare mediante diafiltrazione ha mostrato che entrambe le frazioni erano in grado di diminuire il danno al DNA. Lo studio delle correlazioni tra i parametri chimici, polifenoli totali e potere antiossidante, e la riduzione del danno al DNA delle diverse birre, ha mostrato una lieve correlazione positiva e statisticamente significativa. Le diverse birre sono state in grado di inibire la proliferazione delle cellule THP-1, anche se con una diversa efficacia l'una dall'altra. In contrasto, nessuna birra è risultata capace di inibire la proliferazione delle cellule tumorali Caco-2. Tumors represent a chronic-degenerative pathological condition whose incidence and prevalence are constantly increasing in the human population. The prolongation of life expectancy and the aging of the population represent two of the main reasons for this trend, having, such diseases, the need for a very long latency time in order to develop. It is not excluded that other risk factors intervene, interacting and combining with each other, in determining the onset and development of tumors such as, for example, environmental pollution, poor hygiene conditions (in the case of developing countries), inadequate physical activity, poor nutrition and obesity. Nutrition plays a very important role in the onset of tumors and foods, by virtue of the multiple chemical-physical-microbiological properties that distinguish them from each other, can have both beneficial and negative effects towards consumer health. The different types of food and the nature of their interactions with the body allow for a completely different response, in terms of preventive or harmful effects. In this thesis work, some in vitro chemopreventive effects of six different types of beer were assessed in terms of both the prevention of oxidative DNA damage (at the basis of tumor initiation) and the reduction of the proliferation of tumor cells (characteristic correlated with tumor promotion and progression). These chemopreventive effects could be related to the chemical characteristics of the beers, which in turn depend on the recipe used for the production of the beer itself. It cannot be excluded, however, that beers can increase DNA damage and the proliferation of cancer cells, thus acting as a tumor risk factor. The results showed that all six beers tested were able to prevent DNA damage induced by H2O2 on PBMCs freshly isolated from human peripheral blood. On the other hand, there was no evident and statistically significant increase in damage to basal DNA (in the absence of H2O2) after the treatment of the PBMCs with the different beers. The separation of the high and low molecular weight components by diafiltration showed that both fractions were able to decrease DNA damage. The study of the correlations between the chemical parameters, total polyphenols and antioxidant power, and the reduction of the DNA damage of the various beers, showed a slight positive correlation, statistically significant. The different beers have been able to inhibit the proliferation of THP-1 cells, albeit with a different effectiveness from each other. In contrast, no beer was found to inhibit the proliferation of Caco-2 cancer cells.

Tumour Necrosis Factor in Neuroplasticity, Neurogenesis and Alcohol Use Disorder

Article

Full-text available

May 2020

Alcohol use disorder is a pervasive and detrimental condition that involves changes in neuroplasticity and neurogenesis. Alcohol activates the neuroimmune system and alters the inflammatory status of the brain. Tumour necrosis factor (TNF) is a well characterised neuroimmune signal but its involvement in alcohol use disorder is unknown. In this review, we discuss the variable findings of TNF’s effect on neuroplasticity and neurogenesis. Acute ethanol exposure reduces TNF release while chronic alcohol intake generally increases TNF levels. Evidence suggests TNF potentiates excitatory transmission, promotes anxiety during alcohol withdrawal and is involved in drug use in rodents. An association between craving for alcohol and TNF is apparent during withdrawal in humans. While anti-inflammatory therapies show efficacy in reversing neurogenic deficit after alcohol exposure, there is no evidence for TNF’s essential involvement in alcohol’s effect on neurogenesis. Overall, defining TNF’s role in alcohol use disorder is complicated by poor understanding of its variable effects on synaptic transmission and neurogenesis. While TNF may be of relevance during withdrawal, the neuroimmune system likely acts through a larger group of inflammatory cytokines to alter neuroplasticity and neurogenesis. Understanding the individual relevance of TNF in alcohol use disorder awaits a more comprehensive understanding of TNF’s effects within the brain.

Pro‐inflammatory signalling and gut‐liver axis in non‐alcoholic and alcoholic steatohepatitis: Differences and similarities along the path

Article

Full-text available

Apr 2020
J CELL MOL MED

Non‐alcoholic fatty liver disease (NAFLD) and alcohol‐associated liver disease (ALD) represent a spectrum of injury, ranging from simple steatosis to steatohepatitis and cirrhosis. In humans, in fact, fatty changes in the liver, possibly leading to end‐stage disease, were observed after chronic alcohol intake or in conditions of metabolic impairment. In this article, we examined the features and the pro‐inflammatory pathways leading to non‐alcoholic and alcoholic steatohepatitis. The involvement of several events (hits) and multiple inter‐related pathways in the pathogenesis of these diseases suggest that a single therapeutic agent is unlikely to be an effective treatment strategy. Hence, a combination treatment towards multiple pro‐inflammatory targets would eventually be required. Gut‐liver crosstalk is involved not only in the impairment of lipid and glucose homoeostasis leading to steatogenesis, but also in the initiation of inflammation and fibrogenesis in both NAFLD and ALD. Modulation of the gut‐liver axis has been suggested as a possible therapeutic approach since gut‐derived components are likely to be involved in both the onset and the progression of liver damage. This review summarizes the translational mechanisms underlying pro‐inflammatory signalling and gut‐liver axis in non‐alcoholic and alcoholic steatohepatitis. With a multitude of people being affected by liver diseases, identification of possible treatments and the elucidation of pathogenic mechanisms are elements of paramount importance.

Risks of Light and Moderate Alcohol Use in Fatty Liver Disease: Follow-Up of Population Cohorts

Article

Jul 2019

Background and aims: The effects of alcohol use in nonalcoholic fatty liver disease are unclear. We investigated the impact of alcohol use in fatty liver disease on incident liver, cardiovascular, and malignant disease, as well as death. Approach and results: Our study comprised 8,345 persons with hepatic steatosis (fatty liver index >60) who participated in health-examination surveys (FINRISK 1992-2012 or Health 2000), with available data on baseline alcohol intake. Main exclusions were baseline clinical liver disease, viral hepatitis, ethanol intake >50 g/day, and current abstainers. Data were linked with national registers for hospital admissions, malignancies, and death regarding liver, cardiovascular, and malignant disease, as well as all-cause death. Adjustment were for multiple confounders. Alcohol consumption showed a dose-dependent risk increase for incident advanced liver disease and malignancies. Consuming 10-19 g/day of alcohol in general or 0-9 g/day as nonwine beverages doubled the risk for advanced liver disease compared to lifetime abstainers. In contrast, alcohol intake up to 49 g/day was associated with a 22%-40% reduction of incident cardiovascular disease (CVD). We observed a J-shaped association between alcohol intake and all-cause death with a maximal risk reduction of 21% (95% confidence interval, 5%-34%) at alcohol intake of 0-9 g/day compared to lifetime abstainers. However, these benefits on CVD and mortality were only observed in never smokers. Alcohol intake >30 g/day yielded increased risk estimates for mortality compared to lifetime abstainers. In a subpopulation with longitudinal data, alcohol intake remained stable over time in >80% of subjects. Conclusions: Even low alcohol intake in fatty liver disease is associated with increased risks for advanced liver disease and cancer. Low to moderate alcohol use is associated with reduced mortality and CVD risk but only among never smokers.

The sex specific effect of alcohol consumption on circulating levels of CTRP3

Article

Full-text available

Nov 2018
PLOS ONE

The goal of this project was to establish the effect of alcohol consumption on the circulating levels of the adipose tissue derived protein C1q TNF Related Protein 3 (CTRP3). Adipose tissue secretes several adipokines, such as adiponectin and leptin, which exert a multitude of biological effects important for human health. However, adipose tissue is extremely sensitive to alcohol consumption, leading not only to disrupted fat storage, but also to disruptions in adipokine production. Changes to adipokine secretion could have widespread biological effects and potentially contribute to alcohol-induced ailments, such as alcoholic fatty liver disease (ALD). CTRP3 has been previously demonstrated to attenuate fatty liver disease, and suppression of CTRP3 with alcohol consumption could contribute to development of and progression to alcoholic fatty liver disease. To examine the effect of ethanol consumption on circulating adipokine levels, male and female mice were fed an ethanol containing diet (Lieber-DeCarli 5% (v/v) ethanol diet) for 10-days followed by a single gavage of 5 g/kg ethanol (the NIAAA model), or for 6-weeks with no binge added (chronic model). In female mice, adiponectin levels increased ~2-fold in both models of ethanol feeding, but in male mice increased adiponectin levels were only observed after chronic ethanol feeding. On the other hand, in female mice, circulating CTRP3 levels decreased by ~75% and ~50% in the NIAAA and chronic model, respectively, with no changes observed in the male mice in either feeding model. Leptin levels were unchanged with ethanol feeding regardless of model or sex of mice. Lastly, chronic ethanol feeding led to a significant increase in mortality (~50%) in female mice, with no difference in relative ethanol consumption. These findings indicate that ethanol consumption can dysregulate adipokine secretion, but that the effects vary by sex of animal, method of ethanol consumption, and adipokine examined. These findings also indicate that female mice are more sensitive to the chronic effects of ethanol than male mice. Notably, this is the first study to document the effects of ethanol consumption on the circulating levels of CTRP3. Understanding the impact of excessive alcohol consumption on adipokine production and secretion could identify novel mechanisms of alcohol-induced human disease. However, the mechanism responsible for the increased sensitivity remains elusive.

Prospective study of risk factors for development of NIDDM in middle aged British men

Article

Full-text available

Apr 1995

To determine the risk factors for noninsulin dependent diabetes in a cohort representative of middle aged British men. Prospective study. 7735 men aged 40-59, drawn from one group practice in each of 24 towns in Britain. Known and probable cases of diabetes at screening (n = 158) were excluded. Non-insulin dependent diabetes (doctor diagnosed) over a mean follow up period of 12.8 years. There were 194 new cases of non-insulin dependent diabetes. Body mass index was the dominant risk factor for diabetes, with an age adjusted relative risk (upper fifth to lower fifth) of 11.6; 95% confidence interval 5.4 to 16.8. Men engaged in moderate levels of physical activity had a substantially reduced risk of diabetes, relative to the physically inactive men, after adjustment for age and body mass index (0.4; 0.2 to 0.7), an association which persisted in full multivariate analysis. A nonlinear relation between alcohol intake and diabetes was observed, with the lowest risk among moderate drinkers (16-42 units/week) relative to the baseline group of occasional drinkers (0.6; 0.4 to 1.0). Additional significant predictors of diabetes in multivariate analysis included serum triglyceride concentration, high density lipoprotein cholesterol concentration (inverse association), heart rate, uric acid concentration, and prevalent coronary heart disease. These findings emphasise the interrelations between risk factors for non-insulin dependent diabetes and coronary heart disease and the potential value of an integrated approach to the prevention of these conditions based on the prevention of obesity and the promotion of physical activity.

Prospective Study of Cigarette Smoking, Alcohol Use, and the Risk of Diabetes in Men

Article

Full-text available

Mar 1995

To examine the association between smoking, alcohol consumption, and the incidence of non-insulin dependent diabetes mellitus in men of middle years and older. Cohort questionnaire study of men followed up for six years from 1986. The health professionals' follow up study being conducted across the United States. 41,810 male health professionals aged 40-75 years and free of diabetes, cardiovascular disease, and cancer in 1986 and followed up for six years. Incidence of non-insulin dependent diabetes mellitus diagnosed in the six years. During 230,769 person years of follow up 509 men were newly diagnosed with diabetes. After controlling for known risk factors men who smoked 25 or more cigarettes daily had a relative risk of diabetes of 1.94 (95% confidence interval 1.25 to 3.03) compared with non-smokers. Men who consumed higher amounts of alcohol had a reduced risk of diabetes (P for trend < 0.001). Compared with abstainers men who drank 30.0-49.9 g of alcohol daily had a relative risk of diabetes of 0.61 (95% confidence interval 0.44 to 0.91). Cigarette smoking may be an independent, modifiable risk factor for non-insulin dependent diabetes mellitus. Moderate alcohol consumption among healthy people may be associated with increased insulin sensitivity and a reduced risk of diabetes.

Insulin sensitivity and regular alcohol consumption: Large, prospective, cross sectional population study (Bruneck study)

Article

Full-text available

Oct 1996

To assess the relation between regular alcohol consumption and insulin sensitivity, and to estimate the importance of insulin in the association of alcohol with multiple vascular risk factors and cardiovascular disease. Prospective and cross sectional study of a large randomly selected population sample. Part of the Bruneck study 1990-5 (Bolzano province, Italy). 820 health, non-diabetic women and men aged 40-79 years. Concentrations of fasting and post-glucose insulin, cholesterol, apolipoproteins, triglycerides, Lp(a) lipoprotein glucose, fibrinogen, and antithrombin III; blood pressure; insulin resistance estimated by the homeostasis model assessment. Fasting insulin concentrations in those who did not drink alcohol and subjects reporting low (1-50 g/day), moderate (51-99 g/day), and heavy (> or = 100 g/day) alcohol intake were 12.4, 10.0, 8.7, and 7.1 mU/l (P < 0.001). Likewise, post-glucose insulin concentrations and estimates for insulin resistance assessed by the homeostasis model assessment decreased significantly with increasing amounts of regular alcohol consumption. These trends were independent of sex, body mass index, physical activity, cigarette smoking, medication, and diet (P < 0.001). Regular alcohol intake predicted multiple changes in vascular risk factors over a five year period including increased concentrations of high density lipoprotein cholesterol and apolipoprotein A I; higher blood pressure; and decreased concentration of antithrombin III. These associations were in part attributable to the decrease in insulin concentrations observed among alcohol consumers. Low to moderate amounts of alcohol, when taken on a regular basis, improve insulin sensitivity. Insulin is a potential intermediate component in the association between alcohol consumption and vascular risk factors (metabolic syndrome).

Lazarus R, Sparrow D, Weiss STAlcohol intake, insulin levels. The Normative Aging Study. Am J Epidemiol 145: 909-916

Article

Full-text available

Jun 1997
AM J EPIDEMIOL

Much remains to be clarified in the apparently protective effect of moderate alcohol use against coronary heart disease risk. Insulin levels are positively associated with coronary heart disease risk, so recent reports of decreased insulin sensitivity among nondrinkers and lower fasting insulin levels with increasing alcohol intake suggest the possibility that insulin may play a role. Between 1987 and 1991, the authors examined fasting insulin concentrations and the empiric fasting insulin resistance index in relation to reported alcohol intake (mean, 15.3 g/day; standard deviation, 19.6; range, 0-120.6) and potential confounders. The latter included age, obesity, fat distribution, smoking, energy, saturated fat intake, antihypertensive medication, and physical activity. Participants in this cross-sectional analysis were 938 nondiabetic men from the Boston, Massachusetts, area who were part of the Normative Aging Study. Unadjusted fasting insulin levels were significantly different (p = 0.008) between categories of alcohol intake, as were fasting insulin resistance index values (p = 0.01). After adjustment for potential confounders, analysis revealed that subjects consuming moderate amounts of alcohol had the lowest fasting insulin and fasting insulin resistance index values. Compared with values from moderate drinkers, fasting insulin resistance index values were higher in those subjects reporting no alcohol intake (p = 0.011), low intake (p = 0.004), and high intake (p = 0.04). A similar pattern was observed for fasting insulin values. Among this sample of nondiabetic men, moderate drinkers had the lowest levels of fasting insulin resistance index and fasting insulin, consistent with lower levels of insulin resistance and thus lower risk for coronary heart disease. These findings suggest the possibility that the coronary heart disease-protective effects of moderate alcohol use are at least partially mediated by insulin.

Kopelman PG. Obesity as a medical problem. Nature 404, 635-643

Article

Full-text available

May 2000

Peter Kopelman

Obesity is now so common within the world's population that it is beginning to replace undernutrition and infectious diseases as the most significant contributor to ill health. In particular, obesity is associated with diabetes mellitus, coronary heart disease, certain forms of cancer, and sleep-breathing disorders. Obesity is defined by a body-mass index (weight divided by square of the height) of 30 kg m(-2) or greater, but this does not take into account the morbidity and mortality associated with more modest degrees of overweight, nor the detrimental effect of intra-abdominal fat. The global epidemic of obesity results from a combination of genetic susceptibility, increased availability of high-energy foods and decreased requirement for physical activity in modern society. Obesity should no longer be regarded simply as a cosmetic problem affecting certain individuals, but an epidemic that threatens global well being.

Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner AJ, Tomiyama Y, Matsuzawa YAdiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96: 1723-1732

Article

Full-text available

Oct 2000

We investigated the functions of adiponectin, an adipocyte-specific secretory protein and a new member of the family of soluble defense collagens, in hematopoiesis and immune responses. Adiponectin suppressed colony formation from colony-forming units (CFU)-granulocyte-macrophage, CFU-macrophage, and CFU-granulocyte, whereas it had no effect on that of burst-forming units-erythroid or mixed erythroid-myeloid CFU. In addition, adiponectin inhibited proliferation of 4 of 9 myeloid cell lines but did not suppress proliferation of erythroid or lymphoid cell lines except for one cell line. These results suggest that adiponectin predominantly inhibits proliferation of myelomonocytic lineage cells. At least one mechanism of the growth inhibition is induction of apoptosis because treatment of acute myelomonocytic leukemia lines with adiponectin induced the appearance of subdiploid peaks and oligonucleosomal DNA fragmentation. Aside from inhibiting growth of myelomonocytic progenitors, adiponectin suppressed mature macrophage functions. Treatment of cultured macrophages with adiponectin significantly inhibited their phagocytic activity and their lipopolysaccharide-induced production of tumor necrosis factor alpha. Suppression of phagocytosis by adiponectin is mediated by one of the complement C1q receptors, C1qRp, because this function was completely abrogated by the addition of an anti-C1qRp monoclonal antibody. These observations suggest that adiponectin is an important negative regulator in hematopoiesis and immune systems and raise the possibility that it may be involved in ending inflammatory responses through its inhibitory functions. (Blood. 2000;96:1723-1732)

Circulating Concentrations of the Adipocyte Protein Adiponectin Are Decreased in Parallel With Reduced Insulin Sensitivity During the Progression to Type 2 Diabetes in Rhesus Monkeys

Article

Full-text available

May 2001
DIABETES

Adiponectin is an adipose-specific plasma protein whose plasma concentrations are decreased in obese subjects and type 2 diabetic patients. This protein possesses putative antiatherogenic and anti-inflammatory properties. In the current study, we have analyzed the relationship between adiponectin and insulin resistance in rhesus monkeys (Macaca mulatta), which spontaneously develop obesity and which subsequently frequently progress to overt type 2 diabetes. The plasma levels of adiponectin were decreased in obese and diabetic monkeys as in humans. Prospective longitudinal studies revealed that the plasma levels of adiponectin declined at an early phase of obesity and remained decreased after the development of type 2 diabetes. Hyperinsulinemic-euglycemic clamp studies revealed that the obese monkeys with lower plasma adiponectin showed significantly lower insulin-stimulated peripheral glucose uptake (M rate). The plasma levels of adiponectin were significantly correlated to M rate (r = 0.66, P < 0.001). Longitudinally, the plasma adiponectin decreased in parallel to the progression of insulin resistance. No clear association was found between the plasma levels of adiponectin and its mRNA levels in adipose tissue. These results suggest that reduction in circulating adiponectin may be related to the development of insulin resistance.

Hypoadiponectinemia in Obesity and Type 2 Diabetes: Close Association with Insulin Resistance and Hyperinsulinemia

Article

Full-text available

May 2001

Plasma concentrations of adiponectin, a novel adipose-specific protein with putative antiatherogenic and antiinflammatory effects, were found to be decreased in Japanese individuals with obesity, type 2 diabetes, and cardiovascular disease, conditions commonly associated with insulin resistance and hyperinsulinemia. To further characterize the relationship between adiponectinemia and adiposity, insulin sensitivity, insulinemia, and glucose tolerance, we measured plasma adiponectin concentrations, body composition (dual-energy x-ray absorptiometry), insulin sensitivity (M, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) in 23 Caucasians and 121 Pima Indians, a population with a high propensity for obesity and type 2 diabetes. Plasma adiponectin concentration was negatively correlated with percent body fat (r = -0.43), waist-to-thigh ratio (r = -0.46), fasting plasma insulin concentration (r = -0.63), and 2-h glucose concentration (r = -0.38), and positively correlated with M (r = 0.59) (all P < 0.001); all relations were evident in both ethnic groups. In a multivariate analysis, fasting plasma insulin concentration, M, and waist-to-thigh ratio, but not percent body fat or 2-h glucose concentration, were significant independent determinates of adiponectinemia, explaining 47% of the variance (r(2) = 0.47). Differences in adiponectinemia between Pima Indians and Caucasians (7.2 +/- 2.6 vs. 10.2 +/- 4.3 microg/ml, P < 0.0001) and between Pima Indians with normal, impaired, and diabetic glucose tolerance (7.5 +/- 2.7, 6.1 +/- 2.0, 5.5 +/- 1.6 microg/ml, P < 0.0001) remained significant after adjustment for adiposity, but not after additional adjustment for M or fasting insulin concentration. These results confirm that obesity and type 2 diabetes are associated with low plasma adiponectin concentrations in different ethnic groups and indicate that the degree of hypoadiponectinemia is more closely related to the degree of insulin resistance and hyperinsulinemia than to the degree of adiposity and glucose intolerance.

Decreased Expression Of apM1 in Omental and Subcutaneous Adipose Tissue of Humans With Type 2 Diabetes

Article

Full-text available

Feb 2000
Int J Exp Diabetes Res

We have screened a subtracted cDNA library in order to identify differentially expressed genes in omental adipose tissue of human patients with Type 2 diabetes. One clone (#1738) showed a marked reduction in omental adipose tissue from patients with Type 2 diabetes. Sequencing and BLAST analysis revealed clone #1738 was the adipocyte-specific secreted protein gene apM1 (synonyms ACRP30, AdipoQ, GBP28). Consistent with the murine orthologue, apM1 mRNA was expressed in cultured human adipocytes and not in preadipocytes. Using RT-PCR we confirmed that apM1 mRNA levels were significantly reduced in omental adipose tissue of obese patients with Type 2 diabetes compared with lean and obese normoglycemic subjects. Although less pronounced, apM1 mRNA levels were reduced in subcutaneous adipose tissue of Type 2 diabetic patients. Whereas the biological function of apM1 is presently unknown, the tissue specific expression, structural similarities to TNFalpha, and the dysregulated expression observed in obese Type 2 diabetic patients suggest that this factor may play a role in the pathogenesis of insulin resistance and Type 2 diabetes.

Weight Reduction Increases Plasma Levels of an Adipose-Derived Anti-Inflammatory Protein, Adiponectin

Article

Full-text available

Sep 2001

Adiponectin, an adipose tissue-specific plasma protein, was recently revealed to have anti-inflammatory effects on the cellular components of vascular wall. Its plasma levels were significantly lower in men than in women and lower in human subjects with obesity, type 2 diabetes mellitus, or coronary artery disease. Therefore, it may provide a biological link between obesity and obesity-related disorders such as atherosclerosis, against which it may confer protection. In this study, we observed the changes of plasma adiponectin levels with body weight reduction among 22 obese patients who received gastric partition surgery. A 46% increase of mean plasma adiponectin level was accompanied by a 21% reduction in mean body mass index. The change in plasma adiponectin levels was significantly correlated with the changes in body mass index (r = -0.5, P = 0.01), waist (r = -0.4, P = 0.04) and hip (r = -0.6, P = 0.0007) circumferences, and steady state plasma glucose levels (r = -0.5, P = 0.04). In multivariate linear regression models, the increase in adiponectin as a dependent variable was significantly related to the decrease in hip circumference (beta = -0.16, P = 0.028), after adjusting body mass index and waist circumference. The change in steady state plasma glucose levels as a dependent variable was related to the increase of adiponectin with a marginal significance (beta = -0.92, P = 0.053), after adjusting body mass index and waist and hip circumferences. In conclusion, body weight reduction increased the plasma levels of a protective adipocytokine, adiponectin. In addition, the increase in plasma adiponectin despite the reduction of the only tissue of its own synthesis suggests that the expression of adiponectin is under feedback inhibition in obesity.

A Prospective Study of Drinking Patterns in Relation to Risk of Type 2 Diabetes Among Men

Article

Full-text available

Oct 2001
DIABETES

Using data from a 12-year prospective study, we determined the importance of the pattern of alcohol consumption as a risk factor for type 2 diabetes in a cohort of 46,892 U.S. male health professionals who completed biennial postal questionnaires. Overall, 1,571 new cases of type 2 diabetes were documented. Compared with zero alcohol consumption, consumption of 15-29 g/day of alcohol was associated with a 36% lower risk of diabetes (RR = 0.64; 95% CI 0.53-0.77). This inverse association between moderate consumption and diabetes remained if light drinkers rather than abstainers were used as the reference group (RR = 0.60, CI 0.50-0.73). There were few heavy drinkers, but the inverse association persisted to those drinking >/=50 g/day of alcohol (RR = 0.60, CI 0.43-0.84). Frequency of consumption was inversely associated with diabetes. Consumption of alcohol on at least 5 days/week provided the greatest protection, even when less than one drink per drinking day was consumed (RR = 0.48, CI 0.27-0.86). Compared with infrequent drinkers, for each additional day per week that alcohol was consumed, risk was reduced by 7% (95% CI 3-10%) after controlling for average daily consumption. There were similar and independent inverse associations for beer, liquor, and white wine. Our findings suggested that frequent alcohol consumption conveys the greatest protection against type 2 diabetes, even if the level of consumption per drinking day is low. Beverage choice did not alter risk.

Synthetic Peroxisome Proliferator-Activated Receptor- Agonist, Rosiglitazone, Increases Plasma Levels of Adiponectin in Type 2 Diabetic Patients

Article

Full-text available

Feb 2002
DIABETES CARE

Adiponectin, a plasma protein exclusively synthesized and secreted by adipose tissue, has recently been shown to have anti-inflammatory, antiatherogenic properties in vitro and beneficial metabolic effects in animals. Lower plasma levels of adiponectin have been documented in human subjects with metabolic syndrome and coronary artery disease. We investigated whether the level of this putative protective adipocytokine could be increased by treatment with a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist in diabetic patients. Type 2 diabetic patients (30 in the treatment group and 34 in the placebo group) were recruited for a randomized double-blind placebo-controlled trial for 6 months with the PPAR-gamma agonist rosiglitazone. Blood samples were collected and metabolic variables and adiponectin levels were determined in all patients before initiation of the study. In the rosiglitazone group, mean plasma adiponectin level was increased by more than twofold (P < 0.0005), whereas no change was observed in the placebo group. Multivariate linear regression analysis showed that whether rosiglitazone was used was the single variable significantly related to the changes of plasma adiponectin. The amount of variance in changes of plasma adiponectin level explained by the treatment was approximately 24% (r(2) = 0.24) after adjusting for age, sex, and changes in fasting plasma glucose, HbA(1c), insulin resistance index, and BMI. Rosiglitazone increases plasma adiponectin levels in type 2 diabetic subjects. Whether this may contribute to the antihyperglycemic and putative antiatherogenic benefits of PPAR-gamma agonists in type 2 diabetic patients warrants further investigation.

Moderate alcohol consumption is associated with lower risk for incident diabetes and mortality: the Hoorn Study

Article

Full-text available

Aug 2002
DIABETES RES CLIN PR

In the present study we examined the association between baseline alcohol consumption and 10-year mortality in subjects with normal and abnormal glucose levels (diabetes, impaired fasting glucose (IFG) or impaired glucose tolerance (IGT)). Furthermore, we assessed the 6-year cumulative incidence of diabetes in categories of alcohol consumption. In the Hoorn Study, which started in 1989, alcohol intake was assessed by questionnaire in 2393 subjects who were subsequently categorised into four groups of alcohol consumption (non-drinkers, up to 10 g per day, 10-30 and >or=30 g per day). Glucose tolerance status by oral glucose tolerance test was classified according to the WHO-1999 diagnostic criteria. Subjects who drank up to 10 g per day of alcohol had the lowest mortality risk. The age- and sex-adjusted mortality risks for non-drinkers were 1.55 (1.04-2.32) for subjects with normal glucose levels and 1.72 (1.05-2.82) for subjects with abnormal glucose levels. The risk of diabetes was also lowest for subjects who consumed up to 10 g per day: 8.0 versus 12.9% for non-drinkers (P<0.05). Higher alcohol intakes were associated with increasing risks for mortality and diabetes. Adjustment for classical cardiovascular risk factors and other lifestyle variables did not materially affect the estimates. In conclusion, moderate alcohol consumption was associated with a lower risk for mortality and diabetes.

Davies MJ, Baer DJ, Judd JT, Brown ED, Campbell WS, Taylor PREffects of moderate alcohol intake on fasting insulin and glucose concentrations and insulin sensitivity in postmenopausal women: a randomized controlled trial. JAMA 287(19): 2559-2562

Article

Full-text available

Jun 2002

Epidemiologic data demonstrate that moderate alcohol intake is associated with improved insulin sensitivity in nondiabetic individuals. No controlled-diet studies have addressed the effects of daily moderate alcohol consumption on fasting insulin and glucose concentrations and insulin sensitivity. To determine whether daily consumption of low to moderate amounts of alcohol influences fasting insulin and glucose concentrations and insulin sensitivity in nondiabetic postmenopausal women. Randomized controlled crossover trial of 63 healthy postmenopausal women, conducted at a clinical research center in Maryland between 1998 and 1999. Participants were randomly assigned to consume 0, 15, or 30 g/d of alcohol for 8 weeks each as part of a controlled diet. All foods and beverages were provided during the intervention. An isocaloric beverage was provided in the 0-g/d arm. Energy intake was adjusted to maintain constant body weight. Fasting insulin, triglyceride, and glucose concentrations, measured at the end of each dietary period; insulin sensitivity, estimated with a published index of glucose disposal rate corrected for fat-free mass based on fasting insulin and fasting triglyceride concentrations, compared among treatments with a mixed-model analysis of variance. A complete set of plasma samples was collected and analyzed for 51 women who completed all diet treatments. Consumption of 30 g/d of alcohol compared with 0 g/d reduced fasting insulin concentration by 19.2% (P =.004) and triglyceride concentration by 10.3% (P =.001), and increased insulin sensitivity by 7.2% (P =.002). Normal-weight, overweight, and obese individuals responded similarly. Only fasting triglyceride concentration was significantly reduced when comparing 0 and 15 g/d of alcohol (7.8%; P =.03), and no difference was found between consumption of 15 and 30 g/d of alcohol; however, there was a significant linear trend (P =.001). Fasting glucose concentrations were not different across treatments. Consumption of 30 g/d of alcohol (2 drinks per day) has beneficial effects on insulin and triglyceride concentrations and insulin sensitivity in nondiabetic postmenopausal women.

Plasma Adiponectin Concentration Is Associated With Skeletal Muscle Insulin Receptor Tyrosine Phosphorylation, and Low Plasma Concentration Precedes a Decrease in Whole-Body Insulin Sensitivity in Humans

Article

Full-text available

Jul 2002
DIABETES

Adiponectin, the most abundant adipose-specific protein, has been found to be negatively associated with degree of adiposity and positively associated with insulin sensitivity in Pima Indians and other populations. Moreover, adiponectin administration to rodents has been shown to increase insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and also increase whole-body insulin sensitivity. To further characterize the relationship between plasma adiponectin concentration and insulin sensitivity in humans, we examined 1) the cross-sectional association between plasma adiponectin concentration and skeletal muscle IR tyrosine phosphorylation and 2) the prospective effect of plasma adiponectin concentration at baseline on change in insulin sensitivity. Fasting plasma adiponectin concentration, body composition (hydrodensitometry or dual energy X-ray absorptiometry), insulin sensitivity (insulin-stimulated glucose disposal, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) were measured in 55 Pima Indians (47 men and 8 women, aged 31 +/- 8 years, body fat 29 +/- 8% [mean +/- SD]; 50 with normal glucose tolerance, 3 with impaired glucose tolerance, and 2 with diabetes). Group 1 (19 subjects) underwent skeletal muscle biopsies for the measurement of basal and insulin-stimulated tyrosine phosphorylation of the IR (stimulated by 100 nmol/l insulin). The fold increase after insulin stimulation was calculated as the ratio between maximal and basal phosphorylation. Group 2 (38 subjects) had follow-up measurements of insulin-stimulated glucose disposal. Cross-sectionally, plasma adiponectin concentration was positively associated with insulin-stimulated glucose disposal (r = 0.58, P < 0.0001) and negatively associated with percent body fat (r = -0.62, P < 0.0001) in the whole group. In group 1 plasma adiponectin was negatively associated with the basal (r = -0.65, P = 0.003) and positively associated with the fold increase in IR tyrosine phosphorylation (r = 0.69, P = 0.001) before and after the adjustment for percent body fat (r = -0.58, P = 0.01 and r = 0.54, P = 0.02, respectively). Longitudinally, after adjustment for age, sex, and percent body fat, low plasma adiponectin concentration at baseline was associated with a decrease in insulin sensitivity (P = 0.04). In conclusion, our cross-sectional data suggest a role of physiological concentration of fasting plasma adiponectin in the regulation of skeletal muscle IR tyrosine phosphorylation. Prospectively, low plasma adiponectin concentration at baseline precedes a decrease in insulin sensitivity. Our data indicate that adiponectin plays an important role in regulation of insulin sensitivity in humans.

Adiponectin is not altered with exercise training despite enhanced insulin action

Article

Full-text available

Nov 2002

Adiponectin is an adipocytokine that is hypothesized to be involved in the regulation of insulin action. The purpose of the present investigation was to determine whether plasma adiponectin is altered in conjunction with enhanced insulin action with exercise training. An insulin sensitivity index (S(I)) and fasting levels of glucose, insulin, and adiponectin were assessed before and after 6 mo of exercise training (4 days/wk for approximately 45 min at 65-80% peak O(2) consumption) with no loss of body mass (PRE, 91.9 +/- 3.8 kg vs. POST, 91.6 +/- 3.9 kg) or fat mass (PRE, 26.5 +/- 1.8 kg vs. POST, 26.7 +/- 2.2 kg). Insulin action significantly (P < 0.05) improved with exercise training (S(I) +98%); however, plasma adiponectin concentration did not change (PRE, 6.3 +/- 1.5 microg/ml vs. POST, 6.6 +/- 1.8 microg/ml). In contrast, in a separate group of subjects examined before and after weight loss, there was a substantial increase in adiponectin (+281%), which was accompanied by enhanced insulin action (S(I), +432%). These data suggest that adiponectin is not a contributory factor to the exercise-related improvements in insulin sensitivity.

The Effect of Thiazolidinediones on Plasma Adiponectin Levels in Normal, Obese, and Type 2 Diabetic Subjects

Article

Full-text available

Nov 2002
DIABETES

The insulin-sensitizing effects of thiazolidinediones are thought to be mediated through peroxisome proliferator-activated receptor-gamma, a nuclear receptor that is highly abundant in adipose tissue. It has been reported that adipocytes secrete a variety of proteins, including tumor necrosis factor-alpha, resistin, plasminogen activator inhibitor-1, and adiponectin. Adiponectin is a fat cell-secreted protein that has been reported to increase fat oxidation and improve insulin sensitivity. Our aim was to study the effects of troglitazone on adiponectin levels in lean, obese, and diabetic subjects. Ten diabetic and 17 nondiabetic subjects (8 lean, BMI <27 kg/m(2) and 9 obese, BMI >27 kg/m(2)) participated in the study. All subjects underwent an 80 mU. m(-2). min(-1) hyperinsulinemic-euglycemic glucose clamp before and after 3 months' treatment with the thiazolidinedione (TZD) troglitazone (600 mg/day). Fasting plasma glucose significantly decreased in the diabetic group after 12 weeks of treatment compared with baseline (9.1 +/- 0.9 vs. 11.1 +/- 0.9 mmol/l, P < 0.005) but was unchanged in the lean and obese subjects. Fasting insulin for the entire group was significantly lower than baseline (P = 0.02) after treatment. At baseline, glucose disposal rate (R(d)) was lower in the diabetic subjects (3.4 +/- 0.5 mg. kg(-1). min(-1)) than in the lean (12.3 +/- 0.4) or obese subjects (6.7 +/- 0.7) (P < 0.001 for both) and was significantly improved in the diabetic and obese groups (P < 0.05) after treatment, and it remained unchanged in the lean subjects. Baseline adiponectin levels were significantly lower in the diabetic than the lean subjects (9.0 +/- 1.7 vs. 16.7 +/- 2.7 micro g/ml, P = 0.03) and rose uniformly in all subjects (12.2 +/- 2.3 vs. 25.7 +/- 2.6 micro g/ml, P < 10(-4)) after treatment, with no significant difference detected among the three groups. During the glucose clamps, adiponectin levels were suppressed below basal levels in all groups (10.2 +/- 2.3 vs. 12.2 +/- 2.3 micro g/ml, P < 0.01). Adiponectin levels correlated with R(d) (r = 0.46, P = 0.016) and HDL cholesterol levels (r = 0.59, P < 0.001) and negatively correlated with fasting insulin (r = -0.39, P = 0.042) and plasma triglyceride (r = -0.61, P < 0.001). Our findings show that TZD treatment increased adiponectin levels in all subjects, including normal subjects in which no other effects of TZDs are observed. Insulin also appears to suppress adiponectin levels. We have confirmed these results in normal rats. These findings suggest that adiponectin can be regulated by obesity, diabetes, TZDs, and insulin, and it may play a physiologic role in enhancing insulin sensitivity.

Plasma Adiponectin Concentrations Predict Insulin Sensitivity of Both Glucose and Lipid Metabolism

Article

Full-text available

Feb 2003
DIABETES

In animals, the adipocyte-derived hormone adiponectin has been shown to improve insulin sensitivity, a key factor in the pathogenesis of type 2 diabetes. In Pima Indians, high plasma adiponectin levels are associated with increased insulin sensitivity and reduced risk of type 2 diabetes. It is unclear whether this is also the case in white individuals and whether an additional beneficial effect on lipid metabolism exists. We therefore analyzed in nondiabetic individuals the associations between plasma adiponectin concentrations and insulin sensitivity measured by a euglycemic-hyperinsulinemic clamp (n = 262) and estimated by an oral glucose tolerance test (OGTT; n = 636) and serum lipid parameters using correlational analysis. Plasma adiponectin concentrations were positively correlated with insulin sensitivity, both measured with the clamp (r = 0.28, P = 0.0015 in women; r = 0.42, P < 0.0001 in men) and estimated from the OGTT (r = 0.37, P < 0.0001 in women; r = 0.41, P < 0.0001 in men) before and after adjusting for sex and percentage of body fat (all P < 0.001). Fasting triglycerides and the free fatty acid (FFA) concentrations during the OGTT (area under the curve) and at 120 min were negatively correlated in both women and men, whereas HDL was positively correlated with plasma adiponectin concentrations (all P < 0.004). Most notable, these relationships remained significant after adjusting for insulin sensitivity of glucose disposal in addition to sex and percentage of body fat (all P < 0.05). In conclusion, high adiponectin predicts increased insulin sensitivity. This relationship is independent of low body fat mass and affects not only insulin-stimulated glucose disposal but also lipoprotein metabolism and insulin-mediated suppression of postprandial FFA release. This suggests pleiotropic insulin sensitizing effects of adiponectin in humans.

Relationship of Adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: Evidence for independent roles of age and sex

Article

Full-text available

May 2003

Increased intra-abdominal fat is associated with insulin resistance and an atherogenic lipoprotein profile. Circulating concentrations of adiponectin, an adipocyte-derived protein, are decreased with insulin resistance. We investigated the relationships between adiponectin and leptin, body fat distribution, insulin sensitivity and lipoproteins. We measured plasma adiponectin, leptin and lipid concentrations, intra-abdominal and subcutaneous fat areas by CT scan, and insulin sensitivity index (S(I)) in 182 subjects (76 M/106F). Adiponectin concentrations were higher in women than in men (7.4+/-2.9 vs 5.4+/-2.3 micro g/ml, p<0.0001) as were leptin concentrations (19.1+/-13.7 vs 6.9+/-5.1 ng/ml, p<0.0001). Women were more insulin sensitive (S(I): 6.8+/-3.9 vs 5.9+/-4.4 x 10(-5) min(-1)/(pmol/l), p<0.01) and had more subcutaneous (240+/-133 vs 187+/-90 cm(2), p<0.01), but less intra-abdominal fat (82+/-57 vs 124+/-68 cm(2), p<0.0001). By simple regression, adiponectin was positively correlated with age ( r=0.227, p<0.01) and S(I) ( r=0.375, p<0.0001), and negatively correlated with BMI ( r=-0.333, p<0.0001), subcutaneous ( r=-0.168, p<0.05) and intra-abdominal fat ( r=-0.35, p<0.0001). Adiponectin was negatively correlated with triglycerides ( r=-0.281, p<0.001) and positively correlated with HDL cholesterol ( r=0.605, p<0.0001) and Rf, a measure of LDL particle buoyancy ( r=0.474, p<0.0001). By multiple regression analysis, adiponectin was related to age ( p<0.0001), sex ( p<0.005) and intra-abdominal fat ( p<0.01). S(I) was related to intra-abdominal fat ( p<0.0001) and adiponectin ( p<0.0005). Both intra-abdominal fat and adiponectin contributed independently to triglycerides, HDL cholesterol and Rf. These data suggest that adiponectin concentrations are determined by intra-abdominal fat mass, with additional independent effects of age and sex. Adiponectin could link intra-abdominal fat with insulin resistance and an atherogenic lipoprotein profile.

Blockade of the Renin-Angiotensin System Increases Adiponectin Concentrations in Patients With Essential Hypertension

Article

Full-text available

Aug 2003
Hypertension

Adiponectin, an adipocyte-derived protein, has been suggested to play an important role in insulin sensitivity. We examined the association between insulin sensitivity (M value) evaluated by the euglycemic-hyperinsulinemic glucose clamp and adiponectin concentrations in 30 essential hypertensives (EHT) and 20 normotensives (NT) and investigated the effect of blockade of the renin-angiotensin system (RAS) on adiponectin concentrations. EHT were divided into 12 insulin-resistant EHT (EHT-R) and 18 non-insulin-resistant EHT (EHT-N) using mean-1 SD of the M value in NT. There were no intergroup differences in age, gender, and body mass index (BMI). EHT-R had significantly higher levels of insulin and triglyceride and lower levels of adiponectin than did NT and EHT-N. EHT-R had higher levels of free fatty acid and lower levels of high-density lipoprotein (HDL) cholesterol than did EHT-N. Adiponectin concentrations were positively correlated with M value and HDL cholesterol and negatively correlated with BMI, insulin, free fatty acid, and triglyceride but not with blood pressure. M value, BMI, and HDL cholesterol were independent determinants of adiponectin concentrations in multiple and stepwise regression analyses. Sixteen EHT were treated with an angiotensin-converting enzyme inhibitor (temocapril, 4 mg/d; n=9) or an angiotensin II receptor blocker (candesartan, 8 mg/d; n=7) for 2 weeks. Treatment with temocapril or candesartan significantly decreased blood pressure and increased M value and adiponectin concentrations but did not affect BMI and HDL cholesterol. These results suggest that hypoadiponectinemia is related to insulin resistance in essential hypertension and that RAS blockade increases adiponectin concentrations with improvement in insulin sensitivity.

Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages

Article

Sep 2000

We investigated the functions of adiponectin, an adipocyte-specific secretory protein and a new member of the family of soluble defense collagens, in hematopoiesis and immune responses. Adiponectin suppressed colony formation from colony-forming units (CFU)—granulocyte-macrophage, CFU-macrophage, and CFU-granulocyte, whereas it had no effect on that of burst-forming units—erythroid or mixed erythroid-myeloid CFU. In addition, adiponectin inhibited proliferation of 4 of 9 myeloid cell lines but did not suppress proliferation of erythroid or lymphoid cell lines except for one cell line. These results suggest that adiponectin predominantly inhibits proliferation of myelomonocytic lineage cells. At least one mechanism of the growth inhibition is induction of apoptosis because treatment of acute myelomonocytic leukemia lines with adiponectin induced the appearance of subdiploid peaks and oligonucleosomal DNA fragmentation. Aside from inhibiting growth of myelomonocytic progenitors, adiponectin suppressed mature macrophage functions. Treatment of cultured macrophages with adiponectin significantly inhibited their phagocytic activity and their lipopolysaccharide-induced production of tumor necrosis factor α. Suppression of phagocytosis by adiponectin is mediated by one of the complement C1q receptors, C1qRp, because this function was completely abrogated by the addition of an anti-C1qRp monoclonal antibody. These observations suggest that adiponectin is an important negative regulator in hematopoiesis and immune systems and raise the possibility that it may be involved in ending inflammatory responses through its inhibitory functions.

Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages

Article

Sep 2000

We investigated the functions of adiponectin, an adipocyte-specific secretory protein and a new member of the family of soluble defense collagens, in hematopoiesis and immune responses. Adiponectin suppressed colony formation from colony-forming units (CFU)—granulocyte-macrophage, CFU-macrophage, and CFU-granulocyte, whereas it had no effect on that of burst-forming units—erythroid or mixed erythroid-myeloid CFU. In addition, adiponectin inhibited proliferation of 4 of 9 myeloid cell lines but did not suppress proliferation of erythroid or lymphoid cell lines except for one cell line. These results suggest that adiponectin predominantly inhibits proliferation of myelomonocytic lineage cells. At least one mechanism of the growth inhibition is induction of apoptosis because treatment of acute myelomonocytic leukemia lines with adiponectin induced the appearance of subdiploid peaks and oligonucleosomal DNA fragmentation. Aside from inhibiting growth of myelomonocytic progenitors, adiponectin suppressed mature macrophage functions. Treatment of cultured macrophages with adiponectin significantly inhibited their phagocytic activity and their lipopolysaccharide-induced production of tumor necrosis factor α. Suppression of phagocytosis by adiponectin is mediated by one of the complement C1q receptors, C1qRp, because this function was completely abrogated by the addition of an anti-C1qRp monoclonal antibody. These observations suggest that adiponectin is an important negative regulator in hematopoiesis and immune systems and raise the possibility that it may be involved in ending inflammatory responses through its inhibitory functions.

Erratum: Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin (Journal of Clinical Endocrinology and Metabolism 86(3815-3819))

Article

Jan 2002

Glucose Clamp Technique − Method for Quantifying Insulin-Secretion and Resistance

Article

Sep 1979

Methods for the quantification of beta-cell sensitivity to glucose (hyperglycemic clamp technique) and of tissue sensitivity to insulin (euglycemic insulin clamp technique) are described. Hyperglycemic clamp technique. The plasma glucose concentration is acutely raised to 125 mg/dl above basal levels by a priming infusion of glucose. The desired hyperglycemic plateau is subsequently maintained by adjustment of a variable glucose infusion, based on the negative feedback principle. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of glucose metabolism. Under these conditions of constant hyperglycemia, the plasma insulin response is biphasic with an early burst of insulin release during the first 6 min followed by a gradually progressive increase in plasma insulin concentration. Euglycemic insulin clamp technique. The plasma insulin concentration is acutely raised and maintained at approximately 100 muU/ml by a prime-continuous infusion of insulin. The plasma glucose concentration is held constant at basal levels by a variable glucose infusion using the negative feedback principle. Under these steady-state conditions of euglycemia, the glucose infusion rate equals glucose uptake by all the tissues in the body and is therefore a measure of tissue sensitivity to exogenous insulin.

PPAR Ligands Increase Expression and Plasma Concentrations of Adiponectin, an Adipose-Derived Protein

Article

Sep 2001
DIABETES

Insulin resistance and its dreaded consequence, type 2 diabetes, are major causes of atherosclerosis. Adiponectin is an adipose-specific plasma protein that possesses anti-atherogenic properties, such as the suppression of adhesion molecule expression in vascular endothelial cells and cytokine production from macrophages. Plasma adiponectin concentrations are decreased in obese and type 2 diabetic subjects with insulin resistance. A regimen that normalizes or increases the plasma adiponectin might prevent atherosclerosis in patients with insulin resistance. In this study, we demonstrate the inducing effects of thiazolidinediones (TZDs), which are synthetic PPARgamma ligands, on the expression and secretion of adiponectin in humans and rodents in vivo and in vitro. The administration of TZDs significantly increased the plasma adiponectin concentrations in insulin resistant humans and rodents without affecting their body weight. Adiponectin mRNA expression was normalized or increased by TZDs in the adipose tissues of obese mice. In cultured 3T3-L1 adipocytes, TZD derivatives enhanced the mRNA expression and secretion of adiponectin in a dose- and time-dependent manner. Furthermore, these effects were mediated through the activation of the promoter by the TZDs. On the other hand, TNF-alpha, which is produced more in an insulin-resistant condition, dose-dependently reduced the expression of adiponectin in adipocytes by suppressing its promoter activity. TZDs restored this inhibitory effect by TNF-alpha. TZDs might prevent atherosclerotic vascular disease in insulin-resistant patients by inducing the production of adiponectin through direct effect on its promoter and antagonizing the effect of TNF-alpha on the adiponectin promoter.

The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor

Article

Mar 1998
CURR BIOL

ACRP30--adipocyte complement-related protein of 30 kDa or AdipoQ--is an abundant serum protein, secreted exclusively from fat cells, which is implicated in energy homeostasis and obesity [1,2]. ACRP30 is a close homologue of the complement protein C1q, which is involved in the recognition of microbial surfaces [3-5] and antibody-antigen complexes [6,7] in the classical pathway of complement. We have determined the crystal structure of a homotrimeric fragment from ACRP30 at 2.1 A resolution. The structure reveals an unexpected homology to the tumor necrosis factor (TNF) family. Identical folding topologies, key residue conservations, and similarity of trimer interfaces and intron positions firmly establish an evolutionary link between the TNF and C1q families. We suggest that TNFs--which control many aspects of inflammation, adaptive immunity, apoptosis and energy homeostasis--arose by divergence from a primordial recognition molecule of the innate immune system. The evolutionary connection between C1q-like proteins and TNFs illuminates the shared functions of these two important groups of proteins.

DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237, E214-E223

Article

Oct 1979
Am J Physiol

Alcohol consumption and its relation to cardiovascular factors in British women

Article

Feb 1992

To examine the relation between alcohol consumption and risk factors for coronary heart disease in women. Cross sectional study of a stratified random sample of the population grouped into five categories of habitual alcohol consumption. People registered with general practitioners at two large health centres in east Bristol, England. 1048 women aged 25-69 years. Fasting plasma concentrations of insulin, total cholesterol, total triglycerides, and high density lipoprotein cholesterol, including its subfractions HDL2 and HDL3, and body mass index. Compared with non-drinkers women consuming a moderate amount of alcohol (1-20 g/day) had lower plasma concentrations of triglycerides, by 0.19 mmol/l (95% confidence interval 0.07 to 0.35); cholesterol, by 0.4 mmol/l (0.19 to 0.61); and insulin, by 1.4 mU/l (0.43 to 1.97) and a lower body mass index, by 1.2 kg/m2 (0.43 to 1.97). They also had higher concentrations of high density lipoprotein cholesterol, by 0.09 mmol/l (0.03 to 0.15); HDL2 cholesterol by 0.05 mmol/l (-0.02 to 0.10) and HDL3 cholesterol, by 0.06 mmol/l (0.06 to 0.11). All these were independent of body mass index, smoking habits, and taking oral contraceptives. Moderate alcohol consumption is associated with lower levels of cardiovascular risk factors in women. Insulin may have a central role.

Hotamisligil, G.S. , Shargill, N.S. & Spiegelman, B.M. Adipose expression of tumor necrosis factor-: Direct role in obesity-linked insulin resistance. Science 259, 87-91

Article

Feb 1993

Tumor necrosis factor-alpha (TNF-alpha) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-alpha messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-alpha protein was also elevated locally and systemically. Neutralization of TNF-alpha in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for TNF-alpha in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.

Hotamisligil, G.S., Arner, P., Caro, J.F., Atkinson, R.L. & Spiegelman, B.M. Increased adipose tissue expression of tumor necrosis factor- in human obesity and insulin resistance. J. Clin. Invest. 95, 2409−2415

Article

Jun 1995

Obesity is frequently associated with insulin resistance and abnormal glucose homeostasis. Recent studies in animal models have indicated that TNF-alpha plays an important role in mediating the insulin resistance of obesity through its overexpression in fat tissue. However, the mechanisms linking obesity to insulin resistance and diabetes in humans remain largely unknown. In this study we examined the expression pattern of TNF-alpha mRNA in adipose tissues from 18 control and 19 obese premenopausal women by Northern blot analysis. TNF-alpha protein concentrations in plasma and in conditioned medium of explanted adipose tissue were measured by ELISA. Furthermore, the effects of weight reduction by dietary treatment of obesity on the adipose expression of TNF-alpha mRNA were also analyzed in nine premenopausal obese women, before and after a controlled weight-reduction program. These studies demonstrated that obese individuals express 2.5-fold more TNF-alpha mRNA in fat tissue relative to the lean controls (P < 0.001). Similar increases were also observed in adipose production of TNF-alpha protein but circulating TNF-alpha levels were extremely low or undetectable. A strong positive correlation was observed between TNF-alpha mRNA expression levels in fat tissue and the level of hyperinsulinemia (P < 0.001), an indirect measure of insulin resistance. Finally, body weight reduction in obese subjects which resulted in improved insulin sensitivity was also associated with a decrease in TNF-alpha mRNA expression (45%, P < 0.001) in fat tissue. These results suggest a role for the abnormal regulation of this cytokine in the pathogenesis of obesity-related insulin resistance.

Light-to-Moderate Alcohol Intake Is Associated With Enhanced Insulin Sensitivity

Article

Feb 1994
DIABETES CARE

To test the hypothesis that insulin-mediated glucose uptake is enhanced in light-to-moderate alcohol consumption. This is a case-control study of healthy volunteers, divided into nondrinkers and light-to-moderate drinkers based on their history of alcohol consumption. The study was performed at the General Clinical Research Center at Stanford University Medical Center and involved 40 volunteers, 20 men and 20 women. Measurements were made of the plasma glucose and insulin responses to an oral glucose challenge, fasting plasma lipid and lipoprotein concentrations, and steady-state plasma insulin (SSPI) and steady-state plasma glucose (SSPG) concentrations in response to a continuous infusion of somatostatin, insulin, and glucose. Light-to-moderate drinkers (10-30 g/day) had lower integrated plasma glucose (17.8 +/- 0.8 vs. 19.8 +/- 0.9 mM/h, P < 0.02) and insulin (600 +/- 65 vs. 1,075 +/- 160 pM/h, P < 0.01) responses to the glucose challenge and higher fasting plasma high-density lipoprotein (HDL) cholesterol concentrations (1.46 +/- 0.08 vs. 1.25 +/- 0.08, P < 0.02). Despite similar SSPI concentrations of approximately 300 pM, SSPG concentrations were lower (P < 0.01) in light-to-moderate drinkers (6.7 +/- 0.8 vs. 10.7 +/- 1.2 mM). Results were independent of age, body mass index, ratio of waist-to-hip girth, and estimates of level of habitual physical activity. Light-to-moderate alcohol consumption in healthy men and women is associated with enhanced insulin-mediated glucose uptake, lower plasma glucose and insulin concentrations in response to oral glucose, and a higher HDL-cholesterol concentration. The changes in glucose and insulin metabolism may contribute to the lower risk of coronary heart disease described in light-to-moderate drinkers.

Tumor Necrosis Factor ?? Inhibits Signaling From the Insulin Receptor

Article

Jun 1994

Insulin resistance is a common problem associated with infections and cancer and, most importantly, is the central component of non-insulin-dependent diabetes mellitus. We have recently shown that tumor necrosis factor (TNF) alpha is a key mediator of insulin resistance in animal models of non-insulin-dependent diabetes mellitus. Here, we investigate how TNF-alpha interferes with insulin action. Chronic exposure of adipocytes to low concentrations of TNF-alpha strongly inhibits insulin-stimulated glucose uptake. Concurrently, TNF-alpha treatment causes a moderate decrease in the insulin-stimulated autophosphorylation of the insulin receptor (IR) and a dramatic decrease in the phosphorylation of IR substrate 1, the major substrate of the IR in vivo. The IR isolated from TNF-alpha-treated cells is also defective in the ability to autophosphorylate and phosphorylate IR substrate 1 in vitro. These results show that TNF-alpha directly interferes with the signaling of insulin through its receptor and consequently blocks biological actions of insulin.

Alcohol consumption and insulin concentrations. Role of insulin in associations of alcohol intake with high-density lipoprotein cholesterol and triglycerides

Article

Nov 1993

The relation between alcohol intake and insulin levels may explain, in part, the reported associations of alcohol with cardiovascular disease risk factors, including high-density lipoprotein (HDL) cholesterol, triglycerides, blood pressure, and glucose levels, each of which has been recognized as a component of the insulin resistance syndrome. Subjects included nondiabetic participants of the Kaiser Permanente Women Twins Study (1989 through 1990). Usual alcohol intake was assessed as part of a food frequency questionnaire. For women from twin pairs in which both twins drank (n = 338), an increment of 12 g of alcohol per day (about one drink) was associated with an 8% lower 2-hour post-glucose-load insulin (P < .01) in a multiple regression analysis for twin data, adjusted for age, body mass index, waist-to-hip ratio, total caloric intake, and family history of diabetes. With genetic influences removed by matched analysis of the subset of 98 monozygotic twin pairs, an intrapair difference of 12 g of alcohol per day was associated with a 12.4% intrapair decrement in postload insulin (P < .01). Inverse associations were also seen for fasting insulin. Alcohol consumption was inversely associated with postload glucose but not with fasting glucose in unmatched (P = .05) and matched (P = .005) analyses. A significant positive association of alcohol intake with high-density lipoprotein cholesterol and an inverse relation of alcohol intake with triglycerides were each independent of insulin levels (P < or = .02 in the matched models). Neither systolic nor diastolic blood pressures were related to alcohol consumption in this sample, perhaps because of the rather low level of alcohol intake in the study population (median, 4 g/d). Within the range of light to moderate drinking habits, alcohol consumption was inversely related to fasting and postload insulin levels. This relation did not explain associations of alcohol intake with lipid levels and may instead reflect an additional mechanism by which moderate alcohol consumption impacts cardiovascular disease risk.

Paradoxical Decrease of an Adipose-Specific Protein, Adiponectin, in Obesity

Article

May 1999

We isolated the human adipose-specific and most abundant gene transcript, apM1 (Maeda, K., et al., Biochem. Biophys. Res. Commun. 221, 286-289, 1996). The apM1 gene product was a kind of soluble matrix protein, which we named adiponectin. To quantitate the plasma adiponectin concentration, we have produced monoclonal and polyclonal antibodies for human adiponectin and developed an enzyme-linked immunosorbent assay (ELISA) system. Adiponectin was abundantly present in the plasma of healthy volunteers in the range from 1.9 to 17.0 mg/ml. Plasma concentrations of adiponectin in obese subjects were significantly lower than those in non-obese subjects, although adiponectin is secreted only from adipose tissue. The ELISA system developed in this study will be useful for elucidating the physiological and pathophysiological role of adiponectin in humans.

3. Role of Adipocytokines on the Pathogenesis of Atherosclerosis in Visceral Obesity

Article

Mar 1999

Obesity which is defined as accumulation of excess body fat, is a major cause of atherosclerotic vascular disease in industrial countries. Recent advances in the biology of adipose tissue have revealed that adipose tissue is not simply an energy storage organ but it also secretes a variety of molecules which affect the metabolism of the whole body. Through a systematic search of active genes in adipose tissue, we found that adipose tissue, especially visceral fat expressed numerous genes for secretory proteins (about 30% of total genes analyzed). Among them, plasminogen activator-1 (PAI-1), which is a regulator of the fibrinolytic system, was overexpressed in the visceral fat in an animal model of obesity. Plasma levels of PAI-1 were closely correlated with visceral fat adiposity. Thus, PAI-1 secreted from visceral fat may play some role in thrombotic vascular disease in visceral obesity. Adiponectin, a novel adipose-specific gene product, which has a matrix-like structure, is abundantly present in the bloodstream. Dysregulated secretion of adiponectin may be related to vascular disease in obesity. Biologically active molecules secreted from adipose tissue (adipocytokines) may have important roles in the development of atherosclerotic disease in obesity.

Novel Modulator for Endothelial Adhesion Molecules : Adipocyte-Derived Plasma Protein Adiponectin

Article

Dec 1999

Among the many adipocyte-derived endocrine factors, we recently found an adipocyte-specific secretory protein, adiponectin, which was decreased in obesity. Although obesity is associated with increased cardiovascular mortality and morbidity, the molecular basis for the link between obesity and vascular disease has not been fully clarified. The present study investigated whether adiponectin could modulate endothelial function and relate to coronary disease. For the in vitro study, human aortic endothelial cells (HAECs) were preincubated for 18 hours with the indicated amount of adiponectin, then exposed to tumor necrosis factor-alpha (TNF-alpha) (10 U/mL) or vehicle for the times indicated. The adhesion of human monocytic cell line THP-1 cells to HAECs was determined by adhesion assay. The surface expression of vascular cell adhesion molecule-1 (VCAM-1), endothelial-leukocyte adhesion molecule-1 (E-selectin), and intracellular adhesion molecule-1 (ICAM-1) was measured by cell ELISA. Physiological concentrations of adiponectin dose-dependently inhibited TNF-alpha-induced THP-1 adhesion and expression of VCAM-1, E-selectin, and ICAM-1 on HAECs. For the in vivo study, the concentrations of adiponectin in human plasma were determined by a sandwich ELISA system that we recently developed. Plasma adiponectin concentrations were significantly lower in patients with coronary artery disease than those in age- and body mass index-adjusted control subjects. These observations suggest that adiponectin modulates endothelial inflammatory response and that the measurement of plasma adiponectin levels may be helpful in assessment of CAD risk.

Alcohol consumption and insulin resistance in young adults

Article

Apr 2000

Alcohol may have a cardioprotective effect. One possible mechanism is by reducing insulin resistance, a known cardiovascular risk factor. The aim of this study was to assess the relationship between alcohol consumption, insulin resistance and other parameters determining glucose tolerance in 154 young men and women. Subjects completed a questionnaire documenting weekly alcohol consumption. Insulin sensitivity and glucose tolerance were measured using the intravenous glucose tolerance test with minimal model analysis. Height, weight, usual level of exercise, smoking habits and socio-economic status were also recorded. Insulin sensitivity correlated inversely with body mass index (r = - 0.529, P < 0.001) but not with level of physical fitness. Women were significantly less insulin sensitive than men (4.19 and 5.63 104 min-1 pmol-1 L-1, respectively; P < 0.001). Insulin sensitivity correlated positively with alcohol consumption and this trend remained significant allowing for body mass index and gender (beta = 0.17, P < 0.014). First-phase insulin secretion showed a weak but non-significant trend in the opposite direction. Fasting glucose, fasting insulin and glucose tolerance showed no relationships with alcohol consumption. These data suggest a close relationship between alcohol consumption and insulin resistance in young adults. Regular alcohol consumption is associated with decreased insulin resistance and this may partly explain the cardioprotective effect of alcohol.

Alcohol Consumption and Risk of Type 2 Diabetes Mellitus Among US Male Physicians

Article

May 2000
ARCH INTERN MED

To examine the association between low to moderate alcohol consumption and the incidence of type 2 diabetes mellitus (DM) in men. Prospective cohort study. Over an average period of 12.1 years, we evaluated 20 951 participants in the Physicians' Health Study between ages 40 and 84 years who were free of cardiovascular disease, cancer, and diabetes and provided data on alcohol consumption at baseline. Type 2 DM diagnosed after randomization. Among 20 951 physicians, 766 cases of incident DM were reported over an average follow-up period of 12.1 years. After adjustment for age, randomized treatment assignment, smoking, physical activity, and body mass index, the relative risk estimates and 95% confidence intervals for those reporting alcohol use of rarely/ never, 1 to 3 drinks per month, 1 drink per week, 2 to 4 drinks per week, 5 to 6 drinks per week, and 1 or more drinks per day were 1.00 (referent), 1.03 (0.80-1.33), 0.89 (0.70-1.14), 0.74 (0.59-0.93), 0.67 (0.51-0.89), and 0.57 (0.45-0.73), respectively (linear trend, P<.001). Additional adjustment for baseline history of hypertension, high cholesterol level, or parental history of myocardial infarction or family history of diabetes (data collected at 9 years) did not materially alter the results. These associations persisted in analyses stratified by age, smoking status, body mass index, physical activity, and family history of DM. These data indicate that apparently healthy men who self-select for light to moderate alcohol consumption have a decreased subsequent risk of type 2 DM.

Plasma Concentrations of a Novel, Adipose-Specific Protein, Adiponectin, in Type 2 Diabetic Patients

Article

Jul 2000

Adiponectin is a novel, adipose-specific protein abundantly present in the circulation, and it has antiatherogenic properties. We analyzed the plasma adiponectin concentrations in age- and body mass index (BMI)-matched nondiabetic and type 2 diabetic subjects with and without coronary artery disease (CAD). Plasma levels of adiponectin in the diabetic subjects without CAD were lower than those in nondiabetic subjects (6.6+/-0.4 versus 7.9+/-0.5 microg/mL in men, 7.6+/-0.7 versus 11.7+/-1.0 microg/mL in women; P<0.001). The plasma adiponectin concentrations of diabetic patients with CAD were lower than those of diabetic patients without CAD (4.0+/-0.4 versus 6.6+/-0.4 microg/mL, P<0.001 in men; 6.3+/-0.8 versus 7.6+/-0. 7 microg/mL in women). In contrast, plasma levels of leptin did not differ between diabetic patients with and without CAD. The presence of microangiopathy did not affect the plasma adiponectin levels in diabetic patients. Significant, univariate, inverse correlations were observed between adiponectin levels and fasting plasma insulin (r=-0.18, P<0.01) and glucose (r=-0.26, P<0.001) levels. In multivariate analysis, plasma insulin did not independently affect the plasma adiponectin levels. BMI, serum triglyceride concentration, and the presence of diabetes or CAD remained significantly related to plasma adiponectin concentrations. Weight reduction significantly elevated plasma adiponectin levels in the diabetic subjects as well as the nondiabetic subjects. These results suggest that the decreased plasma adiponectin concentrations in diabetes may be an indicator of macroangiopathy.

Alcohol Intake and incidence of type 2 diabetes in men

Article

Jan 2000
DIABETES CARE

To evaluate the relation between alcohol intake and incidence of type 2 diabetes. This prospective study included 8,663 men with fasting plasma glucose measurements from at least two medical examinations. Alcohol intake was classified into five groups: nondrinkers and four quartiles (Qs) of drinkers according to the amount of alcohol intake. Type 2 diabetes was diagnosed by 1997 American Diabetes Association criteria. There were 149 incident cases of type 2 diabetes during 52,588 person-years of follow-up. There was a U-shaped association between alcohol intake and diabetes, with the lowest incidence of diabetes at Q2 (61.9-122.7 g/week). As compared with Q2, men in Q3 and Q4 had a 2.2- (95% CI 1.2-3.9, P = 0.01) and 2.4-fold (1.4-4.4, P<0.01) risk of developing diabetes, while nondrinkers and men in Q1 had 1.8- (1.0-3.3, P<0.05) and 1.4-fold (0.7-2.6, P = 0.34) higher risk of diabetes, respectively. These associations persisted after adjustment for age, fasting plasma glucose, smoking, BMI, blood pressure, serum triglyceride concentration, cardiorespiratory fitness, HDL cholesterol, waist circumference, and parental diabetes. We observed an elevated risk of developing type 2 diabetes in nondrinkers and men with high alcohol intakes, when compared with men who reported moderate alcohol intake. Men with a high alcohol intake may be able to reduce their risk of developing type 2 diabetes if they drink less.

Adiponectin, an Adipocyte-Derived Plasma Protein, Inhibits Endothelial NF- B Signaling Through a cAMP-Dependent Pathway

Article

Oct 2000
CIRCULATION

Among the many adipocyte-derived endocrine factors, we found an adipocyte-derived plasma protein, adiponectin, that was decreased in obesity. We recently demonstrated that adiponectin inhibited tumor necrosis factor-alpha (TNF-alpha)-induced expression of endothelial adhesion molecules and that plasma adiponectin level was reduced in patients with coronary artery disease (CIRCULATION: 1999;100:2473-2476). However, the intracellular signal by which adiponectin suppressed adhesion molecule expression was not elucidated. The present study investigated the mechanism of modulation for endothelial function by adiponectin. The interaction between adiponectin and human aortic endothelial cells (HAECs) was estimated by cell ELISA using biotinylated adiponectin. HAECs were preincubated for 18 hours with 50 microg/mL of adiponectin, then exposed to TNF-alpha (10 U/mL) or vehicle for the times indicated. NF-kappaB-DNA binding activity was determined by electrophoretic mobility shift assays. TNF-alpha-inducible phosphorylation signals were detected by immunoblotting. Adiponectin specifically bound to HAECs in a saturable manner and inhibited TNF-alpha-induced mRNA expression of monocyte adhesion molecules without affecting the interaction between TNF-alpha and its receptors. Adiponectin suppressed TNF-alpha-induced IkappaB-alpha phosphorylation and subsequent NF-kappaB activation without affecting other TNF-alpha-mediated phosphorylation signals, including Jun N-terminal kinase, p38 kinase, and Akt kinase. This inhibitory effect of adiponectin is accompanied by cAMP accumulation and is blocked by either adenylate cyclase inhibitor or protein kinase A (PKA) inhibitor. These observations raise the possibility that adiponectin, which is naturally present in the blood stream, modulates the inflammatory response of endothelial cells through cross talk between cAMP-PKA and NF-kappaB signaling pathways.

Influence of moderate chronic wine consumption on insulin sensitivity and other correlates of syndrome X in moderately obese women

Article

Dec 2000
METABOLISM

Epidemiologic studies indicate that alcohol consumption is associated with improved insulin sensitivity; however, scant experimental evidence confirms this observation. To determine the effects of regular moderate wine consumption on insulin sensitivity, 20 overweight women (body mass index [BMI], 29.8 +/- 2.2 kg/m2) participated in a 20-week free-living randomized crossover trial. The subjects, serving as their own controls, consumed wine (190 mL red wine, 13% vol/vol ethanol, 5 days per week) for 10 weeks and abstained for 10 weeks or vice versa. The dependent variables (body weight, BMI, percent body fat, blood pressure, fasting blood glucose and insulin, blood lipids, dietary intake, and insulin sensitivity by intravenous glucose tolerance test [IVGTT]) were measured at the pretest, at the 10-week crossover, and at the 20-week completion of the study. Data were analyzed at the pretest and at completion of the wine drinking and abstention periods of the study using ANOVA by order of treatment. Fasting glucose remained unchanged (mean +/- SD; P > .05) throughout the experiment (pretest, drinking, and abstention, 91.1 +/- 9.2, 91.6 +/- 9.1, and 88.5 +/- 11.2 mg/dL), as did the measures of insulin sensitivity, fasting insulin (pretest, drinking, and abstention, 8.6 +/- 3.3, 8.6 +/- 4.1, and 9.1 +/- 4.7 microU/mg) and the insulin sensitivity index (3.60 +/- 2.96, 3.25 +/- 2.17, and 3.30 +/- 1.84). Body composition and blood lipids also remained unchanged (P > .05) during treatment. Moderate wine consumption at this dose in overweight women did not improve or impair insulin sensitivity, nor did it change any of the known correlates of insulin sensitivity, including body weight and composition, blood lipids, and blood pressure.

Control of energy homeostasis and insulin action by adipocyte hormones: Leptin, acylation stimulating protein, and adiponectin

Article

Mar 2002

Peter J Havel

Adipose tissue performs complex metabolic and endocrine functions. This review will focus on the recent literature on the biology and actions of three adipocyte hormones involved in the control of energy homeostasis and insulin action, leptin, acylation-stimulating protein, and adiponectin, and mechanisms regulating their production. Results from studies of individuals with absolute leptin deficiency (or receptor defects), and more recently partial leptin deficiency, reveal leptin's critical role in the normal regulation of appetite and body adiposity in humans. The primary biological role of leptin appears to be adaptation to low energy intake rather than a brake on overconsumption and obesity. Leptin production is mainly regulated by insulin-induced changes of adipocyte metabolism. Consumption of fat and fructose, which do not initiate insulin secretion, results in lower circulating leptin levels, a consequence which may lead to overeating and weight gain in individuals or populations consuming diets high in energy derived from these macronutrients. Acylation-stimulating protein acts as a paracrine signal to increase the efficiency of triacylglycerol synthesis in adipocytes, an action that results in more rapid postprandial lipid clearance. Genetic knockout of acylation-stimulating protein leads to reduced body fat, obesity resistance and improved insulin sensitivity in mice. The primary regulator of acylation-stimulating protein production appears to be circulating dietary lipid packaged as chylomicrons. Adiponectin increases insulin sensitivity, perhaps by increasing tissue fat oxidation resulting in reduced circulating fatty acid levels and reduced intramyocellular or liver triglyceride content. Adiponectin and leptin together normalize insulin action in severely insulin-resistant animals that have very low levels of adiponectin and leptin due to lipoatrophy. Leptin also improves insulin resistance and reduces hyperlipidemia in lipoatrophic humans. Adiponectin production is stimulated by agonists of peroxisome proliferator-activated receptor-gamma; an action may contribute to the insulin-sensitizing effects of this class of compounds. The production of all three hormones is influenced by nutritional status. These adipocyte hormones, the pathways controlling their production, and their receptors represent promising targets for managing obesity, hyperlipidemia, and insulin resistance.

Alcohol consumption, the metabolic syndrome and insulin resistance in 58-year-old clinically healthy men (AIR study)

Article

Apr 2002

It has been shown that a light-to-moderate intake of alcohol may enhance insulin sensitivity; a decrease in insulin sensitivity is a component of the clustering of risk factors known as the metabolic syndrome. However, previous studies have been limited to relatively small or heterogeneous study groups, or have used suboptimal methods of measuring insulin action. Hence the aim of the present study was to examine whether the metabolic syndrome (as recently defined),components of this syndrome and smoking are associated with alcohol consumption. The study was performed in a population-based sample of clinically healthy men (n=391), all 58 years old and not undergoing any treatment with cardiovascular drugs. Insulin-mediated glucose uptake (euglycaemic hyperinsulinaemic clamp) was measured in a subgroup of these subjects (n=104). Trend analysis showed no difference in alcohol intake across the groups of men with none of the criteria in the definition of the metabolic syndrome (n=77),men with one or more of the criteria (n=252) and men fulfilling all criteria (n=62). However, in the whole group (n=391), alcohol consumption was significantly positively associated with serum triacylglycerols (triglycerides), high-density lipoprotein (HDL) cholesterol and cigarette-years. Furthermore, alcohol consumption was positively associated with insulin-mediated glucose uptake (r=0.20, P<0.05). In multiple regression analyses, body mass index, alcohol consumption and serum triacylglycerols were independent co-variates to insulin-mediated glucose uptake. Thus, in 58-year-old healthy men recruited from the general population, there was a significant association between alcohol consumption, serum triacylglycerols, HDL cholesterol and cigarette-years. In a subgroup of 104 subjects, alcohol consumption was independently and positively associated with insulin-mediated glucose uptake. To our knowledge, this is the first study to show an independent relationship between insulin sensitivity, as measured by the clamp technique, and alcohol intake.

Effects of pioglitazone on metabolic parameters, body fat distribution, and serum adiponectin levels in Japanese male patients with type 2 diabetes

Article

Apr 2002
METABOLISM

The aim of this study was to evaluate the effects of pioglitazone on clinical and metabolic parameters, body fat distribution, and serum adiponectin, a recently discovered antiatherosclerotic hormone, in Japanese patients with type 2 diabetes. Ten male patients aged 40 to 66 (57.7 +/- 7.4) years, who were being treated with dietary therapy alone (n = 7) or with a stable dose of sulfonylurea (n = 3), were studied at baseline and after 3 months of pioglitazone treatment (30 mg/d). Body mass index (BMI), blood pressure, fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), serum insulin, adiponectin, and lipid profile were measured. Also, visceral adipose tissue area (VAT) and subcutaneous adipose tissue area (SAT) at the umbilical level were determined by computed tomographic (CT) scanning. Mean blood pressure (109 +/- 14 to 101 +/- 10 mm Hg), FPG (8.6 +/- 1.4 to 7.0 +/- 1.0 mmol/L), serum insulin (54 +/- 11 to 30 +/- 8 pmol/L, P <.01 for all), and HbA1c (6.7 +/- 0.8 to 6.1% +/- 0.6%, P =.013) decreased significantly during 3 months of pioglitazone treatment. BMI (26.4 +/- 3.2 to 27.0 +/- 3.5 kg/m2), low-density lipoprotein (LDL) cholesterol (124 +/- 24 to 138 +/- 24 mg/dL) and SAT (155 +/- 69 to 179 +/- 81cm2, P <.05 for all) increased, while triglycerides and high-density lipoprotein (HDL) cholesterol did not change significantly after 3 months of pioglitazone treatment. Serum adiponectin level increased in all patients (4.8 +/- 1.7 to 14.4 +/- 2.1 microg/mL, P =.005). VAT tended to increase (165 +/- 38 to 180 +/- 46 cm2) and VAT/SAT ratio tended to decrease (1.2 +/- 0.3 to 1.1 +/- 0.3), but these differences did not reach statistical significance. These results suggest that pioglitazone exerts good glycemic and blood pressure control despite increased BMI and SAT in Japanese male patients with type 2 diabetes. It is also suggested that pioglitazone may have an antiatherosclerotic effect by increasing serum adiponectin level.

Alcohol consumption alters insulin secretion and cardiac autonomic activity

Article

Apr 2002

Alcohol may have a cardioprotective effect. One possible mechanism is by modifying insulin resistance/secretion. The aims of this study were: (i) to examine the effect of short-term alcohol consumption on the metabolic control of glucose tolerance; (ii) to study the influence of short-term alcohol consumption on cardiac autonomic activity using spectral analysis of heart rate variability. Twenty-one healthy subjects, in a randomized crossover design, either received three units of ethanol daily for 1 week or abstained from ethanol. The control of glucose tolerance was assessed using the intravenous glucose tolerance test with minimal modelling. There was no difference in fasting glucose, fasting insulin or insulin sensitivity between the two groups. Alcohol showed a lower insulin first phase insulin response (no alcohol 659.0 +/- 394.1 SD, alcohol 535.2 +/- 309.1) pmol L-1 min-1, P = 0.027). There was no difference in heart rate or blood pressure but a significant difference in the ratio of high to low frequency spectral power of heart rate variability; (no alcohol 4.55 +/- 3.78, alcohol 8.16 +/- 6.77, P = 0.033). This suggests decreased sympathetic and/or increased vagal modulation of heart rate in the alcohol group. The finding of no difference in insulin sensitivity between the two groups contrasts with, but does not entirely contradict, the results of previous epidemiological studies--perhaps suggesting that longer term changes such as liver enzyme induction may be important. The difference in insulin secretion questions the validity of previous studies of the influence of alcohol on insulin sensitivity, where insulin levels were used as a surrogate for insulin resistance.

Increased Fat Intake, Impaired Fat Oxidation, and Failure of Fat Cell Proliferation Result in Ectopic Fat Storage, Insulin Resistance, and Type 2 Diabetes Mellitus

Article

Jul 2002

It is widely accepted that increasing adiposity is associated with insulin resistance and increased risk of type 2 diabetes. The predominant paradigm used to explain this link is the portal/visceral hypothesis. This hypothesis proposes that increased adiposity, particularly in the visceral depots, leads to increased free fatty acid flux and inhibition of insulin action via Randle's effect in insulin-sensitive tissues. Recent data do not entirely support this hypothesis. As such, two new paradigms have emerged that may explain the established links between adiposity and disease. (A) Three lines of evidence support the ectopic fat storage syndrome. First, failure to develop adequate adipose tissue mass in either mice or humans, also known as lipodystrophy, results in severe insulin resistance and diabetes. This is thought to be the result of ectopic storage of lipid into liver, skeletal muscle, and the pancreatic insulin-secreting beta cell. Second, most obese patients also shunt lipid into the skeletal muscle, the liver, and probably the beta cell. The importance of this finding is exemplified by several studies demonstrating that the degree of lipid infiltration into skeletal muscle and liver correlates highly with insulin resistance. Third, increased fat cell size is highly associated with insulin resistance and the development of diabetes. Increased fat cell size may represent the failure of the adipose tissue mass to expand and thus to accommodate an increased energy influx. Taken together, these three observations support the acquired lipodystrophy hypothesis as a link between adiposity and insulin resistance. (B) The endocrine paradigm developed in parallel with the ectopic fat storage syndrome hypothesis. Adipose tissue secretes a variety of endocrine hormones, such as leptin, interleukin-6, angiotensin II, adiponectin (also called ACRP30 and adipoQ), and resistin. From this viewpoint, adipose tissue plays a critical role as an endocrine gland, secreting numerous factors with potent effects on the metabolism of distant tissues. These two new paradigms provide a framework to advance our understanding of the pathophysiology of the insulin-resistance syndrome.

Obesity as a medical prob-lem

Jan 2000
635-643

Kopelman
Pg

Kopelman PG: Obesity as a medical prob-lem. Nature 404:635– 643, 2000

Increased adipose tissue expression of tumor necrosis factor-in human obesity and insulin resistance

Jan 1995
2409-2415

Gs Hotamisligil
P Arner
Jf Caro
Rl Atkinson
Bm Spiegelman

Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM: Increased adipose tissue expression of tumor necrosis factor-in human obesity and insulin resistance. J Clin Invest 95:2409 –2415, 1995

Alcohol intake and insulin levels: the Normative Aging Study

Jan 1997
909-916

R Lazarus
D Sparrow
St Weiss

Lazarus R, Sparrow D, Weiss ST: Alcohol intake and insulin levels: the Normative Aging Study. Am J Epidemiol 145:909 – 916, 1997

Effect of Moderate Alcohol Consumption on Adiponectin, Tumor Necrosis Factor- , and Insulin Sensitivity

Abstract

No full-text available

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