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The metabolic syndrome: Linking oxidative stress and inflammation to obesity, type 2 diabetes, and the syndrome
Abstract
Metabolic syndrome defined by a cluster of clinical features increases the risk of cardiovascular disease and type 2 diabetes mellitus. The original hypothesis linking this syndrome to these diseases was based on insulin resistance and the effect of hyperinsulinemia on atherogenesis. However, inflammatory processes have now been linked to the pathogenesis of atherosclerosis and insulin resistance. Novel data have shown the effect of macronutrients on inflammatory mediators and the anti-inflammatory effects of insulin that is secreted in response to food intake. This review attempts to provide an alternative explanation for the pathogenesis of the metabolic syndrome and the increase in risk of cardiovascular disease and diabetes on the basis of these findings. Drug Dev. Res. 67:619–626, 2006. © 2006 Wiley-Liss, Inc.
... Since the pattern of SCFAs formed is dependent on several food factors, the cholesterol metabolism, for example, could possibly be controlled by diet [23]. Altered cholesterol level is one of the key components of the metabolic syndrome [24]. Other components of the metabolic syndrome are obesity, high blood pressure and high fasting blood glucose levels [24]. ...
... Altered cholesterol level is one of the key components of the metabolic syndrome [24]. Other components of the metabolic syndrome are obesity, high blood pressure and high fasting blood glucose levels [24]. Dietary fibres may also modulate the colonic microbiota to a more protective one, and alter systemic and mucosal immune response [25]. ...
Obesity is linked to type 2 diabetes and risk factors associated to the metabolic syndrome. Consumption of dietary fibres has been shown to have positive metabolic health effects, such as by increasing satiety, lowering blood glucose and cholesterol levels. These effects may be associated with short-chain fatty acids (SCFAs), particularly propionic and butyric acids, formed by microbial degradation of dietary fibres in colon, and by their capacity to reduce low-grade inflammation.
To investigate whether dietary fibres, giving rise to different SCFAs, would affect metabolic risk markers in low-fat and high-fat diets using a model with conventional rats for 2, 4 and 6 weeks.
Conventional rats were administered low-fat or high-fat diets, for 2, 4 or 6 weeks, supplemented with fermentable dietary fibres, giving rise to different SCFA patterns (pectin - acetic acid; guar gum - propionic acid; or a mixture - butyric acid). At the end of each experimental period, liver fat, cholesterol and triglycerides, serum and caecal SCFAs, plasma cholesterol, and inflammatory cytokines were analysed. The caecal microbiota was analysed after 6 weeks.
Fermentable dietary fibre decreased weight gain, liver fat, cholesterol and triglyceride content, and changed the formation of SCFAs. The high-fat diet primarily reduced formation of SCFAs but, after a longer experimental period, the formation of propionic and acetic acids recovered. The concentration of succinic acid in the rats increased in high-fat diets with time, indicating harmful effect of high-fat consumption. The dietary fibre partly counteracted these harmful effects and reduced inflammation. Furthermore, the number of Bacteroides was higher with guar gum, while noticeably that of Akkermansia was highest with the fibre-free diet.
... The metabolic syndrome, and obesity as one of its main pathological manifestations is directly related to inflammation [12]. It is widely accepted that the alteration of adipose tissue endothelial function and signalling may be the consequence of long-term or sustained excess nutrient availability [13]; this results in a continued saturation of the adipose tissue capability to store fat that elicits a cytokine-driven response [14,15] that, in the long-term, results in additional alteration of energy metabolism and homeostasis [16]. ...
... It is widely accepted that the alteration of adipose tissue endothelial function and signalling may be the consequence of long-term or sustained excess nutrient availability [13]; this results in a continued saturation of the adipose tissue capability to store fat that elicits a cytokine-driven response [14,15] that, in the long-term, results in additional alteration of energy metabolism and homeostasis [16]. The basis of the tissue insult lies on the endothelium, which inflammation (involving active radicals of oxygen and nitrogen) [12,17] starts a response cascade in which the counteractive actions of adipokines, cytokines and other hormonal signals, both peptidic and steroidal acquire a protagonist role [17,18]. The removal of the adrenal gland prevents or even reverses obesity in several animal models [19,20] enhancing the slimming effects of leptin [21] and oleoyl-estrone [22]. ...
Oleoyl-estrone (OE) induces a marked loss of body fat in rats by maintaining energy expenditure, body protein and blood glucose despite decreasing food intake. OE increases glucocorticoids, but they arrest OE lipid-mobilization. We studied here whether OE induces a direct effect on adrenal glands function as part of this feedback regulation. Dietary overweight male rats were given oral 10 nmol/g OE gavages for ten days. A group (PF) of pair-fed to OE rats, and controls received vehicle-only gavages. OE rats lost slightly more body than PF, but had larger adrenal glands. Tissue corticosterone levels, and gene expressions for glucocorticoid-synthesizing enzymes were increased in OE versus controls and PF; thus, we assumed that adrenal growth affected essentially its cortex since OE also lowered the expression of the medullar catecholamine synthesis enzyme genes. Serum corticosterone was higher in PF than in OE and controls, but liver expression of corticosteroid-disposing steroid 5α-reductase was 3× larger in OE than PF and controls. Circulating glucocorticoids changed little under OE, in spite of higher adrenal gland and liver content, hinting at modulation of glucocorticoid turnover as instrumental in their purported increased activity. In conclusion, we have observed that OE considerable enhanced the expression of the genes controlling the synthesis of glucocorticoids from cholesterol in the rat and increasing the adrenal glands’ corticosterone, size and cellularity, but also the liver disposal of corticosteroids, suggesting that OE increases corticosterone synthesis and degradation (i.e. serum turnover), a process not driven by limited energy availability but directly related to the administration of OE.
... It is well established that MetS is a proinflammatory state in which inflammation-related mechanisms may contribute to insulin resistance. On the other hand, insulin resistance can also alter the antiinflammatory effect of insulin and, thus, promote inflammation itself (Dandona et al., 2006). When insulin homeostasis is lost and insulin resistance develops, especially in obese people, this state also contributes to MetS (Darroudi et al., 2019). ...
Metabolic syndrome (MetS) is a common disorder involving a cluster of metabolic abnormalities, such as abdominal obesity, hypertension, dyslipidemia, insulin resistance, and atherogenic profile. MetS is characterized by an increase in oxidative stress and a chronic proinflammatory state, which are directly related to the development and progression of this pathology. It has been seen how a healthy lifestyle and good dietary practices are key to improving the different metabolic parameters and, therefore , play a fundamental role in reducing the risk of developing diabetes. The present review focuses on the research evidence related to the therapeutic properties of Lycium barbarum L. in MetS gathered in the last years. Several preclinical studies This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
... Obesity is closely related to the inflammatory state of the body by increasing the expression of inflammatory factors. [4] Interleukin 6 (IL-6), tumor necrosis factora are shown to be positively correlated with increased adiposity [5] and C-reactive protein (CRP) increases with visceral obesity. [6] Shenqi compound is a traditional Chinese medicine compound established under the guidance of traditional Chinese medicine theory. ...
Background:
Diabetes is a chronic disease characterized by chronic hyperglycemia, absolute or relative deficiency of insulin secretion, and chronic inflammation. Shenqi compound (SC) is a traditional Chinese medicine formula widely used in the treatment of diabetes and diabetic complications. Although many randomized clinical trials have proved that SC can benefit a lot from diabetes and its complications, the systematic evaluation of the effect of SC on diabetic blood glucose control and inflammatory markers has not yet appeared. The purpose of this study is to provide evidence that the therapeutic effect of SC on diabetes and its multiple system complications is related to its control of blood glucose and inflammatory mediators.
Methods:
Three English database and 4 Chinese medical databases will be searched from its inception to May 2020. Then 2 methodological trained researchers will screen the qualified articles by reading the title, abstract, and full texts according to an established inclusion and exclusion criteria. The assessment of risk of bias will be conducted by using the Cochrane collaboration's tool. We will conduct meta-analyses for fasting blood glucose, postprandial blood glucose, glycated hemoglobin, tumor necrosis factor, C-reactive protein or high-sensitivity C-reactive protein, and other outcomes. The heterogeneity of data will be evaluated by Cochrane X and I tests. Subgroup analysis will also be carried out. We will conduct sensitivity analysis to evaluate the stability of the results, funnel plot analysis, and Egger test to evaluate the publication bias, and assessment for the quality of evidence by the grading of recommendations assessment, development, and evaluate system.
Results:
The results of our research will be published in a peer-reviewed journal.
Conclusion:
In this study, we will systematically evaluate the influences of SC on glycemic measures and inflammatory markers of diabetes mellitus. Our research is supposed to provide evidence-based support for clinical practice.
Registration number:
INPLASY202040179.
... Sitokin adiposit tersebut dapat menginduksi terjadinya resistensi insulin. Menurut Dandona et al. (2006), tingginya asupan makronutrisi dan glukosa ke dalam tubuh dapat menyebabkan stres oksidatif dan meningkatkan sitokin pro-inflamasi seperti IL-6 dan TNF-α. eberadaan IL-6 dan TNF-α dapat mengganggu kerja insulin dengan cara menekan sinyal transduksi insulin. ...
Type 2 diabetes mellitus (T2DM) subjects have a hyperglycemia condition. Hyperglycemia can cause oxidative stress that trigger glucose autooxidation and reactive oxygen species (ROS). ROS also triggers the inflammation and induces the cytokine signalling from cells and body tissues, such as interleukin and prostaglandin enzyme (COX-2). The purpose of this research was to analyze the effect of dietary fiber rich-tofu from black soybean (DFT) on bloods glucose and inflammations of T2DM patients. Intervention group (n=9) was given 80 grams DFT during 30 days and control group (n=9) was not. Blood collections were conducted before and after intervention by certified nurses for all groups for analysis in the laboratory. Fasting Blood Glucose (FBG) was measured by glucometer, while the plasma was analyzed with ELISA to measure the optical density value of IL-6 and COX-2 enzyme. Consumption of DFT resulted in the decline of the optical density of IL-6 value (p=0.00), but DFT could not reduce the FBG and optical density of COX-2 enzyme (p=0.22 and p=0.51). Therefore DFT can be considered as an effective food for reduction of T2DM inflammatory.
... In a suitable environment with appropriate stimuli, obesity promotes a pro-inflammatory state by increasing circulating levels of inflammatory cytokines [10]. Interleukin 6 (IL-6), Tumour Necrosis Factor (TNF)-α are shown to be positively correlated with increased adiposity [11] and C-reactive protein (CRP) increases with visceral obesity [12]. Furthermore, obesity decreases adiponectin levels, which have an important role of inhibiting the inflammatory process [13][14][15] and increasing the expression of anti-inflammatory cytokine, interleukin (IL-10) [16,17]. ...
Background:
Obesity induced low-grade chronic inflammation disrupts proper immune and metabolic function. Vitamin D deficiency increases inflammation, which is associated with cardiometabolic risk. This systematic review examines the association between oral vitamin D (VD) supplementation and circulating inflammatory biomarkers and glycemic outcomes from randomized controlled trials (RCTs) of overweight and/or obese adults.
Methods:
MEDLINE OVID, EMBASE and the Cochrane Central Register of Controlled Trials were searched according to a predefined protocol. Eligible RCTs included adults randomized to receive either oral VD or placebo. Two reviewers independently assessed RCTs for inclusion. Bias was assessed using the Cochrane Collaboration risk of bias tool. Mean differences were calculated comparing end-of-study sample means between the independent VD and placebo groups.
Results:
Eleven unique RCTs met inclusion criteria from a total of 3,383 identified citations, including 79 screened articles and 14 full text data extractions. Inflammatory and glycemic measures were reported in 7 and 10 RCTs, respectively. Most trial findings were non-significant with considerable heterogeneity in design, participants and outcomes. All but one trial was rated as either high or unclear risk of bias. Two RCTs reported significant changes in inflammatory biomarkers; however, the mean difference between groups was not statistically significant: C-reactive protein 0.19 mg/L (p = 0.88); Tumor Necrosis Factor -0.54 pg/ml (p = 0.20). Two other trials found significant mean differences in fasting plasma glucose -0.32 mmol/L (p = 0.03), Hemoglobin A1c -0.13% (p = 0.04), and Homeostatic Model Assessment -0.86 (p = 0.02) following VD supplementation.
Conclusions:
Overall, there is no clear established benefit of VD supplementation on inflammatory biomarkers among overweight/obese adults. Baseline serum VD possibly influences the effect of VD repletion on inflammatory markers. Risk of bias was present in most studies, thus supporting the need for higher quality studies in this area to more conclusively understand the role VD supplementation has on inflammatory pathways.
Probiotics are considered to play an crucial role in the treatment of high-fat diet (HFD)-induced lipid metabolic diseases, including metabolic syndrome (MS). This study aimed to investigate the effects of Lactobacillus plantarum S9 on MS in HFD-fed rats, and to explore the underlying role of probiotics in the treatment of MS. Sprague-Dawley rats were fed with HFD for 8 weeks, followed by the treatment of L. plantarum S9 for 6 weeks, and The body weight and blood glucose level of rats were detected on time. The results showed that L. plantarum S9 significantly decreased the body weight gain, Lee’s index, and liver index. Additionally, L. plantarum S9 reduced the levels of serum lipids and insulin resistance. L. plantarum S9 also decreased the levels of alanine aminotransferase (ALT) and aspartate transaminase (AST) in liver. Moreover, the serum levels of MS-related inflammatory signaling molecules, including lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α), were significantly elevated. Western blot analysis showed that L. plantarum S9 inhibited the activation of nuclear factor-κB (NF-κB) pathway, decreased the expression level of Toll-like receptor 4 (TLR4), suppressed the activation of inflammatory signaling pathways, and reduced the expression levels of inflammatory factors in HFD-fed rats. Moreover, it further decreased the ratios of p-IκBα/IκBα, p-p65/NF-κB p65, and p-p38/p38. In summary, L. plantarum S9, as a potential functional strain, prevents or can prevent onset of MS.
Diabetes mellitus is a metabolic syndrome which cannot be cured. Recently, considerable interest has been focused on food ingredients to prevent and intervene in complications of diabetes. Polyphenolic compounds are one of the bioactive phytochemical constituents with various biological activities, which have drawn increasing interest in human health. Fruits are part of the polyphenol sources in daily food consumption. Fruit-derived polyphenols possess the anti-diabetic activity that has already been proved either from in vitro studies or in vivo studies. The mechanisms of fruit polyphenols in treating diabetes and related complications are under discussion. This is a comprehensive review on polyphenols from the edible parts of fruits, including those from citrus, berries, apples, cherries, mangoes, mangosteens, pomegranates, and other fruits regarding their potential benefits in preventing and treating diabetes mellitus. The signal pathways of characteristic polyphenols derived from fruits in reducing high blood glucose and intervening hyperglycemia-induced diabetic complications were summarized.
Metabolic syndrome (MS) is a cluster of risk factors, which further may lead to serious health problems such as cardiovascular diseases. These risk factors are the development of chronic inflammation, insulin resistance, oxidative stress, hypertension, and dyslipidemia, indicating disturbed metabolism. MS affects individuals not only physically but also psychologically and financially. Diet is one of the basic factors responsible for MS that can be easily modified. Mediterranean diet pattern especially inclusion of extra-virgin olive oil (EVOO) is considered to promote health. Here, we have discussed dysregulated metabolic pathways in MS and their modulation by treatment with EVOO.
The complement system is a powerful and vital component of the innate immune system that plays a dual role in neurodegenerative diseases. When present at an optimum level in the normal brain, the complement system plays a neuroprotective role as it is involved in a number of processes like clearance of apoptotic cells, opsonisation of pathogens,etc. However factors such as oxidative stress and age can modify this protective ability can lead to chronic inflammation resulting in neurodegeneration. In a diseased brain, aggregated polypeptides can potentially present their different charge patterns to C1q, which is a vital charge pattern recognition molecule of the complement system. Consequently activation of complement leads to microglial activation which in turn leads to defective clearance of the aggregated polypeptides by macrophages leading to chronic inflammation, especially in age-related neurodegenerative disease (e.g., Alzheimer's disease). The current article aims at discussing the role of the complement system (especially C1q) and its consequences in initiation/progression in neurodegenerative diseases such as amyloid-associated dementias (Alzheimer's disease, Down's syndrome), non-amyloid associated dementia (Familial dementia, Huntington's disease, Parkinson's disease) and pathogen-induced dementia (prion diseases). Evidences point towards the existence of an over-activated complement system in a diseased brain can directly or indirectly lead to neuroinflammation which subsequently leads to neurodegeneration, the effects of which are manifested through the various clinical signs and symptoms. As C1q is the initiation molecule of the classical pathway, C1q-inhibitors that down regulate the complement cascade without negatively affecting the protective functions of complement can pave way for potential future immunotherapeutic approaches.
The relationship between insulin and atherosclerosis is complex. People with type 2 diabetes are affected by three main glycaemic disorders: chronic hyperglycaemia; glycaemic variability; and iatrogenic hypoglycaemia. In addition to this triumvirate, the diabetic condition is characterized by lipid disorders, chronic low-grade inflammation and activation of oxidative stress. All these associated disorders reflect the insulin-resistant nature of type 2 diabetes and contribute to the development and progression of cardiovascular (CV) diseases. By both lowering plasma glucose and improving the lipid profile, insulin exerts beneficial effects on CV outcomes. In addition, insulin has several pleiotropic effects such as anti-inflammatory, antithrombotic and antioxidant properties. Insulin per se exerts an inhibitory effect on the activation of oxidative stress and seems able to counteract the pro-oxidant effects of ambient hyperglycaemia and glycaemic variability. However, insulin actions remain a subject of debate with respect to the risk of adverse CV events, which can increase in individuals exposed to high insulin doses. Evidence from the large-scale, long-term ORIGIN trial suggests that early implementation of insulin supplementation therapy in the course of glycaemic disorders, including type 2 diabetes, has a neutral impact on CV outcomes compared with standard management. Thus, the answer to the question "What impact does insulin have on atherosclerosis?" remains unclear, even though it is logical to deduce that insulin should be initiated as soon as possible and that small doses of insulin early on are better than higher doses later in the disease process.
We measured arterio-venous differences in concentrations of tu- mor necrosis factor-a (TNFa) and interleukin-6 (IL-6) across a sc adipose tissue bed in the postabsorptive state in 39 subjects (22 women and 17 men; median age, 36 yr (interquartile range, 26 - 48 yr); body mass index, 31.8 kg/m2 (range, 22.3- 38.7 kg/m2); percent body fat, 28.7% (range, 17.6 -50.7%)). A subgroup of 8 subjects had arterio- venous differences measured across forearm muscle. Thirty subjects were studied from late morning to early evening; 19 ate a high car- bohydrate meal around 1300 h, and 11 continued to fast. We found a greater than 2-fold increase in IL-6 concentrations across the adipose tissue bed (arterial, 2.27 pg/mL (range, 1.42-3.53 pg/mL); venous, 6.71 pg/mL (range, 3.36 -9.62 pg/mL); P , 0.001), but not across forearm muscle. Arterial plasma concentrations of IL-6 correlated significantly with body mass index (Spearman's r 5 0.48; P , 0.01) and percent body fat (Spearman's r 5 0.49; P , 0.01). Subcutaneous adipose tissue IL-6 production increased by the early evening (1800 - 1900 h) in both subjects who had extended their fasting and those who had eaten. Neither deep forearm nor sc adipose tissue consistently released TNFa (across adipose tissue: arterial, 1.83 pg/mL (range, 1.36 -2.34 pg/mL); venous, 1.85 pg/mL (range, 1.44 -2.53 pg/mL); P 5 NS: across forearm muscle: arterial, 1.22 pg/mL (range, 0.74 -2.76 pg/mL); venous, 0.99 pg/mL (range, 0.69 -1.70 pg/mL); P 5 NS). Al- though both IL-6 and TNFa are expressed by adipose tissue, our results show that there are important differences in their systemic release. TNFa is not released by this sc depot. In contrast, IL-6 is released from the depot and is thereby able to signal systemically. (J Clin Endocrinol Metab 82: 4196 - 4200, 1997)
To elucidate whether troglitazone exerts an antiinflammatory ef- fect in humans, in vivo, we investigated the suppression of nuclear factor kB (NFkB) in mononuclear cells (MNC) by this drug. We mea- sured intranuclear NFkB, total cellular NFkB, inhibitor k B( I kB)a, reactive oxygen species (ROS) generation, and p47phox subunit (a key component protein of nicotinamide adenine dinucleotide phosphate oxidase) in MNC. Plasma tumor necrosis factor (TNF)-a, soluble in- tercellular adhesion molecule-1 (sICAM-1), monocyte chemoat- tractant protein-1 (MCP-1), plasminogen activator inhibitor type 1 (PAI-1), C-reactive protein (CRP), and interleukin (IL)-10 (antiin- flammatory cytokine) concentrations were also measured as media- tors of inflammatory activity that are regulated by the proinflamma- tory transcription factor NFkB. Seven nondiabetic obese patients were given 400 mg troglitazone daily for 4 weeks. Blood samples were collected before and at weekly intervals thereafter. MNC were sep- arated; and the levels of intranuclear NFkB, total cellular NFkB, IkBa, and p47 phox subunit and ROS generation were determined. Plasma was used to measure insulin glucose, TNFa, sICAM, MCP-1, PAI-1, CRP, and IL-10. Plasma insulin concentrations fell signifi- cantly at week 1, from 31.2 6 29.1 to 14.2 6 11.4 mU/L (P , 0.01) and remained low throughout 4 weeks. Plasma glucose concentrations did not alter significantly. There was a fall in intranuclear NFkB, total cellular NFkB, and p47 phox subunit, with an increase in cellular IkBa at week 2, which persisted until week 4. There was a parallel fall in ROS generation by MNC at week 1; this progressed and persisted until week 4 (P , 0.001). Plasma TNF-a, sICAM-1, MCP-1, and PAI-1 concentrations fell significantly at week 4. Plasma IL-10 concentra- tion increased significantly, whereas plasma CRP concentrations de- creased. We conclude that troglitazone has an antiinflammatory ac- tion that may contribute to its putative antiatherosclerotic effects. (J Clin Endocrinol Metab 86: 1306 -1312, 2001)
Weight gain is an important risk factor for the development of the metabolic syndrome, and inflammatory mediators are strongly associated with this syndrome. Our aim was to investigate whether inflammation predicts the development of weight gain in populations.
We investigated selected markers of inflammation in the prediction of weight gain over an approximately 3-year period in a biethnic cohort of 13,017 men and women, 45 to 64 years of age, using multiple linear and logistic regression modeling.
In adjusted models, those in the highest quartile of fibrinogen gained, during the first 3 years of follow-up, an estimated 0.23 kg/year more than those in the lowest quartile (p < 0.001). Adjusted odds of a large (greater than the 90th percentile) weight gain for those in the highest quartile of fibrinogen were 1.65 (95% confidence interval [CI], 1.38 to 1.97) times those in the lowest quartile. Similarly adjusted odds ratios for a large weight gain for those with high levels of white blood cell count, factor VIII, and von Willebrand factor were 1.38 (1.14 to 1.67), 1.28 (1.08 to 1.53), and 1.28 (1.08 to 1.51), respectively.
Fibrinogen and other putative markers of inflammation predict weight gain in middle-aged adults. Given the known links between the inflammatory response and intermediary metabolism and the methodological strengths of the Atherosclerosis Risk in Communities (ARIC) cohort, these findings, though without immediate clinical applicability, suggest that inflammatory processes play a role in the development of the metabolic syndrome and cardiovascular disease in part through stimulation of weight gain.
Stress is a potential contributor to chronic hyperglycemia in diabetes. Stress has long been shown to have major effects on metabolic activity. Energy mobilization is a primary result of the fight or flight response. Stress stimulates the release of various hormones, which can result in elevated blood glucose levels. Although this is of adaptive importance in a healthy organism, in diabetes, as a result of the relative or absolute lack of insulin, stress-induced increases in glucose cannot be metabolized properly. Furthermore, regulation of these stress hormones may be abnormal in diabetes. However, evidence characterizing the effects of stress in type I diabetes is contradictory. Although some retrospective human studies have suggested that stress can precipitate type I diabetes, animal studies have shown that stressors of various kinds can precipitate--or prevent--various experimental models of the disease. Human studies have shown that stress can stimulate hyperglycemia, hypoglycemia, or have no affect at all on glycemic status in established diabetes. Much of this confusion may be attributable to the presence of autonomic neuropathy, common in type I diabetes. In contrast, more consistent evidence supports the role of stress in type II diabetes. Although human studies on the role of stress in the onset and course of type II diabetes are few, a large body of animal study supports the notion that stress reliably produces hyperglycemia in this form of the disease. Furthermore, there is mounting evidence of autonomic contributions to the pathophysiology of this condition in both animals and humans.
Non-insulin-dependent diabetes mellitus (NIDDM) is commonly associated with hypertriglyceridaemia, low serum HDL-cholesterol concentrations, hypertension, obesity and accelerated atherosclerosis (metabolic syndrome X). Since a similar dyslipidaemia occurs with the acute-phase response, we investigated whether elevated acute-phase/stress reactants (the innate immune system's response to environmental stress) and their major cytokine mediator (interleukin-6, IL-6) are associated with NIDDM and syndrome X, and may thus provide a unifying pathophysiological mechanism for these conditions. Two groups of Caucasian subjects with NIDDM were studied. Those with any 4 or 5 features of syndrome X (n = 19) were compared with a group with 0 or 1 feature of syndrome X (n = 25) but similar age, sex distribution, diabetes duration, glycaemic control and diabetes treatment. Healthy non-diabetic subjects of comparable age and sex acted as controls. Overnight urinary albumin excretion rate, a risk factor for cardiovascular disease, was also assayed in subjects to assess its relationship to the acute-phase response. Serum sialic acid was confirmed as a marker of the acute-phase response since serum concentrations were significantly related to established acute-phase proteins such as alpha-1 acid glycoprotein (r = 0.82, p < 0.0001). There was a significant graded increase of serum sialic acid, alpha-1 acid glycoprotein, IL-6 and urinary albumin excretion rate amongst the three groups, with the lowest levels in non-diabetic subjects, intermediate levels in NIDDM patients without syndrome X and highest levels in NIDDM patients with syndrome X. C-reactive protein and cortisol levels were also higher in syndrome X-positive compared to X-negative patients and serum amyloid A was higher in both diabetic groups than in the control group. We conclude that NIDDM is associated with an elevated acute-phase response, particularly in those with features of syndrome X. Abnormalities of the innate immune system may be a contributor to the hypertriglyceridaemia, low HDL cholesterol, hypertension, glucose intolerance, insulin resistance and accelerated atherosclerosis of NIDDM. Microalbuminuria may be a component of the acute-phase response.
In view of the recent demonstration that obesity in animals and humans is associated with an increase in tumor necrosis factor-alpha (TNFalpha) expression, that this expression falls with weight loss, and that TNFalpha may specifically inhibit insulin action, the possibility that TNFalpha may be a mediator of insulin resistance has been raised. We have undertaken this study to investigate whether serum TNFalpha concentrations are elevated in obese subjects, whether they fall after weight loss, and whether this fall parallels the fall in insulin release after glucose challenge. Obese patients (age range: 25-54, weight mean +/- SD: 96.4 +/- 13.8 kg, body mass index: 35.7 +/- 5.6 kg/m2) were started on a diet program. The mean weight fell to 84.5 +/- 11.3 (P < 0.0001) and body mass index to 31.3 +/- 4.9 (P < 0.0001). Plasma TNFalpha concentrations were markedly elevated in the obese (3.45 +/- 0.16 pg/mL), when compared with controls (0.72 +/- 0.28 pg/mL), and fell significantly (2.63 +/- 1.40 pg/mL) after weight loss (P < 0.02). The magnitude of insulin release after glucose (75 g) challenge (area under the curve) also fell significantly (P < 0.01) after weight loss. The magnitude of weight loss and fall in TNFalpha were related to basal body weight (r = 0.57, P < 0.001) and basal TNFalpha (r = 0.55, P < 0.001) concentrations, respectively, but not to each other or to the glucose-induced insulin release (area under the curve). We conclude that obesity is associated with increased plasma TNFalpha concentrations, which fall with weight loss. Because circulating TNFalpha may mediate insulin resistance in the obese, a fall in TNFalpha concentrations may contribute to the restoration of insulin resistance after weight loss, Thus, TNFalpha may be an important circulating cytokine, which may provide a potentially reversible mechanism for mediating insulin resistance.
Since an increase in tumor necrosis factor alpha (TNFalpha) expression has been associated with insulin resistance, this study was undertaken to determine the status of circulating TNFalpha and the relationship of TNFalpha with insulin levels, body weight, or both in women with polycystic ovary syndrome (PCOS). Fasting serum samples were analyzed in 34 subjects with PCOS, of whom 22 were obese (body mass index [BMI]>27 kg/m2), and in 40 normal control women, of whom 20 were obese. Women with PCOS exhibited a significantly (P<.02) higher mean serum TNFalpha concentration compared with the controls. The serum TNFalpha level and BMI were directly correlated in women with PCOS (r=.48, P<.005) and highly correlated in controls (r=.78, P<.001). When subjects were classified by body weight, the mean serum TNFalpha concentration was significantly (P<.001) elevated in normal-weight women with PCOS compared with normal-weight controls. On the other hand, mean serum TNFalpha concentrations in obese women with PCOS and obese controls were similar and significantly (P<.02) higher than in normal-weight women with PCOS. A direct correlation between serum fasting insulin and TNFalpha was evident in controls (r=.35, P<.03), but not in women with PCOS. However, in the subgroup of obese women with PCOS, fasting insulin directly correlated (r=.49, P<.03) with TNFalpha and the median fasting serum insulin concentration was significantly (P<.05) higher compared with the level in normal-weight women with PCOS and all controls. Fasting insulin and TNFalpha were no longer correlated in controls as a group and in obese women with PCOS when controlling for body weight. Serum TNFalpha did not correlate with luteinizing hormone (LH), testosterone (T), or dehydroepiandrosterone sulfate (DHEAS) in women with PCOS. However, serum insulin was significantly correlated (r=.49, P<.0004) with T and the BMI exhibited a trend for correlation with serum T (r=.33, P=.05) in women with PCOS. Finally, the mean serum LH concentration was significantly (P<.02) higher in normal-weight women with PCOS versus obese women with PCOS, and serum LH levels exhibited a trend for an inverse correlation with the BMI (r=.31, P=.09) in women with PCOS. We conclude that (1) serum TNFalpha is increased in normal-weight women with PCOS and is even higher in obese individuals regardless of whether they have PCOS; (2) factors other than obesity are the cause of elevated serum TNFalpha in normal-weight women with PCOS; and (3) whereas increased circulating TNFalpha may mediate insulin resistance in obesity, which may in turn promote hyperandrogenism in obese women with PCOS, it remains to be demonstrated whether this is also the case in normal-weight women with PCOS.
Plasma leptin levels are elevated in most obese individuals, and obesity is accompanied by a high incidence of cardiovascular disease. Therefore, leptin could be involved in the pathogenesis of cardiovascular disease. In the present study, the role of leptin was explored in the regulation of platelet function. The expression of the long form of the leptin receptor was detected in human platelets. At 50 ng/ml, human leptin induced phosphorylation of several proteins of platelets at the tyrosine residue. Neither leptin at concentrations < or = 100 ng/ml nor ADP at concentrations > or = 1 micromol/l affected platelet aggregation. However, after pretreatment with 100 ng/ml leptin for 5 min, 1 micromol/l ADP caused aggregation. Thus, leptin and ADP acted synergistically. At a concentration of 2 micromol/l, ADP induced platelet aggregation, which was markedly enhanced by 30-100 ng/ml leptin in a concentration-dependent manner. This concentration range corresponds to that of plasma leptin levels in obese individuals. At the lower concentrations (< 10 ng/ml) that are observed in normal individuals, leptin had no effect on platelet aggregation. In conclusion, leptin at high concentrations has the novel function of promoting platelet aggregation, which may be a key coupling factor between obesity and the cardiovascular disease associated with syndrome X and diabetes.
Diabetes mellitus is associated with increased ROS generation, oxidative injury and obesity. To elucidate the relationship between nutrition and ROS generation, we have investigated the effect of glucose challenge on ROS generation by leucocytes, p47phox protein, a key protein in the enzyme NADPH oxidase and alpha-tocopherol levels. Blood samples were drawn from 14 normal subjects prior to, at 1, 2 and 3 h following ingestion of 75 g glucose. ROS generation by polymorphonuclear leucocytes (PMNL) and mononuclear cells (MNC) increased to a peak of 244 +/- 42% and 233 +/- 34% of the basal respectively at 2h. The levels of p47phox in MNC homogenates increased significantly at 2 h and 3 h after glucose intake. alpha-Tocopherol levels decreased significantly at 1 h, 2 h and 3 h. We conclude that glucose intake stimulates ROS generation and p417phox of NADPH oxidase; increases oxidative load and causes a fall in alpha-tocopherol concentration.
Because troglitazone has been shown to have antioxidant properties, we investigated whether troglitazone administration to obese subjects causes a reduction in (1) reactive oxygen species (ROS) generation by polymorphonuclear leukocytes (PMNLs) and mononuclear cells (MNCs) and (2) lipid peroxidation as reflected in the plasma concentrations of 9-hydroxyoctadecadienoic acid (9-HODE) and 13-hydroxyoctadecadienoic acid (13-HODE). Seven obese subjects were given 400 mg/d troglitazone for 4 weeks. Blood samples were obtained before troglitazone administration and at weekly intervals thereafter. Insulin concentrations fell significantly at week 1 and remained low at weeks 2 and 4 (P:<0.001). ROS generation by PMNLs fell to 77.6+/-25.1% of the basal at week 1 and 47.9+/-41.1% at week 4 (P:<0.001). ROS generation by MNCs fell to 59.8+/-15.7% of the basal at week 1 and 35.1+/-17.6% at week 4 (P:<0.001). 9-HODE and 13-HODE concentrations fell significantly from 787.4+/-52.4 and 713. 1+/-44.7 pg/mL to 720.4+/-66.7 (P:<0.004) and 675.2+/-65.0 pg/mL (P:<0.01) after 4 weeks, respectively. Postischemic dilatation of the brachial artery was measured by ultrasonography. The mean percent dilatation after forearm ischemia before and after troglitazone was 5.5+/-3.01% and 8.75+/-3.37% (P:<0.02), respectively. The percent increase in diameter after nitroglycerin was 17.08+/-1.18% before troglitazone, whereas it was 18.9+/-1.91% (P:<0.02) after troglitazone. We conclude that troglitazone has a potent and rapid biological inhibitory effect on ROS generation by PMNLs and MNCs and that it inhibits lipid peroxidation significantly. These changes are associated with a significant improvement in postischemic flow-mediated vasodilation in the brachial artery over a relatively short period of 4 weeks.
Increased reactive oxygen species generation by the leukocytes of the obese may be responsible for increased oxidative injury to lipids and proteins and, hence, atherosclerosis. We have investigated whether reactive oxygen species generation by leukocytes and other indexes of oxidative damage in the body fall with short-term dietary restriction and weight loss. Nine nondiabetic obese subjects (body mass index, 32.5-64.4 kg/m(2)), not taking any antioxidants, were put on a 1000-Cal diet. Fasting blood samples were taken at 0, 1, 2, 3, and 4 weeks and at 12 weeks after the cessation of dietary restriction. Blood samples were also obtained at 1 and 2 h after administration of 75 g oral glucose at 0 and 4 weeks. Mononuclear cells (MNC) and polymorphonuclear leukocytes (PMN) were isolated, and reactive oxygen species generation was measured. Plasma concentrations of thiobarbituric acid-reactive species (TBARS), 13-hydroxyoctadecadienoic acid (13-HODE), 9-hydroxyoctadecadienoic acid (9-HODE), carbonylated proteins, o-tyrosine, and m-tyrosine as indexes of oxidative damage to lipids, proteins and amino acids, respectively, were measured. Antioxidant vitamins were measured as indexes of antioxidant reserves. Plasma tumor necrosis factor-alpha concentrations were also measured. Mean weight loss was 2.4 +/- 0.6 kg at week 1, 2.5 +/- 1.7 kg at week 2, 3.9 +/- 0.8 kg at week 3, and 4.5 +/- 2.8 kg at week 4 (P < 0.05). Reactive oxygen species generation by PMN fell from 236.4 +/- 95.8 to 150.9 +/- 69.0, 125.9 +/- 24.3, 96.0 +/- 39.9, and 103.1 +/- 35.7 mV at weeks 1, 2, 3, and 4, respectively (P < 0.001). It increased 3 months after the cessation of dietary restriction to 270.0 +/- 274.3 mV. Reactive oxygen species generation by MNC fell from 187.8 +/- 75.0 to 101.7 +/- 64.5, 86.9 +/- 42.8, 63.8 +/- 14.3, and 75.1 +/- 32.2 mV and increased thereafter to 302.0 +/- 175.5 mV at 1, 2, 3, 4, and 16 weeks, respectively (P < 0.005). Reactive oxygen species generation by PMN and MNC increased in response to glucose; the relative increase was greater at 4 weeks than that at week 0 due to a fall in the basal levels of reactive oxygen species generation. Consistent with the fall in reactive oxygen species generation, there was a reduction in plasma TBARS from 1.68 +/- 0.17 micromol/L at week 0 to 1.47 micromol/L at 4 weeks (P < 0.05). The 13-HODE to linoleic acid ratio fell from a baseline of 100% to 56.4 +/- 36.1% at 4 weeks (P < 0.05), and the 9-HODE to linoleic acid ratio fell from a baseline of 100% to 60.5 +/- 37.7% at 4 weeks (P < 0.05). Carbonylated proteins fell from 1.39 +/- 0.27 microgram/mg protein at week 0 to 1.17 +/- 0.12 microgram/mg protein at week 4 (P < 0.05); o-tyrosine fell from 0.42 +/- 0.03 mmol/mol phenylalanine at week 0 to 0.36 +/- 0.02 mmol/mol phenylalanine at 4 weeks (P < 0.005), and m-tyrosine fell from 0.45 +/- 0.04 mmol/mol phenylalanine at week 0 to 0.40 +/- 0.03 mmol/mol phenylalanine at 4 weeks (P < 0.05). The basal concentrations of TBARS, 9-HODE, 13-HODE, carbonylated proteins, o-tyrosine, and m-tyrosine in the obese were significantly greater than those in normal subjects. On the other hand, tumor necrosis factor-alpha concentrations did not change during this 4-week period, nor was there any change in antioxidant vitamins. This is the first demonstration of 1) an increase in reactive oxygen species-induced damage in lipids, proteins, and amino acids in the obese compared with normal subjects; and 2) a decrease in reactive oxygen species generation by leukocytes and oxidative damage to lipids, proteins, and amino acids after dietary restriction and weight loss in the obese over a short period.
ABSTRACT Since glucose intake acutely increases reactive oxygen species (ROS) generation by polymorphonuclear leucocytes (PMN) and mononuclear cells (MNC), we have now investigated whether a fast over a period of 48h reduces ROS generation by these cells. Eight normal subjects were fasted for 48h. Blood samples were obtained at 0, 24h and 48h. ROS generation by PMN fell significantly at 24h (66.1 +/- 19.5% of basal) and further at 48h (45.9 +/- 23.0 % of basal; p < 0.001). ROS generation by MNC fell to 62.4 +/- 16.5% at 24h and by 48.4 +/- 16.5% (p < 0.001) by 48h. The level of p47(phox) subunit, an index of NADPH oxidase, the enzyme converting molecular oxygen to superoxide (O(.)(2)(-)) radical, also fell in parallel. Plasma o-tyrosine/phenylalanine ratio fell significantly from 0.326 +/- 0.053 mmol/mol to 0.303 +/- 0.055 mmol/mol at 48h and m-tyrosine/phenylalanine ratio fell from 0.363 +/- 0.063 mmol/mol to 0.340 +/- 0.064 mmol/mol (p < 0.05). Thus, a 48h fast may reduce ROS generation, total oxidative load and oxidative damage to amino acids.
In view of the fact that insulin resistance is associated with atherogenesis and that troglitazone, an insulin sensitizer, has anti-inflammatory effects, which may be potentially antiatherogenic in the long term, we have now investigated whether insulin has potential anti-inflammatory effects. We infused 2.0 to 2.5 IU/h in 5% dextrose (100 mL/h) iv into 10 obese subjects for 4 h followed by 5% dextrose alone for 2 h. The rate of insulin infusion was varied to maintain glucose concentrations as close to the baseline as possible. Blood samples were obtained before and at 2, 4, and 6 h. Subjects were also infused with 5% dextrose without insulin and with saline on separate occasions. Intranuclear nuclear factor kappaB (NFkappaB) in mononuclear cells fell at 2 and further at 4 h, reverting toward the baseline at 6 h (P < 0.05). IkappaB increased significantly at 2 h, increasing further at 4 h and remaining elevated at 6 h (P < 0.001). Reactive oxygen species (ROS) generation by mononuclear cells fell significantly at 2 h and fell further at 4 h; it partially reverted to baseline at 6 h (P < 0.005). p47(phox) subunit, the key protein of nicotinamide adenine dinucleotide phosphate oxidase also fell at 2 h and 4 h, reverting toward the baseline at 6 h (P < 0.05). In addition, soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1) fell significantly following insulin infusion. Glucose or saline infusions without insulin caused no alteration in NFkappaB, IkappaB, ROS generation, p47(phox) subunit, sICAM-1, MCP-1, or PAI-1. We conclude that insulin has a potent acute anti-inflammatory effect including a reduction in intranuclear NFkappaB, an increase in IkappaB, and decreases in ROS generation, p47(phox) subunit, plasma soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1. This acute anti-inflammatory effect, if demonstrated in the long term, may have implications for atherosclerosis and its complications.
Inflammation is hypothesized to play a role in development of type 2 diabetes mellitus (DM); however, clinical data addressing this issue are limited.
To determine whether elevated levels of the inflammatory markers interleukin 6 (IL-6) and C-reactive protein (CRP) are associated with development of type 2 DM in healthy middle-aged women.
Prospective, nested case-control study.
The Women's Health Study, an ongoing US primary prevention, randomized clinical trial initiated in 1992.
From a nationwide cohort of 27 628 women free of diagnosed DM, cardiovascular disease, and cancer at baseline, 188 women who developed diagnosed DM over a 4-year follow-up period were defined as cases and matched by age and fasting status with 362 disease-free controls.
Incidence of confirmed clinically diagnosed type 2 DM by baseline levels of IL-6 and CRP.
Baseline levels of IL-6 (P<.001) and CRP (P<.001) were significantly higher among cases than among controls. The relative risks of future DM for women in the highest vs lowest quartile of these inflammatory markers were 7.5 for IL-6 (95% confidence interval [CI], 3.7-15.4) and 15.7 for CRP (95% CI, 6.5-37.9). Positive associations persisted after adjustment for body mass index, family history of diabetes, smoking, exercise, use of alcohol, and hormone replacement therapy; multivariate relative risks for the highest vs lowest quartiles were 2.3 for IL-6 (95% CI, 0.9-5.6; P for trend =.07) and 4.2 for CRP (95% CI, 1.5-12.0; P for trend =.001). Similar results were observed in analyses limited to women with a baseline hemoglobin A(1c) of 6.0% or less and after adjustment for fasting insulin level.
Elevated levels of CRP and IL-6 predict the development of type 2 DM. These data support a possible role for inflammation in diabetogenesis.
Circulating levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are elevated in diabetic patients. We assessed the role of glucose in the regulation of circulating levels of IL-6, TNF-alpha, and interleukin-18 (IL-18) in subjects with normal or impaired glucose tolerance (IGT), as well as the effect of the antioxidant glutathione.
Plasma glucose levels were acutely raised in 20 control and 15 IGT subjects and maintained at 15 mmol/L for 5 hours while endogenous insulin secretion was blocked with octreotide. In control subjects, plasma IL-6, TNF-alpha, and IL-18 levels rose (P<0.01) within 2 hours of the clamp and returned to basal values at 3 hours. In another study, the same subjects received 3 consecutive pulses of intravenous glucose (0.33 g/kg) separated by a 2-hour interval. Plasma cytokine levels obtained at 3, 4, and 5 hours were higher (P<0.05) than the corresponding values obtained during the clamp. The IGT subjects had fasting plasma IL-6 and TNF-alpha levels higher (P<0.05) than those of control subjects. The increase in plasma cytokine levels during the clamping lasted longer (4 hours versus 2 hours, P<0.01) in the IGT subjects than in the control subjects, and the cytokine peaks of IGT subjects after the first glucose pulse were higher (P<0.05) than those of control subjects. On another occasion, 10 control and 8 IGT subjects received the same glucose pulses as above during an infusion of glutathione; plasma cytokine levels did not show any significant change from baseline after the 3 glucose pulses.
Hyperglycemia acutely increases circulating cytokine concentrations by an oxidative mechanism, and this effect is more pronounced in subjects with IGT. This suggests a causal role for hyperglycemia in the immune activation of diabetes.
Recent evidence suggests that C-reactive protein (CRP) may predict development of diabetes in Caucasian populations. We evaluated CRP as a possible risk factor of the development of diabetes and metabolic syndrome in a 6-year study of 515 men and 729 women from the Mexico City Diabetes Study.
Baseline CRP, indexes of adiposity, and insulin resistance (homeostasis model assessment [HOMA-IR]) were used to predict development of the metabolic syndrome, defined as including two or more of the following: 1) dyslipidemia (triglyceride >/=2.26 mmol/l or HDL cholesterol </=0.91 mmol/l in men and </=1.17 mmol/l in women; <35 and 40 mg/dl for men and women); 2) hypertension (blood pressure >140/90 mmHg or on hypertensive medication); or 3) diabetes (1999 World Health Organization criteria).
At baseline, CRP correlated significantly (P < 0.001) with all metabolic indexes in women, but less so in men. After 6 years, 14.2% of men and 16.0% of women developed the metabolic syndrome. Compared with tertile 1, women with CRP in the highest tertile had an increased relative risk of developing the metabolic syndrome by 4.0 (95% CI 2.0-7.9) and diabetes by 5.5 (2.2-13.5); these risks changed minimally after adjusting for BMI or HOMA-IR. The area under receiver-operating characteristic (ROC) curve for the prediction of the development of the syndrome was 0.684 for CRP, increasing to 0.706 when combined with BMI and to 0.710 for a complex model of CRP, BMI, and HOMA-IR.
CRP was not a significant predictor of the development of the metabolic syndrome in men. Our data strongly support the notion that inflammation is important in the pathogenesis of diabetes and metabolic disorders in women.
Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines implicated in insulin resistance during infection, cachexia, and obesity. We recently demonstrated that IL-6 inhibits insulin signaling in hepatocytes (Senn, J. J., Klover, P. J., Nowak, I. A., and Mooney, R. A. (2002) Diabetes 51, 3391-3399). Members of the suppressors of cytokine signaling (SOCS) family associate with the insulin receptor (IR), and their ectopic expression inhibits IR signaling. Since several SOCS proteins are induced by IL-6, a working hypothesis is that IL-6-dependent insulin resistance is mediated, at least in part, by induction of SOCS protein(s) in insulin target cells. To examine the involvement of SOCS protein(s) in IL-6-dependent inhibition of insulin receptor signaling, HepG2 cells were treated with IL-6 (20 ng/ml) for periods from 1 min to 8 h. IL-6 induced SOCS-3 transcript at 30 min with a maximum effect at 1 h. SOCS-3 protein levels were also markedly elevated at 1 h. Transcript and protein levels returned to near basal levels by 2 h. SOCS-3 induction by IL-6 paralleled IL-6-dependent inhibition of IR signal transduction. Ectopically expressed SOCS-3 associated with the IR and suppressed insulin-dependent receptor autophosphorylation, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, and activation of Akt. SOCS-3 was also a direct inhibitor of insulin receptor autophosphorylation in vitro. In mice exposed to IL-6 for 60-90 min, hepatic SOCS-3 expression was increased. This was associated with inhibition of hepatic insulin-dependent receptor autophosphorylation and IRS-1 tyrosine phosphorylation. These data suggest that induction of SOCS-3 in liver may be an important mechanism of IL-6-mediated insulin resistance.
High levels of cytokines are risk factors for type 2 diabetes. Therefore, we investigated whether the promoter polymorphisms of the tumor necrosis factor-alpha (TNF-alpha; G-308A) and interleukin 6 (IL-6; C-174G) genes predict the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in the Finnish Diabetes Prevention Study. Altogether, 490 overweight subjects with IGT whose DNA was available were randomly divided into one of the two treatment assignments: the control group and the intensive, individualized diet and exercise intervention group. The -308A allele of the TNF-alpha gene was associated with an approximate twofold higher risk for type 2 diabetes compared with the G-308G genotype (odds ratio 1.80, 95% CI 1.05-3.09; P = 0.034). Subjects with both the A allele of the TNF-alpha gene and the C-174C genotype of the IL-6 gene had a 2.2-fold (CI 1.02-4.85, P = 0.045) higher risk of developing type 2 diabetes than subjects without the risk genotypes. We conclude that the -308A allele of the promoter polymorphism (G-308A) of the TNF-alpha gene is a predictor for the conversion from IGT to type 2 diabetes. Furthermore, this polymorphism seems to have a gene-gene interaction with the C-174C genotype of the IL-6 gene.
To examine the association of low-grade systemic inflammation with diabetes, as well as its heterogeneity across subgroups, we designed a case-cohort study representing the approximately 9-year experience of 10,275 Atherosclerosis Risk in Communities Study participants. Analytes were measured on stored plasma of 581 incident cases of diabetes and 572 noncases. Statistically significant hazard ratios of developing diabetes for those in the fourth (versus first) quartile of inflammation markers, adjusted for age, sex, ethnicity, study center, parental history of diabetes, and hypertension, ranged from 1.9 to 2.8 for sialic acid, orosomucoid, interleukin-6, and C-reactive protein. After additional adjustment for BMI, waist-to-hip ratio, and fasting glucose and insulin, only the interleukin-6 association remained statistically significant (HR = 1.6, 1.01-2.7). Exclusion of GAD antibody-positive individuals changed associations minimally. An overall inflammation score based on these four markers plus white cell count and fibrinogen predicted diabetes in whites but not African Americans (interaction P = 0.005) and in nonsmokers but not smokers (interaction P = 0.13). The fully adjusted hazard ratio comparing white nonsmokers with score extremes was 3.7 (P for linear trend = 0.008). In conclusion, a low-grade inflammation predicts incident type 2 diabetes. The association is absent in smokers and African-Americans.
Inhibition of tumor necrosis factor (TNF)-α action has recently been shown to reverse insulin resistance dramatically and to improve glycemic control in obese rodents. This double-blind study was designed to assess the effects of a recombinant-engineered human TNF-α-neutralizing antibody (CDP571) on glucose homeostasis in obese NIDDM patients. Glycemic control and insulin sensitivity were monitored in 21 NIDDM subjects for a 2-week run-in and then for 6 weeks after treatment in a randomized fashion with a single intravenous dose of either CDP571 (5 mg/kg) or an equivalent volume of normal saline. The prolonged half-life of the antibody ensured adequate plasma levels as measured throughout the study. Concentrations of fasting glucose (CDP571: 10.0 ± 0.8, 10.1 ± 0.8, 10.0 ± 1.0; placebo: 8.5 ± 0.6, 8.1 ± 0.5, 8.7 ± 0.8 mmol/l at baseline, day 1, and week 4, respectively), fasting serum insulin (CDP571:21.2 ± 2.8,21.0 ± 2.8,24.8 ± 3.3; placebo: 19.0 ± 2.8, 20.8 ± 2.9, 17.5 ± 2.2 pmol/l, respectively), and C-peptide remained unaffected by the type of treatment throughout the study. The percentage rate of glucose clearance per minute (KITT) during intravenous insulin sensitivity tests was identical in the CDP571 and placebo groups at baseline and also at 1 and 4 weeks after treatment (mean ± SE; CDP571: 1.33 ± 0.21,1.44 ± 0.25,1.26 ± 0.18; placebo: 1.38 ± 0.15,1.47 ± 0.20, 1.52 ± 0.20;P=0.85, 0.93, and 0.36, respectively). TNF-α neutralization over a period of 4 weeks had no effect on insulin sensitivity in obese NIDDM subjects.Diabetes45:881–885, 1996
The advanced lesions of atherosclerosis represent the culmination of a specialized form of chronic inflammation followed by a fibroproliferative process that takes place within the intima of the affected artery. Proliferation of smooth muscle cells and generation of connective tissue occur. Proliferation results from interactions between arterial smooth muscle, monocyte-derived macrophages, T lymphocytes, and endothelium. The initial lesion of atherosclerosis, the fatty streak, begins as an accumulation of monocytederived macrophages and T lymphocytes, which adhere and migrate into the intima of the affected artery. Smooth muscle cells, which are present in the intima or which migrate into the intima from the media, then replicate. Monocyte-derived macrophages and T cells also replicate during lesion formation and progression due to the production of cytokines and growth-regulatory molecules. These molecules determine whether there is proliferation and lesion progression or inhibition of proliferation and lesion regression. Several growthregulatory molecules may play critical roles in this process, including platelet-derived growth factor (PGDF), transforming growth factor beta, fibroblast growth factor, heparinbinding epidermal growth factor-like growth factor, and others. PDGF may be one of the principal components in this process because protein containing the PDGF B-chain has been demonstrated within activated lesion macrophages during every phase of atherogenesis. The presence of this growth factor and its receptors on lesion smooth muscle cells creates opportunities for smooth muscle chemotaxis and replication. Smooth muscle proliferation depends upon a series of complex signals based upon cellular interactions in the local microenvironment of the artery. The intracellular signalling pathways for mitogenesis versus chemotaxis are being investigated for smooth muscle. The roles of the cytokines and growth-regulatory peptides involved in these cellular interactions represent critical points of departure for intervention and the development of new diagnostic methods. In addition, magnetic resonance imaging has been developed to demonstrate the fine structure of lesions of atherosclerosis in peripheral arteries not subject to cardiac motion. This noninvasive methodology holds great promise for the future of these approaches.
Insulin resistance is an important metabolic abnormality often associated with infections, cancer, obesity, and especially non-insulin-dependent diabetes mellitus (NIDDM). We have previously demonstrated that tumor necrosis factor-alpha produced by adipose tissue is a key mediator of insulin resistance in animal models of obesity-diabetes. However, the mechanism by which TNF-alpha interferes with insulin action is not known. Since a defective insulin receptor (IR) tyrosine kinase activity has been observed in obesity and NIDDM, we measured the IR tyrosine kinase activity in the Zucker (fa/fa) rat model of obesity and insulin resistance after neutralizing TNF-alpha with a soluble TNF receptor (TNFR)-lgG fusion protein. This neutralization resulted in a marked increase in insulin-stimulated autophosphorylation of the IR, as well as phosphorylation of insulin receptor substrate 1 (IRS-1) in muscle and fat tissues of the fa/fa rats, restoring them to near control (lean) levels. In contrast, no significant changes were observed in insulin-stimulated tyrosine phosphorylations of IR and IRS-1 in liver. The physiological significance of the improvements in IR signaling was indicated by a concurrent reduction in plasma glucose, insulin, and free fatty acid levels. These results demonstrate that TNF-alpha participates in obesity-related systemic insulin resistance by inhibiting the IR tyrosine kinase in the two tissues mainly responsible for insulin-stimulated glucose uptake: muscle and fat.
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.
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.
In view of the possible link between serum sialic acid and cardiovascular disease in the general population, we investigated whether serum total and lipid-associated sialic concentrations are elevated in NIDDM patients compared with normal subjects. We also investigated how sialic acid levels relate to glycemic control, blood pressure, microalbuminuria, retinopathy, and serum lipid levels.
We selected 20 NIDDM patients at random and matched them for age and sex with 20 normal subjects. The patients also had a similar BMI as the control subjects. A first morning blood sample was taken for sialic acid, glucose, fructosamine, and lipid analysis, as was a first morning urine sample for assessment of microalbuminuria. Retinopathy was assessed by fundoscopy.
Both total and lipid-associated sialic acid levels were elevated in the NIDDM patients compared with control subjects (mean +/- SD, total: 0.74 +/- 0.11 vs. 0.60 +/- 0.22 g/L, P < 0.02; lipid-associated: 0.18 +/- 0.04 vs 0.12 +/- 0.04 g/L, P < 0.001). Total serum sialic acid was correlated with systolic blood pressure (r = 0.58, P < 0.01) and diastolic blood pressure (r = 0.58, P < 0.02). There was no significant relationship of total sialic acid with age, duration of diabetes, BMI, microalbuminuria, serum triglyceride, blood glucose, or serum fructosamine. A relationship of lipid-associated sialic acid levels and systolic blood pressure did not reach significance (P = 0.09). In 9 patients with background retinopathy with or without maculopathy, the total serum sialic acid concentration was higher than in those without retinopathy (0.81 +/- 0.09 vs. 0.69 +/- 0.10 g/L, P < 0.008). Lipid-associated sialic acid levels were similar in those with and without retinopathy. (The conversion factor for standard units to SI units is 1 gL = 3.2 mM.)
Total serum sialic acid levels were significantly elevated in a relatively small group of NIDDM patients and were correlated with hypertension and retinopathy. A larger study of circulating sialic acid concentrations as a risk factor for the development or marker of diabetic angiopathy is therefore justified.
Obesity is known to predispose to attenuated fibrinolysis attributable to increased concentrations in plasma of type-1 plasminogen activator inhibitor (PAI-1), the primary physiological inhibitor of endogenous fibrinolysis. PAI-1 is present in neointimal vascular smooth muscle cells and lipid-laden macrophages.
The present study was designed to determine whether PAI-1 expression occurs in adipose tissue as well, thereby potentially contributing to increased cardiovascular risk associated with obesity. 3T3-L1 preadipocytes were differentiated into adipocytes by exposing them to isobutylxanthine (0.5 mmol/L) and dexamethasone (0.25 mumol/L) over 7 days and incubated for 24 hours with transforming growth factor-beta (TGF-beta), known to augment PAI-1 synthesis in several cell types and to be released from platelets when they are activated. TGF-beta increased PAI-1 activity in the conditioned media of the 3T3-L1-derived cells in a concentration-dependent fashion without significantly affecting cell proliferation. Western blotting and immunoprecipitation of 35S-labeled PAI-1 showed that the increased PAI-1 activity paralleled increased PAI-1 protein. Northern blotting showed that increased PAI-1 mRNA preceded increased accumulation of PAI-1 activity and protein in the conditioned media. Furthermore, TGF-beta (10 ng/g body wt) administered in vivo increased PAI-1 activity in mouse plasma and PAI-1 mRNA expression in mouse adipose tissue.
Increased plasma PAI-1 activity in obese human subjects may result from PAI-1 release from an increased mass of adipose tissue, particularly in association with thrombosis and elaboration of TGF-beta from platelet alpha-granules into the circulation. The increased PAI-1 may exacerbate vascular disease by shifting the balance between thrombosis and thrombolysis toward thrombosis and consequently exposing luminal surfaces of vessels to mitogens associated with microthrombi over protracted intervals.
Inhibition of tumor necrosis factor (TNF)-alpha action has recently been shown to reverse insulin resistance dramatically and to improve glycemic control in obese rodents. This double-blind study was designed to assess the effects of a recombinant-engineered human TNF-alpha-neutralizing antibody (CDP571) on glucose homeostasis in obese NIDDM patients. Glycemic control and insulin sensitivity were monitored in 21 NIDDM subjects for a 2-week run-in and then for 6 weeks after treatment in a randomized fashion with a single intravenous dose of either CDP571 (5 mg/kg) or an equivalent volume of normal saline. The prolonged half-life of the antibody ensured adequate plasma levels as measured throughout the study. Concentrations of fasting glucose (CDP571: 10.0 +/- 0.8, 10.1 +/- 0.8, 10.0 +/- 1.0; placebo: 8.5 +/- 0.6, 8.1 +/- 0.5, 8.7 +/- 0.8 mmol/l at baseline, day 1, and week 4, respectively), fasting serum insulin (CDP571: 21.2 +/- 2.8, 21.0 +/- 2.8, 24.8 +/- 3.3; placebo: 19.0 +/- 2.8, 20.8 +/- 2.9, 17.5 +/- 2.2 pmol/l, respectively), and C-peptide remained unaffected by the type of treatment throughout the study. The percentage rate of glucose clearance per minute (KITT) during intravenous insulin sensitivity tests was identical in the CDP571 and placebo groups at baseline and also at 1 and 4 weeks after treatment (mean +/- SE; CDP571: 1.33 +/- 0.21, 1.44 +/- 0.25, 1.26 +/- 0.18; placebo: 1.38 +/- 0.15, 1.47 +/- 0.20, 1.52 +/- 0.20; P = 0.85, 0.93, and 0.36, respectively). TNF-alpha neutralization over a period of 4 weeks had no effect on insulin sensitivity in obese NIDDM subjects.
The expression of leptin, an adipocyte-derived protein whose circulating levels reflect energy stores, can be induced by tumor necrosis factor (TNF)alpha in rodents, but an association between the TNF alpha system and leptin levels has not been reported in humans. To evaluate the potential association between serum leptin and the TNF alpha system, we measured the levels of soluble TNF alpha-receptor (sTNF alpha-R55), which has been validated as a sensitive indicator of activation of the TNF alpha system. We studied two groups: 1) 82 young healthy normal controls and 2) 48 patients with noninsulin dependent diabetes mellitus (NIDDM) and 24 appropriately matched controls. By simple regression analysis in controls, there was a strong positive association between leptin and 3 parameters: body mass index, sTNF alpha-R55, and insulin levels. In a multiple regression analysis model, leptin remained significantly and strongly associated with body mass index, and the association of leptin with both insulin and sTNF alpha-R55, although weakened, remained significant. Patients with NIDDM had leptin concentrations similar to controls of similar weight. Importantly, serum levels of sTNF alpha-R55 were also positively and independently associated with leptin in this group of diabetic subjects and matched controls. These data are consistent with the hypothesis that the TNF alpha system plays a role in regulating leptin levels in humans. Further elucidation of a possible role of the TNF alpha system in leptin expression and circulating levels may have important implications for our understanding of obesity and cachexia in humans.
We measured arterio-venous differences in concentrations of tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6) across a sc adipose tissue bed in the postabsorptive state in 39 subjects [22 women and 17 men; median age, 36 yr (interquartile range, 26-48 yr); body mass index, 31.8 kg/m2 (range, 22.3- 38.7 kg/m2); percent body fat, 28.7% (range, 17.6-50.7%)]. A subgroup of 8 subjects had arteriovenous differences measured across forearm muscle. Thirty subjects were studied from late morning to early evening; 19 ate a high carbohydrate meal around 1300 h, and 11 continued to fast. We found a greater than 2-fold increase in IL-6 concentrations across the adipose tissue bed [arterial, 2.27 pg/mL (range, 1.42-3.53 pg/mL); venous, 6.71 pg/mL (range, 3.36-9.62 pg/mL); P < 0.001], but not across forearm muscle. Arterial plasma concentrations of IL-6 correlated significantly with body mass index (Spearman's r = 0.48; P < 0.01) and percent body fat (Spearman's r = 0.49; P < 0.01). Subcutaneous adipose tissue IL-6 production increased by the early evening (1800-1900 h) in both subjects who had extended their fasting and those who had eaten. Neither deep forearm nor sc adipose tissue consistently released TNF alpha [across adipose tissue: arterial, 1.83 pg/mL (range, 1.36-2.34 pg/mL); venous, 1.85 pg/mL (range, 1.44-2.53 pg/mL); P = NS: across forearm muscle: arterial, 1.22 pg/mL (range, 0.74-2.76 pg/mL); venous, 0.99 pg/mL (range, 0.69-1.70 pg/mL); P = NS]. Although both IL-6 and TNF alpha are expressed by adipose tissue, our results show that there are important differences in their systemic release. TNF alpha is not released by this sc depot. In contrast, IL-6 is released from the depot and is thereby able to signal systemically.
C-reactive protein, a hepatic acute phase protein largely regulated by circulating levels of interleukin-6, predicts coronary heart disease incidence in healthy subjects. We have shown that subcutaneous adipose tissue secretes interleukin-6 in vivo. In this study we have sought associations of levels of C-reactive protein and interleukin-6 with measures of obesity and of chronic infection as their putative determinants. We have also related levels of C-reactive protein and interleukin-6 to markers of the insulin resistance syndrome and of endothelial dysfunction. We performed a cross-sectional study in 107 nondiabetic subjects: (1) Levels of C-reactive protein, and concentrations of the proinflammatory cytokines interleukin-6 and tumor necrosis factor-alpha, were related to all measures of obesity, but titers of antibodies to Helicobacter pylori were only weakly and those of Chlamydia pneumoniae and cytomegalovirus were not significantly correlated with levels of these molecules. Levels of C-reactive protein were significantly related to those of interleukin-6 (r=0.37, P<0.0005) and tumor necrosis factor-alpha (r=0.46, P<0.0001). (2) Concentrations of C-reactive protein were related to insulin resistance as calculated from the homoeostasis model assessment model, blood pressure, HDL, and triglyceride, and to markers of endothelial dysfunction (plasma levels of von Willebrand factor, tissue plasminogen activator, and cellular fibronectin). A mean standard deviation score of levels of acute phase markers correlated closely with a similar score of insulin resistance syndrome variables (r=0.59, P<0.00005), this relationship being weakened only marginally by removing measures of obesity from the insulin resistance score (r=0.53, P<0.00005). These data suggest that adipose tissue is an important determinant of a low level, chronic inflammatory state as reflected by levels of interleukin-6, tumor necrosis factor-alpha, and C-reactive protein, and that infection with H pylori, C pneumoniae, and cytomegalovirus is not. Moreover, our data support the concept that such a low-level, chronic inflammatory state may induce insulin resistance and endothelial dysfunction and thus link the latter phenomena with obesity and cardiovascular disease.
Type 2 diabetes mellitus and atherosclerotic cardiovascular disease have common antecedents. Since markers of inflammation predict coronary heart disease and are raised in patients with type 2 diabetes, we investigated whether they predict whether people will develop type 2 diabetes.
12,330 men and women, aged 45-64 years, were followed up for a mean of 7 years. We analysed the association between different markers of acute inflammation and subsequent diagnosis of diabetes. In a subgroup of 610 individuals selected originally for an unrelated atherosclerosis case-control study, we also investigated diabetes associations with total sialic acid and orosomucoid, haptoglobin, and alpha1-antitrypsin.
1335 individuals had a new diagnosis of diabetes. Adjusted odds ratios for developing diabetes for quartile extremes were 1.9 (95% CI 1.6-2.3) for raised white-cell count, 1.3 (1.0-1.5) for low serum albumin, and 1.2 (1.0-1.5) for raised fibrinogen. In the subgroup analysis, individuals with concentrations of orosomucoid and sialic acid of more than the median had odds ratios of 7.9 (2.6-23.7) and 3.7 (1.4-9.8), respectively. Adjustment for body-mass index and waist-to-hip ratio lessened the associations; those for white-cell count (1.5 [1.3-1.8]), orosomucoid (7.1 [2.1-23.7]), and sialic acid (2.8 [1.0-8.1]) remained significant.
Markers of inflammation are associated with the development of diabetes in middle-aged adults. Although autoimmunity may partly explain these associations, they probably reflect the pathogenesis of type 2 diabetes.
Obesity, the insulin resistance syndrome, and atherosclerosis are closely linked and may all be determinants of an increased acute-phase response. In this study, we examined the relationship of C-reactive protein (CRP) with measures of obesity, variables of the insulin resistance syndrome, and intima-media thickness of the common carotid arteries in 186 healthy, middle-aged women selected from the general population. Associations were assessed by regression analysis. CRP was strongly associated with body mass index (BMI) and waist circumference. CRP was also associated with other variables of the insulin resistance syndrome, including blood pressure, insulin, high density lipoprotein cholesterol, triglycerides, apolipoprotein A1 (inversely), plasminogen activator inhibitor-1 antigen, and tissue-type plasminogen activator antigen. Associations between CRP and the variables of the insulin resistance syndrome disappeared after controlling for BMI but remained significant for plasminogen activator inhibitor-1 antigen only. The association of CRP with common carotid artery intima-media thickness was weak and limited to ever-smokers. BMI explained 29.7% of the variance of CRP, whereas common carotid artery intima-media thickness explained only 3.7%. The results of this population-based study indicate that adiposity is strongly associated with CRP in healthy, middle-aged women. In this population, BMI accounted for the relationship between CRP and other variables of the insulin resistance syndrome. Further studies should determine whether losing weight ameliorates the inflammatory state.
Recent studies have suggested that elevated plasma C-reactive protein (CRP) levels are associated with the features of insulin resistance syndrome. In the present study, we have examined the contribution of body composition measured by hydrostatic weighing and of abdominal adipose tissue (AT) accumulation assessed by computed tomography to the variation in plasma CRP levels associated with atherogenic dyslipidemia of the insulin resistance syndrome in a sample of 159 men, aged 22 to 63 years, covering a wide range of adiposity (body mass index values from 21 to 41 kg/m(2)). Plasma CRP levels showed positive and significant correlations with body fat mass (r=0.41, P<0.0001), waist girth (r=0.37, P<0.0001), and visceral AT accumulation measured by computed tomography at L4 to L5 (r=0.28, P<0.0003). Although CRP levels were associated with plasma insulin levels measured in the fasting state and after a 75-g oral glucose load, no significant correlations were found with plasma lipoprotein levels. Finally, comparison of body fatness, of abdominal fat accumulation, and of the features of the insulin resistance syndrome across quintiles of CRP revealed major differences in body fatness and in indices of abdominal AT accumulation between the lowest and the highest CRP quintiles, whereas no significant differences were found for variables of the plasma lipoprotein-lipid profile. These results suggest that obesity and abdominal AT accumulation are the critical correlates of elevated plasma CRP levels found in men with atherogenic dyslipidemia of the insulin resistance syndrome.
Several studies suggest that inflammation plays a role in the pathogenesis of some glucose disorders in adults. We tested this hypothesis in a longitudinal cohort study of older individuals who had normal fasting glucose (FG) values at baseline. We compared the baseline levels of six inflammatory markers in participants who had developed glucose disorders at follow-up with those of participants whose FG remained normal at follow-up. Participants were members of the Cardiovascular Health Study, a prospective study of risk factors for cardiovascular disease in adults > or =65 years. All 5,888 participants had baseline testing, including FG and markers of inflammation: white blood cell and platelet counts and albumin, fibrinogen, C-reactive protein (CRP), and factor VIIIc levels. At 3-4 years of follow-up, 4,481 (84.5%) of those who were alive had FG levels retested. Participants who developed diabetes (n = 45) had higher median levels of CRP at baseline than those who remained normoglycemic. On multivariate analysis, those with elevated CRP levels (75th percentile [2.86 mg/l] vs. 25th percentile [0.82 mg/l]) were 2.03 times (95% confidence intervals, 1.44-2.86) more likely to have diabetes on follow-up. Adjustment for confounders and other inflammatory markers did not appreciably change this finding. There was no relationship between the development of diabetes and other markers of inflammation. Inflammation, as measured by CRP levels, is associated with the development of diabetes in the elderly. Understanding the role of inflammation in the pathogenesis of glucose disorders in this age-group may lead to better classification and treatment of glucose disorders among them.
We have recently demonstrated that an infusion of a low dose of insulin reduces the intranuclear NF-kappa B (a pro-inflammatory transcription factor) content in MNC while also reducing the plasma concentration of NF-kappa B dependent pro-inflammatory cytokines and adhesion molecules. We have now tested the effect of insulin on the pro-inflammatory transcription factor, early growth response-1 (Egr-1) and plasma concentration of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1), two major proteins whose expression is modulated by Egr-1. Insulin was infused at the rate of 2 IU/h in 5% dextrose (100 mL/h) and KCI (8 mmol/h) for 4 h in the fasting state in ten obese subjects. Blood samples were obtained at 0, 2, 4 and 6 h. MNC were isolated and their total homogenates and nuclear fractions were prepared and Egr-1 was measured by electrophoretic mobility shift assay (EMSA). Plasma TF and PAI-1 were assayed by ELISA. There was a significant fall in Egr-1 at 2 (66 +/- 14% of basal level) and 4 h (47 +/- 17% of the basal level; P<0.01). PAI-1 levels (basal = 100%) decreased significantly after insulin infusion at 2 h (57 +/- 6.7% of the basal level) and at 4 h (58 +/- 8.3% of the basal level; P<0.001). Plasma TF levels (basal = 100%) decreased to 76 +/- 7.7% of the basal level at 2 h and to 85 +/- 10.4% of the basal level at 4 h (P<0.05). Thus, insulin reduces intranuclear Egr-1 and the expression of TF and PAI-1. These data provide further evidence that insulin has an anti-inflammatory effect including the inhibition of TF and PAI-1 expression. These effects suggest a potential beneficial effect of insulin in thrombin formation and fibrinolysis in atherothrombosis.
Insulin exerts a vasodilatory effect through the release of nitric oxide (NO) from the endothelium. We have recently demonstrated that insulin also inhibits the expression of intracellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1), 2 major proinflammatory mediators, by human aortic endothelial cells (HAEC) and the proinflammatory mediator, nuclear factor (NF-kappa B), in the nucleus in parallel with an increase in endothelial nitric oxide synthase (e-NOS) expression. The inhibition of ICAM-1 by insulin is NO dependent. Because tumor necrosis factor-alpha (TNF-a ) is proinflammatory and may thus inhibit the action of insulin at the endothelial cell level, we have now investigated whether TNF-a affects (1) insulin receptor content; (2) insulin receptor (IR) autophosphorylation induced by insulin, and (3) e-NOS expression by the endothelial cells. TNF-alpha (1 to 5 ng/mL) caused e-NOS inhibition in a dose-dependent fashion as measured by Western blotting. This inhibition was reduced with insulin addition. TNF-alpha also inhibited tyrosine autophosphorylation of the IR in HAEC induced by insulin and reduced IR beta-subunit protein expression in HAEC. These effects of insulin and TNF-alpha were independent of cell proliferation, as cell counts did not change with insulin or TNF-alpha. Our data demonstrate that TNF-alpha may exert its effect by inhibiting IR autophosphorylation in HAEC and also by reducing IR protein (IRP) expression. Although the inhibition of IR autophosphorylation by TNF-alpha is known to occur at the adipocyte level, the data on the inhibitory effect of TNF-alpha on insulin-induced e-NOS expression and IRP contents are novel.
The immune responses to many infections have long been known to share features with autoimmune responses. In particular, both types of response are typified by the enhanced reactivity of T helper 1 cells - with high levels of interleukin-2, interferon gamma and tumor necrosis factor alpha - and are accompanied often by organ-specific and/or systemic damage and the production of IgG. Paradoxically, the geographical distributions of incidence of infectious diseases and autoimmunity are complementary, rather than coincident. In less-developed societies, an epidemiological association between susceptibility to infection and malnutrition has been observed, whereas in affluent countries, an increased incidence of autoimmune diseases has been described. We suggest that these observations can be explained partly by taking into consideration the immune effects of the adipocyte-derived hormone leptin, which has been shown recently to act as a link between nutritional status and the immune response.
Markers of systemic inflammation (eg, C-reactive protein [CRP] and interleukin-6 [IL-6]) have been proposed to be "nontraditional" risk factors for cardiovascular disease in patients with type 2 diabetes mellitus. Matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis of atherosclerotic plaque rupture, which raises the possibility of the use of MMP-9 levels as a marker for future myocardial infarction or unstable angina. In vitro and animal studies suggest that thiazolidinediones can reduce the expression of these markers. The purpose of this analysis was to determine whether rosiglitazone alters serum concentrations of CRP, IL-6, MMP-9, and white blood cell count (WBC) and to examine the relationship of these effects with demographic and disease variables.
CRP, IL-6, MMP-9, and WBC were analyzed from stored frozen serum samples obtained from patients with type 2 diabetes who completed a 26-week randomized, double-blind, placebo-controlled study. After 26 weeks of rosiglitazone treatment, the percentage reductions in mean CRP, MMP-9, and WBC levels were statistically significant compared with baseline and placebo (P<0.01). The percentage reduction in mean IL-6 was small and similar in the rosiglitazone and placebo groups. The change in each inflammatory marker from baseline to week 26 was significantly correlated (P<0.05) with each of the other markers, as well as with the homeostasis model assessment estimate of insulin resistance.
Rosiglitazone reduces serum levels of MMP-9 and the proinflammatory marker CRP in patients with type 2 diabetes, which indicates potentially beneficial effects on overall cardiovascular risk.
Interleukin (IL)-6 is one of several proinflammatory cytokines that have been associated with insulin resistance and type 2 diabetes. A two- to threefold elevation of circulating IL-6 has been observed in these conditions. Nonetheless, little evidence supports a direct role for IL-6 in mediating insulin resistance. Here, we present data that IL-6 can inhibit insulin receptor (IR) signal transduction and insulin action in both primary mouse hepatocytes and the human hepatocarcinoma cell line, HepG2. This inhibition depends on duration of IL-6 exposure, with a maximum effect at 1-1.5 h of pretreatment with IL-6 in both HepG2 cells and primary hepatocytes. The IL-6 effect is characterized by a decreased tyrosine phosphorylation of IR substrate (IRS)-1 and decreased association of the p85 subunit of phosphatidylinositol 3-kinase with IRS-1 in response to physiologic insulin levels. In addition, insulin-dependent activation of Akt, important in mediating insulin's downstream metabolic actions, is markedly inhibited by IL-6 treatment. Finally, a 1.5-h preincubation of primary hepatocytes with IL-6 inhibits insulin-induced glycogen synthesis by 75%. These data suggest that IL-6 plays a direct role in insulin resistance at the cellular level in both primary hepatocytes and HepG2 cell lines and may contribute to insulin resistance and type 2 diabetes.
Insulin resistance is associated with chronic subclinical inflammation, and both conditions are linked with increased risk for type 2 diabetes mellitus and atherothrombotic cardiovascular disease.
In a cross-sectional study conducted among participants in the Women's Health Study, an ongoing US primary prevention trial of cardiovascular disease and cancer, we evaluated the correlates of elevated fasting insulin, a marker of insulin resistance, among 349 healthy, nondiabetic women who remained free from clinically diagnosed type 2 diabetes mellitus during a 4-year period from biomarker assessment. Fasting insulin was strongly associated with body mass index (BMI) (r=0.53, P<0.001), C-reactive protein (CRP) (r=0.38, P<0.001), and interleukin-6 (r=0.33, P<0.001). Physical activity level, alcohol consumption, and use of hormone replacement therapy were also related to fasting insulin. However, in multivariable linear regression analysis, BMI and CRP were the only independent correlates of log-normalized fasting insulin. Overall, the final model explained 32% of the variance in log insulin level. In multivariable logistic regression, the fully adjusted odds ratio (OR) for elevated fasting insulin (>or=51.6 pmol/L) increased with tertile of BMI, CRP, and IL-6, such that the ORs in the highest versus lowest tertile of each parameter were 9.0 (95% confidence interval [CI], 4.4 to 18.7), 4.4 (95% CI, 1.9 to 10.1), and 2.0 (95% CI, 0.9 to 4.2), respectively. Furthermore, increasing levels of CRP were associated with a stepwise gradient in odds for elevated fasting insulin among both lean and overweight women.
CRP is independently associated with fasting hyperinsulinemia in nondiabetic women. These data provide additional support for previously reported associations between subclinical inflammation and the risk of type 2 diabetes and cardiovascular disease.
Inflammation plays a pivotal role in both the development of atherosclerosis and the acute activation of the vascular wall with consequent local thrombosis and vasoconstriction (with or without plaque fissure). In many patients with unstable angina and acute myocardial infarction, systemic signs of inflammation are detectable. The use of systemic inflammatory markers, such as C-reactive protein as marker of disease activity and short- and long-term prognosis, seems to be of clinical value. Therefore, acute inflammatory reaction, detectable systematically, appears to be an independent determinant of prognosis in some patients with acute ischemic syndromes, but is not detectable in all. Understanding the causes of inflammation and the additional elusive components that result in the progression to aggressive acute coronary syndromes, is the future goal of cardiology.
Despite mounting evidence that depression increases risk for cardiovascular morbidity and mortality, little is known about the mechanisms responsible for this association. The current study examined the inter-relationships between depression, adiposity, and inflammatory molecules implicated in the pathogenesis of coronary heart disease. One hundred adults were enrolled. Half were clinically depressed; the others were matched controls with no history of psychiatric illness. All subjects were in excellent health, defined as having no acute infectious disease, chronic medical illness, or prescribed medication regimen. Structural equation modeling yielded support for a model in which depressive symptoms promote weight accumulation, which in turn activates an inflammatory response through two distinct pathways: expanded adipose tissue release of interleukin-6 and leptin-induced upregulation of interleukin-6 release by white blood cells (CFI =.99; NNFI =.99; RMSEA =.05). It did not support a sickness behavior model in which the inflammatory molecules arising from expanded adipose tissue promote depressive symptoms.
Overproduction of IL-6, a proinflammatory cytokine, is associated with a spectrum of age-related conditions including cardiovascular disease, osteoporosis, arthritis, type 2 diabetes, certain cancers, periodontal disease, frailty, and functional decline. To describe the pattern of change in IL-6 over 6 years among older adults undergoing a chronic stressor, this longitudinal community study assessed the relationship between chronic stress and IL-6 production in 119 men and women who were caregiving for a spouse with dementia and 106 noncaregivers, with a mean age at study entry of 70.58 (SD = 8.03) for the full sample. On entry into this portion of the longitudinal study, 28 of the caregivers' spouses had already died, and an additional 50 of the 119 spouses died during the 6 years of this study. Levels of IL-6 and health behaviors associated with IL-6 were measured across 6 years. Caregivers' average rate of increase in IL-6 was about four times as large as that of noncaregivers. Moreover, the mean annual changes in IL-6 among former caregivers did not differ from that of current caregivers even several years after the death of the impaired spouse. There were no systematic group differences in chronic health problems, medications, or health-relevant behaviors that might have accounted for caregivers' steeper IL-6 slope. These data provide evidence of a key mechanism through which chronic stressors may accelerate risk of a host of age-related diseases by prematurely aging the immune response.
Elevated plasma plasminogen activator inhibitor-1 (PAI-1) level is a core feature of insulin-resistance syndrome (IRS). Atherothrombotic complications in IRS are partly attributed to impaired fibrinolysis caused by increased plasma PAI-1 levels. Although the etiology of IRS is far from being explained, the clustering of inflammation, adipose tissue accumulation and insulin resistance suggests an etiopathological link. Proinflammatory cytokines might regulate PAI-1 expression in IRS; however, more studies are needed to confirm this complex mechanism in humans. Furthermore, modifying PAI-1 expression by PAI-1 inhibitors provides a new challenge and may reveal the true role of PAI-1 in atherosclerotic and insulin resistance processes.