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Hyperinsulinemic syndrome: The metabolic syndrome is broader than you think
Abstract
Background:
Type 2 diabetes mellitus (T2DM) is characterized by hyperinsulinemia. In 2011 we showed that gastric bypass (RYGB) corrects these high levels even though insulin resistance remains high, ie, the operation "dissociates" hyperinsulinemia from insulin resistance. RYGB produces reversal of T2DM along with other diseases associated with the metabolic syndrome. This observation led us to examine whether these illnesses also were characterized by hyperinsulinemia.
Methods:
A systematic review was performed to determine whether hyperinsulinemia was present in disorders associated with the metabolic syndrome. We reviewed 423 publications. 58 were selected because of appropriate documentation of insulin measurements. Comparisons were based on whether the studies reported patients as having increased versus normal insulin levels for each metabolic disorder.
Results:
The presence (+) or absence (-) of hyperinsulinemia was documented in these articles as follows: central obesity (4+ vs 0-), diabetes (5+ vs 0-), hypertension (9+ vs 1-), dyslipidemia (2+ vs 0-), renal failure (4+ vs 0-), nonalcoholic fatty liver disease (5+ vs 0-), polycystic ovary syndrome (7+ vs 1-), sleep apnea (7+ vs 0-), certain cancers (4+ vs 1-), atherosclerosis (4+ vs 0-), and cardiovascular disease (8+ vs 0-). Four articles examined insulin levels in the metabolic syndrome as a whole (4+ vs 0-).
Conclusion:
These data document that disorders linked to the metabolic syndrome are associated with high levels of insulin, suggesting that these diseases share a common etiology that is expressed by high levels of insulin. This leads us to propose the concept of a "hyperinsulinemic syndrome" and question the safety of insulin as a chronic therapy for patients with T2DM.
... The metabolic consequences of hyperinsulinemia justify the need for standardized diagnostic testing and clinical treatment guidelines. Hyperinsulinemia has been linked with the development of health conditions including T2D, obesity, dyslipidemia, hypertension, and cardiovascular disease [2][3][4][6][7][8]. Guidelines for the diagnosis and treatment of hyperinsulinemia in adults are not available. ...
... In a systematic review of 423 prospective, retrospective, and cross-sectional studies, hyperinsulinemia was present in a number of disorders that are linked to metabolic syndrome (e.g., obesity, diabetes, hypertension, dyslipidemia). The researchers proposed a syndrome of hyperinsulinemia as a causative condition rather than an event that occurs secondary to these conditions [7]. In a secondary data analysis of 7,755 participants who had plasma glucose and plasma insulin levels drawn following a glucose tolerance test, Crofts C, et al. (2016) [2], found that the majority of participants with normal glucose metabolism had hyperinsulinemia. ...
... Previous research revealed associations between hyperinsulinemia and genetic, environmental, and dietary factors [4]. Further, findings suggested that hyperinsulinemia is the primary factor in the development of T2D and insulin resistance is a secondary response due to excess exposure to insulin [7]. Evidence supports that hyperinsulinemia precedes hyperglycemia so that by the time increases in blood glucose are observed, damage has already occurred to beta cells [18]. ...
... 20 For every 1% of HbA1c >7.0%, cardiovascular mortality in people with type 1 diabetes increases by 52%. 22 Treatment for people with type 1 diabetes consists of daily applications of insulin doses. 22,23 However, despite insulin replacement therapy being essential for the survival of people with type 1 diabetes, and delaying complications in the short and long term, insulin therapy still presents challenges. ...
... 22 Treatment for people with type 1 diabetes consists of daily applications of insulin doses. 22,23 However, despite insulin replacement therapy being essential for the survival of people with type 1 diabetes, and delaying complications in the short and long term, insulin therapy still presents challenges. Exogenous insulin replacement, even with the use of an insulin pump, still cannot effectively and accurately replace the kinetics of insulin secretion performed by the pancreatic beta cells. ...
... 24 Furthermore, high amounts of insulin used to achieve glycemic control goals have impacting consequences for long-term health, such as hyperinsulinemia, which is directly associated with obesity, atherosclerosis and metabolic syndrome. 22,23 Additionally, large amounts of insulin increase the risk of hypoglycemia. 25 Constant episodes of hypoglycemia affect the quality of life of people with diabetes and result in difficult control of blood glucose. ...
p class="abstract"> Background: Type 1 diabetes mellitus is an autoimmune disease characterized by the destruction of pancreatic beta cells and absolute insulin deficiency. After the discovery of insulin, guidelines recommended 50% to 60% of carbohydrate consumption in individuals with diabetes. However, this recommendation is ineffective, since carbohydrate is the macronutrient that causes the greatest increase in blood glucose. The aim of this research is to evaluate the efficacy of a low-carbohydrate diet in adults with type 1 diabetes mellitus.
Methods: The study is a 26 weeks clinical trial. During the first 15 days, participants will receive approximately 130 g of daily carbohydrates, followed by a phase of 7 days, with the consumption of 90 g of daily carbohydrates, and finally, the consumption of 50 g of carbohydrates. The target audience is 20 participants diagnosed with type 1 diabetes mellitus, glycated hemoglobin (HbA1c) >7.0% and aged between 21 and 50 years, in addition to the parameters defined in the established inclusion and exclusion criteria. The primary outcome is HbA1c. Glycemic variability, frequency of hypoglycemia, total daily insulin and improvement in quality of life will also be evaluated.
Conclusions: Despite the evidence that low carbohydrate is effective for treating type 2 diabetes, there is low evidence for the recommendation in people with type 1 diabetes. In order to improve quality of life of this group and guidelines of clinical practice, and to promote development of health care professionals, further well-designed trials are needed.
Trial registration: The trial was registered at https://ensaiosclinicos.gov.br/rg/RBR-107jk4tn.</p
... Interestingly, BMI in young Finns (11)(12)(13)(14) was not associated with adult T2D but fasting insulin was (15): in assessing parameters that predict T2D, it was found that progressors had high fasting and 2-h insulin levels. These limited data predict that HI can be a cause of both obesity (16) and IR. However, the frequency of specific trajectories in defined populations is not known and further research is needed to document the sequence of appearance of these biomarkers in the progression to T2D in order to identify the appropriate focus for prevention. ...
... The majority of patients with T2D are rapidly "cured" following bariatric surgery. Normalization of circulating insulin and glucose levels occurs within a week of surgery without appreciable weight loss (16). In contrast, normalization of muscle insulin sensitivity requires at least 3 months, although it too is eventually achieved (53). ...
... T2D recurs in a percentage of bariatric surgery patients after several years (55,56), and more frequently in African Americans. T2D is characterized by HI and that is the abnormality that is reset most rapidly following surgery but is also the earliest to recur in patients in whom T2D returns (16). ...
This review is motivated by the need to question dogma that has not yielded significant improvements in outcomes of Type 2 Diabetes treatment: that insulin resistance is the driver of ß-Cell failure and resulting hyperglycemia. We highlight the fact that hyperlipidemia, insulin resistance, and hyperinsulinemia all precede overt diabetes diagnosis and can each induce the other when tested experimentally. New research highlights the importance of high levels of circulating insulin as both a driver of weight gain and insulin resistance. Data from our lab and others document that several nutrients and environmental toxins can stimulate insulin secretion at non-stimulatory glucose in the absence of insulin resistance. This occurs either by direct action on the ß-Cell or by shifting its sensitivity to known secretagogues. We raise the next logical question of whether ß-Cell dysfunction in Type 2 Diabetes is due to impaired function, defined as failure, or if chronic overstimulation of the ß-Cell that exceeds its capacity to synthesize and secrete insulin, defined as abuse, is the main abnormality in Type 2 Diabetes. These questions are important as they have direct implications for how to best prevent and treat Type 2 Diabetes.
... These insights led to numerous recent articles calling for a reappraisal of insulin therapy for the treatment for T2DM (6,11,13,(23)(24)(25). Those workers argue that the liberal or reflexive use of insulin therapy -usage that was based on its initial promise -is not supportable by the composite of updated outcomes data. ...
... [ Figure 1 here ] As shown in Figure 1, hyperinsulinemia engenders a number of downstream physiologic perturbations that directly or indirectly effect β-cells and metabolism: IR, weight gain, T2DM, hypoglycemia, hypertension and other CV risk factors, inflammation, and, more distantly related conditions including cancer and Alzheimer's disease (13,24,(27)(28)(29)(30)(31)(32)(33)(34). IR and high insulin are pro-inflammatory (35), which mounting data has linked to β-cell apoptosis and dysfunction (24,30). ...
... [ Figure 1 here ] As shown in Figure 1, hyperinsulinemia engenders a number of downstream physiologic perturbations that directly or indirectly effect β-cells and metabolism: IR, weight gain, T2DM, hypoglycemia, hypertension and other CV risk factors, inflammation, and, more distantly related conditions including cancer and Alzheimer's disease (13,24,(27)(28)(29)(30)(31)(32)(33)(34). IR and high insulin are pro-inflammatory (35), which mounting data has linked to β-cell apoptosis and dysfunction (24,30). Hyperinsulinemia disrupts the suprachiasmic nucleus of the hypothalamus, increasing appetite and decreasing morning dopamine surges, which further exacerbate sympathetic tone and peripheral IR (36). ...
Current processes of care for diabetes mellitus (DM) were shaped during the era when insulin therapy was considered inexorable to the management of advanced stage type 2 (T2DM), though this no longer appears to be categorically true. There are also dashed hopes that insulin therapy can prevent or stall diabetes. While exogenous insulin remains a life-sparing tool for fully insulin-dependent DM, insulin therapy-induced hyperinsulinemia now appears to contribute to serious safety issues beyond hypoglycemia and weight gain. Iatrogenic and compensatory hyperinsulinemia are metabolic disruptors of β-cells, liver, muscle, kidney, brain, heart and vasculature, inflammation, and lipid homeostasis, among other systems. This may compromise β-cells, exacerbate insulin resistance (IR), and increase risk of cardiovascular (CV) disease. Striking associations between exogenous insulin and risks of CV events, cancer, and all-cause mortality in clinical trial and real-world cohorts caution that insulin may pose more harm than previously evidenced. At our disposal are numerous alternate tools that, alone or in combination, efficaciously manage hyperglycemia and glucolipotoxicity, and do so without inducing hypoglycemia, weight gain, or hyperinsulinemia. Moreover, these new tools support true precision therapy, as modern day drug classes can be aligned with the various mediating pathways of hyperglycemia at work in any given patient. Some also appear to promote β-cell survival, with intriguing data being presented for newer agents, such as incretins. As such, we encourage preferential use of non-insulin antidiabetic agents to injected insulin for the management of non-insulin-dependent patients with T2DM, including in advanced stage T2DM. The goal of this article is to augment existing literature to 1) correct misconceptions on the rationale and necessity for insulin therapy in T2DM, 2) discuss emerging negative safety data with insulin therapy, and, 3) offer a practical means to reduce reliance on insulin through delayed initiation, minimized dose, and, drug switching to safer agents, and, potentially, reframes processes of care.
... This further supports the idea that hyperinsulinemia may be a primary driver of insulin resistance [41,42]. Moreover, it has been shown that gastric bypass surgery in type 2 diabetes corrects and normalizes plasma insulin levels within some days after surgery, even though there is, at that moment, no significant weight loss (yet) and insulin resistance remains high [43]. This post-operative course clearly dissociates hyperinsulinemia from insulin resistance, further supporting the idea that hyperinsulinemia is primary, rather than a consequence occurring secondary (as a compensation) to insulin resistance [43,44]. ...
... Moreover, it has been shown that gastric bypass surgery in type 2 diabetes corrects and normalizes plasma insulin levels within some days after surgery, even though there is, at that moment, no significant weight loss (yet) and insulin resistance remains high [43]. This post-operative course clearly dissociates hyperinsulinemia from insulin resistance, further supporting the idea that hyperinsulinemia is primary, rather than a consequence occurring secondary (as a compensation) to insulin resistance [43,44]. ...
The metabolic syndrome is a cluster of overlapping conditions resulting in an increased incidence of type 2 diabetes, cardiovascular disease, and cancer. In the last few decades, prevalence of the metabolic syndrome in the Western world has reached epidemic proportions and this is likely due to alterations in diet and the environment as well as decreased physical activity. This review discusses how the Western diet and lifestyle (Westernization) has played an important etiological role in the pathogenesis of the metabolic syndrome and its consequences by exerting negative effects on activity of the insulin–insulin-like growth factor-I (insulin–IGF-I) system. It is further proposed that interventions that normalize/reduce activity of the insulin–IGF-I system may play a key role in the prevention and treatment of the metabolic syndrome. For successful prevention, limitation, and treatment of the metabolic syndrome, the focus should be primarily on changing our diets and lifestyle in accordance with our genetic make-up, formed in adaptation to Paleolithic diets and lifestyles during a period of several million years of human evolution. Translating this insight into clinical practice, however, requires not only individual changes in our food and lifestyle, starting in pediatric populations at a very young age, but also requires fundamental changes in our current health systems and food industry. Change is needed: primary prevention of the metabolic syndrome should be made a political priority. New strategies and policies should be developed to stimulate and implement behaviors encouraging the sustainable use of healthy diets and lifestyles to prevent the metabolic syndrome before it develops.
... Hyperinsulinaemia is becoming recognised as the primary driver of a plethora of metabolic disorders, especially insulin resistance and type 2 diabetes, but also certain cancers and dementias and cardiovascular disease [1][2][3][4]. Diagnosing hyperinsulinaemia could assist in the early diagnosis and management of many metabolic disorders. ...
... Cerutti et al. suggested that the use of c-peptide as a proxy measurement of insulin on account of its molar relationship may not be valid due to the difference in their kinetics and half-life [1]. However, the combination of insulin's instability and the c-peptide's longer half-life has led to significant interest in using c-peptide as a proxy for insulin in measures of insulin resistance [3,[12][13][14]. C-peptide is used as a biological marker in its own right in the measurement of excessive insulin both clinically and forensically [13,15]. ...
Hyperinsulinaemia is the precursor to numerous metabolic disorders. Early diagnosis and intervention could improve population health. Diagnosing hyperinsulinaemia is problematic because insulin has a very short half-life (2–5minutes). It is theorised that c-peptide levels (half-life 20–30minutes) would be a better proxy for insulin due to both hormones being released in equimolar amounts. However, the correlation between c-peptide and insulin levels is unknown. We aim to identify their correlation following a four-hour oral glucose tolerance test (OGTT). Data were obtained from records of routine medical care at St Joseph’s Hospital, Chicago, IL, USA, during 1977. Two hundred and fifty-five male and female participants aged over 20 years undertook a fourhour OGTT with plasma glucose, insulin and c-peptide levels recorded. Correlation was assessed with Pearson’s correlation. There was a weak correlation between insulin and c-peptide, which increased to moderate across the four-hour OGTT (r = 0.482–0.680). There was no significant change in this relationship when data was subdivided according to either the WHO glucose status or Kraft insulin response. Although there was a correlation between insulin and c-peptide, it was too weak to recommend the use of c-peptide as an alternative biomarker for the diagnosis of hyperinsulinaemia.
... T2DM has been found not to be, as once thought, an individual, unique, and separate disease, but rather, only one expression of the metabolic syndrome. An additional clue that these various diseases are related is a recent review of the literature by Kelly and colleagues, which documented that each of these expressions of the metabolic syndrome presented with elevated insulin levels [31]. The basis for insulin therapy in T2DM patients who already have high insulin levels has been "to overcome insulin resistance;" i.e., more insulin is needed to control glucose levels with the advancement of disease. ...
... Insulin sensitivity (ISI), however, is not corrected even after 3 months (Fig. 4). In spite of full remission of T2DM, insulin resistance remained unchanged [31]. [18] The American Diabetes Association is well aware of these advances. ...
On August 9–10, 2017, the American College of Surgeons hosted a symposium on metabolic surgery, with 12 follow-on papers published serially in the Bulletin of the College. The current synopsis outlines the varied contents of these papers, often in the original words of their authors, who are cited within their topic sections. Topics covered include the following: history and definition of metabolic surgery, bariatric surgery, international bariatric surgery, mechanisms of metabolic surgery, diabetes and the metabolic syndrome, frontiers of metabolic surgery, institutional collaborations, accreditations and quality initiatives, professional training, the role of the National Institutes of Health, and advocacy. Based on these insights, an enthusiastic affirmation for the future of metabolic surgery is warranted.
... 26 Although previous research has focused on diagnosing insulin resistance for the early diagnosis of many metabolic diseases, hyperinsulinaemia is an emerging field. 3,27 Although there is an accepted association between insulin resistance and hyperinsulinaemia, the direction of causality is unknown and there are multiple plausible aetiologies that could start with either condition. 3,27 It is also becoming accepted that hyperinsulinaemia may be corrected while insulin resistance is maintained. ...
... 3,27 Although there is an accepted association between insulin resistance and hyperinsulinaemia, the direction of causality is unknown and there are multiple plausible aetiologies that could start with either condition. 3,27 It is also becoming accepted that hyperinsulinaemia may be corrected while insulin resistance is maintained. Given the high degree of overlap between the conditions, it is also plausible that diagnostic tests for hyperinsulinaemia and insulin resistance may overlap. ...
Background: Hyperinsulinaemia is emerging as an independent risk factor for metabolic disease, but diagnostic measures are limited. It is plausible that insulin resistance measures, such as homeostatic model assessment (HOMA) type 2 variants, may model hyperinsulinaemia, but repeatability data are limited. Kraft and Hayashi insulin response patterns may not only add value in diagnosing hyperinsulinaemia, but also lack suitable repeatability data.
Aim: The aim of this study was to investigate the repeatability of insulin response patterns, and fasting and dynamic measures of insulin resistance, and to determine whether these latter measures can predict the insulin response pattern.
Setting: This study was conducted at Auckland University of Technology Millennium Institute’s sports performance laboratories.
Methods: Oral glucose (100 g) tolerance tests were conducted weekly on eight people. Six people completed four tests, while two completed at least two tests. Each test assessed insulin resistance and response patterns. Insulin resistance measures included fasting tests (HOMA2, McAuley Index) and a dynamic test (oral glucose insulin sensitivity [OGIS]). The insulin response patterns were assessed with both Kraft and Hayashi methodologies. Repeatability characteristics of ordinal variables were assessed by Bland and Altman methods, while Fleiss’ κ was applied to categorical variables.
Results: Fasting measures of insulin resistance recorded poor repeatability (HOMA2) or poor sensitivity (McAuley Index) compared to the dynamic measure (OGIS). Kraft insulin response patterns were more repeatable compared to Hayashi patterns, based on a combination of Fleiss’ κ (0.290 vs. 0.186,) p-value (0.15 vs. 0.798) and 95% confidence intervals.
Conclusions: Both hyperinsulinaemia and insulin resistance should be dynamically assessed with a multi-sampled oral glucose tolerance test. Further investigations are required to confirm a preferred methodology.
... Hyperinsulinemia is regarded as the root cause of these noncommunicable diseases 7,45 . In modern society, excessive energy uptake and lower energy expenditure lead to hyperinsulinemia and fat accumulation in humans 5,46 . Persistent hyperinsulinemia leads to cellular and target organ dysfunction 46,47 . ...
... In modern society, excessive energy uptake and lower energy expenditure lead to hyperinsulinemia and fat accumulation in humans 5,46 . Persistent hyperinsulinemia leads to cellular and target organ dysfunction 46,47 . Therefore, caloric restriction and physical exercise are essential to maintain energy balance by antagonizing the action of hyperinsulinemia [48][49][50] . ...
Abstract Insulin is critical for glucose homeostasis, and insulin deficiency or resistance leads to the development of diabetes. Recent evidence suggests that diabetes can be remitted independent of insulin. However, the underlying mechanism remains largely elusive. In this study, we utilized metabolic surgery as a tool to identify the non-insulin determinant mechanism. Here, we report that the most common metabolic surgery, Roux-en-Y gastric bypass (RYGB), reduced insulin production but persistently maintained euglycemia in healthy Sprague-Dawley (SD) rats and C57 mice. This reduction in insulin production was associated with RYGB-mediated inhibition of pancreatic preproinsulin and polypyrimidine tract-binding protein 1. In addition, RYGB also weakened insulin sensitivity that was evaluated by hyperinsulinemic-euglycemic clamp test and downregulated signaling pathways in insulin-sensitive tissues. The mechanistic evidence suggests that RYGB predominately shifted the metabolic profile from glucose utilization to fatty acid oxidation, enhanced the energy expenditure and activated multiple metabolic pathways through reducing gut energy uptake. Importantly, the unique effect of RYGB was extended to rats with islet disruption and patients with type 2 diabetes. These results demonstrate that compulsory rearrangement of the gastrointestinal tract can initiate non-insulin determinant pathways to maintain glucose homeostasis. Based on the principle of RYGB action, the development of a noninvasive intervention of the gastrointestinal tract is a promising therapeutic route to combat disorders characterized by energy metabolism dysregulation.
... The pathogenesis of obesity-induced type-2 diabetes is chronologically included the cascade of hyperinsulinemia (HI), insulin resistance (IR) and β-cell degeneration (Fonseca, 2009,Shanik, Xu, Skrha et al., 2008). HI is the key pitfall observed in obesity and now considered as an important determinant in obesity-associated IR (Kelly, Mansoor, Dohm et al., 2014,Yang, Mei, Gu et al., 2014. The notion that insulin itself can cause IR was put forward in 1938 by Somogyi et al (Somogyi M, 1938 Implications of HI in low-grade inflammation at immune cell levels are still a conundrum. ...
... An imperative review proposed the HI is a common factor observed in metabolic syndrome and termed as the 'hyperinsulinemic syndrome' (Kelly et al., 2014). This observation has direct implications in the clinical perspective of insulin therapy as per pathophysiological concern. ...
Various imperative studies support the notion that hyperinsulinemia (HI) itself serves as the common link between adipose tissue inflammation (ATI) and metabolic syndrome. However, the contribution of HI mediated ATI and its metabolic consequences are yet to be explored. We induced chronic HI per se in mice by administration of exogenous insulin for 8 weeks through mini-osmotic pumps. For the reduction of circulating insulin in response to excess calorie intake, we have partially ablated β-cells by using streptozotocin (STZ) in the diet-induced obesity (DIO) and genetic mice models (db/db). Flow cytometry analysis was performed for the quantification of immune cells in stromal vascular fraction (SVF) isolated from epididymal white adipose tissue (eWAT). Our studies demonstrated that chronic HI augmented ATI in terms of elevated pro-inflammatory cells (M1 macrophages and NK-cells) and suppressed anti-inflammatory cells (M2 macrophages, eosinophils and regulatory T-cells). These results were correlated with altered obesity-associated metabolic phenotype. Partial reduction of circulating insulin level attenuated excess calorie-induced ATI and improved insulin sensitivity. Mechanistically, an imbalance in M1 and M2 macrophage proportions in eWAT promoted iNOS (inducible nitric oxide synthase): arginase-1 imbalance that resulted into extracellular matrix (ECM) deposition and insulin resistance (IR) development. However, iNOS-/- mice were protected from HI-induced M1:M2 macrophage imbalance, ECM deposition and IR in adipose tissue. Overall, we conclude that chronic HI per se contributed in ATI and iNOS corroborated ECM deposition.
... Insulin resistance is considered to be the most important pathophysiological mechanism of MetS [18,19]. IR is characterized by impaired lowering of blood glucose through reduced glucose uptake in muscles, and lack of insulin effect on endogenous glucose production in liver. ...
... IR is characterized by impaired lowering of blood glucose through reduced glucose uptake in muscles, and lack of insulin effect on endogenous glucose production in liver. IR is also characterized by impaired insulin effect on lipid and protein metabolism, as well as impaired effect on a number of other organs [18,20]. ...
Background
The metabolic syndrome is a worldwide health issue, with non-alcoholic fatty liver disease (liver steatosis) being one of its features, particularly closely related to insulin resistance. This study aims to investigate whether quantification of hepatic steatosis by abdominal ultrasonography, using hepatorenal index, is a feasible tool for the prediction of insulin resistance, and thus the metabolic syndrome. Methods
Patients were recruited from the Centre of Obesity at the University Hospital of North Norway, and among participants from the Sixth Tromsø Study. Homeostasis Model Assessment of Insulin Resistance (HOMA1-IR) was measured, body mass index (BMI, kg/m2) calculated, and hepatorenal index (HRI), i.e. the ratio of liver to kidney optical densities, was measured by transabdominal ultrasonography. Receiver operating characteristic (ROC) analyses were performed, detecting insulin resistance at HOMA1-IR cut-off values >2.3 and >2.5. ResultsNinety participants were included in the study, of which 46 (51 %) had BMI ≥30 and 27 (30 %) had BMI ≥35. Overall, HRI at level 1.17 had sensitivity 0.90 and specificity 0.70 for predicting insulin resistance (HOMA1-IR >2.3) in all participants. For participants with BMI ≥30, HRI at level 1.17 had sensitivity 0.94 and specificity 0.70, and for BMI ≥35, HRI at level 1.17 had sensitivity 0.93 and specificity 0.75 for predicting HOMA1-IR >2.3. Setting the HRI limit at 1.42 gave low sensitivities and high specificities in all BMI groups. In the analysis predicting HOMA1-IR >2.5, sensitivity values were almost the same as in the analysis predicting HOMA1-IR >2.3, but specificity values were lower in this analysis. Conclusion
Detection and quantification of hepatic steatosis by ultrasound and the hepatorenal index is a feasible screening tool for identifying patients with low risk of having insulin resistance (IR, HRI <1.17), patients at risk of having IR (HRI 1.17-1.41) and patients with likely IR (HRI ≥1.42), especially in obese individuals.
... Hyperinsulinaemia is emerging as a risk factor for subsequent metabolic disease that is independent to insulin resistance [1,2]. Although the two conditions have an intertwined pathophysiology, quantifying insulin resistance has failed to translate to clinical benefit [3]. ...
... The impact of this focus on insulin homeostasis of these patients remains uncertain as many people only achieve glycaemic control through the administration of insulin secretagogues or exogenous insulin. Although glycaemic control must be maintained the question remains whether administering high doses of insulin aggravates cardiovascular disease, or increases the risk of developing cancer or dementia [2]. Research should explore alternatives to maintaining glycaemic control that minimises insulin requirements; both endogenous and exogenous. ...
Objective:
Hyperinsulinaemia is associated with development of chronic metabolic disease and is emerging as a health risk independent to that of insulin resistance. However, little is known to what extent hyperinsulinaemia occurs with normal glucose tolerance in lean subjects.
Method:
Oral glucose tolerance tests with concurrent insulin assay were conducted during the 1970s-1990s. Participants were classified according to glucose tolerance and insulin response pattern. Analysis of variance compared differences in plasma glucose, plasma insulin, and demographic and metabolic risk factors between groups.
Results:
Participants with normal glucose tolerance comprised 54% (n=4185) of the total cohort. Of these, just over half (n=2079) showed hyperinsulinaemia despite normal glucose clearance. Obesity had a modest association with hyperinsulinaemia in people with normal glucose tolerance. Fasting insulin had limited value in diagnosing hyperinsulinaemia. The majority of participants (93%) with impaired glucose tolerance or diabetes had concurrent hyperinsulinaemia.
Conclusion:
Hyperinsulinaemia in the absence of impaired glucose tolerance may provide the earliest detection for metabolic disease risk and likely occurs in a substantial proportion of an otherwise healthy population. Dynamic insulin patterning may produce more meaningful and potentially helpful diagnoses. Further research is needed to investigate clinically useful hyperinsulinaemia screening tools.
... Compensatory hyperinsulinemia (further referred to as "hyperinsulinemia") is associated, mechanistically and epidemiologically, with many chronic metabolic diseases. 1,2 The aetiology of hyperinsulinemia is likely heterogeneous 2 and in the earliest stages asymptomatic. 3 Early management of hyperinsulinemia may prevent, delay, or mitigate the severity of subsequent pathologies. ...
... Corresponding Author, E-mail: ccrofts@aut.ac.nz.1 Human Potential Centre & 2 Biostatistics and Epidemiology, Auckland University of Technology (AUT), PO Box 92006, Auckland 1142, New Zealand. ...
Chronic hyperinsulinemia associated with insulin resistance is directly and indirectly associated with many metabolic disorders that contribute to significant morbidity and mortality. Because hyperinsulinemia is not widely recognised as an independent health risk, there are few studies that assess management strategies. Medication management may not address the multiple issues associated with hyperinsulinemia. Lifestyle management includes physical activity, especially high intensity interval training, and dietary management. Reducing carbohydrate quantity and increasing nutrient density are discussed with carbohydrate-restricted and Mediterranean diets conferring additional benefits to a low-fat diet. Physical activity and dietary management provide the foundation for hyperinsulinemia management and may work synergistically. Of these principles, a combination of resistance and high intensity interval training, and carbohydrate restriction provide the two most effective frontline management strategies for managing hyperinsulinemia.
... Insulin resistance is closely linked to hyperinsulinemia. Both insulin resistance (IR) and inadequate insulin secretion are the primary pathogenic factors contributing to impaired glucose tolerance (IGT) and the onset of type 2 diabetes (T2D) (Kelly et al., 2014;Crofts et al., 2015). Mortality associated with hyperglycemia and overweight/obesity is estimated at 6% and 5%, respectively (Wylie-Rosett & Jhangiani, 2015). ...
Fermented dairy products with a low percentage of fat play a role in modulating the function of β-cells of the pancreas and increased sensitivity to insulin. The purpose of this research is to verify the influence of the type and quantity, of consumed fermented milk products (yogurt and kefir), on the degree of insulin resistance, through Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). The research was conducted on 175 people, from whom 103 women and 73 men, aged 25 to 75 years, with hyperinsulinemia and have increased body mass. Respondents were interviewed with a survey questionnaire that refers to the frequency, quantity, and type of consumed fermented milk products with different percentages of fats. From the obtained results, 56 (32%) have a habit of daily consumption, and the most frequently used daily amount is 250 mL in 127 (74.70%) participants. Statistical significance (p=0.015) was determined between the frequency of consumption and HOMA-IR in the age group between 41 and 55 years. The participants of this age group who have a higher value of the index tend to consume fermented milk products more often, which leads to the conclusion that the consumption of the fermented milk products can have an impact on HOMA-IR in this age group. The statistical analysis of the results obtained for the age groups: 25 to 40 years, and 56 to 75 years showed that there is no significant difference between the frequency of fermented dairy products consumption and HOMA-IR index of the subjects in the groups.
... Insulin is an endocrine hormone that regulates body glucose homeostasis and has anabolic effects on protein and lipid metabolism [97]. Hyperinsulinemia responds to IR, and IR, or hyperinsulinemia, is a significant cause of MetS [98], so it has been suggested that MetS be renamed "insulin resistance syndrome" [99]. Additionally, in some definitions of MetS, such as the World Health Organization's (WHO, 1998) criteria, IR is included as a component of MetS [100]. ...
Specific biomarkers for metabolic syndrome (MetS) may improve diagnostic specificity for clinical information. One of the main pathophysiological mechanisms of MetS is insulin resistance (IR). This systematic review aimed to summarize IR-related biomarkers that predict MetS and have been investigated in Iranian populations.
An electronic literature search was done using the PubMed and Scopus databases up to June 2022. The risk of bias was assessed for the selected articles using the instrument suggested by the Joanna Briggs Institute (JBI). This systematic review protocol was registered with PROSPERO (registration number CRD42022372415).
Among the reviewed articles, 46 studies investigated the association between IR biomarkers and MetS in the Iranian population. The selected studies were published between 2009 and 2022, with the majority being conducted on adults and seven on children and adolescents. The adult treatment panel III (ATP III) was the most commonly used criteria to define MetS. At least four studies were conducted for each IR biomarker, with LDL-C being the most frequently evaluated biomarker. Some studies have assessed the diagnostic potency of markers using the area under the curve (AUC) with sensitivity, specificity, and an optimal cut-off value. Among the reported values, lipid ratios and the difference between non-HDL-C and LDL-C levels showed the highest AUCs (≥ 0.80) for predicting MetS.
Considering the findings of the reviewed studies, fasting insulin, HOMA-IR, leptin, HbA1c, and visfatin levels were positively associated with MetS, whereas adiponectin and ghrelin levels were negatively correlated with this syndrome. Among the investigated IR biomarkers, the association between adiponectin levels and components of MetS was well established.
... values in HINS, IGT, and T2DM groups were lower than those in the NGT group ( = 0.005); however, the differences among the HINS, IGT, and T2DM groups were not statistically significant ( = 0.835). The independent factors influencing the value were waistline and fasting insulin level (FINS [10] suggested that increased serum insulin levels be used as a clinical marker in a primary care setting for early diagnosis and preventative care, which may be beneficial for patients at high risk of diabetes.Another study showed similar results; 515 healthy normoglycemic adults with hyperinsulinemia were followed up for 24 years. Half of the participants developed dysglycemia by the end of the study [11]. ...
... Over the same period, there was a substantial increase in the absolute intake of carbohydrate, a dietary pattern temporally associated with the marked rise in obesity and MetS (4) and increased total mortality rates across multiple countries (5). Hyperinsulinemia is strongly linked to MetS pathogenesis and risk for CVD (6). Carbohydrate intake stimulates insulin secretion, which promotes fat storage and strongly inhibits adipose tissue lipolysis and fatty acid oxidation. ...
Demonstrates the major benefits of dietary carbohydrate restriction by reversing metabolic syndrome without weight loss in a 3-way randomized crossover study
... попротеинов высокой плотности, способствующий образованию атеросклеротических бляшек, приводящих к коронарной болезни сердца и цереброваскулярным заболеваниям [4]; инсулинорезистентность способствует более высокому уровню сывороточного инсулина и глюкозы, предшественников развития сахарного диабета, гиперинсулинемия приводит к чрезмерной задержке натрия почками и повышению артериального давления [5]; изменение внутренней клеточной экспрессии эндотелиальных факторов вызывает повышение артериального давления, связанное с эндотелиальной дисфункцией и нарушением выработки оксида азота [6]. Помимо генетической предрасположенности существуют важные факторы окружающей среды, которые могут влиять на патогенез метаболического синдрома; положительные изменения в образе жизни могут благотворно повлиять на все симптомы метаболического синдрома [7]. ...
... 1,2 However, the high amounts of exogenous insulin commonly being used to achieve glycaemic control targets in people with T1D also has long-term health consequences, including hyperinsulinemia, which is associated with obesity, the metabolic syndrome and atherosclerosis. 3,4 Ultimately, adjunctive therapies that achieve glycaemic control and minimise reliance on excessive insulin are needed to improve the health and wellbeing of individuals living with T1D. ...
p> Background: Type 1 diabetes (T1D) is an autoimmune condition characterised by pancreatic beta cell destruction and absolute insulin deficiency. The varying impact of dietary factors on blood glucose levels is well-known, yet there remains a lack of consensus surrounding the optimal dietary approaches to achieve glycaemic control in T1D. The aim of this research is to assess the efficacy of a low-carbohydrate (LC) diet in adults with T1D. We will set out to determine whether significant differences in T1D management outcomes exist between a LC diet and habitual diets higher in carbohydrate. Our primary hypothesis is that a LC diet will result in improved T1D management compared to habitual diets higher in carbohydrates.
Methods: This is a 28-week single arm within-participant intervention study involving a 4-week control period, a 12-week intervention period and a 12-week follow-up. We plan to recruit 20 adults (18-60 years) with T1D (duration ≥6 months) who have suboptimal glycaemic control (HbA1c>7.0%). The primary outcome is haemoglobin A1c (HbA1c) and secondary outcomes include glycaemic variability, frequency of hypoglycaemia, total daily insulin, and quality of life. This LC diet will start at 50 g of digestible carbohydrate per day and then there will be opportunity to increase or decrease within a broader range of 25-75 g/day according to individual blood glucose levels and personal preference. Participants will meet individually with the study dietitian for a total of six fortnightly sessions to receive dietary instruction, strategies, and education. Participants will continue to work with a member of their usual diabetes care team for specific advice regarding insulin management.
Conclusions: Current dietary management strategies for T1D appear to be lacking in effect and additional dietary therapies, including LC diets, require urgent consideration. Therefore, an interventional study investigating a patient-led LC dietary approach will be of important clinical relevance for healthcare practitioners and may help to better inform clinical practice guidelines for T1D management.
Trial Registration : https://www.anzctr.org.au/ACTRN12621000764831.aspx </p
... The salutary outcomes of bariatric surgery compel a re-evaluation of our concepts about T2D and its comorbidities. The metabolic syndrome is not a group of separate diseases, but rather, multiple expressions of a shared defect in the utilization of carbohydrates and lipids [49][50][51]. That error is probably caused by a dysmetabolic signal from the foregut, stimulated by food, that limits entry of 2-carbon fragments into the tricarboxylic acid cycle, the accumulation of lactate, and, in turn, increases in glucose and insulin. ...
The broad effects of bariatric/metabolic surgery on virtually every tissue and organ system remain unexplained. Weight loss, although a major factor, does not fully account for the rapid, full, and durable remission of type 2 diabetes, return of islet function, reduction of the prevalence of cancers, increase in gray matter of the brain, and decrease in all-cause mortality. This review supports the thesis that the metabolic syndrome is not a group of separate diseases but rather multiple expressions of a shared defect in the utilization of carbohydrates and lipids. That error is probably caused by a dysmetabolic signal from the foregut, stimulated by food, that limits entry of 2-carbon fragments into the tricarboxylic acid cycle, the accumulation of lactate and, in turn, increases in glucose and insulin. Surgery limits that signal by reducing contact between food and foregut mucosa. Speciation of that signal(s) may offer a new pathway for drug development.
... Hyperinsulinemia is strongly associated with metabolic syndrome that is typified by obesity, hypertension, dyslipidemia, renal failure, fatty liver disease, certain cancers and cardiovascular diseases, among others. Despite the fact that such syndrome is clearly characterized, we still do not understand the system-level underlying mechanisms, as well as the global health consequences associated to hyperinsulinemia (18). CD4+ T cells are fundamental modulators of immune challenges and the homeostasis of the immune system. ...
Obesity is linked to insulin resistance, high insulin levels, chronic inflammation, and alterations in the behavior of CD4+ T cells. Despite the biomedical importance of this condition, the system-level mechanisms that alter CD4+ T cell differentiation and plasticity are not well understood. We model how hyperinsulinemia alters the dynamics of the CD4+ T regulatory network, and this, in turn, modulates cell differentiation and plasticity. Different polarizing micro-environments are simulated under basal and high levels of insulin to assess impacts on cell-fate attainment and robustness in response to transient perturbations. In the presence of high levels of insulin Th1 and Th17 become more stable to transient perturbations and their basin sizes are augmented, IL10 producing regulatory T cells become less stable or disappear, while TGFB producing cells remain unaltered. Hence, the model provides a dynamic system-level explanation for the documented apparently paradoxical role of TGFB in both inflammation and regulation of immune responses and the emergence of the adipose Treg phenotype. Furthermore, our simulations provide novel predictions on the impact of the micro-environment in the coexistence of the different cell types, proposing that in pro-Th1, pro-Th2 and pro-Th17 environments effector and regulatory cells can coexist, but that high levels of insulin severely affect regulatory cells, specially in a pro-Th17 environment. This work provides a system-level formal and dynamic framework to integrate further experimental data in the study of complex inflammatory diseases.
... On a biological level chronic hyperinsulinemia and/or insulin resistance is strongly associated in the pathogenesis and likely causal. (6) But just as racism is endemic in the UK National Health Service (NHS) racial bias exists in the identification and management of patients from BAME backgrounds at high risk. Using Body Mass Index (BMI) as a proxy for "healthy weight" may provide the illusion of protection and will miss a substantial proportion of those from black and south Asian ethnic minority groups with METS risk. ...
We also cannot ignore the bigger picture issue. All the biological risk factors (as well as increased psychological stress) in ethnic minority groups will also be fuelled by socio-economic factors. The disproportionate impact of COVID-19 on BAME communities has also highlighted racial and social injustices. The power of modern medicine is dwarfed by the power of prevention and the wider determinants of health. In our view, the medical profession and policymakers have an ethical and moral duty to be advocates for policy change to reduce health inequalities.
... This evidence has a relevant outcome from the bio-pharmacological point of view, since the modulation of insulin secretion could counteract the negative effects of hyperinsulinemic syndromes. Several studies demonstrated the onset of hyperinsulinemia in patients affected by metabolic syndrome [27][28][29]. On this basis, PTS could be used as pure active principle or in its functional food preparations to assist the therapy of insulin-dependent metabolic disorders. ...
Pterostilbene, the 3,5-dimethoxy derivative of resveratrol, is a well-known polyphenolic compound, mainly found in blueberries, grapevines, and Pterocarpus marsupium heartwood, which has recently attracted a great deal of attention due to its wide bio-pharmacological profile. Moreover, pterostilbene is more lipophilic than resveratrol, with a consequently better bioavailability and a more interesting therapeutic potential. In this work, a chemoproteomic approach, based on affinity chromatography, was applied on pterostilbene in the attempt to identify the biological targets responsible for its bioactivity. On this basis, syntaxins, a group of proteins involved in the formation of SNARE complexes mediating vesicles exocytosis, were selected among the most interesting pterostilbene interactors. In vitro and in cell assays gave evidence of the pterostilbene ability to reduce insulin secretion on glucose-stimulated pancreatic beta cells, opening the way to potential applications of pterostilbene as a supplement in the care of insulin-dependent metabolic disorders.
... One of the potential underlying mechanisms linking these lifestyle factors to adverse health outcomes is hyperinsulinemia, a condition characterized by excess circulating insulin relative to glucose concentrations in the blood (4). Insulin insensitivity and/or hyperinsulinemia have been linked to type 2 diabetes, obesity, cardiovascular diseases, and metabolic syndrome (5,6). In addition, evidence suggests that hyperinsulinemia and its biomarkers (i.e., plasma insulin and C-peptide concentrations) may be associated with cancer risk (7,8), including endometrial (9), gastric (10), and pancreatic cancer (11), as well as colorectal adenoma and colorectal cancer, probably due to these cancers' shared risk factors with metabolic syndrome (12)(13)(14)(15). ...
Background:
Poor lifestyles have been linked to insulin insensitivity/hyperinsulinemia, which may contribute to downstream changes such as inflammation and oxidative damage and the development of chronic diseases. As a biomarker of intracellular oxidative stress, leukocyte mitochondrial DNA copy number (mtDNA-CN) has been related to lifestyle factors including diet and weight. No epidemiologic study has examined the relation between combined insulinemic potential of lifestyle and mtDNA-CN.
Objectives:
Our aim was to examine the association between Empirical Lifestyle Index for Hyperinsulinemia (ELIH) and leukocyte mtDNA-CN in US men and women.
Methods:
This cross-sectional analysis included 2835 white adults without cancers, diabetes, or cardiovascular disease at blood collection, including 2160 women from the Nurses' Health Study and 675 men from the Health Professionals Follow-Up Study. ELIH is an index based on plasma C-peptide that characterizes the insulinemic potential of lifestyle (diet, body weight, and physical activity). Relative mtDNA-CN in peripheral blood leukocytes was measured by qPCR-based assay.
Results:
We found a significant inverse association between ELIH and mtDNA-CN. In multivariable-adjusted linear models, absolute least squares means ± SDs of mtDNA-CN z score across ELIH quintiles in women were as follows: Q1: 0.14 ± 0.05; Q2: 0.04 ± 0.06; Q3: 0.008 ± 0.05; Q4: 0.01 ± 0.05; and Q5: -0.06 ± 0.05 (P-trend = 0.006). Means ± SDs in men were as follows: Q1: 0.25 ± 0.09; Q2: 0.23 ± 0.09; Q3: 0.07 ± 0.09; Q4: 0.02 ± 0.09; and Q5: -0.04 ± 0.09 (P-trend = 0.007). Means ± SDs in all participants were as follows: Q1: 0.16 ± 0.05; Q2: 0.07 ± 0.05; Q3: 0.01 ± 0.05; Q4: 0.01 ± 0.05; and Q5: -0.05 ± 0.05 (P-trend = 0.0004).
Conclusions:
Hyperinsulinemic lifestyles (i.e., higher ELIH) were associated with lower leukocyte mtDNA-CN among subjects without major diseases, suggesting that the difference in lifestyle insulinemic potential may be related to excessive oxidative stress damage.
... IR produces a disproportionate insulin concentration to the level of glycaemia [63]. Therefore, IR is associated with a hyperinsulinemic state [63,[83][84][85]. A reduction in intrinsic tyrosine kinase activity of the insulin receptor is considered the primary mechanism responsible for IR [86,87]. ...
... Hyperinsulinaemia is conclusively linked with many metabolic diseases, 1,27 but this disease may be silent and not be associated with obesity. 2 Identifying the normoglycaemic individual with concurrent hyperinsulinaemia may benefit public health initiatives. We recommend that a fasting level combined with a 2-h plasma insulin level > 30 µU/mL following a 100 g oral glucose tolerance test be used to identify the hyperinsulinaemic individual. ...
Background: Ascertaining Kraft dynamic insulin response patterns following a 3-h 100 g oral glucose tolerance test seems to be the most reliable method for diagnosing hyperinsulinaemia. However, this test may be too resource-intensive for standard clinical use.
Aim: This study aims to see if Kraft patterns can be accurately predicted using fewer blood samples with sensitivity and specificity analyses.
Setting: St Joseph Hospital, Chicago, Illinois, United States and Human Potential Centre, Auckland University of technology, Auckland, New Zealand.
Method: We analysed the results of 4185 men and women with a normal glucose tolerance, who had a 100 g oral glucose tolerance test with Kraft pattern analysis. Participants were dichotomised into normal–low insulin tolerance (Kraft I or V patterns) or hyperinsulinaemia (Kraft IIA–IV patterns). Sensitivity and specificity analysis was applied to available variables (including age, body mass index, fasting insulin or glucose) both individually and in combination.
Results: Out of a maximal combined sensitivity and specificity score of 2.0, 2-h insulin level > 45 µU/mL attained the highest score (1.80). Two-hour insulin also attained the highest sensitivity (> 30 µU/mL, 0.98) and the highest specificity (> 50 µU/mL, 0.99) scores. Combining the 2-h insulin with other variables reduced the sensitivity and/or specificity. Dynamic measures had a better combined sensitivity and specificity compared to fasting or anthropological measures.
Conclusion: People with a 2-h plasma insulin level < 30 µU/mL are unlikely to be hyperinsulinaemic. Given that first-line treatment is lifestyle modification, we recommend that a 2-h plasma insulin level > 30 µU/mL following a 100 g oral glucose tolerance test be used to identify the hyperinsulinaemic individual.
... Over the same period, there was a substantial increase in the absolute intake of carbohydrate, a dietary pattern temporally associated with the marked rise in obesity and MetS (4) and increased total mortality rates across multiple countries (5). Hyperinsulinemia is strongly linked to MetS pathogenesis and risk for CVD (6). Carbohydrate intake stimulates insulin secretion, which promotes fat storage and strongly inhibits adipose tissue lipolysis and fatty acid oxidation. ...
BACKGROUND
Metabolic syndrome (MetS) is highly correlated with obesity and cardiovascular risk, but the importance of dietary carbohydrate independent of weight loss in MetS treatment remains controversial. Here, we test the theory that dietary carbohydrate intolerance (i.e., the inability to process carbohydrate in a healthy manner) rather than obesity per se is a fundamental feature of MetS.METHODS
Individuals who were obese with a diagnosis of MetS were fed three 4-week weight-maintenance diets that were low, moderate, and high in carbohydrate. Protein was constant and fat was exchanged isocalorically for carbohydrate across all diets.RESULTSDespite maintaining body mass, low-carbohydrate (LC) intake enhanced fat oxidation and was more effective in reversing MetS, especially high triglycerides, low HDL-C, and the small LDL subclass phenotype. Carbohydrate restriction also improved abnormal fatty acid composition, an emerging MetS feature. Despite containing 2.5 times more saturated fat than the high-carbohydrate diet, an LC diet decreased plasma total saturated fat and palmitoleate and increased arachidonate.CONCLUSION
Consistent with the perspective that MetS is a pathologic state that manifests as dietary carbohydrate intolerance, these results show that compared with eucaloric high-carbohydrate intake, LC/high-fat diets benefit MetS independent of whole-body or fat mass.TRIAL REGISTRATIONClinicalTrials.gov Identifier: NCT02918422.FUNDINGDairy Management Inc. and the Dutch Dairy Association.
... Regardless of the underlying mechanism of T2D pathogenesis, it is clear that hyperinsulinemia is a serious problem and is related to several deleterious conditions such as dyslipidemia, cardiovascular diseases, cancer and obesity (Kelly et al., 2014). However, whether age-dependent hyperinsulinemia occurs due to changes in insulin secretion or clearance, or even both, is unclear. ...
Human life expectancy is increasing faster lately and, consequently, the number of patients with age‐related diseases such as type 2 diabetes (T2D) is rising every year. Cases of hyperinsulinemia have been extensively reported in elderly subjects and this alteration in blood insulin concentration is postulated to be a cause of insulin resistance, which in some cases triggers T2D onset. Thus, it is important to know the underlying mechanisms of age‐dependent hyperinsulinemia to find new strategies to prevent T2D in elderly subjects. Two processes control blood insulin concentration: Insulin secretion by the endocrine portion of the pancreas and insulin clearance, which occurs mainly in the liver by the action of the insulin‐degrading enzyme (IDE). Here, we demonstrated that 10‐month‐old mice (old) display increased body and fat pad weight, compared with 3‐month‐old mice (control), and these alterations were accompanied by glucose and insulin intolerance. We also confirm hyperinsulinemia in the old mice, which was related to increased insulin secretion but not to reduced insulin clearance. Although no changes in insulin clearance were observed, IDE activity was lower in the liver of old compared with the control mice. However, this decreased IDE activity was compensated by increased expression of IDE protein in the liver, thus explaining the similar insulin clearance observed in both groups. In conclusion, at the beginning of aging, 10‐month‐old mice do not display any alterations in insulin clearance. Therefore, hyperinsulinemia is initiated primarily due to a higher insulin secretion in the age‐related metabolic dysfunction in mice.
... Insulin resistance and obesity are the main factors in MS development (Kaur, 2014). Increase in insulin level which is caused by insulin resistance not only plays a role in the development of MS and impairment of its indices, but also its footprint has also been observed in cardiovascular diseases, arthrosclerosis, renal failure, and some cancers (Kelly et al., 2014). Several tracer elements such as zinc (Zn), selenium (Se), magnesium (Mg) and copper (Cu)) are population-dependent and it might be different among the different populations (Shahbazian et al., 2018). ...
Background and Aim
The prevalence of metabolic syndrome (MS) increased in recent years in both adolescents and children groups. The aim of the study is evaluating the relationship between insulin and uric acid (UA) level in MS in adolescents
Materials and Methods
we studied 120 adolescence aged 10 to 19 in two groups: control group without metabolic syndrome and case group with metabolic syndrome. The Criteria of ATP III was considered as a diagnosis factor for metabolic syndrome.
Discussion
Various studies have been conducted in various populations to evaluate the relationship between UA level and MS in adolescents. Abdominal obesity, low HDL, hypertriglyceridemia and hypertension are associated with high UA level. In their analysis, the MS OR in UA level⩽4.9, 4.9-5.8 and ⩾5.8 mg/dl was 1, 2.53 and 9.03, respectively, which were higher than our findings in current study. Hyperinsulinemia caused by insulin resistance is one of the complications associated with MS, which puts individuals at risk of diabetes and cardiovascular events.
Results
Uric acid level in the Case group was significantly higher than the control group (p = 0.0001, 43.8±1.4 vs. 4.1±1 mg/dl, respectively). Insulin level was significantly higher in the case group in compare to the control group (p = 0.008, 9.8± 5.3 vs. 12.2±6 μU/ml, respectively).
Conclusion
The findings of this case-control study showed that adolescents with metabolic syndrome have a higher uric acid and insulin level in compare to normal subjects. We hypothesis that increase in serum insulin and uric acid level can be a risk factor in the development of metabolic syndrome.
... Diet-induced HI and associated inflammatory consequences are well reported in the literature. An imperative review proposed the HI is a common factor observed in metabolic syndrome and termed as the 'hyperinsulinemic syndrome' (Kelly et al., 2014). This observation has direct implications in the clinical perspective of insulin therapy as per pathophysiological concern. ...
... The development of MetS in obese Zucker rats was associated to alterations in glucose and lipid metabolism as reported by other authors [31,32]. Our results showed a positive action of AIT protocol in plasma lipid profile, and point out to improved insulin sensitivity of trained obese animals exemplified by plasma AUC after an oral glucose overload. ...
Metabolic syndrome (MetS) is a group of related metabolic alterations that increase the risk of developing non-alcoholic fatty liver disease (NAFLD). Several lifestyle interventions based on dietary treatment with functional ingredients and physical activity are being studied as alternative or reinforcement treatments to the pharmacological ones actually in use. In the present experiment, the combined treatment with mung bean (Vigna radiata), a widely used legume with promising nutritional and health benefits that was included in the experimental diet as raw or 4 day-germinated seed flour, and aerobic interval training protocol (65–85% VO2 max) has been tested in lean and obese Zucker rats following a 2 × 2 × 2 (2 phenotypes, 2 dietary interventions, 2 lifestyles) factorial ANOVA (Analysis of Variance) statistical analysis. Germination of V. radiata over a period of four days originated a significant protein hydrolysis leading to the appearance of low molecular weight peptides. The combination of 4 day-germinated V. radiata and aerobic interval training was more efficient compared to raw V. radiata at improving the aerobic capacity and physical performance, hepatic histology and functionality, and plasma lipid parameters as well as reverting the insulin resistance characteristic of the obese Zucker rat model. In conclusion, the joint intervention with legume sprouts and aerobic interval training protocol is an efficient treatment to improve the alterations of glucose and lipid metabolism as well as hepatic histology and functionality related to the development of NAFLD and the MetS.
... Metabolic syndrome is characterized mainly by: central obesity, hypertension, dyslipidemia, hyperinsulinemia, insulin resistance and glucose intolerance. Despite the fact that such syndrome is well described, the system-level underlying mechanisms, as well as the global health consequences associated with hyperinsulinemia have not been fully understood [19]. CD4+ T cells are fundamental modulators of immune challenges and the homeostasis of the immune system. ...
Background
Obesity is frequently linked to insulin resistance, high insulin levels, chronic inflammation, and alterations in the behaviour of CD4+ T cells. Despite the biomedical importance of this condition, the system-level mechanisms that alter CD4+ T cell differentiation and plasticity are not well understood.
Results
We model how hyperinsulinemia alters the dynamics of the CD4+ T regulatory network, and this, in turn, modulates cell differentiation and plasticity. Different polarizing microenvironments are simulated under basal and high levels of insulin to assess impacts on cell-fate attainment and robustness in response to transient perturbations. In the presence of high levels of insulin Th1 and Th17 become more stable to transient perturbations, and their basin sizes are augmented, Tr1 cells become less stable or disappear, while TGFβ producing cells remain unaltered. Hence, the model provides a dynamic system-level framework and explanation to further understand the documented and apparently paradoxical role of TGFβ in both inflammation and regulation of immune responses, as well as the emergence of the adipose Treg phenotype. Furthermore, our simulations provide new predictions on the impact of the microenvironment in the coexistence of the different cell types, suggesting that in pro-Th1, pro-Th2 and pro-Th17 environments effector and regulatory cells can coexist, but that high levels of insulin severely diminish regulatory cells, especially in a pro-Th17 environment.
Conclusions
This work provides a first step towards a system-level formal and dynamic framework to integrate further experimental data in the study of complex inflammatory diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s12918-017-0436-y) contains supplementary material, which is available to authorized users.
... 4 It is estimated that~10-25% of adults worldwide 5 and~42% of Iranian population suffer from MetS. 2 The prevalence of MetS among Iranian women is higher than other women in the world. 6 Recent studies have shown that hyperinsulinemia 7,8 and central obesity 9 have a fundamental role in MetS pathogenesis and has as a main interface between other MetS risk factors. ...
Background/objectives:
Nowadays, metabolic syndrome (MetS) is deemed as a major public health challenge in both developed and developing countries. Therefore, the aim of this study was to determine the association between Healthy Eating Index-2010 (HEI-2010) score and MetS and its features among Iranian female nurses.
Subjects/methods:
This cross-sectional study was performed among 1036 Iranian women. A validated, self-administered, dish-based, semiquantitative food frequency questionnaire was used to assess the habitual intake of participants. HEI-2010 score was used to assess diet quality of participants. MetS was defined based on the guidelines of the National Cholesterol Education Program Adult Treatment Panel III (ATP III). Multivariate logistic regression adjusted for potential confounders was used to assess the relation between HEI-2010 and MetS.
Results:
After adjusting for potential confounders, participants in the highest quartile of HEI-2010 had the lowest risk of MetS compared with those in the first quartile (odds ratio: 0.72; 95% confidence interval: 0.50-0.96). Furthermore, the risk of MetS features including abdominal obesity, high blood pressure, high serum triacylglycerol and low serum high-density lipoprotein-cholesterol significantly decreased across HEI-2010 quartiles (P<0.05).
Conclusions:
Higher HEI-2010 scores were inversely associated with lower risk of MetS and its components among Iranian women.European Journal of Clinical Nutrition advance online publication, 28 September 2016; doi:10.1038/ejcn.2016.173.
... Newer agents present alternatives to insulin therapy, including in patients with "advanced" type 2 DM with residual insulin production. Insulin therapy induces hypoglycemia, weight gain, and a range of adverse consequences of hyperinsulinemia with both shortand long-term outcomes (77)(78)(79)(80)(81)(82)(83)(84)(85). Newer antidiabetes classes may be used to delay insulin therapy in candidate patients with endogenous insulin production (19). ...
The current classification system presents challenges to the diagnosis and treatment of patients with diabetes mellitus (DM), in part due to its conflicting and confounding definitions of type 1 DM, type 2 DM, and latent autoimmune diabetes of adults (LADA). The current schema also lacks a foundation that readily incorporates advances in our understanding of the disease and its treatment. For appropriate and coherent therapy, we propose an alternate classification system. The beta-cell-centric classification of DM is a new approach that obviates the inherent and unintended confusions of the current system. The beta-cell-centric model presupposes that all DM originates from a final common denominator-the abnormal pancreatic beta-cell. It recognizes that interactions between genetically predisposed beta-cells with a number of factors, including insulin resistance (IR), susceptibility to environmental influences, and immune dysregulation/ inflammation, lead to the range of hyperglycemic phenotypes within the spectrum of DM. Individually or in concert, and often self-perpetuating, these factors contribute to beta-cell stress, dysfunction, or loss through at least 11 distinct pathways. Available, yet underutilized, treatments provide rational choices for personalized therapies that target the individual mediating pathways of hyperglycemia at work in any given patient, without the risk of drug-related hypoglycemia or weight gain or imposing further burden on the beta-cells. This article issues an urgent call for the review of the current DM classification system toward the consensus on a new, more useful system.
Malnutrition is a hidden, subtle, and dangerous challenge in bariatric surgery. The severely obese, almost always burdened by other comorbidities, and mixed dietary histories are also, all too often, malnourished, especially in micronutrients, a setting that leads to complications not only in the perioperative period but also during the years after the surgery. The objective of this review was to offer a case report, review the assessment of obesity and malnutrition, note approaches to prevention and treatment, and suggest the founding of metabolic centers to facilitate interdisciplinary approaches to this serious and common problem.
Insulin secretion is a signal‐triggered process that requires membrane fusion between the secretory granules and plasma membrane (PM) in pancreatic β cells. The exocytosis of insulin is mediated by t‐SNAREs on the PM and v‐SNARE on the vesicles, which assemble into a quaternary trans‐SNARE complex to initiate the fusion. Expression of fusion proteins is reduced in the islets of patients with type II diabetes (T2D), indicating that SNARE‐mediated fusion defect is closely related to insulin‐based metabolic diseases. Previous studies have suggested that epigallocatechin gallate (EGCG) has an inhibitory effect on membrane fusion. In this study, we performed in vitro reconstitution assays to unravel the molecular mechanisms of EGCG in SNARE‐mediated insulin secretory vesicle fusion. Our data show that EGCG efficiently inhibits insulin secretory SNARE‐mediated membrane fusion. Mechanistic studies indicated that EGCG blocks the formation of the trans‐SNARE complex. Furthermore, calcium/synaptotagmin‐7‐stimulated fusion kinetics were largely reduced by EGCG, confirming it is a potential regulator of SNARE‐dependent insulin secretion. Our findings suggest that the trans‐SNARE complex might be a promising target for controlling SNARE‐dependent vesicle fusion.
The decades-long dietary experiment embodied in the Dietary Guidelines for Americans (DGA) focused on limiting fat, especially saturated fat, and higher carbohydrate intake has coincided with rapidly escalating epidemics of obesity and type 2 diabetes (T2D) that are contributing to the progression of cardiovascular disease (CVD) and other diet-related chronic diseases. Moreover, the lack of flexibility in the DGA as it pertains to low carbohydrate approaches does not align with the contemporary trend toward precision nutrition. We argue that personalizing the level of dietary carbohydrate should be a high priority based on evidence that Americans have a wide spectrum of metabolic variability in their tolerance to high carbohydrate loads. Obesity, metabolic syndrome, and T2D are conditions strongly associated with insulin resistance, a condition exacerbated by increased dietary carbohydrate and improved by restricting carbohydrate. Low-carbohydrate diets are grounded across the time-span of human evolution, have well-established biochemical principles, and are now supported by multiple clinical trials in humans that demonstrate consistent improvements in multiple established risk factors associated with insulin resistance and cardiovascular disease. The American Diabetes Association (ADA) recently recognized a low carbohydrate eating pattern as an effective approach for patients with diabetes. Despite this evidence base, low-carbohydrate diets are not reflected in the DGA. As the DGA Dietary Patterns have not been demonstrated to be universally effective in addressing the needs of many Americans and recognizing the lack of widely available treatments for obesity, metabolic syndrome, and T2D that are safe, effective, and sustainable, the argument for an alternative, low-carbohydrate Dietary Pattern is all the more compelling.
Non-alcoholic fatty liver disease (NAFLD) is a fast-spreading epidemic across the globe and has serious implications far beyond that of a "benign" liver condition. It is usually an outcome of ectopic fat storage due to chronic positive energy balance leading to obesity and is associated with multiple health problems. While association with cardiovascular disease and hepatocellular cancer is well recognized, it is becoming clear the NAFLD carries with it an increased risk of cancers of extrahepatic tissues. Studies have reported a higher risk for cancers of the colon, breast, prostate, lung, and pancreas. Fatty liver is associated with increased mortality; there is an urgent need to understand that fatty liver is not always benign, and not always associated with obesity. It is, however, a reversible condition and early recognition and intervention can alter its natural history and associated complications.
Pancreatic beta-cells are the only cells in the body that can synthesize and secrete insulin. Through the process of glucose-stimulated insulin secretion, beta-cells release insulin into circulation, stimulating GLUT4-dependent glucose uptake into peripheral tissue. Insulin is normally secreted in pulses that promote signaling at the liver. Long before type 2 diabetes is diagnosed, beta-cells become oversensitive to glucose, causing impaired pulsatility and overstimulation in fasting levels of glucose. The resulting hypersecretion of insulin can cause poor insulin signaling and clearance at the liver, leading to hyperinsulinemia and insulin resistance. Continued overactivity can eventually lead to beta-cell exhaustion and failure at which point type 2 diabetes begins. To prevent or reverse the negative effects of overstimulation, beta-cell activity can be reduced. Clinical studies have revealed the potential of beta-cell rest to reverse new cases of diabetes, but treatments lack durable benefits. In this perspective, we propose an intervention that reduces overactive glucokinase activity in the beta-cell. Glucokinase is known as the glucose sensor of the beta-cell due to its high control over insulin secretion. Therefore, glycolytic overactivity may be responsible for hyperinsulinemia early in the disease and can be reduced to restore normal stimulus-secretion coupling. We have previously reported that reducing glucokinase activity in prediabetic mouse islets can restore pulsatility and enhance insulin secretion. Building on this counterintuitive finding, we review the importance of pulsatile insulin secretion and highlight how normalizing glucose sensing in the beta cell during prediabetic hyperinsulinemia may restore pulsatility and improve glucose homeostasis.
The metabolic syndrome (MS) refers
to the conglomeration of various risk
factors for cardiovascular disease
(CVD) and type 2 diabetes mellitus (DM2), and includes
central obesity, hypertension, atherogenic dyslipidemia, and
dysglycemia. Approximately one quarter of the total world
population, or more than one billion people, has been estimated to have MS at present day. This condition has a
complex pathophysiology where several endocrine and metabolic disorders converge, among which insulin resistance
(IR) plays a central role. In recent years, various pleiotropic functions of vitamin D have been described beyond its
traditional role beyond calcium and phosphate metabolism.
Indeed, it has been related to modulatory actions in the cardiovascular, immunological, and endocrine systems; and
may actively participate in the pathogenesis of MS, CVD, and DM2. These findings have ignited great scientific interest in vitamin D as preventive and therapeutic tool for MS.
Vitamin D may intervene in the pathogenesis of MS via various potential mechanisms, among which the attenuation of
IR and control of chronic inflammation are most prominent.
A considerable body of research has been produced regarding the influence of vitamin D in the prevalence of MS and
its individual components. Although there appears to be a
relatively clear relationship between low vitamin D levels and
MS prevalence, the specific threshold for the onset of each
of the components remains unclear, and probably varies between populations. Similarly, the target levels required for
the prevention and treatment of MS and its components,
as well as the clinical utility of supplementation, both need
further investigation. This review revises the metabolism and
physiology of vitamin D, as well as its possible implications
for the clinical management of MS.
There are endocrine and immunological changes that occur during onset and progression of the overweight and obese states. The inhibitor of nuclear factor kappa B kinase subunit epsilon (IKKε) was originally described as an inducible protein kinase; whole-body gene deletion or systemic pharmaceutical targeting of this kinase improved insulin sensitivity and glucose tolerance in mice. To investigate the primary sites of action associated with IKKε during weight gain, we describe the first mouse line with conditional elimination of IKKε in the liver (IKKε alb-/- ). IKKε alb-/- mice and littermate controls gain weight, show similar changes in body composition, and do not display any improvements in insulin sensitivity or whole-body glucose tolerance. These studies were conducted using both breeder chow diets and also matched low- versus high-fat diets. While glycogen accumulation in the liver is reduced in IKKε alb-/- mice, lipid storage in liver is similar IKKε alb-/- mice and littermate controls. Our results using IKKε alb-/- mice suggest that the primary action of this kinase to impact insulin sensitivity during weight gain lies predominantly within extrahepatic tissues.
Objective:
The aim of this study was to determine the distribution of homeostatic model assessment of insulin resistance (HOMA-IR) values and define its cutoff associated with metabolic syndrome (MetS) in the participants of the Study of Cardiovascular Risk in Adolescents (Estudo de Risco Cardiovascular em Adolescentes).
Methods:
MetS was defined according to the International Diabetes Federation criteria. HOMA-IR values were calculated and tabulated by corresponding percentiles for age and sex. Receiver operating characteristic curves were constructed to identify the optimal cutoff values of HOMA-IR associated with MetS in the total population and by sex.
Results:
We evaluated 37 815 adolescents ages 12 to 17 y. The highest HOMA-IR medians were found among girls and boys ages 12 and 14 y, respectively. Thereafter, values tended to decrease with age. The optimal cutoff values of the HOMA-IR associated with MetS in the total population, in female adolescents, and in male adolescents were 2.80, 2.32, and 2.87, respectively. Insulin resistance was prevalent in 19.1% (95% confidence interval, 17.7-20.7) of the total population, and the prevalence was higher among girls and overweight Brazilian adolescents.
Conclusions:
These findings may serve as new reference points for detecting insulin resistance in Brazilian adolescents.
Aims:
We hypothesized that patients with dysregulated type 2 diabetes may be stratified based on routine clinical markers.
Methods:
In this retrospective cohort study, diabetes related clinical measures including age at onset, diabetes duration, HbA1c, BMI, HOMA2-β, HOMA2-IR and GAD65 autoantibodies, were used for sub-grouping patients by K-means clustering and for adjusting. Probability of diabetes complications (95% confidence interval), were calculated using logistic regression.
Results:
Based on baseline data from patients with type 2 diabetes (n=2,290), the cluster analysis suggested up to five sub-groups. These were primarily characterized by autoimmune β-cell failure (3%), insulin resistance with short disease duration (21%), non-autoimmune β-cell failure (22%), insulin resistance with long disease duration (32%), and presence of metabolic syndrome (22%), respectively. Retinopathy was more common in the sub-group characterized by non-autoimmune β-cell failure (52% (47.7-56.8)) compared to other sub-groups (22% (20.1-24.1)), adj. p<0.001. The prevalence of cardiovascular disease, nephropathy and neuropathy also differed between sub-groups, but significance was lost after adjustment.
Conclusions:
Patients with type 2 diabetes cluster into clinically relevant sub-groups based on routine clinical markers. The prevalence of diabetes complications seems to be sub-group specific. Our data suggests the need for a tailored strategy for the treatment of type 2 diabetes.
Various imperative studies support the notion that hyperinsulinemia (HI) itself serves as the common link between adipose tissue inflammation (ATI) and metabolic syndrome. However, the contribution of HI mediated ATI and its metabolic consequences are yet to be explored. We induced chronic HI per se in mice by administration of exogenous insulin for 8 weeks through mini-osmotic pumps. For the reduction of circulating insulin in response to excess calorie intake, we have partially ablated β-cells by using streptozotocin (STZ) in the diet-induced obesity (DIO) and genetic mice models (db/db). Flow cytometry analysis was performed for the quantification of immune cells in stromal vascular fraction (SVF) isolated from epididymal white adipose tissue (eWAT). Our studies demonstrated that chronic HI augmented ATI in terms of elevated pro-inflammatory cells (M1 macrophages and NK-cells) and suppressed anti-inflammatory cells (M2 macrophages, eosinophils and regulatory T-cells). These results were correlated with altered obesity-associated metabolic phenotype. Partial reduction of circulating insulin level attenuated excess calorie-induced ATI and improved insulin sensitivity. Mechanistically, an imbalance in M1 and M2 macrophage proportions in eWAT promoted iNOS (inducible nitric oxide synthase): arginase-1 imbalance that resulted into extracellular matrix (ECM) deposition and insulin resistance (IR) development. However, iNOS−/- mice were protected from HI-induced M1:M2 macrophage imbalance, ECM deposition and IR in adipose tissue. Overall, we conclude that chronic HI per se contributed in ATI and iNOS corroborated ECM deposition.
Background
The scale and variables linked to bariatric surgery‘s effect on dyslipidemia have not been conclusive.
Objective
To compare the effect of Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), and adjustable gastric banding (LAGB) on dyslipidemia
Setting
National bariatric surgery registry.
Methods
Plasma lipids and associated variables were compared at baseline and 1 year (12±4 mo) after surgery for registry patients with dyslipidemia enrolled from June 2013 to August 2014.
Results
The greatest mean total-cholesterol (TC) reduction was observed post-RYGB, 226.7±26.4 to 181.3±30.9 mg/dL (19.9%, n = 208), followed by post-SG, 227.9±24.4 to 206.7±34.2 mg/dL (8.9%, n = 1515; P<.001). Normal TC levels of below 200 mg/dL were achieved by 76% post-RYGB patients compared with 43.5% post-SG patients (odds ratio [OR] = 6.24, 95% confidence interval [CI]: 3.69–10.53) and 25.6% post-LABG patients (OR = 9.66, 95% CI: 4.11–22.67; P<.01). Although equivalent patterns were observed for low-density-lipoprotein cholesterol (LDL), the levels of high-density-lipoprotein cholesterol (HDL) were most improved post-SG, reaching normal levels in 58.1% of SG male patients versus 39.5% of RYGB male patients (OR = 1.56, 95% CI: 1.04–2.35), (P = .02). The lowering of triglyceride levels by approximately 75% was comparable after SG and RYGB procedures. The type of surgery was the strongest independent predictor for all lipid level improvements or remissions. Male sex was an independent predictor for LDL normalization only (OR = 1.88, 95% CI: 1.24–2.85). Excess weight loss offered no meaningful prediction for lipid improvement (OR = 1.01–1.03).
Conclusion
Particular types of bariatric surgeries had different effects on dyslipidemia, independent of weight loss. Overall, the RYGB achieved the biggest reduction in plasma lipids (TC and LDL), although SG did affect HDL. Our results could aid in the decision-making process regarding the most appropriate procedure for patients with dyslipidemia.
Studies have reported significant improvement of obstructive sleep apnea (OSA) in obese patients after bariatric surgery (BS). Weight loss following BS is rapid in the first few months, but it can take at least 1 year to reach the final result. The aim of this study is to measure the effect of BS on various clinical, respiratory, and sleep parameters of OSA at two postoperative intervals.
Prospectively, all patients being evaluated for BS underwent a polysomnography (PSG). Patients diagnosed with OSA preoperatively were invited to undergo a PSG at least 6 months postoperatively and if OSA persisted, again at least 12 months postoperatively.
One hundred ten patients underwent a first postoperative PSG 7.7 months after surgery. The mean apnea-hypopnea index (AHI) significantly decreased from 39.5 to 15.6/h. In 58.2 %, the AHI was reduced to below 10 and in 25.5 % to below 5. Fifty patients underwent a first PSG 7.1 months and a second PSG 16.9 months after surgery. The mean AHI decreased from 49.1 to 22.7 to 17.4/h following BS.
BS initiates dramatic improvement and even remission of clinical and sleep parameters during the first 7 months, which continues at a slower rate over the next 10 months. We recommend a follow-up PSG after surgery to check for residual disease and if necessary retritration of continuous positive airway pressure, which may lead to higher treatment compliance.
Obesity and diabetes mellitus are associated with an increased risk of pancreatic cancer. These associations may be secondary to consequences of peripheral insulin resistance, pancreatic β-cell dysfunction, or hyperglycemia itself. Hemoglobin A1c (HbA1c) is a measure of hyperglycemia, whereas plasma insulin and proinsulin are markers of peripheral insulin resistance, and the proinsulin to insulin ratio marks pancreatic β-cell dysfunction.
This was a prospective, nested case-control study of 449 case patients and 982 control subjects with prediagnostic blood samples and no diabetes history from five prospective US cohorts followed through 2008. Two or three control subjects were matched to each case patient by year of birth, cohort, smoking, and fasting status. Pancreatic cancer risk was assessed by prediagnostic HbA1c, insulin, proinsulin, and proinsulin to insulin ratio with multivariable-adjusted logistic regression. All P values were two-sided.
The highest vs lowest quintiles of HbA1c, insulin, and proinsulin were associated with with an increased risk for pancreatic cancer (odds ratio [OR] = 1.79; 95% confidence interval [CI] = 1.17 to 2.72, P trend = .04 for HbA1c; OR = 1.57; 95% CI = 1.08 to 2.30; Ptrend = .002 for insulin; and OR = 2.22; 95% CI = 1.50 to 3.29; P trend < .001 for proinsulin). Proinsulin to insulin ratio was not associated with pancreatic cancer risk. Results were similar across studies (all P heterogeneity > .29). In cancers developing 10 or more years after blood collection, the associations with insulin and proinsulin became stronger (highest vs lowest quintile, OR = 2.77; 95% CI = 1.28 to 5.99 for insulin and OR = 3.60; 95% CI = 1.68 to 7.72 for proinsulin). In mutually adjusted models including HbA1c, insulin, and proinsulin, only proinsulin remained statistically significant ( highest vs lowest quintile, OR = 2.55; 95% CI = 1.54 to 4.21; Ptrend < .001).
Among participants from five large prospective cohorts, circulating markers of peripheral insulin resistance, rather than hyperglycemia or pancreatic β-cell dysfunction, were independently associated with pancreatic cancer risk.
Increased sympathetic activity is a well-known pathophysiological mechanism in insulin resistance (IR) and hypertension (HT). The carotid bodies (CB) are peripheral chemoreceptors that classically respond to hypoxia by increasing chemosensory activity in the carotid sinus nerve (CSN), causing hyperventilation and activation of the sympathoadrenal system. Besides its role in the control of ventilation, the CB has been proposed as a glucose sensor being implicated in the control of energy homeostasis. However, to date no studies have anticipated its role in the development of IR. Herein we propose that CB overstimulation is involved in the aetiology of IR and HT, core metabolic and hemodynamic disturbances of highly prevalent diseases like the metabolic syndrome, type 2 diabetes and obstructive sleep apnoea. We demonstrated CB activity is increased in IR animal models and that CSN resection prevents CB-overactivation and diet-induced IR and HT. Moreover we showed that insulin triggers CB, highlighting a new role for hyperinsulinemia as a stimulus for CB-overactivation. We propose that CB is implicated in the pathogenesis of metabolic and hemodynamic disturbances through sympathoadrenal overactivation and may represent a novel therapeutic target in these diseases.
The fundamental importance of the hypothalamus in the regulation of autonomic and cardiovascular func-tions is well established. However, the molecular processes involved are not well understood. Here, we show that the mammalian (or mechanistic) target of rapamycin (mTOR) signaling in the hypothalamus is tied to the activity of the sympathetic nervous sys-tem and to cardiovascular function. Modulation of mTOR complex 1 (mTORC1) signaling caused dra-matic changes in sympathetic traffic, blood flow, and arterial pressure. Our data also demonstrate the importance of hypothalamic mTORC1 signaling in transducing the sympathetic and cardiovascular actions of leptin. Moreover, we show that the PI3K pathway links the leptin receptor to mTORC1 signaling and that changes in its activity impact sym-pathetic traffic and arterial pressure. These findings establish mTORC1 activity in the hypothalamus as a key determinant of sympathetic and cardiovascular regulation and suggest that dysregulated hypotha-lamic mTORC1 activity may influence the develop-ment of cardiovascular diseases.
Aims/hypothesis:
Proinsulin is possibly associated with cancer through activation of insulin receptor isoform A. We sought to investigate the associations between proinsulin and 20 year cancer mortality rates.
Methods:
The study was performed within the Hoorn Study, a population-based study of glucose metabolism in individuals aged 50-75 years in the Dutch population. Fasting proinsulin levels were measured twice by a double-antibody radioimmunoassay. Participants were continuously followed to register mortality; causes of death were derived from medical records. Cox survival analyses were performed to assess the 20 year risk of death from cancer in relation to proinsulin. All analyses were adjusted for age and sex, with additional adjustments for traditional risk factors. The effect modification of glucose metabolism and sex was tested.
Results:
Proinsulin levels were measured in 438 individuals (41% normal glucose tolerance, 35.7% impaired glucose metabolism, 23.3% type 2 diabetes). Of these participants, 53 died from cancer. After adjustment for age and sex, proinsulin >16.5 pmol/l (the upper tertile) was significantly associated with a twofold risk of cancer mortality (HR 2.01, 95% CI 1.16, 3.46) compared with individuals with lower proinsulin levels. Additional adjustment for glucose metabolism, BMI and smoking did not substantially change the results (HR 1.91, 95% CI 1.04, 3.52). No interaction with glucose metabolism or sex was observed.
Conclusions/interpretation:
Individuals with fasting proinsulin levels >16.5 pmol/l have a twofold risk of cancer mortality over a 20 year time span. These findings provide population-based evidence for the independent association between high proinsulin levels and cancer mortality rates.
Morbid obesity is strongly associated with nonalcoholic fatty liver disease (NAFLD) which is one of the most common causes of chronic liver disease worldwide. The current best treatment of NAFLD and NASH is weight reduction through life style modifications, antiobesity medication, and bariatric surgery. Importantly, bariatric surgery is the best alternative option for weight reduction if lifestyle modifications and pharmacological therapy have not yielded long-term success. Bariatric surgery is an effective treatment option for individuals who are grossly obese and associated with marked decrease in obesity-related morbidity and mortality. The most common performed bariatric surgery is Roux-en-Y gastric bypass (RYGB). The current evidence suggests that bariatric surgery in these patients will decrease the grade of steatosis, hepatic inflammation, and fibrosis. NAFLD
per se
is not an indication for bariatric surgery. Further research is urgently needed to determine (i) the benefit of bariatric surgery in NAFLD patients at high risk of developing liver cirrhosis (ii) the role of bariatric surgery in modulation of complications of NAFLD like diabetes and cardiovascular disease. The outcomes of the future research will determine whether bariatric surgery will be one of the recommended choice for treatment of the most progressive type of NAFLD.
Insulin resistance, characterized by hyperinsulinemia and normal or elevated serum glucose, is an established precursor to diabetes and cardiovascular disease. Despite fasting serum C-peptide levels being an accurate and stable marker of endogenous insulin production used in patients with diabetes, it is unknown whether C-peptide could serve as a marker of insulin resistance and predict outcomes in patients without diabetes.
This is a retrospective cohort study using data from the NHANES-3 (1988-1994) survey with mortality follow-up through December 31, 2006. Participants included 5153 subjects, 40 to 74 years of age with fasting glucose ≥70 mg/dL, without diabetes by history or laboratory testing. Receiver-operating-curve analysis compared fasting C-peptide against known insulin resistance measures such as fasting plasma glucose, serum insulin, HOMA-IR, quantitative-insulin-sensitivity-check-index, and metabolic syndrome for the prediction of cardiovascular and overall death. Subjects were then stratified by quartiles of C-peptide levels. Cox proportional-hazards modeling compared hazards of cardiovascular and overall death amongst C-peptide quartiles and adjusted for potential confounders of cardiovascular and diabetes risk. Fasting serum C-peptide levels predicted cardiovascular and overall death better than other studied measures (AUC=0.62 and 0.60 respectively vs the rest, with AUC≤0.58 and ≤0.57 respectively, P<0.001). When compared with the lowest C-peptide quartile, subjects in the highest quartile had significantly higher adjusted hazard ratios (HR) of cardiovascular death (HR=1.60, 95%CI 1.07 to 2.39) and overall mortality (HR=1.72, 95%CI 1.34 to 2.21) after controlling for confounders.
C-peptide levels significantly related to hazards of cardiovascular and overall death in nondiabetic adults and was a better predictor of these outcomes than serum insulin and/or glucose derived measures.
Background:
The effects of bariatric surgery (BS) in metabolically healthy morbidly obese (MO) subjects are not well established. Against this background, we characterized the metabolic and inflammatory profiles of MO subjects with insulin sensitivity (IS) in the normal range, and evaluated the changes on these parameters following BS in this population.
Methods:
We conducted a retrospective analysis of prospectively collected data in MO women undergoing BS between 2006 and 2010. Anthropometric, metabolic comorbidities, and inflammatory markers were compared at baseline and 12 months after BS, between 52 women (10.4%) presenting with a HOMA-IR < 2.94 (80th percentile reference population) (IS-MO group) and an age- and BMI-matched group of women (n = 52) with HOMA-IR > 2.94.
Results:
The IS-MO women presented a more favorable metabolic and inflammatory profile as compared to the IR-MO group. However, an enlarged waist circumference (WC), a high-sensitivity C-reactive protein (hs-CRP) > 3 mg/dL, and metabolic syndrome (MS) were present in 100%, 90%, and 51.9% of the IS-MO group at baseline. At 12 months after surgery, all the MS components and hs-CRP improved in IS-MO subjects (p < 0.01). The prevalence of the MS in the IS-MO group significantly decreased (11%, p < 0.05) despite WC and hs-CRP being abnormal respectively in 53.3% and 20.0% of women in this group.
Conclusions:
In MO women, an IS in the normal range is associated with a limited protection from metabolic co-morbidities. Nonetheless, BS results in the amelioration of the altered metabolic and inflammatory profiles also in this group of subjects.
In this “clinical” contribution to the Bench to Clinic Symposia, we will show data to support the hypothesis that fasting hyperinsulinemia is the initial underlying cause of type 2 diabetes mellitus (T2DM) and that the remission of the disease following bariatric surgery may be due to the correction of hyperinsulinemia. The intent of this article is to elicit critical thinking about the pathophysiology of T2DM in view of the effects of surgery and to open debate. If our hypothesis is correct, then more research resources should be focused on the cause(s) of fasting hyperinsulinemia and the therapies that may correct it.
The study of diabetes has always focused on glucose. Whether the diagnosis was made by the attraction of flies to urine as described in ancient India in 1552 BC (1), the sweet taste of the urine noted by Shushruta in 400 BC (2), or our current dependence on fasting blood glucose levels, HbA1c, and glucose tolerance curves, the severity of the disease is still measured by the level of hyperglycemia.
Similarly, our therapeutic directions also aim, almost exclusively, to reverse the hyperglycemia. In 1921 when Banting and Best reported that a pancreatic extract reversed the soaring glucose levels following a pancreatectomy in a dog, the use of insulin spread rapidly to children and adults alike. By the time Sir Harold Percival Himsworth noted, in 1936, that there were at least two types of diabetes (3), the objectives of T2DM treatment were already set; goals that still continue today. Even though type 1 diabetes mellitus (T1DM) and T2DM are virtually two opposite diseases, i.e., a total lack of insulin production versus abnormally high levels, the therapeutic goals for both entities continue to be the same: lower glucose levels by 1 ) giving insulin, 2 ) increasing insulin production, and/or 3 …
Objectives To determine the point prevalences of metabolic syndrome (MetS) and its components among healthy weight, overweight, and obese inner-city public high school students, to compare the prevalences of MetS when using 2 different definitions (one with the impaired fasting glucose [IFG] level and the other with a homeostasis model assessment of insulin resistance [HOMA-IR] of 3.99 or higher to define the glucose regulation component), and to compare the degree to which HOMA-IR and fasting glucose level are associated with the other MetS components.
Design Cross-sectional analysis.
Setting Two New York City public high schools, from April 2008 through August 2011.
Participants Convenience sample of 1185 high school youth, comprising predominantly Hispanic and African American students from low-income households, participating in The Banishing Obesity and Diabetes in Youth Project, a medical screening and education program.
Main Outcome Measures Prevalences of the following individual MetS components: IFG threshold, HOMA-IR, hypertension, central adiposity, hypertriglyceridemia, and low high-density lipoprotein cholesterol. Rates of MetSIFG and MetSHOMA-IR were also assessed.
Results MetSIFG and MetSHOMA-IR point prevalences were both 0.3% in the healthy weight group; they were 2.6% and 5.9%, respectively, in the overweight group and were 22.9% and 35.1%, respectively, in the obese group (P < .05 for both). An IFG threshold of 100 mg/dL or higher was found in 1.0% of participants, whereas a HOMA-IR of 3.99 or higher was found in 19.5% of participants.
Conclusions An elevated HOMA-IR is much more sensitive than an IFG threshold in identifying adolescents with metabolic dysregulation. Using a HOMA-IR threshold of 3.99 identifies more youth with MetS than using an IFG threshold of 100 mg/dL. In addition to increasing the sensitivity of MetS detection, HOMA-IR has a much higher association with the other MetS components than the IFG threshold and may better reflect a unified underlying pathologic process useful to identify youth at risk for disease.
OBJECTIVE
Sleep disorders and subjective sleep complaints have been associated with increased risk of type 2 diabetes. The evidence with respect to insulin resistance (IR) and insulin secretion in individuals without type 2 diabetes has been scarce and elusive. We examined if subjective sleep complaints and their co-occurrence were associated with IR and insulin secretion in adult women and men without diabetes.
RESEARCH DESIGN AND METHODS
Women (n = 442) and men (n = 354) 18–75 years of age without type 2 diabetes underwent an oral glucose tolerance test (OGTT), with insulin and glucose measured at fasting and at 30 and 120 min. Complaints related to sleep apnea, insomnia, and daytime sleepiness were self-rated with the Basic Nordic Sleep Questionnaire.
RESULTS
In comparison with individuals with no or minor sleep complaints, those with more frequent complaints of sleep apnea, insomnia, and daytime sleepiness were more insulin resistant, as evidenced by higher fasting insulin concentrations and insulin and glucose responses to OGTT, and more frequently had high homeostasis model assessment of IR and low insulin sensitivity index values. The likelihood of being insulin resistant increased significantly and linearly according to the accumulation of co-occurring sleep complaints. These associations changed only a little when adjusted for mediating and confounding factors and for depressive symptoms. Sleep complaints were not associated with indices of deficiency in insulin secretion.
CONCLUSIONS
Subjective sleep complaints were associated with IR. The likelihood of being insulin resistant increased according to accumulation of co-occurring sleep complaints. Sleep complaints were not associated with deficiency in insulin secretion.
Diabetes is associated with many forms of cancer. Recent evidence has suggested that some treatments for diabetes are associated with an increased cancer risk. Less is known about the association between endogenous insulin in the prediabetes state and cancer risk.
We investigated cumulative cancer incidence and cancer incidence density over 29 years, according to basal insulin, in a cohort of 1,695 nondiabetic men and women of four ethnic origins, aged 51.8 ± 8.0 years at baseline. Total mortality among the 317 subjects (18.7%) who developed cancer at least 2 years after baseline was assessed.
In a Cox proportional hazards model, the all-site hazard ratio of cancer incidence comparing the highest insulin quartile with the other three quartiles was 1.09 (95% CI 0.85-1.40), adjusted for age, sex, and ethnicity. BMI, smoking, and fasting blood glucose were not statistically significant in this model. Basal insulin level was not significantly associated with cancer of specific sites (breast, prostate, colon/rectum, or bladder). Fasting insulin in the upper quartile conferred a 37% increased risk for total mortality among cancer patients, adjusting for age, sex, and ethnic origin (95% CI 0.94-2.00, P = 0.097) compared with that of the lower quartiles. Male sex, older age, and North African origins were associated with a greater risk of mortality during follow-up time.
This long-term cohort study may suggest a role for basal elevated insulin levels, mainly as a negative predictor in cancer prognosis.
Increased exposure to endogenous estrogen and/or insulin may partly explain the relationship of obesity, physical inactivity, and alcohol consumption and postmenopausal breast cancer. However, these potential mediating effects have not been formally quantified in a survival analysis setting.
We combined data from two case-cohort studies based in the Women's Health Initiative-Observational Study with serum estradiol levels, one of which also had insulin levels. A total of 1,601 women (601 cases) aged 50 to 79 years who were not using hormone therapy at enrollment were included. Mediating effects were estimated by applying a new method based on the additive hazard model.
A five-unit increase in body mass index (BMI) was associated with 50.0 [95% confidence interval (CI), 23.2-76.6] extra cases per 100,000 women at-risk per year. Of these, 23.8% (95% CI, 2.9-68.4) could be attributed to estradiol and 65.8% (95% CI, 13.6-273.3) through insulin pathways. The mediating effect of estradiol was greater (48.8%; 95% CI, 18.8-161.1) for BMI when restricted to estrogen receptor positive (ER(+)) cases. Consuming 7+ drinks/wk compared with abstinence was associated with 164.9 (95% CI, 45.8-284.9) breast cancer cases per 100,000, but no significant contribution from estradiol was found. The effect of alcohol on breast cancer was restricted to ER(+) breast cancers.
The relation of BMI with breast cancer was partly mediated through estradiol and, to a greater extent, through insulin.
The findings provide support for evaluation of interventions to lower insulin and estrogen levels in overweight and obese postmenopausal women to reduce breast cancer risk.
Background:
Although migraine headache (MH) is more severe in the obese, the risk of developing MH in the obese population is controversial. The effect of surgical weight loss on morbidly obese patients with MH provides a unique opportunity to evaluate this potential association.
Methods:
We analyzed the data from 702 morbidly obese patients who underwent Roux-en-Y gastric bypass (RYGB) from 2000 to 2009. We identified patients with physician-diagnosed MH taking antimigraine medication.
Results:
The data are presented as the mean ± SEM, with the range in parentheses. Of the 102 patients with preoperative MH, 21 were excluded because they had <12-month follow-up data and 81 were followed up for 38.6 ± 3 months (range 12-123). Of the 81 patients, 90% were women. Their body mass index was 48 ± 1 kg/m(2) (range 37-85), and their age was 40 ± 1 years (range 18-62). After surgical weight loss, clinical improvement in MH was seen in 89% of patients within 5.6 ± .9 months (range 1-36; P < .01, chi-square test), with 57 reporting total resolution and 15 reporting partial resolution (9 experienced no change). Using logistic regression analysis, we showed that the improvement in MH after RYGB was independent of the improvement in migraine-associated co-morbidities, such as sleep apnea, menstrual dysfunction, depression, and anxiety. We also compared patients who developed MH after obesity onset with those who had MH before obesity. The MH after obesity onset group included 51 patients, of whom 48 showed clinical improvement (41 complete, 7 partial, and 3 no improvement). The MH before obesity group included 24 patients, of whom 18 showed clinical improvement (11 complete, 7 partial, and 6 no improvement). The MH after obesity group showed a greater rate of complete resolution of MH after RYGB than did the MH before obesity group (P < .01; chi-square test).
Conclusions:
Weight loss after RYGB substantially resolves MH, especially when obesity onset precedes MH onset. It remains to be determined whether RYGB-induced endocrine alterations or a reduction in adipokine burden contribute to migraine improvement.
Abdominal adiposity and obesity influence the association of polycystic ovary syndrome (PCOS) with insulin resistance and diabetes. We aimed to characterize the intermediate metabolism phenotypes associated with PCOS and obesity.
We applied a nontargeted GC-MS metabolomic approach to plasma samples from 36 patients with PCOS and 39 control women without androgen excess, matched for age, body mass index, and frequency of obesity.
Patients with PCOS were hyperinsulinemic and insulin resistant compared with the controls. The increase in plasma long-chain fatty acids, such as linoleic and oleic acid, and glycerol in the obese patients with PCOS suggests increased lipolysis, possibly secondary to impaired insulin action at adipose tissue. Conversely, nonobese patients with PCOS showed a metabolic profile consisting of suppression of lipolysis and increased glucose utilization (increased lactic acid concentrations) in peripheral tissues, and PCOS patients as a whole showed decreased 2-ketoisocaproic and alanine concentrations, suggesting utilization of branched-chain amino acids for protein synthesis and not for gluconeogenesis. These metabolic processes required effective insulin signaling; therefore, insulin resistance was not universal in all tissues of these women, and different mechanisms possibly contributed to their hyperinsulinemia. PCOS was also associated with decreased α-tocopherol and cholesterol concentrations irrespective of obesity.
Substantial metabolic heterogeneity, strongly influenced by obesity, underlies PCOS. The possibility that hyperinsulinemia may occur in the absence of universal insulin resistance in nonobese women with PCOS should be considered when designing diagnostic and therapeutic strategies for the management of this prevalent disorder.
Polycystic ovary syndrome (PCOS) is a common cause of infertility, especially in the morbidly obese. We evaluated the long-term effects of Roux-en-Y gastric bypass on PCOS and infertility.
A total of 566 morbidly obese women underwent Roux-en-Y gastric bypass from 2000 to 2009. A total of 31 patients (5.5%) had a history of PCOS. Of the 31 patients, 6 were postmenopausal and 5 lost to follow-up and were excluded. Telephone interviews were conducted with the 20 eligible patients.
The mean age and body mass index was 32 ± 5.8 years (range 22-42) and 52.8 ± 9.08 kg/m(2) (range 37-76) before surgery. All 20 patients had ≥ 2 of 3 diagnostic criteria for PCOS, including clinical or biochemical evidence of hyperandrogenism, anovulation, or polycystic ovaries. Of these, 85% had oligomenorrhea, 70% had hirsutism, and 45% had type 2 diabetes mellitus with medication. Before surgery, 8 patients conceived with or without hormonal treatment, 2 did not desire pregnancy, and 10 did not conceive. The mean follow-up was 46.7 months. After surgical weight loss, menstruation was corrected in 82%, hirsutism had resolved in 29%, and 77.8% of those with diabetes had complete remission. Of the 10 patients who did not conceive before surgery, 4 no longer desired pregnancy, and the remaining 6 patients had become pregnant within 3 years of surgery-5 without any hormonal treatment and 1 with in utero insemination.
Surgical weight loss after Roux-en-Y gastric bypass achieves excellent amelioration of PCOS manifestations and the postoperative conception rate in infertile PCOS subjects desiring pregnancy was 100%.
Metabolic syndrome (MetS) is a complex disorder defined by a cluster of interconnected factors that increase the risk of cardiovascular atherosclerotic diseases and diabetes mellitus type 2. Currently, several different definitions of MetS exist, causing substantial confusion as to whether they identify the same individuals or represent a surrogate of risk factors. Recently, a number of other factors besides those traditionally used to define MetS that are also linked to the syndrome have been identified. In this review, we critically consider existing definitions and evolving information, and conclude that there is still a need to develop uniform criteria to define MetS, so as to enable comparisons between different studies and to better identify patients at risk. As the application of the MetS model has not been fully validated in children and adolescents as yet, and because of its alarmingly increasing prevalence in this population, we suggest that diagnosis, prevention and treatment in this age group should better focus on established risk factors rather than the diagnosis of MetS.
To determine whether patients with prediabetes can be accurately and easily identified in clinical settings using a predictive clinical and laboratory model.
This retrospective study examined demographic and laboratory data from patients who had undergone 2-hour glucose testing for suspected prediabetes or diabetes between 2000 and 2004. Patients who met the diagnostic criteria for diabetes mellitus were excluded. Prediabetes was defined as a fasting glucose concentration > or = 100 mg/dL and < or = 125 mg/dL or a 2-hour postprandial glucose concentration > or = 140 mg/dL and < 200 mg/dL. Multivariate logistic regression was conducted to identify calculated or measured clinical and laboratory attributes that predict the presence of prediabetes, including fasting insulin quartiles, homeostasis model assessment of insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index.
Of 965 patients, 287 (29.7%) had prediabetes. The study population primarily consisted of white, obese, female patients. A multivariate model revealed that compared with the referent lowest quartile of fasting insulin (mu = 4.9 [+/-SD] +/-1.2 microIU/mL), subsequent insulin quartiles increased the likelihood of identifying prediabetes (quartile 2: mu = 8.0 +/-0.8 microIU/mL, odds ratio [OR] = 2.076, confidence interval [CI] = 1.241-3.273; quartile 3: mu = 12.2 +/-1.7 microIU/mL, OR = 3.151, CI = 1.981-5.015; quartile 4: mu = 25.9 +/-12.4 microIU/mL, OR = 5.035, CI = 3.122-8.122). Older age and increased diastolic blood pressure also contributed modestly to this model. Further analysis using the area under the curve revealed that at a fasting insulin level > 9.0 microIU/mL, prediabetes would be correctly identified in 80% of affected patients. A second model revealed that increased HOMA-IR index (OR = 1.303, CI = 1.205-1.410) and older age (OR = 1.037, CI = 1.024-1.05) predicted prediabetes.
The most robust model, which used fasting insulin levels, may provide the most utility as a clinical tool because the highest quartiles suggest significantly greater likelihood of identifying prediabetes.
Polycystic Ovary Syndrome (PCOS) was originally described as a syndrome of amenorrhea, hirsutism and obesity associated with enlarged polycystic ovaries. There is increased androgen level and in some, insulin resistance (IR). Etiological relationship of androgen excess and IR in PCOS is not established. Influence of obesity on PCOS is controversial. This study was designed to see the androgen and insulin status in PCOS among obese and non-obese patients. It was a case-control study. Of total 80 study subjects, 60 primary infertile women suffering from PCOS were cases (30 obese and 30 non-obese). Age and BMI matched 20 healthy women having normal menstrual cycles were controls (10 obese and 10 non-obese). Age range of all were 20-40 years. Fasting plasma glucose, fasting S. Insulin and free Testosterone were measured. Insulin resistance (IR) was assessed by fasting glucose to insulin ratio ( 0.5, in each) were observed. Significant difference of fasting S. Insulin and testosterone were observed between PCOS (both obese and non-obese) and respective controls (P 0.05). There was no significant difference of S.Testosterone between obese and non-obese PCOS(P>0.05). There was also no significant difference of IR between obese and non-obese PCOS, but the ratio was 0.05). Increased S.Insulin and Testosterone was seen in PCOS irrespective of BMI. Further studies with larger sample size is recommended to assess etiological relationship between insulin and testosterone in PCOS. DOI: http://dx.doi.org/10.3329/bjmb.v3i1.13801 Bangladesh J Med Biochem 2010; 3(1): 11-15
OBJECTIVE To determine whether insulin resistance or insulin deficiency is primary in the pathogenesis of type II diabetes. DESIGN Cohort analytic study of persons with normal glucose tolerance but with a high risk for developing type II diabetes (average follow-up time, 13 years). SETTING Outpatients had an intravenous glucose tolerance test and were contacted periodically to ascertain diagnoses of diabetes. PARTICIPANTS One hundred and fifty-five normal offspring, ranging in age from 16 to 60 years, of two parents with type II diabetes and 186 normal control subjects in the same age range who had no family history of diabetes. MEASUREMENTS AND MAIN RESULTS Two phenotypic characteristics distinguished the offspring of diabetic parents from control subjects. They had slower glucose removal rates (Kg) (P less than 0.01) and higher insulin levels (fasting and during the second phase of insulin response to intravenous glucose; P less than 0.0001) than did control subjects, even after adjustment for differences in obesity. Sixteen percent of the offspring developed type II diabetes. Mean Kg at baseline was 1.7%/min among offspring who subsequently developed diabetes, 2.2%/min among offspring who remained nondiabetic, and 2.3%/min among control subjects. Corresponding means for first-phase insulin were 498, 354, and 373 pM, respectively, whereas second-phase insulin means were 329, 117, and 87 pM, respectively. In multivariate analysis, low Kg and high serum insulin levels independently increased the risk for developing diabetes among the offspring of diabetic parents. CONCLUSIONS One to two decades before type II diabetes is diagnosed, reduced glucose clearance is already present. This reduced clearance is accompanied by compensatory hyperinsulinemia, not hypoinsulinemia, suggesting that the primary defect is in peripheral tissue response to insulin and glucose, not in the pancreatic beta cell.
It is unknown whether hyperinsulinemia plays a role in the pathogenesis of polycystic ovary syndrome (PCOS) in normal weight or thin women. Evidence indicates that these women are insulin resistant and hyperinsulinemic, and this study was conducted to test the hypothesis that hyperinsulinemia stimulates ovarian cytochrome P450c17 alpha activity in nonobese women with PCOS, thereby increasing serum androgen concentrations. We assessed ovarian P450c17 alpha activity (by measuring the response of 17 alpha-hydroxyprogesterone to a GnRH agonist), fasting serum steroids, and oral glucose tolerance before and after oral administration of either metformin (500 mg) or placebo three times daily for 4-6 weeks in 31 nonobese women with PCOS. In the 19 women given metformin, the mean (+/-SE) area under the serum insulin curve after oral glucose administration decreased from 44 +/- 5 to 24 +/- 3 nmol/L.min (P = 0.003). Basal serum 17 alpha-hydroxyprogesterone decreased from 3.4 +/- 0.3 to 2.5 +/- 0.4 nmol/L (P = 0.05), and GnRH-stimulated peak serum 17 alpha-hydroxyprogesterone decreased from 12.2 +/- 1.6 to 7.5 +/- 0.7 nmol/L (P = 0.005). Serum 17 alpha-hydroxyprogesterone values did not change in the placebo group. In the metformin group, serum free testosterone decreased by 70% from 18.2 +/- 3.1 to 5.5 +/- 0.7 pmol/L (P < 0.001), and serum sex hormone-binding globulin increased from 84 +/- 6 to 134 +/- 15 nmol/L (P = 0.002). None of these values changed in the placebo group. These findings suggest that hyperinsulinemia stimulates ovarian P450c17 alpha activity in nonobese women with PCOS. They also indicate that decreasing serum insulin with metformin reduces ovarian cytochrome P450c17 alpha activity and ameliorates the hyperandrogenism of these women.
Context.— Epidemiological studies have established a relationship between cholesterol
and low-density lipoprotein cholesterol (LDL-C) concentrations and the risk
of ischemic heart disease (IHD), but up to half of patients with IHD may have
cholesterol levels in the normal range.
Objective.— To assess the ability to predict the risk of IHD using a cluster of
nontraditional metabolic risk factors that includes elevated fasting insulin
and apolipoprotein B levels as well as small, dense LDL particles.
Design.— Nested case-control study.
Setting.— Cases and controls were identified from the population-based cohort
of the Québec Cardiovascular Study, a prospective study conducted in
men free of IHD in 1985 and followed up for 5 years.
Participants.— Incident IHD cases were matched with controls selected from among the
sample of men who remained IHD free during follow-up. Matching variables were
age, smoking habits, body mass index, and alcohol consumption. The sample
included 85 complete pairs of nondiabetic IHD cases and controls.
Main Outcome Measures.— Ability of fasting insulin level, apolipoprotein B level, and LDL particle
diameter to predict IHD events, defined as angina, coronary insufficiency,
nonfatal myocardial infarction, and coronary death.
Results.— The risk of IHD was significantly increased in men who had elevated
fasting plasma insulin and apolipoprotein B levels and small, dense LDL particles,
compared with men who had normal levels for 2 of these 3 risk factors (odds
ratio [OR], 5.9; 95% confidence interval [CI], 2.3-15.4). Multivariate adjustment
for LDL-C, triglycerides, and high-density lipoprotein cholesterol (HDL-C)
did not attenuate the relationship between the cluster of nontraditional risk
factors and IHD (OR, 5.2; 95% CI, 1.7-15.7). On the other hand, the risk of
IHD in men having a combination of elevated LDL-C and triglyceride levels
and reduced HDL-C levels was no longer significant (OR, 1.4; 95% CI, 0.5-3.5)
after multivariate adjustment for fasting plasma insulin level, apolipoprotein
B level, and LDL particle size.
Conclusion.— Results from this prospective study suggest that the measurement of
fasting plasma insulin level, apolipoprotein B level, and LDL particle size
may provide further information on the risk of IHD compared with the information
provided by conventional lipid variables.
Recent international cancer prevention guidelines recommend weight loss, where appropriate, for the purpose of cancer risk reduction. However, limited research associates voluntary weight loss to subsequent cancer incidence because of the difficulty of achieving long-term weight loss maintenance among large participant groups. Bariatric surgery has demonstrated long-term sustained weight loss, and as a result, patients after bariatric surgery represent an ideal population to explore the relationship between long-term, voluntary weight loss and cancer incidence. This paper briefly reviews cancers that have shown to be associated with overweight and obesity and looks at studies that demonstrate reduced total mortality after bariatric surgery. Reduced cancer mortality and incidence as well as reduced cancer-related physician visits after bariatric surgery are presented. Study limitations and future research questions related to cancer and bariatric surgery are briefly discussed.
The National Cholesterol Education Program’s Adult Treatment Panel III report (ATP III)1 identified the metabolic syndrome as a multiplex risk factor for cardiovascular disease (CVD) that is deserving of more clinical attention. The cardiovascular community has responded with heightened awareness and interest. ATP III criteria for metabolic syndrome differ somewhat from those of other organizations. Consequently, the National Heart, Lung, and Blood Institute, in collaboration with the American Heart Association, convened a conference to examine scientific issues related to definition of the metabolic syndrome. The scientific evidence related to definition was reviewed and considered from several perspectives: (1) major clinical outcomes, (2) metabolic components, (3) pathogenesis, (4) clinical criteria for diagnosis, (5) risk for clinical outcomes, and (6) therapeutic interventions.
ATP III viewed CVD as the primary clinical outcome of metabolic syndrome. Most individuals who develop CVD have multiple risk factors. In 1988, Reaven2 noted that several risk factors (eg, dyslipidemia, hypertension, hyperglycemia) commonly cluster together. This clustering he called Syndrome X , and he recognized it as a multiplex risk factor for CVD. Reaven and subsequently others postulated that insulin resistance underlies Syndrome X (hence the commonly used term insulin resistance syndrome ). Other researchers use the term metabolic syndrome for this clustering of metabolic risk factors. ATP III used this alternative term. It avoids the implication that insulin resistance is the primary or only cause of associated risk factors. Although ATP III identified CVD as the primary clinical outcome of the metabolic syndrome, most people with this syndrome have insulin resistance, which confers increased risk for type 2 diabetes. When diabetes becomes clinically apparent, CVD risk rises sharply. Beyond CVD and type 2 diabetes, individuals with metabolic syndrome seemingly are susceptible to other conditions, notably polycystic ovary syndrome, fatty liver, cholesterol gallstones, asthma, sleep disturbances, and some …
This study examined the relationship of fasting serum glucose, insulin, C-peptide, glycosylated hemoglobin A (HbA1c), and Homeostasis Model Assessment (HOMA)-insulin resistance to risk of chronic kidney disease (CKD) among 6453 persons without diabetes (fasting glucose <126 mg/dl and not taking diabetes medication) who participated in the Third National Health and Nutrition Examination Survey and were aged 20 yr or older. CKD was defined as an estimated GFR <60 ml/min per 1.73 m². The prevalence of CKD was significantly and progressively higher with increasing levels of serum insulin, C-peptide, HbA1c, and HOMA-insulin resistance. After adjustment for potential confounding variables, the odds ratio of CKD for the highest compared with the lowest quartile was 4.03 (95% confidence interval [CI], 1.81 to 8.95; P = 0.001), 11.4 (95% CI, 4.07 to 32.1; P < 0.001), 2.67 (95% CI, 1.31 to 5.46; P = 0.002), and 2.65 (95% CI, 1.25 to 5.62; P = 0.008) for serum insulin, C-peptide, HbA1c levels, and HOMA-insulin resistance, respectively. For a one SD higher level of serum insulin (7.14 μU/ml), C-peptide (0.45 Δmol/ml), HbA1c (0.52%), and HOMA-insulin resistance (1.93), the odds ratio (95% CI) of CKD was 1.35 (1.16 to 1.57), 2.78 (2.25 to 3.42), 1.69 (1.28 to 2.23), and 1.30 (1.13 to 1.50), respectively. These findings combined with knowledge from previous studies suggest that the insulin resistance and concomitant hyperinsulinemia are presented in CKD patients without clinical diabetes. Further studies into the causality between insulin resistance and CKD are warranted. E-mail address: jhe@tulane.edu
The aim of this study was to investigate whether insulin clearance is independently associated with carotid artery intima-media thickness (IMT), a well-recognized index of vascular damage.
361 Non-diabetic Caucasian subjects were subjected to euglycemic hyperinsulinemic clamp to assess insulin sensitivity, and insulin clearance. IMT of the common carotid was measured by ultrasonography.
Among the study group, 270 subjects had normal glucose tolerance, 33 had impaired fasting glucose, and 58 had impaired glucose tolerance. Univariate correlations showed that age, BMI, waist, blood pressure, triglycerides, fasting and 2-h post-load glucose and insulin levels were positively correlated with carotid IMT whereas HDL, insulin clearance, and insulin-stimulated glucose disposal were negatively correlated with IMT. A multivariate regression analysis in a model including, in addition to insulin clearance, age, gender, BMI, waist, blood pressure, triglycerides, HDL, fasting and 2-h post-load glucose, insulin-stimulated glucose disposal, fasting and 2-h post-load insulin showed that the traits independently associated with carotid IMT were BMI (β = 0.42, P < 0.0001), insulin clearance (β = -0.29, P < 0.0001), age (β = 0.19, P < 0.0001), waist (β = 0.18, P = 0.01), diastolic blood pressure (β = 0.17, P = 0.01), and 2-h post-load glucose (β = 0.12, P = 0.03). These factors explained 26% of the variance in carotid IMT. Subjects in the lowest tertile of insulin clearance had a 4.06-fold higher odds of having vascular damage (IMT > 0.9 mm) as compared with those in the highest tertile (OR 4.06, 95%CI 1.15-13.24).
Insulin clearance is independently associated with carotid IMT in adult non-diabetic subjects. Individuals with lower levels of insulin clearance have a higher odds of vascular damage.
As well as the pronounced effect on body mass index (BMI), bariatric surgery is increasingly recognized as being associated with improvements in morbidity and mortality in a range of conditions, from airways disease to cancer. In metabolic disease, the impact of bariatric surgery is particularly obvious with marked improvements in glycemic control in patients with type 2 diabetes mellitus, to the point of effecting diabetes remission in some. Hypertension and dyslipidemia, key components of the metabolic syndrome, also respond to bariatric surgery. Despite the increasing evidence of benefit in metabolic disease, the major national guidelines for selecting candidates for bariatric surgery retain their emphasis on body weight. In these guidelines, a BMI ≥35 kg/m(2) is needed to indicate surgery, even in those with profound metabolic disturbance. The recent International Diabetes Federation guidelines have identified the need to reorientate our focus from BMI to metabolic disease. In this review, we examine the developing indications for the use of bariatric surgery in metabolic disease. We will focus on type 2 diabetes mellitus and the metabolic syndrome. Within this, we will outline the data for using bariatric surgery as metabolic surgery, including those with a BMI <35 kg/m(2).
Introduction:
To evaluate the association between abdominal and gynoid fat, glucose and lipid metabolism markers, and serum androgens in women with polycystic ovary syndrome (PCOS).
Material and methods:
Anthropometric measurements were performed in 40 women with PCOS aged 19-49 years with body mass index (BMI) 18.7-53.8 kg/m2. Fasting serum glucose, lipids, insulin, leptin, LH, FSH, oestradiol, androgens, SHGB and TSH were estimated. Body composition was measured by DEXA scan.
Results:
Four women (10%) were overweight, and 23 (57.5%) were obese. All subjects were hyperandrogenic (in 33 serum androgen levels were increased), and 16 of them were insulin resistant. All of the obese subjects had the abdominal type of obesity. Body weight, BMI, fat mass, fat mass of the trunk, abdominal and gynoidal fat mass correlated with serum triglyceride, glucose and insulin levels, and with HOMA index and blood pressure. Free androgen index (FAI) correlated with body weight (r = 0.43, p 〈 0.01), and BMI (r = 0.46, p 〈 0.05).
Conclusions:
Using the DEXA method, we demonstrated abdominal type of obesity in all our obese subjects. There were positive significant correlations between fatness, lipids and glucose metabolism indices and blood pressure. Direct positive correlations between free androgen index, body weight and BMI were found.
Insulin resistance characterized by hyperinsulinemia is associated with increased risk of atherosclerosis. Acyl-coenzyme A: cholesterol acyltransferase (ACAT) is an intracellular enzyme involved in cellular cholesterol homeostasis and in atherosclerotic foam cell formation. To investigate the relationship between hyperinsulinemia and atherosclerosis, we investigated whether insulin induced ACAT1 gene expression and found that insulin up-regulated ACAT1 mRNA, protein and enzyme activity in human THP-1 cells and THP-1-derived macrophages. Moreover, luciferase assays revealed that insulin enhanced the ACAT1 gene P1 promoter activity but not the P7 promoter. To explore the molecular mechanisms involved, deletion analysis of the human ACAT1 P1 promoter revealed an insulin response element (IRE) upstream of the P1 promoter (from -603 to -580), EMSA experiments demonstrated that CCAAT/enhancer binding protein α(C/EBPα) bound to the P1 promoter IRE. Insulin-induced ACAT1 upregulation was blocked by the presence of PD98059 (an inhibitor of extracellular signal-regulated kinase, ERK) and SB203580 (an inhibitor of p38 mitogen-activated protein kinase, p38MAPK) but not by Wortmannin (an inhibitor of phosphatidylinositol 3-kinase, PI3K) or U73122 (an inhibitor of phospholipase C-γ, PLCγ). These studies demonstrate that insulin promotes ACAT1 gene expression at the transcriptional level. The molecular mechanism of insulin action is mediated via interaction of the functional IRE upstream of the ACAT1 P1 promoter with C/EBPα and is MAPK-dependent. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.
The presence of insulin resistance is increasingly recognized as an important contributor to early stage kidney disease independent of the contribution of diabetes. Important in this relationship is the strong correlation between hyperinsulinemia and low levels of albuminuria (e.g. microalbuminuria). Recent work highlight mechanisms for glomerular/tubulointerstitial injury with excess insulin and emerging evidence identifies a unique role for insulin metabolic signaling and altered handling of salt reabsorption at the level of the proximal tubule. Evidence is also emerging for the role of insulin signaling in the glomerulus both epithelial and endothelial. Central to the mechanism of injury is inappropriate activation of the RAAS.
Background and aims:
This study aimed to investigate the association between baseline fasting insulin levels, changes in fasting insulin levels, and future development of hypertension in normotensive, non-diabetic, healthy adults.
Methods:
We analyzed data from 11,123 adults, aged 20-65years, who had no history of hypertension or diabetes mellitus at a 2004 medical examination in a health promotion program and had attended a repeat examination in 2008. Subjects were divided into four groups according to baseline quartiles of fasting insulin and dichotomized fasting insulin levels at baseline and after 4years: low-low, low-high, high-low, high-high. We also assessed whether the association differed between the younger (20-40years) and older subjects (41-65years).
Results:
In four years, 1142 subjects (10.3%) developed hypertension. The odds ratio (OR) for the development for hypertension increased as the quartiles of baseline fasting insulin levels and changes in fasting insulin levels increased from the first to the fourth quartile (OR 1.15, 1.35, and 1.95 vs. 1.07, 1.22, and 1.41, respectively), after adjusting for multiple factors. The OR for hypertension was 2.0-fold higher in the high-high group and 1.34-fold higher in the low-high group than in the low-low group. In comparing the results by age group, we found that these relationships were more prominent in younger subjects.
Conclusion:
High baseline and continuously increasing fasting insulin levels appeared to be independent determinants for the future development of hypertension during this 4-year follow-up study in normotensive, non-diabetic, healthy adults.
Insulin resistance and hyperinsulinemia are already present in patients with incipient renal disease. In uremic patients resistance to the action of insulin has been documented, but it is not known at what stage of renal disease it appears. We therefore examined 29 patients with IgA glomerulonephritis (IgAGN) and 21 patients with adult polycystic kidney disease (ADPKD) in different stages of renal failure, and in addition, healthy age-matched subjects. Insulin sensitivity and other variables of glucose metabolism were assessed using a frequent sampling intravenous glucose tolerance test (minimal-model technique). Glomerular filtration rate (GFR) was assessed in renal patients using the inulin-clearance technique. Mean insulin sensitivity index (SI), that is, insulin sensitivity, was significantly lower (P < 0.001) in all patients combined than in matched healthy subjects (N = 16; 14 males, mean age 42 3 years; mean SI 8.6 0.8 min-1 U/ml). The mean SI was not significantly different in patients with renal disease of immune (IgAGN) or non-immune (ADPKD) origin, and it was not correlated with GFR (r = 0.01, P < 0.52), intact PTH (r = -0.23, P < 0.11) or calcitriol concentration (r = -0.03, P < 0.82). Consequently, the mean SI was similar in renal patients with GFR within the normal range (N = 19; 17 males, mean age 41 2 years; mean GFR 119 5 ml/min/1.73 m2; mean SI 5.1 0.7 min-1 U/ml), in patients with mild to moderate renal failure (N = 16; 15 males, 46 3 years; 67 4 ml/min/1.73 m2; 5.1 0.7 min-1 U/ml) and in patients with advanced renal failure (N = 15; 13 males, 46 3 years; 25 2 ml/min/1.73 m2; 4.7 0.6 min-1 U/ml). Mean fasted plasma insulin concentration, the area under the curve for plasma insulin concentration (AUC) and total insulin delivery (TID) during the glucose tolerance test were significantly higher in patients than in healthy subjects, reflecting hyperinsulinemia in renal patients. Further, fasted plasma insulin concentration (r = -0.32, P < 0.009), AUC (r = -0.62, P < 0.0001) and TID (r = -0.34, P < 0.004) in patients were significantly correlated with insulin sensitivity (SI). The present data document that insulin resistance and concomitant hyperinsulinemia are present early in the course of renal disease, that is, even in patients with GFR within the normal range, irrespective of the type of renal disease. This observation may have potential implications with respect to the high cardiovascular morbidity and mortality in patients with renal disease.Keywords: ADPKD, insulin resistance, glucose metabolism, IgA glomerulonephritis, renal disease, uremia
In a preliminary report, we found an association between hyperinsulinemia in the basal (fasting) state and the development of diabetes.
The current analysis further explored the long term link between basal hyperinsulinemia and conversion to dysglycemia.
This is a prospective study with up to 24 years of follow-up of 515 normoglycemic individuals (mean age at follow up = 70.3 ± 7.0; range 58-94) of an Israeli cohort. Fasting glucose and insulin were measured, and dysglycemia was defined as fasting glucose > 100 mg/dL.
At the end of the follow-up period, almost half had progressed to dysglycemia. Male sex and elevated baseline levels of basal insulin, body mass index, blood glucose and blood pressure each favoured progression to dysglycemia over the subsequent two decades. A multivariate logistic regression model identified basal hyperinsulinemia as the strongest predictor for progression to dysglycemia (odds ratio = 1.79; 95% confidence interval 1.12-2.88), while controlling for ethnicity, blood pressure, fasting glucose, male sex, body mass index and age.
Basal hyperinsulinemia in normoglycemic adults constitutes an independent risk factor for metabolic deterioration to dysglycemia over adulthood, and may help to identify apparently healthy subjects at increased risk for diabetes. Copyright © 2012 John Wiley & Sons, Ltd.
The remission rates of type 2 diabetes mellitus (T2DM) after Roux-en-Y gastric bypass (RYGB) vary according to the glycosylated hemoglobin A1c (HbA1c), fasting blood glucose (FG), and medication status. Our objectives were to describe remission using the American Diabetes Association standards for defining normoglycemia and to identify the factors related to the preoperative severity of T2DM that predict remission to normoglycemia, independent of weight loss, after RYGB. The setting was an urban not-for-profit community hospital.
We performed a retrospective analysis of prospectively collected data from a cohort of 2275 patients who qualified for bariatric surgery (2001-2008). Five different models for defining remission (no diabetes medication and a FG <100 mg/dL; no diabetes medication and HbA1c <6.0; no diabetes medication and HbA1c <5.7%; no diabetes medication, FG <100 mg/dL, and HbA1c <6.0%; and no diabetes medication, FG <100 mg/dL, and HbA1c <5.7%) were compared in 505 obese patients with T2DM 14 months after RYGB. The secondary aims were to determine the effects of preoperative insulin therapy and the duration of known T2DM on remission.
Of the 505 patients, 43.2% achieved remission using the most stringent criteria (no diabetes medication, HbA1c <5.7%, and FG <100 mg/dL) compared with 59.4% using the most liberal definition (no diabetes medication and FG <100 mg/dL; P < .001). The remission rates were greater for patients not taking insulin preoperatively (53.8% versus 13.5%, P < .001) and for patients with a more recent preoperative T2DM diagnosis (8.9 versus 3.7 yr, P < .001).
Remission, defined at a threshold less than what would be expected to result in microvascular damage, was achieved in 43.2% of diabetic patients by 14 months after RYGB. A more recent diagnosis of T2DM and the absence of preoperative insulin therapy were significant predictors, regardless of how remission was defined, independent of the percentage of excess weight loss.
The prevalence of atherosclerotic cardiovascular disease is higher in patients with type 2 diabetes, a disorder characterized by hyperinsulinemia and insulin resistance. The role of hyperinsulinemia as an independent participant in the atherogenic process has been controversial. In the current study, we tested the effect of insulin and the insulin sensitizer, adiponectin, on human macrophage foam cell formation. We found that both insulin and adiponectin increased the expression of the type 2 scavenger receptor CD36 by approximately twofold and decreased the expression of the ATP-binding cassette transporter ABCA1 by >80%. In both cases regulation was post-transcriptional. As a consequence of these changes, we found that oxidized LDL (oxLDL) uptake was increased by 80% and cholesterol efflux to apolipoprotein A1 (apoA1) was decreased by ∼25%. This led to two- to threefold more cholesterol accumulation over a 16-h period. As reported previously in studies of murine systems, scavenger receptor-A (SR-A) expression on human macrophages was downregulated by insulin and adiponectin. Insulin and adiponectin did not affect oxLDL-induced secretion of monocyte attractant protein-1 (MCP-1) and interleukin-6 (IL-6). These studies suggest that hyperinsulinemia could promote macrophage foam cell formation and thus may contribute to atherosclerosis in patients with type 2 diabetes.
In vitro data show that insulin may enhance basal and LH-stimulated ovarian androgen secretion, particularly in theca cells from women with polycystic ovary syndrome (PCOS). However, in vivo studies gave inconsistent results.
The objective of the study was to assess whether hyperinsulinemia affects in vivo ovarian steroid secretion and steroid metabolism.
This was a controlled cross-sectional study, conducted in a tertiary care academic center.
Nine young PCOS women participated in the study.
Participants were submitted, in two separate days, to a GnRH agonist stimulation (buserelin 100 μg, s.c.), during a 17-h hyperinsulinemic (80 mU/m(2) · min) euglycemic clamp and, as a control, during saline infusion. Adrenal steroid secretion was suppressed by dexamethasone.
During both protocols, before and after GnRH agonist stimulation, serum insulin, gonadotropins, cortisol, progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, estradiol, and urinary androgen metabolites were measured.
Insulin increased from 25.1 ± 13.3 to 341.5 ± 102.6 mU/liter during the clamp, whereas it did not significantly change during saline infusion. Baseline steroids and gonadotropins were similar in the two protocols. During hyperinsulinemia, GnRH agonist-stimulated serum progesterone and androstenedione were significantly higher than during saline infusion, and 17-hydroxyprogesterone was of borderline significance. Moreover, 24 h after GnRH agonist stimulation, testosterone was higher after hyperinsulinemia. Serum gonadotropins and estradiol response did not differ between the protocols. Urinary androgen metabolites excretion significantly increased after GnRH agonist stimulation, but the increase was similar during insulin and saline infusions.
These in vivo data show that sustained hyperinsulinemia potentiates gonadotropin-stimulated ovarian androgen steroidogenesis. Insulin-induced increase in ovarian hormone secretion is not accompanied by an increased steroid metabolism.
Osteoarthritis is a common progressive disease leading to joint pain and severe disability. It is a complex multifactorial disease leading to damage of cartilage, deposition of subchondral bone matrix and release of pro-inflammatory cytokines. Obesity is an emerging epidemic and also an important risk factor for osteoarthritis. Weight loss has been shown to improve pain and function in hip and knee joints with osteoarthritis. Bariatric surgery currently is the only evidence-based approach to marked weight loss in obese individuals. However, there is currently limited literature to evaluate the role of bariatric surgery in hip and knee osteoarthritis. The objective of the present study was to systematically review the literature regarding the effectiveness of bariatric surgery in obese adult patients in improving large weight-bearing joint (hip and knee) osteoarthritis. Published English-language manuscripts were considered for review inclusion. A comprehensive search of electronic databases using broad search terms was completed. From a total of 400 articles, eight articles were identified. A total of six studies were included for qualitative analysis. A general trend was identified indicating improved hip and knee osteoarthritis following marked weight loss secondary to bariatric surgery. This systematic review demonstrates that bariatric surgery may benefit obese patients with hip or knee osteoarthritis. However, this review identifies the need for randomized controlled trials to clarify the role and indications for bariatric surgery.
Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in ∼25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the β-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration.Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulinstimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one. However, even if insulin resistance and hyperinsulinemia are not involved in the etiology of hypertension, it is likely that the increased risk of coronary artery disease (CAD) in patients with hypertension and the fact that this risk if not reduced with antihypertensive treatment are due to the clustering of risk factors for CAD, in addition to high blood pressure, associated with insulin resistance. These include hyperinsulinemia, IGT, increased plasma triglyceride concentration, and decreased high-density lipoprotein cholesterol concentration, all of which are associated with increased risk for CAD. It is likely that the same risk factors play a significant role in the genesis of CAD in the population as a whole. Based on these considerations the possibility is raised that resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of three major related diseases— NIDDM, hypertension, and CAD.
Recent international cancer prevention guidelines recommend weight loss, where appropriate, for the purpose of cancer risk
reduction. However, limited research associates voluntary weight loss to subsequent cancer incidence because of the difficulty
of achieving long-term weight loss maintenance among large participant groups. Bariatric surgery has demonstrated long-term
sustained weight loss, and as a result, patients after bariatric surgery represent an ideal population to explore the relationship
between long-term, voluntary weight loss and cancer incidence. This paper briefly reviews cancers that have shown to be associated
with overweight and obesity and looks at studies that demonstrate reduced total mortality after bariatric surgery. Reduced
cancer mortality and incidence as well as reduced cancer-related physician visits after bariatric surgery are presented. Study
limitations and future research questions related to cancer and bariatric surgery are briefly discussed.
Roux-en-Y gastric bypass (RYGB) has been shown to induce rapid and durable reversal of type 2 diabetes.
The aim of the study was to investigate a possible mechanism for the remission of type 2 diabetes after RYGB.
A cross-sectional, nonrandomized, controlled study was conducted. Surgery patients were studied before RYGB and 1 wk and 3 months after surgery.
This study was conducted at East Carolina University.
Subjects were recruited into three groups: 1) lean controls with no surgery [body mass index (BMI) < 25 kg/m²; n = 9], 2) severely obese type 2 diabetic patients (BMI > 35 kg/m²; n = 9), and 3) severely obese nondiabetic patients (BMI > 35 kg/m²; n = 9).
Intervention was RYGB.
One week after RYGB, diabetes was resolved despite continued insulin resistance (insulin sensitivity index was approximately 50% of lean controls) and reduced insulin secretion during an iv glucose tolerance test (acute insulin response to glucose was approximately 50% of lean controls). Fasting insulin decreased and was no different from lean control despite continued elevated glucose in the type 2 diabetic patients compared with lean.
After RYGB, fasting insulin decreases to levels like those of lean control subjects and diabetes is reversed (fasting blood glucose < 125 mg/dl). This leads us to propose that 1) exclusion of food from the foregut corrects hyperinsulinemia and 2) fasting insulin is dissociated from the influence of fasting glucose, insulin resistance, and BMI. The mechanisms for reversal of diabetes in the face of reduced insulin remain a paradox.
Increases in the prevalence of obesity and gastroesophageal reflux disease (GERD) have paralleled one another over the past decade, which suggests the possibility of a linkage between these two processes. In both instances, surgical therapy is recognized as the most effective treatment for severe, refractory disease. Current surgical therapies for severe obesity include (in descending frequency) Roux-en-Y gastric bypass, adjustable gastric banding, sleeve gastrectomy, and biliopancreatic diversion with duodenal switch, while fundoplication remains the mainstay for the treatment of severe GERD. In several large series, however, the outcomes and durability of fundoplication in the setting of severe obesity are not as good as those in patients who are not severely obese. As such, bariatric surgery has been suggested as a potential alternative treatment for these patients. This article reviews current concepts in the putative pathophysiological mechanisms by which obesity contributes to gastroesophageal reflux and their implications with regards to surgical therapy for GERD in the setting of severe obesity.
Increases in the prevalence of obesity and gastroesophageal reflux disease (GERD) have paralleled one another over the past decade, which suggests the possibility of a linkage between these two processes. In both instances, surgical therapy is recognized as the most effective treatment for severe, refractory disease. Current surgical therapies for severe obesity include (in descending frequency) Roux-en-Y gastric bypass, adjustable gastric banding, sleeve gastrectomy, and biliopancreatic diversion with duodenal switch, while fundoplication remains the mainstay for the treatment of severe GERD. In several large series, however, the outcomes and durability of fundoplication in the setting of severe obesity are not as good as those in patients who are not severely obese. As such, bariatric surgery has been suggested as a potential alternative treatment for these patients. This article reviews current concepts in the putative pathophysiological mechanisms by which obesity contributes to gastroesophageal reflux and their implications with regards to surgical therapy for GERD in the setting of severe obesity.
The purpose of this study was to investigate whether the presence of the NCEP-ATP III defined metabolic syndrome (MS) is associated with the future development of cardiovascular disease (CVD) and diabetes in Koreans.
The study subjects were recruited from among those who visited the Health Promotion Center at the Samsung Medical Center. 2435 subjects (1761 men and 674 women), 20 to 78 years of age, were enrolled and evaluated for the development of new onset CVD (coronary heart disease [CHD] and stroke) during a mean 8.7 years of follow-up.
The prevalence of the MS at baseline was 21.7% (382/1761) and 11.4% (77/674) in men and women respectively, and the MS was found to be associated with the risk for CVD in both men and women (OR, 1.98; 95% CI, 1.30-3.03 in men, 4.04; 95% CI, 1.78-9.14 in women). More specifically, the MS was associated with the risk for future CHD (OR, 3.68; 95% CI, 1.93-7.01) in men and stroke (OR, 3.96; 95% CI, 1.58-9.94) in women. However, no statistical differences were found between the HOMA-IR tertiles with regard to the risk for CVD. After controlling for fasting plasma glucose (FPG) levels, the predictive power of the MS for an increased risk for diabetes was dramatically decreased (OR, from 3.69 to 1.77) in men, and it no longer was a predictor in women.
The NCEP-defined MS was found to be associated with the risk for future CVD, i.e., CHD in men and stroke in women.
Excess body-mass index (BMI) has been associated with adverse outcomes in prostate cancer, and hyperinsulinaemia is a candidate mediator, but prospective data are sparse. We assessed the effect of prediagnostic BMI and plasma C-peptide concentration (reflecting insulin secretion) on prostate cancer-specific mortality after diagnosis.
This study involved men diagnosed with prostate cancer during the 24 years of follow-up in the Physicians' Health Study. BMI measurements were available at baseline in 1982 and eight years later in 1990 for 2546 men who developed prostate cancer. Baseline C-peptide concentration was available in 827 men. We used Cox proportional hazards regression models controlling for age, smoking, time between BMI measurement and prostate cancer diagnosis, and competing causes of death to assess the risk of prostate cancer-specific mortality according to BMI and C-peptide concentration.
Of the 2546 men diagnosed with prostate cancer during the follow-up period, 989 (38.8%) were overweight (BMI 25.0-29.9 kg/m(2)) and 87 (3.4%) were obese (BMI >/=30 kg/m(2)). 281 men (11%) died from prostate cancer during this follow-up period. Compared with men of a healthy weight (BMI <25 kg/m(2)) at baseline, overweight men and obese men had a significantly higher risk of prostate cancer mortality (proportional hazard ratio [HR] 1.47 [95% CI 1.16-1.88] for overweight men and 2.66 [1.62-4.39] for obese men; p(trend)<0.0001). The trend remained significant after controlling for clinical stage and Gleason grade and was stronger for prostate cancer diagnosed during the PSA screening era (1991-2007) compared with during the pre-PSA screening era (1982-1990) or when using BMI measurements obtained in 1990 compared with those obtained in 1982. Of the 827 men with data available for baseline C-peptide concentration, 117 (14%) died from prostate cancer. Men with C-peptide concentrations in the highest quartile (high) versus the lowest quartile (low) had a higher risk of prostate cancer mortality (HR 2.38 [95% CI 1.31-4.30]; p(trend)=0.008). Compared with men with a BMI less than 25 kg/m(2) and low C-peptide concentrations, those with a BMI of 25 kg/m(2) or more and high C-peptide concentrations had a four-times higher risk of mortality (4.12 [1.97-8.61]; p(interaction)=0.001) independent of clinical predictors.
Excess bodyweight and a high plasma concentration of C-peptide both predispose men with a subsequent diagnosis of prostate cancer to an increased likelihood of dying of their disease. Patients with both factors have the worst outcome. Further studies are now needed to confirm these findings.
The relationship of glucose tolerance to the incidence of coronary heart disease (CHD) has been investigated in two cohorts of Finnish men: 3267 men ages 40--59 yr from the Social Insurance Institution's (SII) Coronary Heart Disease Study and 1059 men ages 30--59 yr from the Helsinki Policemen Study. The relationship of plasma insulin level to the incidence of CHD was also investigated in the Helsinki Policemen Study. An oral glucose lead of 60, 75, or 90 g according to body surface area was used in both studies. In the SII Study, plasma glucose was determined from venous blood samples taken 1 h after glucose load. In the Helsinki Policemen Study, blood glucose was determined from venous blood samples taken at 0, 1, and 2 h, and at a 5-yr reexamination, plasma insulin was measured during OGTT at 0, 1, 2 h. In the SII Study cohort, the 4-yr mortality from CHD and the 4-yr incidence of nonfatal myocardial infarction (MI) did not show a definite relationship to 1-h postload plasma glucose. In the Helsinki Policemen Study cohort, the 5-yr incidence of "hard criteria" CHD (CHD death and nonfatal MI) was significantly related to high 1-h postload blood glucose level but not to fasting or 2-h postload blood glucose levels. 10-yr mortality from CHD was significantly higher in the top quintile of fasting and 1- and 2-h postload blood glucose levels, as was the incidence of "hard criteria" CHD. However, in multivariate analyses including age, systolic blood pressure, plasma cholesterol, and smoking, the blood glucose variables showed no statistically significant independent contribution in predicted risk of CHD. Univariate analyses by quintiles of plasma insulin levels measured at the 5-yr reexamination showed that the incidence of "hard criteria" CHD during the subsequent 5 yr was significantly higher in the top quintiles of fasting and 1-h and 2-h postload plasma insulin than in the combined lower quintiles. Multivariate analyses showed that the value of high 1-h or 2-h postload plasma insulin level for predicting CHD risk was independent of other risk factors, including blood glucose levels during OGTT.