Role of beta-cell dysfunction, ectopic fat accumulation and insulin resistance in the pathogenesis of type 2 diabetes

n the natural history of type 2 diabetes (T2DM), individuals progress from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to overt T2DM and this progression has been demonstrated in populations of diverse ethnic background. It is widely recognised that both insulin resistance and beta-cell dysfunction are important in the pathogenesis of glucose intolerance. In populations with a high prevalence of T2DM, insulin resistance is well established long before the development of any impairment in glucose homeostasis, particularly in subjects with ectopic fat accumulation. However, as long as the beta cell is able to secrete sufficient amounts of insulin to offset the severity of insulin resistance, glucose tolerance remains normal. This dynamic interaction between insulin secretion and insulin resistance is essential to the maintenance of NGT and interruption of this crosstalk between the beta cell and peripheral tissues results in the progressive deterioration of glucose homeostasis. In this paper the role of beta-cell function is reviewed, as well as the role of ectopic fat accumulation and insulin resistance in the development of type 2 diabetes

Protective role of adiponectin on endothelial dysfunction induced by AGEs: A clinical and experimental approach

Objective: Obesity is characterized by low levels of adiponectin, an adipocytes derived hormone, and by an inflammatory component. Endothelial dysfunction is often found in overweight/obesity, diabetes, and atherosclerosis. Advanced glycation end products (AGEs) induce endothelial dysfunction and are linked to diabetes and increased atherogenicity and inflammation. The aim of the study was to investigate the possible link between adiponectin and N(epsilon)-(carboxymethyl) lysine (CML), the predominant adduct of circulating AGEs in overweight patients, and, in an in vitro model, to test the hypothesis that adiponectin acts as modulator of endothelial dysfunction, induced by AGEs. Results: In 108 overweight patients, plasma levels of CML correlated inversely with adiponectin levels. Preincubation of human vein endothelial cells (HUVECs) with physiological concentrations of adiponectin, followed by stimulation with AGEs, reduced vascular adhesion molecule-1 (VCAM-1) and E-selectin expression, as assessed by surface enzyme immunoassay. Conclusions: Taken together, these findings demonstrate an inverse correlation between CML and adiponectin levels in overweight patients and a protective role of adiponectin on endothelial dysfunction induced by AGEs, suggesting its key role in the treatment of the vascular complications of obesity/metabolic syndrome

Assessing Insulin Secretion by Modeling in Multiple-Meal Tests

We developed a mathematical model of the glucose control of insulin secretion capable of quantifying β-cell function from a physiological meal test. The model includes a static control, i.e., a secretion component that is a function of plasma glucose concentration (the dose-response function), and a dynamic control, i.e., a secretion component that is proportional to the positive values of the glucose concentration derivative. Furthermore, the dose-response function is assumed to be modulated by a time-varying potentiation factor. To test the model, nine nondiabetic control subjects and nine type 2 diabetic patients received three standardized mixed meals over a period of 14–15 h. Blood samples were drawn for the measurement of glucose, insulin, and C-peptide concentration. The dose-response function, the parameter of the dynamic control, and the potentiation factor were determined by fitting the model to glucose and C-peptide concentrations. In diabetic patients, the dose-response function was shifted to the right (glucose concentration at a reference insulin secretion of 300 pmol · min−1 · m−2 was 11.7 ± 1.1 vs. 7.2 ± 0.7 mmol/l; P < 0.05), and decreased in slope (53 ± 15 vs. 148 ± 38 pmol · min−1 · m−2 · mmol−1 · l; P < 0.05) and the parameter of the dynamic control was decreased (220 ± 67 vs. 908 ± 276 pmol · m−2 · mmol−1 · l; P < 0.05) compared with the nondiabetic control subjects. Furthermore, potentiation was markedly blunted and delayed: maximum potentiation was observed at the first meal in normal subjects and at the second meal (about 4 h later) in diabetic subjects; the mean time for the potentiation factor was higher (7.1 ± 0.2 vs. 5.9 ± 0.2 h; P < 0.01), and the size of potentiation was reduced (2.6 ± 0.5 vs. 7.2 ± 1.5 fold increase; P < 0.005). In conclusion, our model of insulin secretion extracts multiple indexes of β-cell function from a physiological meal test. Use of the model in patients with type 2 diabetes retrieves known defects in insulin secretion but also uncovers new facets of β-cell dysfunction

Diet and Exercise in the Treatment of Fatty Liver

In recent years, we came to realize that obesity, broadly defined as increased body mass index or increased total body fat, is not necessarily associated with metabolic dysfunction and greater risk for cardiometabolic disease. In fact, there are several obese persons who are "metabolically healthy," as there are nonobese persons who are "metabolically abnormal." Although the reason(s) underlying this phenomenon are still not entirely clear, a number of studies conducted over the past several years indicate that the anatomical location of excess fat is more important than total body adiposity in determining metabolic outcomes. Ectopic fat accumulation, particularly in the liver, is frequently observed in obese persons and is strongly associated with metabolic dysfunction, including multiorgan insulin resistance and dyslipidemia. Intrahepatic fat, possibly more than visceral or intramyocellular fat, may thus be a prominent factor modifying the metabolic risk associated with increasing whole-body adiposity. However, cause-and-effect relationships have not yet been established, and it is also possible that intrahepatic triglyceride content is not a determinant but merely a marker of metabolic health. Understanding the regulation of fat accumulation in the liver will thus have important implications in both research and clinical practice. Little is known regarding the specific effects of lifestyle factors such as diet and exercise in regulating the accumulation of fat in the liver and its depletion thereof. In this special issue, we have invited a few papers in an attempt to partly fill this gap in our knowledge. In the first paper of this issue, "Putative factors that may modulate the effect of exercise on liver fat: insights from animal studies," several studies in animals are reviewed in order to highlight putative factors that may modulate the effect of exercise on liver fat. This includes the fat content of the diet (exercise appears to be more effective under high-fat feeding), the role of concurrent exercise-induced loss of body weight or visceral fat, sex (males versus females), prandial status (fasted versus fed), and the duration of training, as well as the time elapsed from the last bout of exercise. The potential importance of these factors in modifying the exercise-induced changes in liver fat has not yet been formally tested in man, thereby providing a wide array of opportunities for future research. The second paper of this issue, "Nafld, estrogens, and physical exercise: the animal model," focuses on the effects of exercise on liver fat in relation to estrogen availability. Estrogen deficiency, such as that occurring naturally after menopause in women, is strongly associated with fatty liver in animals. Exercise training exerts an estrogenic-like effect on the expression of genes involved in hepatic lipid metabolism and is a powerful means for preventing liver fat accumulation in estrogen-deficient animals. The third paper of this special issue, "Dietary conjugated linoleic acid and hepatic steatosis: species specific effects on liver and adipose lipid metabolism and gene expression," reviews the effects of dietary conjugated linoleic acid on liver fat content and hepatic and adipose tissue fatty acid metabolism in animals. Conjugated linoleic acids, particularly the trans-10, cis-12, lead to hepatic steatosis owing to increased de novo lipogenesis and increased hepatic fatty acid uptake, at rates far exceeding the rates of disposal of intrahepatic fatty acids towards oxidation, esterification, and triglyceride export. The fourth paper of this issue, "Effects of exercise training on molecular markers of lipogenesis and lipid partitioning in fructose-induced liver fat accumulation," examines the effects of exercise training on liver fat in starved and subsequently fructose-refed animals. Fructose, a simple sugar, is a potent dietary trigger for liver fat accretion. Exercise training in this model is not able to reverse the fructose-induced changes in lipogenic enzymes and does not reduce intrahepatic fat content. Thus, contrary to the large body of evidence demonstrating that exercise is effective in alleviating hepatic steatosis induced by high-fat feeding, exercise is not able to reverse the changes induced by fructose feeding. The final paper of this special issue, "Exercise and omega-3 polyunsaturated fatty acid supplementation for the treatment of hepatic steatosis in hyperphagic OLETF rats," evaluates the effects of exercise on a hyperphagic model of obesity, with or without concurrent omega-3 polyunsaturated fatty acid supplementation. Exercise training in this animal model alleviates hepatic steatosis even under low-fat feeding conditions, predominantly by increasing hepatic fatty acid oxidation, whereas supplementation with omega-3 fatty acids slightly increases liver-fat content and attenuates the liver-fat-depleting effect of exercise. It is noteworthy that omega-3 fatty acid supplementation in this study accounted for only 3% of total dietary energy, whereas in several previous studies showing that omega-3 fatty acids reduce liver fat the supplement was administered at much greater doses. Research presented and reviewed in this special issue not only highlights the independent effects of exercise and diet on liver fat accumulation but also, more importantly, raises the intriguing possibility of interactive effects between exercise and diet on the mechanisms regulating liver fat accretion and depletion. It seems that several dietary factors are able to either augment or attenuate the intrahepatic triglyceride-depleting effect of exercise

Protective role of adiponectin on endothelial dysfunction induced by AGEs: a clinical and experimental approach

OBJECTIVE: Obesity is characterized by low levels of adiponectin, an adipocytes derived hormone, and by an inflammatory component. Endothelial dysfunction is often found in overweight/obesity, diabetes, and atherosclerosis. Advanced glycation end products (AGEs) induce endothelial dysfunction and are linked to diabetes and increased atherogenicity and inflammation. The aim of the study was to investigate the possible link between adiponectin and N(epsilon)-(carboxymethyl) lysine (CML), the predominant adduct of circulating AGEs in overweight patients, and, in an in vitro model, to test the hypothesis that adiponectin acts as modulator of endothelial dysfunction, induced by AGEs. RESULTS: In 108 overweight patients, plasma levels of CML correlated inversely with adiponectin levels. Pre-incubation of human vein endothelial cells (HUVECs) with physiological concentrations of adiponectin, followed by stimulation with AGEs, reduced vascular adhesion molecule-1 (VCAM-1) and E-selectin expression, as assessed by surface enzyme immunoassay. CONCLUSIONS: Taken together, these findings demonstrate an inverse correlation between CML and adiponectin levels in overweight patients and a protective role of adiponectin on endothelial dysfunction induced by AGEs, suggesting its key role in the treatment of the vascular complications of obesity/metabolic syndrom

Bariatric surgery as a treatment of type 2 diabetes

Obesity has reached epidemic proportions, predisposing to the development of type 2 diabetes and cardiovascular diseases. Weight loss is a major objective, although often difficult to achieve with medical treatments. Bariatric surgery has proven its efficacy in obtaining marked and sustained weight loss, and is also associated with a significant improvement in insulin resistance, beta cell function, lipid metabolism, blood pressure and even diabetes remission. We examined the long-term effect of Roux-en-Y gastric bypass (RYGB, a predominantly restrictive procedure) in a patient with uncontrolled type 2 diabetes. One year after surgery, the patient had lost 30% of initial weight with a significant improvement in blood pressure, withdrawal of cholesterol-lowering therapy, complete remission of diabetes

Gut-pancreas-liver axis as a target for treatment of nafld/nash

Non-alcoholic fatty liver disease (NAFLD) represents the most common form of chronic liver disease worldwide. Due to its association with obesity and diabetes and the fall in hepatitis C virus morbidity, cirrhosis in NAFLD is becoming the most frequent indication to liver transplantation, but the pathogenetic mechanisms are still not completely understood. The so-called gut-liver axis has gained enormous interest when data showed that its alteration can lead to NAFLD development and might favor the occurrence of non-alcoholic steatohepatitis (NASH). Moreover, several therapeutic approaches targeting the gut-pancreas-liver axis, e.g., incretins, showed promising results in NASH treatment. In this review, we describe the role of incretin hormones in NAFLD/NASH pathogenesis and treatment and how metagenomic/metabolomic alterations in the gut microbiota can lead to NASH in the presence of gut barrier modifications favoring the passage of bacteria or bacterial products in the portal circulation, i.e., bacterial translocation.publishersversionpublishe

Imaging and Laboratory Biomarkers in Cardiovascular Disease

Imaging and laboratory biomarkers are an essential support to modern practice of medicine, allowing a better identification, severity titration, staging and follow-up of atherosclerosis and heart failure disease. This review provides an overview of imaging, biochemical and genetic biomarkers used in clinical practice and for research purposes in order to evaluate the 4 different aspect of patient vulnerability to cardiovascular disease: arterial; blood; myocardial; metabolic vulnerability. Yet, no single perfect biomarker exists and there is wide room for optimization and integration between clinical evaluation and biomarker evaluation. In general, a targeted approach tailored on the individual patient should be preferred to a carpet diagnostic bombing, which will lead to an exorbitant multiplier of costs, risks and inappropriate testing