Predictive models of insulin resistance derived from simple morphometric and biochemical indices related to obesity and the metabolic syndrome in baboons

<p>Abstract</p> <p>Background</p> <p>Non-human primates are valuable models for the study of insulin resistance and human obesity. In baboons, insulin sensitivity levels can be evaluated directly with the euglycemic clamp and is highly predicted by adiposity, metabolic markers of obesity and impaired glucose metabolism (i.e. percent body fat by DXA and HbA_1c). However, a simple method to screen and identify obese insulin resistant baboons for inclusion in interventional studies is not available.</p> <p>Methods</p> <p>We studied a population of twenty baboons with the euglycemic clamp technique to characterize a population of obese nondiabetic, insulin resistant baboons, and used a multivariate linear regression analysis (adjusted for gender) to test different predictive models of insulin sensitivity (insulin-stimulated glucose uptake = Rd) using abdominal circumference and fasting plasma insulin. Alternatively, we tested in a separate baboon population (n = 159), a simpler model based on body weight and fasting plasma glucose to predict the whole-body insulin sensitivity (Rd/SSPI) derived from the clamp.</p> <p>Results</p> <p>In the first model, abdominal circumference explained 59% of total insulin mediated glucose uptake (Rd). A second model, which included fasting plasma insulin (log transformed) and abdominal circumference, explained 64% of Rd. Finally, the model using body weight and fasting plasma glucose explained 51% of Rd/SSPI. Interestingly, we found that percent body fat was directly correlated with the adipocyte insulin resistance index (r = 0.755, p < 0.0001).</p> <p>Conclusion</p> <p>In baboons, simple morphometric measurements of adiposity/obesity, (i.e. abdominal circumference), plus baseline markers of glucose/lipid metabolism, (i.e. fasting plasma glucose and insulin) provide a feasible method to screen and identify overweight/obese insulin resistant baboons for inclusion in interventional studies aimed to study human obesity, insulin resistance and type 2 diabetes mellitus.</p

Spotlight on ertugliflozin and its potential in the treatment of type 2 diabetes: Evidence to date

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the latest therapeutic strategy in the treatment of type 2 diabetes mellitus (T2DM). Using an insulin-independent mechanism (glycosuria), they reduce glucose toxicity and improve insulin sensitivity and \uce\ub2-cell function. The promising results obtained in clinical trials show that SGLT2 significantly improves glycemic control and provides greater cardiovascular protection, combined with a reduction in body weight and blood pressure (BP). This review focuses on ertugliflozin, a new, highly selective, and reversible SGLT2 inhibitor. Clinical trials published to date show that ertugliflozin, both as a monotherapy and as an add-on to oral antidiabetic agents, is safe and effective in reducing glycosylated hemoglobin (HbA1c), body weight, and BP in T2DM patients

Glucose toxicity: the leading actor in the pathogenesis and clinical history of type 2 diabetes - mechanisms and potentials for treatment

Although it is now well established that the deleterious effects of chronic hyperglycaemia (i.e., glucose toxicity) play an important role in the progressive impairment of insulin secretion and sensitivity, the two major actors of the pathogenesis of type 2 diabetes mellitus, the precise biochemical and molecular mechanisms responsible for the defects induced by glucose toxicity still remain to be defined

Metabolic syndrome in transplant patients: an academic or a health burden?

Metabolic syndrome is a cluster of risk factors that predispose to major cardiovascular diseases, liver steatosis and fibrosis, as well as reduced renal function. Metabolic syndrome and its early hepatic manifestation, non-alcoholic fatty liver disease, are prevalent both among the general population and in pre- and posttransplantation settings. Because indications for solid-organ transplantation are gradually increasing, attention should focus on the incidence of metabolic syndrome among transplanted patients, defined as posttransplant metabolic syndrome (PTMS). Subjects with worse metabolic profiles with two or more criteria of the syndrome show lower survival rates and greater co-morbidities. However, it is still unclear whether the pathophysiology of posttransplantation metabolic syndrome differ from that of the general population and may be determined by the primary disease affecting the liver or kidney, or amplified or altered by the immunosuppressive treatment, as it has already been established that corticosteroids and calcineurin inhibitors cause metabolic disarrangements. Although there is controversy regarding the definition and the impact of PTMS on overall survival rates following transplantation, these patients are at increased risk for cardiovascular morbidity and mortality. Early recognition, prevention, and treatment of these conditions may impact long-term survival after transplantation. Thus, even if metabolic syndrome in transplant patients remains an unclear definition, an insulin resistance is present in these patients. The treatment of this condition represents a health problem that requires intervention by clinicians before and after transplantation

Hypovitaminosis D Is Associated with Liver Insulin Resistance in Obese Subjects

Hypovitaminosis D is highly prevalent in obese subjects. Serum 25-hydroxy vitamin D3 [25(OH)D] concentration, the best marker of human vitamin D status, has been reported to be associated with glucose status, insulin resistance (IR) and beta cell function. To specifically investigate the relationship between 25(OH)D and liver IR we performed a comprehensive metabolic assessment (2-h OGTT, hyperinsulinemic euglycemic clamp [HEC], body composition by DXA) in 20 obese non-diabetic subjects (42.9±2.7 yrs; BMI 37.7±0.8 kg/m2) with 25(OH)D insufficiency (&lt;30 ng/mL). Liver IR was estimated using the index by Vangipurapu et al. (-0.091 + [log insulin AUC 0-120 min x 0.400] + [log fat mass% x 0.346] - [log HDL cholesterol x 0.408] + [log BMI x 0.435]). There was a significant inverse correlation between 25(OH)D and the liver IR index (r = -0.514, p = 0.02). This correlation maintained its significance after adjusting for age, gender, total cholesterol, triglycerides and whole body insulin sensitivity (M value assessed by HEC) in multiple linear regression analysis. There was no significant correlation between 25(OH)D and beta cell function estimated by the Disposition Index. Our data suggest that, in obese subjects, low 25(OH)D levels are independently associated with liver insulin resistance, but not with beta cell function. Further studies are needed to clarify the relationship between glucose homeostasis and vitamin D levels

Association of vitamin D with insulin resistance and beta-cell dysfunction in subjects at risk for type 2 diabetes

We read with interest the article by Kayaniyil et al. that supplied elegant data suggesting that 25- hydroxyvitamin D [25(OH)D] is related to insulin resistance and _-cell function in a large population at high risk for type 2 diabetes and/or metabolic syndrome, thus concluding that 25(OH)D may be an independent risk factor for diabetes. We have, however, some concerns. First, the studied population was mainly composed of obese subjects (the mean BMI was 30.5 kg/m2). Clearly, within a population with such a high BMI, the major variable influencing insulin sensitivity is fat mass. An increased fat mass (within the same BMI) could determine both the reduced insulin sensitivity and 25(OH)D. The two variables therefore correlate, but are not causally related. In our recently published article, we approached this important question by comparing two groups of obese subjects matched by BMI but different in terms of insulin sensitivity: no differences in 25(OH)D concentrations could be found, suggesting that the adipose tissue is its reservoir. Kayaniyil et al. themselves reported a weaker correlation in their obese (BMI 30 kg/m2) subpopulation but, unfortunately, they did not provide data on body composition. Second, although the correlation within the high risk (for diabetes) population is intriguing, a control population is missing. In particular, it is not reported whether the studied population has lower 25(OH)D concentration than an hypothetical control cohort. If this was not the case, the working hypothesis fails. How could normal 25(OH)D determine insulin resistance? Third, if 25(OH)D is involved in the pathogenesis of type 2 diabetes, one would expect that a supplementation of calcitriol or its analogues would ameliorate the glucose metabolism. This was not the case either in insulin-resistant diabetic patients or in healthy subjects (4). As we and others reported, 25(OH)D concentration mainly reflects body fat mass; the reduction of fat mass, rather than vitamin D supplementation, is the main road for the prevention and treatment of insulin resistance and diabetes

Will vitamin D reduce insulin resistance? Still a long way to go

We read with interest the article by Alvarez et al, which aimed to investigate the relations of circulating 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) concentrations with direct measurements of insulin sensitivity, after robust measures of body composition and fat distribution were accounted for. We would like to express our opinion and a different interpretation of the data provided by authors, with the hope that other points for discussion are brought up. In a very recent publication, Alvarez et al provided novel findings suggesting that dietary vitamin D is independently associated with insulin sensitivity in African Americans (AAs) but not in European Americans (EAs). Interestingly, the 2 groups were identical for hepatic insulin sensitivity [homeostatic model assessment (HOMA)], whereas Si, a method for measuring insulin sensitivity that encompasses both hepatic and peripheral tissues, was lower in AAs, therefore suggesting a pivotal role for insulin resistance in skeletal muscle [especially in the presence of identical body mass index (BMI)] in correlation with 25(OH)D. In the present article, the authors suggest that 25(OH)D and PTH concentrations are independently associated with whole-body insulin sensitivity and suggest that these variables may influence insulin sensitivity through independent mechanisms. In fact, multiple linear regression analysis indicated that 25(OH)D and PTH concentrations were independently related to Si after adjustment for age, race, and intraabdominal adipose tissue. It is well known, however, that adipose tissue is the natural reservoir for lipo-soluble 25(OH)D. The higher BMI and the higher subcutaneous fat content found in AAs (although the latter difference was not statistically significant) could therefore explain the differences in 25(OH)D concentration, as well as in HOMA index, found by the authors. We examined the effect of 25(OH)D on insulin sensitivity in obese subjects and found a linear correlation between them, which is apparently in agreement with Alvarez et al. Obesity, however, is not invariably associated with insulin resistance, because normal insulin sensitivity can be present in some obese subjects. If 25(OH)D concentration influences insulin sensitivity independently of obesity, it should be found to be low in insulin-resistant obese subjects and high in insulin-sensitive obesity. We divided our obese population into 2 subgroups, according to their insulin sensitivity (low and high). The 2 groups were similar in BMI, age, and sex but did not show any difference in 25(OH)D concentration, thus confirming the hypothesis that 25(OH)D concentrations are not influenced by the degree of insulin resistance but mainly by the adipose tissue\u2019s reservoir, at least in our EA participants. Unfortunately, in the presentstudied population but not in the previous one, AAs had higher BMI (and HOMA) and the actual role of these variables in determining hypovitaminosis D was not ruled out. In conclusion, we are certain that 25(OH)D concentration mainly reflects body fatmass, either subcutaneous or visceral; the reduction of fat mass, rather than vitamin D supplementation, is the best route for the prevention and treatment of insulin resistance and diabetes

β-Cell Glucose Sensitivity Is Linked to Insulin/Glucagon Bihormonal Cells in Nondiabetic Humans.

Context: Insulin resistance impacts virtually all tissues, including pancreatic β cells. Individuals with insulin resistance, but without diabetes, exhibit an increased islet size because of an elevated number of both β and α cells. Neogenesis from duct cells and transdifferentiation of α cells have been postulated to contribute to the β-cell compensatory response to insulin resistance. Objective: Our objective was to explore parameters that could potentially predict altered islet morphology. Methods: We investigated 16 nondiabetic subjects by a 2-hour hyperglycemic clamp to evaluate β-cell secretory function. We analyzed pancreas samples obtained during pancreatoduodenectomy in the same patients to examine glucagon and insulin double+ cells to assess islet morphology. Results: Among all the functional in vivo parameters of insulin secretion that were explored (basal, first phase and total secretion, glucose sensitivity, arginine-stimulated insulin secretion), β-cell glucose sensitivity was unique in exhibiting a significant correlation with both islet size and α-β double+ islet cells. Conclusions: Our data suggest that poor β-cell glucose sensitivity is linked to islet transdifferentiation, possibly from α cells to β cells, in an attempt to cope with higher demands for insulin secretion. Understanding the mechanism(s) that underlies the adaptive response of the islet cells to insulin resistance is a potential approach to design tools to enhance functional β-cell mass for diabetes therapy

Single-fiber conduction velocity test allows earlier detection of abnormalities in diabetes

The purpose of this study was to determine whether single-fiber conduction velocity (SF-CV) of a small number of axons increases sensitivity for identification of motor nerve conduction alterations in patients with diabetes. Methods: Twenty-one consecutive diabetic patients in good metabolic control were studied. For each patient, conventional (C-CV) and SF-CV results were correlated with the presence of neuropathic symptoms. Results: Nine of 21 patients reported symptoms suggestive of mild nerve impairment. Three patients had abnormal sural nerve CV, 1 of whom also had abnormal motor nerve conduction. Eighteen patients had normal findings on conventional tests, 3 of whom had slowing of SF-CV. Conclusions: SF-CV is able to detect mild myelin damage with higher sensitivity than conventional tests. The use of SF-CV may be a helpful tool in the early identification of diabetic polyneuropathy, and it may be useful for tailoring an approach to diabetic polyneuropathy