Hepatic insulin resistance is a driving force in the pathogenesis of type 2 diabetes mellitus (T2DM) and is tightly coupled with excessive storage of fat and the ensuing inflammation within the liver. There is compelling evidence that activation of the transcription factor nuclear factor-κB (NF-κB) and downstream inflammatory signaling pathways systemically and in the liver are key events in the etiology of hepatic insulin resistance and β-cell dysfunction, although the molecular mechanisms involved are incompletely understood. We here test the hypothesis that receptor activator of NF-κB ligand (RANKL), a prototypic activator of NF-κB, contributes to this process using both an epidemiological and experimental approach. In the prospective population-based Bruneck Study, a high serum concentration of soluble RANKL emerged as a significant (P< 0.001) and independent risk predictor of T2DM manifestation. In close agreement, systemic or hepatic blockage of RANKL signaling in genetic and nutritional mouse models of T2DM resulted in a marked improvement of hepatic insulin sensitivity and amelioration or even normalization of plasma glucose concentrations and glucose tolerance. Overall, this study provides evidence for a role of RANKL signaling in the pathogenesis of T2DM. If so, translation to the clinic may be feasible given current pharmacological strategies to lower RANKL activity to treat osteoporosis.
Aim
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.
Data synthesis
here we will briefly report on convincing evidence that glucose toxicity acts through oxidative stress, modifications in the exosamine pathway, protein kinase C and others. After inducing or contributing to the genesis of type 2 diabetes, these same mechanisms are considered responsible for the appearance and worsening of diabetic specific microvascular complications, while its role in increasing the risk of cardiovascular diseases is less clear. Recent intervention studies (ADVANCE, ACCORD, VADT), conducted to evaluate the effects of strict glycaemic control, apparently failed to demonstrate an effect of glucose toxicity on cardiovascular diseases, at least in secondary prevention or when diabetes is present for a prolonged time. The re-examination, 20 years later, of the population studied in the UKPDS study, however, clearly demonstrated that the earliest is the strict glycaemic control reached, the lowest is the incidence of cardiovascular diseases observed, including myocardial infarction.
Conclusion
The acquaintance of the role of glucose toxicity should strongly influence the usual therapeutic choices and glycaemic targets where the reduced or absent risk of hypoglycaemia, durability of action, and data on prolonged safety should be the preferred characteristics of the drug of choice in the treatment of type 2 diabetes mellitus.
Background & aims
Recent investigations have identified low vitamin D status as a hypothetical mechanism of insulin-resistance in Polycystic Ovary Syndrome (PCOS). Instead, some authors supported the hypothesis that low vitamin D levels and insulin-resistance are 2 unrelated features of body size in PCOS. Hence, we aimed to explore the association of 25-hydroxyvitamin D (25(OH)D) with anthropometric, metabolic and hormonal features in PCOS.
Methods
We assessed the association of low 25(OH)D levels with endocrine parameters, insulin-sensitivity evaluated by hyperinsulinemic euglycemic clamp (HEC) and body composition measured by DEXA in 38 women affected by PCOS.
Results
Low 25(OH)D (25(OH)D < 50 nmo/L) was detected in 37% of the entire cohort of patients. Body Mass Index (BMI), in particular total fat mass (p < 0.001), resulted to be the most predictor factor of 25(OH)D levels whereas Sex Hormone Binding Globulin (SHBG), Free Androgen Index (FAI), glucose uptake and fat free mass were not.
Conclusions
Our data demonstrated that in PCOS low 25(OH)D levels are significantly determined by the degree of adiposity.
Recent investigations have identified low vitamin D status as a hypothetical mechanism of insulin-resistance in Polycystic Ovary Syndrome (PCOS). Instead, some authors supported the hypothesis that low vitamin D levels and insulin-resistance are 2 unrelated features of body size in PCOS. Hence, we aimed to explore the association of 25-hydroxyvitamin D (25(OH)D) with anthropometric, metabolic and hormonal features in PCOS.
Methods
We assessed the association of low 25(OH)D levels with endocrine parameters, insulin-sensitivity evaluated by hyperinsulinemic euglycemic clamp (HEC) and body composition measured by DEXA in 38 women affected by PCOS.
Results
Low 25(OH)D (25(OH)D < 50 nmo/L) was detected in 37% of the entire cohort of patients. Body Mass Index (BMI), in particular total fat mass (p < 0.001), resulted to be the most predictor factor of 25(OH)D levels whereas Sex Hormone Binding Globulin (SHBG), Free Androgen Index (FAI), glucose uptake and fat free mass were not.
Conclusions
Our data demonstrated that in PCOS low 25(OH)D levels are significantly determined by the degree of adiposity.
We read with interest the article by Kayaniyil et al. (1) that supplied elegant data suggesting that 25-hydroxyvitamin D [25(OH)D] is related to insulin resistance and β-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 (2), 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 (3) or in healthy subjects (4).
As we (2) and others (5) 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.
Several studies have shown that vitamin D may play a role in many biochemical mechanisms in addition to bone and calcium metabolism. Recently, vitamin D has sparked widespread interest because of its involvement in the homeostasis of the cardiovascular system. Hypovitaminosis D has been associated with obesity, related to trapping in adipose tissue due to its lipophilic structure. In addition, vitamin D deficiency is associated with increased risk of cardiovascular disease (CVD) and this may be due to the relationship between low vitamin D levels and obesity, diabetes mellitus, dyslipidaemia, endothelial dysfunction and hypertension. However, although vitamin D has been identified as a potentially important marker of CVD, the mechanisms through which it might modulate cardiovascular risk are not fully understood. Given this background, in this work we summarise clinical retrospective and prospective observational studies linking vitamin D levels with cardio-metabolic risk factors and vascular outcome. Moreover, we review various randomised controlled trials (RCTs) investigating the effects of vitamin D supplementation on surrogate markers of cardiovascular risk. Considering the high prevalence of hypovitaminosis D among patients with high cardiovascular risk, vitamin D replacement therapy in this population may be warranted; however, further RCTs are urgently needed to establish when to begin vitamin D therapy, as well as to determine the dose and route and duration of administration.
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.
Context Adrenal incidentalomas (AI) have often been associated with a high prevalence of insulin resistance (IR) and cardiovascular risk factors, although direct measurement of insulin sensitivity (IS) has never been carried out.
Objective We aimed to investigate whether the morphological and hormonal features of AI correlate with the presence and severity of IR, using the hyperinsulinaemic euglycaemic clamp (HEC).
Design and Measurements Forty patients with AI (22 women) with a mean age of 58·5 ± 11·1 years underwent hormonal and morphological evaluation. Nineteen patients with AI without known history of diabetes mellitus (DM) or impaired glucose tolerance (IGT) and 17 matched controls underwent oral glucose tolerance test (OGTT) and hyperinsulinaemic euglycaemic clamp (HEC).
Results Diabetes mellitus was observed in 13 patients (33%), while three (8%) had IGT. Thirty-one of the AI were nonfunctioning (82·5%), whereas two (5%) secreted cortisol (Cushing’s syndrome) and seven (12·5%) showed subclinical secretion of cortisol. The 19 patients with nonfunctioning AI were more insulin resistant than controls (glucose up-take: 4·58 ± 1·80 vs 5·85 ± 2·48 mg/kg/min respectively; P = 0·01); IS was inversely related to the mass size (r = −0·57; P = 0·04), free urinary cortisol (r = −0·68; P = 0·01), serum cortisol after 1-mg dexamethasone suppression (−0·65; P = 0·02) and percentage of trunk fat mass (−0·77; P = 0·02) and directly related to serum adreno cortico tropic hormone (ACTH) (r = 0·62; P = 0·03). After performing multivariate regression, the mass size was found to be the most powerful predictor of IR.
Conclusion Our study showed a high prevalence of insulin resistance in patients with nonfunctioning AI and suggests its possible involvement in AI growth.
Background
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 HbA1c). However, a simple method to screen and identify obese insulin resistant baboons for inclusion in interventional studies is not available.
Methods
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.
Results
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).
Conclusion
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.
Aims/hypothesis
Chemokines and their receptors such as chemokine (C-C motif) receptor 2 (CCR2) may contribute to the pathogenesis of the metabolic syndrome via their effects on inflammatory monocytes. Increased accumulation of CCR2-driven inflammatory monocytes in epididymal fat pads is thought to favour the development of insulin resistance. Ultimately, the resulting hyperglycaemia and dyslipidaemia contribute to development of the metabolic syndrome complications such as cardiovascular disease and diabetic nephropathy. Our goal was to elucidate the role of CCR2 and inflammatory monocytes in a mouse model that resembles the human metabolic syndrome.
Methods
We generated a model of the metabolic syndrome by backcrossing KKAy+ with Apoe−/− mice (KKAy+Apoe−/−) and studied the role of CCR2 in this model system.
Results
KKAy+Apoe−/− mice were characterised by the presence of obesity, insulin resistance, dyslipidaemia and increased systemic inflammation. This model also manifested two complications of the metabolic syndrome: atherosclerosis and diabetic nephropathy. Inactivation of Ccr2 in KKAy+Apoe−/− mice protected against the metabolic syndrome, as well as atherosclerosis and diabetic nephropathy. This protective phenotype was associated with a reduced number of inflammatory monocytes in the liver and muscle, but not in the epididymal fat pads; circulating levels of adipokines such as leptin, resistin and adiponectin were also not reduced. Interestingly, the proportion of inflammatory monocytes in the liver, pancreas and muscle, but not in the epididymal fat pads, correlated significantly with peripheral glucose levels.
Conclusions/interpretation
CCR2-driven inflammatory monocyte accumulation in the liver and muscle may be a critical pathogenic factor in the development of the metabolic syndrome.
Context:
The aim of treatment in patients affected by anorexia nervosa (AN) is weight recovery. However, during weight gain, anorectic patients’ body composition is changed, with an increase in abdominal fat, particularly in the visceral compartment.
Objective:
We hypothesized that changes in body composition, particularly in abdominal fat, are responsible for the variability in insulin sensitivity (IS) in different stages of AN.
Design and Measurements:
We compared 20 anorectic patients in the acute stage, 19 in the weight-recovery stage and 21 controls. All subjects underwent an oral glucose tolerance test, hyperinsulinaemic euglycaemic clamp and dual energy X-ray absorptiometry to measure body composition.
Results:
The percentage of trunk fat was higher in weight recovery than in the acute phase (47·7 ± 8·4% vs 34·6 ± 7·6%; P ≤ 0·01) and in the control group (33·4 ± 7·6; P < 0·01 vs weight recovery). Although the recovery group gained weight, their body mass index (BMI) was not statistically different from that of the acute group (14·4 ± 1·1 vs 13·6 ± 1·8 kg/m2). Insulin sensitivity was lower in the weight-recovery group than the acute group (4·7 ± 1·5 vs 7·8 ± 1·6 mg/kg/min; P < 0·01) and controls (7·7 ± 1·4 mg/kg/ min; P < 0·01). A linear negative correlation was found between IS and the percentage of abdominal fat in the weight-recovery and acute groups (r = -0·51; P = 0·04 and r = -0·53; P = 0·04 respectively), while IS did not correlate with BMI.
Conclusion:
Although weight-recovery represents the main aim of treatment in AN, refeeding is associated with an increase in abdominal fat which might be responsible of the onset of insulin resistance. As BMI and weight-recovery were associated with impaired IS, they cannot be considered the only aim of treatment of AN.