The role of nateglinide and repaglinide, derivatives of meglitinide, in the treatment of type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases worldwide, presenting a great challenge to the public health systems due to high morbidity and mortality, because of frequent micro-/macro-vascular complications. Many treatment options are now available, with different efficacy as well as mechanisms of action to improve deranged glucose metabolism. We review some of the available data on derivatives of meglitinide, namely nateglinide and repaglinide. These two compounds increase insulin secretion by a mechanism similar to the one of sulfonylureas, but with a shorter half-life. Nateglinide and repaglinide, derivatives of meglitinides, have characteristic pharmacodynamic and pharmacokinetic properties that, together with their proposed mechanism of action, make them useful for type 2 diabetes mellitus, especially when used in combination therapy.

Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases.

Diabetes mellitus is associated to an increased risk of cardiovascular diseases. Hyperglycemia is an important factor in cardiovascular damage, working through different mechanisms such as activation of protein kinase C, polyol and hexosamine pathways, advanced glycation end products production. All of these pathways, in association to hyperglycemia-induced mitochondrial dysfunction and endoplasmic reticulum stress, promote reactive oxygen species (ROS) accumulation that, in turn, promote cellular damage and contribute to the diabetic complications development and progression. ROS can directly damage lipids, proteins or DNA and modulate intracellular signaling pathways, such as mitogen activated protein kinases and redox sensitive transcription factors causing changes in protein expression and, therefore, irreversible oxidative modifications. Hyperglycemia-induced oxidative stress induces endothelial dysfunction that plays a central role in the pathogenesis of micro- and macro-vascular diseases. It may also increase pro-inflammatory and pro-coagulant factors expression, induce apoptosis and impair nitric oxide release. Oxidative stress induces several phenotypic alterations also in vascular smooth-muscle cell (VSMC). ROS is one of the factors that can promote both VSMC proliferation/migration in atherosclerotic lesions and VSMC apoptosis, which is potentially involved in atherosclerotic plaque instability and rupture. Currently, there are contrasting clinical evidences on the benefits of antioxidant therapies in the prevention/treatment of diabetic cardiovascular complications. Appropriate glycemic control, in which both hypoglycemic and hyperglycemic episodes are reduced, in association to the treatment of dyslipidemia, hypertension, kidney dysfunction and obesity, conditions which are also associated to ROS overproduction, can counteract oxidative stress and, therefore, both microvascular and macrovascular complications of diabetes mellitus.

High-normal TSH values in obesity: is it insulin resistance or adipose tissue's guilt?

OBJECTIVE: Clinical evidences reported subclinical alterations of thyroid function in obesity, although the relationship between thyroid status and obesity remains unclear. We cross-sectionally investigated the influence of metabolic features on hypothalamic-pituitary-thyroid axis in obesity. DESIGN AND METHODS: We enrolled 60 euthyroid subjects with no history of type 2 diabetes mellitus and assessed the relationship of thyroid function with insulin resistance, measured using euglycemic clamp, and abdominal fat volume, quantified by computed tomography scan (CT scan). Thyroid stimulating hormone (TSH) correlated with BMI (r = 0.46; P = 0.02), both visceral (r = 0.58; P = 0.02) and subcutaneous adipose tissue volumes (r = 0.43; P = 0.03) and insulin resistance (inverse relationship with insulin sensitivity-glucose uptake: r = -0.40; P = 0.04). RESULTS: After performing multivariate regression, visceral adipose tissue volume was found to be the most powerful predictor of TSH (ß = 3.05; P = 0.01), whereas glucose uptake, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, subcutaneous adipose tissue volume, and triglycerides were not. To further confirm the hypothesis that high-normal TSH values could be dependent on adipose tissue, and not on insulin resistance, we restricted our analyses to moderately obese subjects' BMI ranging 30-35 kg/m(2). This subgroup was then divided as insulin resistant and insulin sensitive according to the glucose uptake (≤ or >5 mg · kg(-1) · min(-1), respectively). We did not find any statistical difference in TSH (insulin resistant: 1.62 ± 0.65 µU/ml vs. insulin sensitive: 1.46 ± 0.48; P = not significant) and BMI (insulin resistant: 32.2 ± 1.6 kg/m(2) vs. insulin sensitive: 32.4 ± 1.4; P = not significant), thus confirming absence of correlation between thyroid function and insulin sensitivity per se. CONCLUSION: Our study suggests that the increase in visceral adipose tissue is the best predictor of TSH concentration in obesity, independently from the eventual concurrent presence of insulin resistance.

Removal of duodenum elicits GLP-1 secretion.

OBJECTIVE: To evaluate the effect of removal of the duodenum on the complex interplay between incretins, insulin, and glucagon in nondiabetic subjects. RESEARCH DESIGN AND METHODS: For evaluation of hormonal secretion and insulin sensitivity, 10 overweight patients without type 2 diabetes (age 61 ± 19.3 years and BMI 27.9 ± 5.3 kg/m(2)) underwent a mixed-meal test and a hyperinsulinemic-euglycemic clamp before and after pylorus-preserving pancreatoduodenectomy for ampulloma. RESULTS: All patients experienced a reduction in insulin (P = 0.002), C-peptide (P = 0.0002), and gastric inhibitory peptide (GIP) secretion (P = 0.0004), while both fasting and postprandial glucose levels increased (P = 0.0001); GLP-1 and glucagon responses to the mixed meal increased significantly after surgery (P = 0.02 and 0.031). While changes in GIP levels did not correlate with insulin, glucagon, and glucose levels, the increase in GLP-1 secretion was inversely related to the postsurgery decrease in insulin secretion (R(2) = 0.56; P = 0.012) but not to the increased glucagon secretion, which correlated inversely with the reduction of insulin (R(2) = 0.46; P = 0.03) and C-peptide (R(2) = 0.37; P = 0.04). Given that the remaining pancreas presumably has preserved intraislet anatomy, insulin secretory capacity, and α- and ß-cell interplay, our data suggest that the increased glucagon secretion is related to decreased systemic insulin. CONCLUSIONS: Pylorus-preserving pancreatoduodenectomy was associated with a decrease in GIP and a remarkable increase in GLP-1 levels, which was not translated into increased insulin secretion. Rather, the hypoinsulinemia may have caused an increase in glucagon secretion.

Low levels of 25(OH)D and insulin-resistance: 2 unrelated features or a cause-effect in PCOS?

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.

The size of adrenal incidentalomas correlates with insulin resistance. Is there a cause-effect relationship?

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.

25-Hydroxyvitamin D concentration correlates with insulin-sensitivity and BMI in obesity.

The prevalence of hypovitaminosis D is high among obese subjects. Further, low 25-hydroxyvitamin D (25(OH)D) concentration has been postulated to be a risk factor for type 2 diabetes, although its relation with insulin-sensitivity is not well investigated. Thus, we aimed to investigate the relationship between 25(OH)D concentration and insulin-sensitivity, using the glucose clamp technique. In total, 39 subjects with no known history of diabetes mellitus were recruited. The association of 25(OH)D concentration with insulin-sensitivity was evaluated by hyperinsulinemic euglycemic clamp. Subjects with low 25(OH)D (<50 nmol/l) had higher BMI (P = 0.048), parathyroid hormone (PTH) (P = 0.040), total cholesterol (P = 0.012), low-density lipoprotein (LDL) cholesterol (P = 0.044), triglycerides (P = 0.048), and lower insulin-sensitivity as evaluated by clamp study (P = 0.047). There was significant correlation between 25(OH)D and BMI (r = -0.58; P = 0.01), PTH (r = -0.44; P < 0.01), insulin-sensitivity (r = 0.43; P < 0.01), total (r = -0.34; P = 0.030) and LDL (r = -0.40; P = 0.023) (but not high-density lipoprotein (HDL)) cholesterol, and triglycerides (r = 0.45; P = 0.01). Multivariate analysis using 25(OH)D concentration, BMI, insulin-sensitivity, HDL cholesterol, LDL cholesterol, total cholesterol, and triglycerides, as the cofactors was performed. BMI was found to be the most powerful predictor of 25(OH)D concentration (r = -0.52; P < 0.01), whereas insulin-sensitivity was not significant. Our study suggested that there is no cause-effect relationship between vitamin D and insulin-sensitivity. In obesity, both low 25(OH)D concentration and insulin-resistance appear to be dependent on the increased body size.