S. De Kreutzenberg

Effect of Metformin on Insulin-Stimulated Glucose Turnover and Insulin Binding to Receptors in Type II Diabetes

Euglycemic insulin glucose-clamp and insulin-binding studies on erythrocytes and monocytes were performed in seven type II (non-insulin-dependent) diabetic subjects before and after 4 wk of metformin treatment (850 mg 3 times/day) and in five obese subjects with normal glucose tolerance. Glucose turnover was also measured at basal insulin concentrations and during hyperinsulinemic euglycemic clamps. During euglycemic insulin-glucose clamps, diabetic subjects showed glucose disposal rates of 3.44 ± 0.42 and 7.34 ± 0.34 mg · kg−1 · min−1 (means ± SD) before metformin at insulin infusion rates of 0.80 and 15.37 mU · kg−1 · min−1, respectively. With the same insulin infusion rates, glucose disposal was 4.94 ± 0.55 (P < .01) and 8.99 ± 0.66 (P < .01), respectively, after metformin treatment. Glucose disposal rates in normal obese subjects were 5.76 ± 0.63 (P < .01) and 10.92 ± 1.11 (P < .01) at 0.80 and 15.37 mU · kg−1 · min−1, respectively. Insulin maximum binding to erythrocytes in diabetics was 9.6 ± 4.2 and 5.8 ± 2.6 × 109 cells (means ± SD) before and after metformin treatment, respectively (NS). Insulin maximum binding to monocytes in diabetics was 6.2 ± 2.3 × 107 cells before and 5.0 ± 1.6% after metformin. Hepatic glucose production was higher in the diabetic patients at basal insulin levels, but not at higher insulin concentrations, and was not significantly changed by drug treatment. Basal glucose and insulin concentrations decreased with metformin. Thus, metformin treatment improved glucose disposal rate without significant effect on insulin-binding capacity on circulating cells. Basal hepatic glucose output was slightly lower after metformin treatment in view of lower (9 vs. 15 μU/ml) insulin levels, potentially indicating increased sensitivity of the liver to insulin.

Gemfibrozil improves insulin sensitivity and flow-mediated vasodilatation in type 2 diabetic patients

Background Endothelial dysfunction is an early feature of atherosclerosis. The relationship between insulin action and hypertriglyceridaemia on endothelial function is still debated.

Optimized glycaemic control achieved with add-on basal insulin therapy improves indexes of endothelial damage and regeneration in type 2 diabetic patients with macroangiopathy: a randomized crossover trial comparing detemir versus glargine

Aims: In diabetes, endothelial damage promotes macroangiopathy and endothelial regeneration is impaired, owing to reduced endothelial progenitor cells (EPCs). Given that insulin influences endothelial biology, we compared the effects of add‐on basal insulin analogues on endothelial damage and regeneration in type 2 diabetes (T2D).

The increased dipeptidyl peptidase-4 activity is not counteracted by optimized glucose control in type 2 diabetes, but is lower in metformin-treated patients

Aim: Dipeptidyl peptidase (DPP)‐4 in responsible for incretin degradation and some observations suggest that DPP‐4 activity is increased in type 2 diabetes (T2D). We aimed to assess the effect of T2D and glucose control on DPP‐4 activity.

Dipeptidyl peptidase‐4 inhibitors can minimize the hypoglycaemic burden and enhance safety in elderly people with diabetes

The prevalence of type 2 diabetes mellitus (T2DM) among elderly people is increasing. Often associated with disabilities/comorbidities, T2DM lowers the chances of successful aging and is independently associated with frailty and an increased risk of hypoglycaemia, which can be further exacerbated by antihyperglycaemic treatment. From this perspective, the clinical management of T2DM in the elderly is challenging and requires individualization of optimum glycaemic targets depending on comorbidities, cognitive functioning and ability to recognize and self‐manage the disease. The lack of solid evidence‐based medicine supporting treatment guidelines for older people with diabetes further complicates the matter. Several classes of medicine for the treatment of T2DM are currently available and different drug combinations are often required to achieve individualized glycaemic goals. Many of these drugs, however, carry disadvantages such as the propensity to cause weight gain or hypoglycaemia. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors, a recent addition to the pharmacological armamentarium, have become widely accepted in clinical practice because of their efficacy, low risk of hypoglycaemia, neutral effect on body weight, and apparently greater safety in patients with kidney failure. Although more information is needed to reach definitive conclusions, growing evidence suggests that DPP‐4 inhibitors may become a valuable component in the pharmacological management of elderly people with T2DM. The present review aims to delineate the potential advantages of this pharmacological approach in the treatment of elderly people with T2DM.

Diabetic ketosis activates lymphomonocyte‐inducible nitric oxide synthase

Aims Inappropriate production of nitric oxide (NO) may be responsible for the haemodynamic disturbances of diabetic ketoacidosis. We investigated whether this metabolic condition is associated with increased plasma nitrate (the stable oxidation product of NO) levels and NO synthase gene expression in lymphomonocytes.

No association between the degree of liver steatosis and early signs of vasculopathy in T2DM

Non alcoholic fatty liver disease (NAFLD) is both an independent and an associated risk factor for cardiovascular (CV) disease in the general population [1]. Whereas the association between NAFLD, and early signs of vasculopathy, such as an increased intima-media thickness (IMT) and a decreased flow-mediated vasodilation (FMD), has been reported in the general population, such an association in type 2 diabetes mellitus (T2DM) is controversial. In T2DM patients with NAFLD FMD was decreased [2], whereas IMT was not different, with respect to patients without liver steatosis [3]. Should a (causative) relationship between hepatic steatosis and early signs of vasculopathy exists, the degree of liver fat should be associated with a worse endothelial function and morphology. However, despite the bulk of data generated on this complex association, insufficient reports exist on T2DM. To this aim, we measured the extent of liver fat, average IMT, the presence and type of carotid plaques, and FMD, in sixty consecutive T2DM patients largely affected by features of the MS. Liver steatosis, IMT, and presence and types of carotid plaques, were evaluated by ultrasonography (using an HDI 5000 Philips Medical Systems apparatus, Bothell, WA, USA), with a broad-band width phased array transducer (2e5 MHz). Steatosis was divided into four classes following the traditional US classification (class 0: absence; classes 1e3: increasing degrees, of steatosis) [4]. IMT was assessed using standard procedures [5]. FMD was evaluated in 45 patients using an internationally validated approach [6]. Only six patients were current smokers, and seven had a positive history for CV disease (five for ischemic heart disease, and two for cerebrovascular disease). No subject was positive for hepatitis C virus infection. The overall prevalence of steatosis was 88% (34% mild, 34% moderate e 20% severe). Average IMT was 0.88 0.03 mm (Mean SE), significantly greater (p < 0.0001) than the mean value of a healthy, ageand sex matched population at our Institution (0.72 0.03 mm). Fifty-eight percent of patients had carotid plaques. Average FMD in the patients (5.02 0.81%) was lower (p < 0.001) than the normal values of healthy, ageand sex matched individuals from our Institution (6.56 0.60%).

Glycaemic fall after a glucose load. A population-based study

BACKGROUND AND AIMS A blood glucose (BG) fall after an oral glucose load has never been described previously at a population level. This study was aimed at looking for a plasma glucose trend after an oral glucose load for possible blood glucose fall if any, and for its impact on coronary mortality at a population level. METHODS AND RESULTS In subjects from an unselected general population, BG and insulin were detected before and 1 and 2h after a 75-g oral glucose load for insulin sensitivity and β-cell function determination. Blood pressure, blood examinations and left ventricular mass were measured, and mortality was monitored for 18.8±7.7 years. According to discriminant analysis, the population was stratified into cluster 0 (1-h BG < fasting BG; n=497) and cluster 1 (1-h BG ≥ fasting BG; n=1733). To avoid any interference of age and sex, statistical analysis was limited to two age-gender-matched cohorts of 490 subjects from each cluster (n=940). Subjects in cluster 0 showed significantly higher insulin sensitivity and β-cell function, lower visceral adiposity and lower blood pressure values. Adjusted coronary mortality was 8 times lower in cluster 0 than 1 (p<0.001). The relative risk of belonging to cluster 1 was 5.40 (95% CI 2.22-13.1). CONCLUSION It seems that two clusters exist in the general population with respect to their response to an oral glucose load, independent of age and gender. Subjects who respond with a BG decrease could represent a privileged sub-population, where insulin sensitivity and β-cell function are better, some risk factors are less prevalent, and coronary mortality is lower.