Mechanisms of the stimulation of insulin release by saturated fatty acids. A study of palmitate effects in mouse beta-cells

The mechanisms by which fatty acids increase insulin release are not known. In this study, mouse islets were used as a model and palmitate as a reference compound to study in vitro how saturated fatty acids influence pancreatic beta-cells. Palmitate (625 microM) was bound to albumin. It did not affect basal insulin release (3 mM glucose) but increased the release induced by 10-15 mM glucose. This effect was dependent on the concentration of free rather than total palmitate. It was reversible and abolished by epinephrine, diazoxide, nimodipine, or omission of extracellular Ca. Bromopalmitate and methyl palmoxirate, two inhibitors of fatty acid oxidation, were ineffective alone, and only bromopalmitate partially inhibited the effects of palmitate on insulin release. The increase in insulin release produced by palmitate could not be ascribed to a blockade of ATP-sensitive K(+)-channels because the fatty acid only barely decreased 86Rb efflux and did not depolarize beta-cells in 3 mM glucose. The small effect on 86Rb efflux might be attributed to a slight rise in the ATP/ADP ratio. No such rise occurred when palmitate was tested in 15 mM glucose, and the fatty acid consistently accelerated 86Rb efflux under these conditions. Measurements of beta-cell membrane potential (intracellular microelectrodes) and of free cytoplasmic calcium (Cai2+) in beta-cells (Fura 2 technique) showed that palmitate increases Ca2+ influx; it also caused a very small mobilization of intracellular Ca. The persistence of this stimulation of Ca2+ influx in the presence of diazoxide and high K+ suggests that palmitate might act on Ca2+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Seismic assessment of an S-shape building with expansion joints

An elastic analysis of an existing 20-storey reinforced concrete moment resisting frame divided in 3 blocks shows that beams supported on corbels of the adjacent block at the expansion joint loose their support when each independent block vibrate on its own under earthquake. Different reconnection hypothesis were considered, ranging from fixing totally each block to the adjacent one to more flexible options leaving some free relative move between blocks. An elastic modal superposition followed by a pushover analysis considering the final reconnection principle were made. The degrees of freedom of the joint reconnections were observed to be an important parameter. The solution found leaves a free relative rotational move between blocks and a flexible translational movement, so that forces at the connection do not become uselessly high. The springs used (long tie rods) work essentially elastically so that no permanent relative displacement exists between blocks after an earthquake

Multisite control of insulin release by glucose

Glucose controls insulin release by beta-cells at two sites at least. By controlling the membrane potential, it controls the influx of Ca2+ and the rise in cytoplasmic Ca2+ which triggers exocytosis. At this level, the principal targets of glucose are the K(+)-ATP channels whose activity may be modulated by changes in the ATP/ADP ratio. A second, newly identified, mechanism of regulation is independent of changes in beta-cell membrane potential and of changes in Cai2+. It is not sufficient to induce insulin release, but serves to increase the response. This appears to be achieved through an amplification of the effectiveness of Cai2+ on the secretory process and may also depend on the changes in energy state of beta-cells

Effets à court et moyen terme d'un traitement par exénatide dans une cohorte de patients diabétiques de type 2: Résultats d'une étude multicentrique au sein du Réseau des diabétologues de l'UCL

Nous avons analysé les effets à court et moyen terme d'un traitement par exenatide chez des patients diabétiques de type 2 en échec d'une bithérapie antihyperglycémiante orale. Nous avons observé à 3 et 6 mois une diminution importante tant des taux de l'hémoglobine glycatée que du poids, confirmant la place de l'exenatide dans l'arsenal thérapeutique moderne

One-year metabolic outcomes in patients with type 2 diabetes treated with exenatide in routine practice

AIM: The study objective was to analyze, in everyday practice, the long-term metabolic effects of exenatide (for 9 and 12months) in patients with type 2 diabetes not responding to treatments with metformin and sulphonylurea at maximum dosages. METHODS: A total of 299 type 2 diabetics were recruited from 14 centres specializing in diabetes care across Belgium. Main study endpoints were changes in HbA(1c), weight and waist circumference, and tolerability and compliance. Two patient cohorts were analyzed for effectiveness, with data available at 9 (n=90) and 12 (n=94) months of follow-up. RESULTS: Significant decreases in HbA(1c) of -1.3% and -1.6% were observed in the 9- and 12-month cohorts, respectively (P<0.001). The decrease in HbA(1c) was greater in patients with higher baseline levels (P<0.001), and the response was independent of baseline weight, body mass index (BMI), age, gender and diabetes duration. A progressive reduction of weight (4.9kg) was also observed in the two cohorts at 9 and 12months (P<0.001), with greater weight loss in patients with higher baseline BMI (P=0.046) and in female subjects (P=0.025). Waist circumference also decreased from baseline to endpoints. A correlation was observed between reduction in HbA(1c) and weight loss (P=0.019). Side effects, mainly of gastrointestinal origin, were reported in 33% (93/284 patients in the safety cohort). The rate of hypoglycaemia was 3.5%. Treatment was discontinued in 27% of patients (n=77) mainly due to drug inefficacy (53%, n=41) or adverse events (26%, n=20), or both (8%, n=6). CONCLUSION: Exenatide leads to long-term improvement of glycaemic control as well as weight loss in a majority of patients not responding to combined oral drug therapy in real-world clinical practice. However, no baseline factors predictive of response could be identified. Exenatide can be considered an effective treatment option in such patients, including those with high baseline HbA(1c) and long duration of diabetes