Molecular control of compound exocytosis: A key role for VAMP8

Exocytosis is the process of fusion of a membrane-bound vesicle with the cell membrane and subsequent release of the vesicle content to the outside. It is now widely accepted that SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) proteins are key components in the molecular machinery of exocytosis. SNARE proteins on the vesicle membrane selectively form complexes with specific SNAREs on the cell membrane. In a variant of exocytosis, called compound exocytosis, secretory vesicles still fuse with the cell membrane but vesicle-to-vesicle fusion enhances secretory output. Two types of compound exocytosis occur, either vesicles fuse with each other and then fuse with the cell membrane, or a vesicle fuses with the cell membrane and then becomes a target for further vesicles to fuse with it. It is expected that SNAREs are important for vesicle-to-vesicle fusion but the mechanism(s) that control these processes is unknown. In our recent paper (Behrendorff et al. 2011) we provide evidence that VAMP8 (a Q-SNARE) is essential in regulating compound exocytosis. Here we discuss the implications of our findings with reference to a new model for the control of vesicle-to-vesicle fusion

UCP2 Regulates the Glucagon Response to Fasting and Starvation

Glucagon is important for maintaining euglycemia during fasting/starvation, and abnormal glucagon secretion is associated with type 1 and type 2 diabetes; however, the mechanisms of hypoglycemia-induced glucagon secretion are poorly understood. We previously demonstrated that global deletion of mitochondrial uncoupling protein 2 (UCP2−/−) in mice impaired glucagon secretion from isolated islets. Therefore, UCP2 may contribute to the regulation of hypoglycemia-induced glucagon secretion, which is supported by our current finding that UCP2 expression is increased in nutrient-deprived murine and human islets. Further to this, we created α-cell–specific UCP2 knockout (UCP2AKO) mice, which we used to demonstrate that blood glucose recovery in response to hypoglycemia is impaired owing to attenuated glucagon secretion. UCP2-deleted α-cells have higher levels of intracellular reactive oxygen species (ROS) due to enhanced mitochondrial coupling, which translated into defective stimulus/secretion coupling. The effects of UCP2 deletion were mimicked by the UCP2 inhibitor genipin on both murine and human islets and also by application of exogenous ROS, confirming that changes in oxidative status and electrical activity directly reduce glucagon secretion. Therefore, α-cell UCP2 deletion perturbs the fasting/hypoglycemic glucagon response and shows that UCP2 is necessary for normal α-cell glucose sensing and the maintenance of euglycemia

Characterization of Zinc Influx Transporters (ZIPs) in pancreatic beta cells: roles in regulating cytosolic zinc homeostasis and insulin secretion

Zinc plays an essential role in the regulation of pancreatic beta cell function, affecting important processes including proinsulin biosynthesis, glucose-stimulated insulin secretion, and cell viability. Mutations in zinc efflux transport protein ZnT8, have been linked with both type 1 and type 2 diabetes, further supporting an important role for zinc in glucose homeostasis. However, very little is known about how cytosolic zinc is controlled by zinc influx proteins (ZIPs). In the current study, we have examined the beta cell and islet ZIP transcriptome and show consistent high expression of ZIP6 (Slc39a6) and ZIP7 (Slc39a7) genes across human, mouse islets and MIN6 beta cells. Modulation of ZIP6 and ZIP7 expression significantly altered cytosolic zinc influx in pancreatic beta cells, indicating an important role for ZIP6 and ZIP7 in regulating cellular zinc homeostasis. Functionally, this deregulated cytosolic zinc homeostasis led to impaired insulin exocytosis and insulin secretion. In parallel studies, we identified both ZIP6 and ZIP7 as potential interacting proteins with GLP-1R by a membrane yeast-two-hybrid (MYTH) assay. Knock-down of ZIP6 but not ZIP7 in MIN6 beta cells impaired the protective effects of GLP-1 on fatty acid-induced cell death possibly via reduced p-ERK pathway. Thus, our data suggests that ZIP6 and ZIP7 function as two important zinc influx transporters to regulate cytosolic zinc concentrations and insulin secretion in beta cells. In particular, ZIP6 is also capable of directly interacting with GLP-1R to facilitate the protective effect of GLP-1 on beta cell survival

Comparison of the Effect of Glycemic Control in Type 2 Diabetes Outpatients Treated With Premixed and Basal Insulin Monotherapy in China

Background: Basal and premixed insulin have been widely used for insulin therapy of type 2 diabetes mellitus (T2DM) in China. The aim of this study is to compare the sustained efficacy of basal and premixed insulin therapies in T2DM outpatients with insulin monotherapy.Materials and Methods: The survey was conducted in 602 hospitals across China from April to June in 2013. The participants included outpatients who were receiving basal or premixed insulin monotherapy for more than 3 months, and the outcome was attaining a glycated hemoglobin A1C (HbA1c) of <7.0% as a measure of sustained glycemic control.Results: A total of 49,119 T2DM outpatients on basal (n = 11,967) or premixed insulin (n = 37,152) monotherapy were included in the final analyses. Using multivariable model analysis, patients using premixed insulin exhibited a better glycemic control, with more outpatients achieving the target HbA1c level than those using basal insulin (model 1, OR 0.695, 95%CI 0.664–0.728; model 2, OR 0.708, 95%CI 0.676–0.742; model 3, OR 0.717, 95%CI 0.684–0.752; model 4, OR 0.750, 95%CI 0.715–0.787). Using subgroup analysis stratified by age, sex, duration of diabetes, duration of insulin treatment, and complications, still more outpatients in every subgroup treated with premixed insulin achieved the target HbA1c (HbA1c < 7%) than those receiving basal insulin.Conclusions: Premixed insulin monotherapy had a better glycemic control (HbA1c < 7.0%) than basal insulin monotherapy for Chinese T2DM outpatients in daily

Erythropoietin protects against diabetes through direct effects on pancreatic β cells

In mouse models of type 1 and type 2 diabetes, administration of human erythropoietin protects against disease by acting directly on pancreatic β cells