Lead


Lay summary
Our research focuses on the mechanisms and therapy of decreased insulin production by the pancreatic islets in the obesity associated type 2 diabetes. In previous studies we demonstrated that the metabolic stress evoked by high glucose and saturated fatty acids (contained in animal fat) may induce death of the insulin producing beta-cells of the islets. Subsequently we identified a factor termed interleukin 1 beta (IL-1b) as a key mediator of these deleterious effects and showed that it is produce by human beta-cells in type 2 diabetes. More recently we published several additional studies supporting the concept that this mechanism leads to an inflammatory process and underlies the failure to produce sufficient amount of insulin in type 2 diabetes. On the basis of this we initiated clinical trials in patients with type 2 diabetes that vindicates this hypothesis and opens the way for a causative treatment.The overall goal of the present project aims at understanding the precise role and regulation of the uncovered islet inflammation in type 2 diabetes and test therapeutic intervention at early stages of the disease. In particular, we propose the following aims:Aim 1: To study the mechanism of nutrient induced islet inflammation: We have shown that metabolic stress (increased glucose and free fatty acids levels) induces islet derived IL-1b production leading to islet inflammation. However, the underlying mechanism remains unclear. We hypothesize that this involves a group of proteins termed inflammasome.Aim 2: To investigate the role of IL-6 in regulating glucagon-like peptide 1. Plasma IL-6 levels are chronically elevated in obese and type 2 diabetic individuals and predict disease progression. In recent studies we observed that IL-6 regulates a hormone termed GLP-1. GLP-1 may increase the mass and capacity of the beta-cells to produce insulin. We aim to investigate the mechanisms and precise consequences of IL-6 regulated GLP-1. Aim 3: To determine the effect of IL-1b antagonism on insulin secretion and action in obese subjects at risk to develop type 2 diabetes. We have shown that he blockade of IL-1 improved type 2 diabetes and insulin secrtion. However, the consequence of IL-1 antagonism in individuals at risk to develop diabetes has not been studied. The overall objective of this study is therefore to determine in obese subjects whether blocking IL-1b improves insulin secretion and action. We will conduct a placebo-controlled, double-blind study in obese subjects with impaired glucose metabolism. We will assess whether IL-1b antagonism is associated with changes in insulin secretion and thus diabetes prevention