Beta-cells in diet-induced diabetes and remission

Type 2 diabetes mellitus (T2DM) is a chronic disease, characterized metabolically by obesity, insulin resistance, and insulin secretory deficit. Long-term treatment of T2DM with sequential addition of therapies, eventually leading to parenteral application of insulin, is often associated with premature severe health issues and immense individual and public health cost. Recent studies using very low calorie diets have convincingly shown that an inevitably progressive nature of T2DM is limited to people with increasing body mass and insulin resistance. Dietary restrictions result in a rapid and long lasting diabetes remission in a good majority of T2DM patients (responders), even on a subsequent isocaloric diet. It is currently not understood why a subset of T2DM patients on very low calorie diet do not enter diabetes remission (non-responders). Irreversible beta cell injury related to gluco- or lipotoxicity could be a key factor determining the responsiveness to the diet. Our primary objective is to study the mechanism and the organizational level of beta cell injury and its reversibility. We attempt to validate a novel diet-induced mouse model of T2DM development and remission (i.e., the so called western diet-fed mouse) using our acute pancreas tissue slice approach in combination with electrophysiological (contributed by the Austrian partner), optophysiological (contributed by the Slovenian partners) as well as advanced computational analytical methods, complemented by a set of in vivo measurements in mice and analysis of measurements on isolated human islets and islets in human slices (both partners). We suggest that a detailed knowledge regarding the mechanism and organizational level of beta cell injury reversal due to dietary interventions will help us find new treatment strategies, better stratify patients to different treatments, and together with existing or novel pharmacological and precision medicine approaches finally cure the disease.

Type 2 diabetes (T2D) is a chronic disease, characterized by obesity, insulin resistance, and insulin secretory deficit. Long-term treatment of T2D with sequential addition of therapies is associated with severe health issues and large individual and public burden. Recent studies using very low calorie diets have shown a rapid and long lasting diabetes remission in a majority of T2D patients, even on a subsequent isocaloric diet. Within the project we evaluated a new experimental model for T2D in mice, confirmed differences between sexes, discovered more accurate lesion sites contributing to the development of T2D and the reversibility of these changes, uncovered novel cellular targets for therapy of T2D, optimized and disseminated the pancreatic tissue slice approach and computational approaches developed in the project.