Defining the importance of intestinal ketogenesis in type 2 diabetes mellitus

The goal of my project is to define the importance of small intestinal ketogenesis in type 2 diabetes mellitus (T2DM) in humans, with special focus on incretin secretion.We have identified the rate-limiting enzyme of ketogenesis, HMGCS2, to be up-regulated in the upper small intestine by high-fat diet and drastically down-regulated after the weight-reducing operation Roux-en-Y gastric bypass.

We hypothesize that it could be an explanation for the weight-independent regression of T2DM following bariatric surgery.

We have preliminary results indicating that ketone bodies inhibit incretin secretion from enteroendocrine cells.With this project I intend to address the gaps in knowledge regarding small intestinal ketogenesis, incretin secretion and T2DM by adressing the following specific aims:1: Test the hypothesis that ketone bodies inhibit incretin secretion from human intestinal organoids.2: Identify the mechanism for ketone body-mediated inhibition of incretin secretion in human intestinal organoids by knocking-out specific receptors.3: Test the hypothesis that knock-out of HMGCS2 in human intestinal organoids improves incretin secretion.This three-year project is a collaboration between University of Gothenburg and University of Cambridge and I will be stationed at University of Cambridge for two years to perform the research in a laboratory with a strong knowledge within this field.