Studies in islets and enteroendocrine cells to identify targets for the treatment of T2D

­­­­Type 2 diabetes (T2D) is a global health problem and there is a need for improved therapies.

Perturbed islet function is the main cause of T2D, but the processes that fail in each of the 5 islet cell types are not understood. The intestine contains 9 types of enteroendocrine cells (EEC).

The role of EECs in T2D is poorly studied, but undoubtedly important as incretin hormones secreted from EECs are critical regulators of islet hormone secretion.

In this 5-year translational project I will identify targetable cell type-specific T2D disease mechanisms by single-cell RNA sequencing of islets and intestinal biopsies from normoglycemic, hyperglycemic and T2D subjects and two mouse models.

Differential gene coordination network analysis (dGCNA) will identify gene networks, representing affected cellular processes in each islet and enteroendocrine cell type, as well as genes with central roles in each process.

Such genes will be subjected to comprehensive functional and mechanistic validation in experimental models, in vivo studies in mice, and studies in human tissue; primarily aiming at identifying regulators of insulin, glucagon, and GLP-1. Finally, antidiabetic effects will be assessed in T2D models.

With this strategy we are well positioned to identify cell type-specific targetable disease mechanism of T2D in islets and EECs. All studies are based on extensive preliminary data generated using methods established in my lab.