Developing an optimal in vitro cellular model to study the mechanism(s) of pancreas lipotoxicity in type 2 diabetes

In addition to losing normal insulin secretory function, the pancreas in type 2 diabetes (T2D) undergoes progressive loss of its mass.

Remission of T2D after weight loss decreases pancreatic fat content, returns normal insulin secretion, and increases total pancreas volume.

However, this dietary approach is challenging, thus understanding the underlying molecular mechanisms that lead to remission at cellular level is critical to develop more durable therapies.

Given than acinar cells constitute most of the pancreas tissue, and the islets represent only ~5%, we hypothesize that lipotoxicity induces similar damage to acinar and β-cells which is reversible at early stages.

This project aims to optimise conditions for isolating and culturing primary pancreatic cells (islet/acinar cells) from human donors.

Secondly, it will develop a vitro cellular model for reconditioning islet cells and assess whether removing the metabolic stimulus (lipotoxic stress) restores normal β-cell function.

Ultimately, this project will help to establish the optimal conditions for recovering pancreatic cell function and study their behaviour in response to toxic lipids.

This will elucidate the mechanism(s) by which excess fat exerts it lipotoxic effects and could lead the way to novel strategies to manage diabetes and maintain normal pancreas health and function.