To transform the understanding of pancreatic beta-cell biology by uncovering the molecular mechanisms that drive insulin granule formation and secretion. Through cutting-edge technologies and innovative research, we aim to lay the foundation for breakthroughs that preserve beta-cell function and ultimately improve the lives of those affected by type 2 diabetes.

At the heart of our research is a deep interest in the biology of the insulin secretory granule. We believe that understanding the life cycle and molecular composition of the insulin granule holds significant promise for uncovering new therapeutic targets in both type 1 and type 2 diabetes.

Our diverse team is comprised of expertise including cell biology, animal physiology, mouse genetics, immunofluorescence microscopy, metabolic studies in mouse, isolation of islets from the mouse and in vitro analysis of insulin secretion.

By understanding the mechanism of pancreatic beta-cell function and failure, the real-world impact of our research will be in describing ways to prevent or treat the progression of beta-cell failure and type 2 diabetes.

Proteomic insights into insulin granule biology

We have recently successfully purified the insulin secretory granule from pancreatic beta-cells and conducted comprehensive proteomic analyses. This work led to the identification of over 200 granule-associated proteins, many of which had not previously been linked to the insulin granule. These findings have opened new avenues of investigation into how the granule forms, matures, and responds to physiological cues. We are now actively studying several of these newly identified proteins to determine their roles in normal beta-cell function and to explore how their dysfunction may contribute to diabetes progression.

Targeting granule age to improve β-cell function

We are also interested in understanding how different populations of insulin secretory granules are prioritized for secretion under normal conditions, and how this process is disrupted in the context of metabolic stress and diabetes. Among the factors known to influence the functional heterogeneity of insulin granules, we are particularly focused on the role of granule age in regulating secretion.

Our work has shown that, in response to glucose, β-cells preferentially secrete young, newly synthesized insulin granules. However, this selective release is dysregulated under metabolic stress and in diabetic conditions. We are now working to define the structural and molecular differences between age-distinct granule populations, and how these differences influence their function and fate.

In parallel, we are investigating how current type 2 diabetes therapies that stimulate insulin secretion such as GLP-1 receptor agonists and sulfonylureas—affect the preferential release of young insulin granules, with the aim of uncovering new strategies to enhance β-cell efficiency and resilience.

• Dr Melkam A Kebede (Research group leader)