Targeting alpha-cell GPCRs to stimulate glucagon and counter hypoglycemia

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PROJECT SUMMARY Hypoglycemia is a dangerous complication of exogenous insulin therapy in Type 1 Diabetes (T1D) that is treated by exogenous glucagon secretion. However, the use of exogenous glucagon has its own side effects and can be complicated to administer in an emergency situation. As an alternative, stimuli that lead to robust endogenous glucagon secretion could be effective to counter severe hypoglycemia. Glucagon secretion can be stimulated by amino acids, like alanine and arginine, as well as by glucose-dependent insulinotropic peptide (GIP). Remarkably, we found that while alanine or GIP alone induce modest increases in glucagon secretion, the combination of alanine and GIP synergistically increase glucagon secretion in both isolated mouse and human islets, as well as mice in vivo. A better understanding of the physiology of this glucagon and the mechanism of its release is needed to determine if stimulating endogenous glucagon can treat hypoglycemia in T1D. We hypothesize that endogenous -cell stimuli, such as GIP + alanine, can counter insulin-induced hypoglycemia. The aims of this project are designed to elucidate whether -cell stimuli can mitigate severe hypoglycemia, how the effects of -cell stimulation are changed in T1D, and what is the mechanism that alanine stimulates the - cell to secrete glucagon. Successful completion of this project will enhance our understanding of the -cell and provide insight for the basis of therapeutics for hypoglycemia or insulin co-therapies. In addition, the aims will broaden the Candidate’s technical expertise and develop conceptual understanding of -cell physiology that will provide a foundation for a career as an independent investigator.