Wednesday, April 2, 2025
4/2/2025
Role of Alpha Cells in Pathogenesis of Type 1 Diabetes - PROJECT SUMMARY Longitudinal studies have shown that individuals at high genetic risk for type 1 diabetes (T1D) progress through several distinct stages prior to the onset of clinical symptoms. Although the factors causally involved in the rate of progression are poorly understood, the presence of islet autoantibodies (AAb) is currently the best biomarker for the future onset of hyperglycemia in T1D. In particular, the single AAb+ stage (generally against glutamic acid decarboxylase (GADA+)) represents a key window for intervention to delay or prevent progression to T1D. Our recent study on pancreatic islets isolated from GADA+ donors revealed early α-cell dysfunction while β-cell mass and function are still normal. Specifically, GADA+ donor islets with normal glucose stimulated insulin secretion have already demonstrable defects in glucose suppression of glucagon secretion (GSGS). This defect of GADA+ donors is even more severe in T1D donor islets indicating progressive loss of GSGS. Our previous study showed that this α-cell dysfunction could be related to elevated cAMP signaling and/or decreased glucose metabolism. Specifically, transcriptomic analysis identified key genes as downregulated in GADA+ donors: Protein Kinase Inhibitor Beta (PKIB, a potent PKA inhibitor), glucokinase (GCK), and genes encoding subunits of mitochondrial complex I. Based on these data, we propose here to test the hypothesis that decreased GSGS during the progression of T1D is causally related to altered cAMP signaling and/or dysregulated bioenergetics in α-cells. We have devised two Aims to test this hypothesis. In Aim 1 we will position the cAMP signaling defect by direct measurements of cAMP in human islets; modification of intracellular cAMP levels using general and PKA- and EPAC-specific analogues; selective reduction of PKIB expression in α-cells; and assessment of electrophysiological changes due to cAMP modulation. In Aim 2 we will explore the role of bioenergetics by evaluation of glycolysis and oxidative phosphorylation in intact donor islets and assessment of changes in GSGS due to drug-induced modulation of GCK and complex I activity. The proposed experiments will elucidate mechanisms underlying the specific defects in α-cell function during the progression of T1D.
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