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252-LB: GRK2 Participates in Islet Function and Glucose-Stimulated Insulin Secretory Responses
Journal article   Peer reviewed

252-LB: GRK2 Participates in Islet Function and Glucose-Stimulated Insulin Secretory Responses

Jonathan Snyder, Sarah Montgomery, Nicolai Doliba, Jeffrey Roman, Yuzhen Tian, Priscila Sato, William Holland and Ran Choi
Diabetes (New York, N.Y.), v 71(Supplement_1)
01 Jun 2022
DOI: https://doi.org/10.2337/db22-252-LB

Abstract

Animal models b-Adrenergic-receptor kinase Beta cells Calcium influx Calcium metabolism Cell culture Cell size Cellular stress response Diabetes Diabetes mellitus G protein-coupled receptors Glucose Glucose tolerance High fat diet Insulin Intolerance Mitochondria Pancreas Secretion Sucrose
Insulin deficiency is central to diabetes and diabetes-related cardiac dysfunction. GPCRs are known modulators of insulin secretion and a main pharmacological target in various tissues, including the heart. GPCR kinase 2 (GRK2) phosphorylates activated GPCRs, targeting receptors for recycling or degradation. Notably, we and others have shown that GRK2 can also localize to the cardiac mitochondria where it participates in substrate utilization, particularly in response to cellular stress. GRK2 is downregulated in the pancreas of diabetogenic mice, and we have shown that pancreatic loss of GRK2 impairs insulin secretion in normal and high fat diet. Mice with pancreatic-specific GRK2 KO showed glucose intolerance (AUC WT 8691 vs. KO 14766 mg/dl*min, n=22/group, p<.05) due to significant decrease in insulin secretion following glucose administration (after 15 minutes WT 2.35 vs. KO 1.616 ng/ml, N=16-19/group, P<.0001) without changes in islet size or cell distribution. Using a model of high fat diet, we observed an impairment in glucose-stimulated insulin release in pancreatic GRK2 KO animals when compared to control animals without significant changes in fasting insulin secretion or insulin sensitivity. To further dissect the role of islet GRK2 in α- or β-cells, we have constructed two novel mouse models of inducible cell type-specific GRK2 KO. Our preliminary studies reveal that β-cell GRK2 deficient animals are prone to glucose intolerance and decreased glucose-induced insulin secretion when exposed to high fat high sucrose diet. This suggests that GRK2 plays a role in islet adaptation to metabolic challenge. Further studies will delineate the mechanistic role of GRK2 in mediating metabolism and calcium influx in β-cells regulating insulin secretion, and subsequently the impact to the heart in the presence or absence of TAC. Our studies will provide new GRK2 mechanistic insight that could be explored as new pharmacological strategies to delay diabetes disease progression.

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Web of Science research areas
Endocrinology & Metabolism
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