Dissertation
Pancreatic islet GRK2 regulates hormone secretion and glycemic control by regulating metabolism and GPCR sensitivity
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2023
DOI:
https://doi.org/10.17918/00001825
Abstract
The adaptation of insulin secretion capacity in response to diet, age, and lifestyle factors is central to metabolic health. Recent advances in GPCR-targeting interventions for type 2 diabetes highlight the importance of this mechanism in controlling acute pancreatic islet function and islet development. Due to the known role of G-protein coupled receptor kinase 2 (GRK2) in regulating key islet GPCRs, and the parallel interest in GRK2 inhibitors for cardiovascular disease, the role of GRK2 in pancreatic hormone secretion was assessed. Experiments in a pancreatic [beta]-cell model revealed that knockdown of GRK2 limits insulin secretion by diminishing the efficiency of oxidative phosphorylation, limiting ATP production, and limiting calcium influx. Restricting inhibitory G[alpha]i/o signaling appears to reverse the deficits in calcium flux and insulin secretion. A pancreatic specific embryonic GRK2 knockout model exhibits robustly increased glycemic exposure with a deficit in insulin secretion. However, separate adult-stage induced [alpha]-cell and [beta]-cell GRK2 knockout models reveal diet and sex dependent roles for GRK2 in regulating glycemic control and metabolic health via hormone secretion. The [beta]-cell GRK2 knockout mice exhibit normal glycemic control and insulin secretion on standard chow diet, but males have exacerbated glycemic excursion after 12-weeks on HFHS diet. Enhanced signaling through the [alpha]2-adrenergic receptor may play a role in restricting [beta]-cell proliferation as [beta]-cell GRK2 knockout mice have smaller islets after high fat high sucrose diet exposure. Further studies will continue to characterize the cardiac phenotype and adaptation to altered diabetic trajectories and specific signaling mechanisms that underlie the observed insulin secretion deficit.
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Details
- Title
- Pancreatic islet GRK2 regulates hormone secretion and glycemic control by regulating metabolism and GPCR sensitivity
- Creators
- Jonathan William Snyder
- Contributors
- Priscila Sato (Advisor)Peter J. Gaskill (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- viii, 193 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991021229615304721