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Defining alpha-cell PC1/3 expression regulation for type 2 diabetes

Award Number: F30DK126538
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/18/2020
PERIOD OF PERFORMANCE END DATE: 05/28/2023

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Defining alpha-cell PC1/3 expression regulation for type 2 diabetes - PROJECT SUMMARY Glucagon-like peptide-1 (GLP-1) enhances islet function by potentiating glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells; however, the mechanisms by which GLP-1 potentiates GSIS remain incompletely defined. In the classic model, GLP-1 secreted by the intestinal L cells in response to the ingestion of nutrients stimulates the β-cell GLP-1 receptor (GLP-1R) to enhance GSIS. This model is currently in question, as the short half-life of GLP-1 and its rapid degradation present limitations as to how GLP-1 can mediate effects in distant targets, such as pancreatic β-cells. In explanation of such limitations, there is an emerging hypothesis suggesting that GLP-1 locally produced by α-cells acts in a paracrine manner on neighboring β-cells to stimulate GSIS, which ultimately promotes lowering of glycemia. Proglucagon is expressed in the gut and α-cells and is cleaved to form GLP-1 or the counter-regulatory hormone, glucagon, depending on the prohormone convertase (PC) type present. It was previously thought that the tissue-specific processing of proglucagon was due to the differential expression of PC1/3 and PC2, but several studies in rodent models and humans have shown that α- cells can produce active GLP-1 and express PC1/3. However, the mechanisms by which α-cell PC1/3 expression is regulated are unknown. Identifying a mechanism to increase α-cell PC1/3 expression to increase GLP-1 production at the expense of glucagon will provide a powerful therapeutic modality for the regulation of blood glucose concentrations in patients with T2DM. We have shown that increased β-cell GLP-1R signaling increases α-cell PC1/3 and GLP-1 expression. My preliminary data suggest that insulin may serve as potential intermediate by which β-cell GLP-1R signaling alters α-cell proglucagon processing. Specifically, I hypothesize that β-cell GLP-1R signaling increases α-cell PC1/3 expression through both α-cell insulin receptor (IR) dependent and independent pathways. In Aim 1, I will assess the role of α-cell IR signaling to determine whether insulin is necessary to alter the secretory phenotype of α-cells by measuring glucose regulation, GSIS, and PC1/3 expression in α-cell-specific Irα-cell +/+ and Irα-cell -/- mice with and without stimulation by exogenous GLP-1. In Aim 2, I will determine the pathways through which β-cell GLP-1R signaling increases α-cell PC1/3 expression by single-cell RNA-sequencing of islets from inducible β-cell-specific Glp-1rβ-cell+/+ and Glp-1r-cell-/- mice, as well as human islets with β-cell-specific GLP-1R knockout. Together, these studies will define a link between the pathways regulating α-cell PC1/3 expression and GLP-1 production; thus, enabling targeting of the α-cell secretory phenotype for the treatment of T2DM.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$43,167 )
2024	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	9/23/2024	NON-COMPETING CONTINUATION	-$19,086
2024	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/30/2024	NON-COMPETING CONTINUATION	-$24,081
														Subtotal = -$43,167

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/27/2023	NON-COMPETING CONTINUATION	$52,694
														Subtotal = $52,694

Issue Date FY: 2022 ( Subtotal = $51,752 )
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	5/20/2022	NON-COMPETING CONTINUATION	-$1
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/14/2022	NON-COMPETING CONTINUATION	$51,036
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/28/2022	NON-COMPETING CONTINUATION	$717
														Subtotal = $51,752

Issue Date FY: 2021 ( Subtotal = $42,516 )
2021	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/23/2021	NON-COMPETING CONTINUATION	$42,516
														Subtotal = $42,516

Issue Date FY: 2020 ( Subtotal = $42,000 )
2020	2020	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/18/2020	NEW	$42,000
2020	2020	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	3/18/2020	NEW	$0
														Subtotal = $42,000

Grand Total All Awards = $145,795

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Defining alpha-cell PC1/3 expression regulation for type 2 diabetes

Award Number: F30DK126538

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/18/2020

PERIOD OF PERFORMANCE END DATE: 05/28/2023

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