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The effect of endogenous GLP-1 secretion on islet function in vivo

Award Number: R01DK126206
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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The effect of endogenous GLP-1 secretion on islet function in vivo - We have recently demonstrated that, in humans, islet function is dependent on Glucagon-Like Peptide-1 (GLP- 1), presumably originating in the α-cell. Islet GLP-1 regulates insulin and glucagon secretion and its effects seem to be more important in type 2 diabetes. However, these observations raise additional questions which we seek to address in this application. The first is whether the isolated defects in the regulation of fasting or postprandial glucose tolerance, seen in prediabetes, represent selective failure of islet GLP-1 to support islet function. Accordingly, we will use GLP-1 receptor blockade with exendin 9-39 to better understand the role (or lack thereof) of islet GLP-1 in the pathogenesis of prediabetes. At present we do not know how the system is regulated. Rodent models suggest that factors secreted by the β-cell in response to agonism of the β-cell’s GLP-1 receptors regulate expression of the prohormone convertase enzyme necessary to convert proglucagon to GLP-1. This is testable in humans with and without functional β-cells. Their response to exendin 9-39 will be compared before and after 4-week treatment with a GLP-1 receptor agonist. The experimental design will also establish if the system is affected by glycemic control and weight loss. Finally, a common genetic variant in TCF7L2 predisposes to type 2 diabetes through effects on α- and β-cell function. However, the mechanism by which it does so remains obscure. TCF7L2 is a transcription factor that mediates proglucagon gene expression in endocrine-derived cells, driving GLP-1 expression in enteroendocrine cells. Therefore, we will test the hypothesis that the diabetes-associated variant at this locus (rs7903146) impairs islet production of GLP-1 thereby impairing islet function. The proposed experiments will help to understand the role and regulation of islet GLP-1, furthering our ability to prevent type 2 diabetes.


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: 2026 ( Subtotal = $0 )
2026	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	1/7/2026	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $742,934 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	8/5/2025	COMPETING CONTINUATION	$94,618
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	3/5/2025	COMPETING CONTINUATION	$648,316
														Subtotal = $742,934

Issue Date FY: 2024 ( Subtotal = $489,334 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/29/2024	NON-COMPETING CONTINUATION	$489,334
														Subtotal = $489,334

Issue Date FY: 2023 ( Subtotal = $510,636 )
2023	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/9/2023	NON-COMPETING CONTINUATION	$510,636
														Subtotal = $510,636

Issue Date FY: 2022 ( Subtotal = $510,636 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/13/2022	NON-COMPETING CONTINUATION	$510,636
														Subtotal = $510,636

Issue Date FY: 2021 ( Subtotal = $510,636 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/28/2021	NON-COMPETING CONTINUATION	$510,636
														Subtotal = $510,636

Issue Date FY: 2020 ( Subtotal = $525,386 )
2020	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	7/3/2020	NEW	$0
2020	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/17/2020	NEW	$525,386
														Subtotal = $525,386

Grand Total All Awards = $3,289,562

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The effect of endogenous GLP-1 secretion on islet function in vivo

Award Number: R01DK126206

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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