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Metabolic Functions of Pyruvate Kinase M2 in Pancreatic Beta-cells

Award Number: R01DK113103
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: 04/01/2017
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Metabolic Functions of Pyruvate Kinase M2 in Pancreatic Beta-cells - ABSTRACT Over 450 million people suffer from type 2 diabetes (T2D), a disease defined by the failure of pancreatic β-cells. In the first period of support, we showed that pharmacologic activators of pyruvate kinase (PK) potentiate insulin secretion from mouse, rat, and human islets, as well as diabetic rats in vivo, identifying PK as a potential therapeutic target for T2D. We further demonstrated that PK plays an important role in β-cell nutrient sensing. We discovered a novel paradigm in which plasma-membrane associated PK closes KATP channels to initiate insulin secretion, and that the PKm1 and PKm2 isoforms tune the amino acid sensitivity of KATP closure via the mitochondrial phosphoenolpyruvate (PEP) cycle. The purpose of renewing this R01 is to ascertain the mechanism by which PK amplifies insulin secretion. Our preliminary studies revealed that PK activators amplify the insulinotropic actions of the incretin hormone glucagon-like peptide 1 (GLP1) but not glucose-dependent insulinotropic peptide (GIP), indicating receptor-specific signaling through pyruvate kinase. Further observations suggest a major unexplored contribution of PK to the kinetics of β-cell cAMP generation during nutrient stimulation. Based on our preliminary studies, our central hypothesis is that pyruvate kinase and GLP1 receptor (GLP1R) signaling converge on cAMP production to amplify insulin release. We will: 1) Determine which PK isoforms control β-cell cAMP levels, and whether the PEP cycle is required, 2) Define the mechanisms by which β-cell GLP1R signaling recruits pyruvate kinase, and 3) Determine, under metabolic stress conditions, whether PK contributes to the mechanism of existing and novel anti-diabetic drugs that target GLP1R and GIPR. Completion of these aims will define the interplay between PK and β-cell GPCR signaling, and shed light on the mechanisms underlying the efficacy of widely used incretin-based therapies for T2D, thus guiding the development of next-generation incretin mimetics biased toward the compartmentalized signaling pathways identified to be most effective for treating β-cell dysfunction at each stage of T2D progression.


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 = $583,915 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	8	1/29/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$583,915
2026	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	1/29/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $583,915

Issue Date FY: 2025 ( Subtotal = $485,459 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	2/27/2025	NON-COMPETING CONTINUATION	$485,459
														Subtotal = $485,459

Issue Date FY: 2024 ( Subtotal = $539,398 )
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	3/25/2024	COMPETING CONTINUATION	$539,398
														Subtotal = $539,398

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/22/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $338,651 )
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/22/2021	NON-COMPETING CONTINUATION	$338,651
														Subtotal = $338,651

Issue Date FY: 2020 ( Subtotal = $338,651 )
2020	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/31/2020	NON-COMPETING CONTINUATION	$338,651
														Subtotal = $338,651

Issue Date FY: 2019 ( Subtotal = $344,264 )
2019	2019	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/29/2019	NON-COMPETING CONTINUATION	$344,264
														Subtotal = $344,264

Issue Date FY: 2018 ( Subtotal = $344,004 )
2018	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/25/2018	NON-COMPETING CONTINUATION	$344,004
														Subtotal = $344,004

Issue Date FY: 2017 ( Subtotal = $355,933 )
2017	2017	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/14/2017	NEW	$355,933
														Subtotal = $355,933

Grand Total All Awards = $3,330,275

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Metabolic Functions of Pyruvate Kinase M2 in Pancreatic Beta-cells

Award Number: R01DK113103

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: 04/01/2017

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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