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The Influence of Developmental Exposure to Maternal Overnutrition and Metformin on Offspring Mitochondrial Health and Beta Cell Function

Award Number: F31DK135164
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: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 06/23/2024

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The Influence of Developmental Exposure to Maternal Overnutrition and Metformin on Offspring Mitochondrial Health and Beta Cell Function - Project Summary/Abstract In collaboration with a non-human primate (NHP) consortium with over a decade of experience studying the developmental origins of health and disease in response to maternal overnutrition, this proposal will evaluate the effect that intrauterine exposure to metformin and overnutrition has on the development of pancreatic beta cells and islet mitochondrial health in fetal Rhesus macaques. In the United States, 31% of women of childbearing age are classified as overweight or obese. As global rates of obesity rise, the influence of developmental exposure to maternal overnutrition and the drugs prescribed to treat maternal metabolic disease on offspring metabolic outcomes is of critical interest. Metformin is typically prescribed for the treatment of Type 2 Diabetes; however, use of metformin has been expanded over the past decade to treatment for gestational diabetes, polycystic ovarian syndrome, and preeclampsia. Data suggests that metformin crosses the placental barrier and equilibrates in fetal circulation, raising concerns for unintended fetal harm. While the target of metformin is unknown, a proposed mechanism of metformin is activation of 5’ adenosine monophosphate kinase (AMPK), a nutrient sensing kinase that is central to regulation of pathways associated with cellular growth, proliferation, metabolism, and epigenetic regulation. Metformin has also been shown to inhibit complex I of the mitochondrial electron transport chain, reducing the production of ATP, which is important for glucose-stimulated insulin secretion from beta cells. The goal of the studies outlined in this proposal is to elucidate the influence that maternal consumption of a western style diet and metformin has on beta-cell mass, identity, and function at the fetal stage of development in a highly relevant NHP model. Additionally, this proposal includes studies investigating the individual and combined effects of maternal overnutrition and metformin on islet mitochondrial morphology and function in offspring. To accomplish these goals, I will use high resolution microscopy, real time metabolic analyses, and single nucleus RNA sequencing to identify programmed mechanisms that may correlate to increased propensity for beta cell failure later in the offspring’s life.


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: 2025 ( Subtotal = -$2,861 )
2025	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/24/2025	NON-COMPETING CONTINUATION	-$2,861
														Subtotal = -$2,861

Issue Date FY: 2024 ( Subtotal = $14,862 )
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	4/30/2024	NON-COMPETING CONTINUATION	$1,280
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/24/2024	NON-COMPETING CONTINUATION	$32,970
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	7/25/2024	NON-COMPETING CONTINUATION	-$19,388
														Subtotal = $14,862

Issue Date FY: 2023 ( Subtotal = $32,970 )
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	2/9/2023	NEW	$1,449
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/13/2023	NEW	$31,521
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	1	2/16/2023	NEW	$0
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	1/13/2023	NEW	$0
														Subtotal = $32,970

Grand Total All Awards = $44,971

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The Influence of Developmental Exposure to Maternal Overnutrition and Metformin on Offspring Mitochondrial Health and Beta Cell Function

Award Number: F31DK135164

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: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 06/23/2024

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