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Examining how the novel S64F MAFA variant produces glucose intolerance or hypoglycemia in a sex-dependent manner

Award Number: K08DK132507
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Examining how the novel S64F MAFA variant produces glucose intolerance or hypoglycemia in a sex-dependent manner - PROJECT ABSTRACT As of 2018, 30.3 million Americans have been diagnosed with diabetes (10% of the U.S. population with a male sex bias). Its close associations with many chronic diseases, such as heart attacks, strokes, and cancers, make diabetes a leading risk factor for morbidity and mortality. In all forms of diabetes, the inability to maintain normal glucose levels results from progressive dysfunction and eventual loss of insulin-producing b-cells in the pancreas. With high rates of treatment failure on standard therapy, developing new therapeutic approaches to preserve or even enhance b-cell function is a priority. Furthermore, differences in metabolism between men and women during healthy aging and disease are appreciated but poorly understood. Pancreatic b-cells require several key factors to appropriately secrete insulin. One such factor is MafA, a transcription factor fundamental to mature b-cell function. The early loss of human MafA (MAFA) in b-cells in patients with type 2 diabetes highlights its importance to human b-cell health. In addition, a naturally occurring, genetic mutation in MAFA (S64F MAFA) was recently identified to predispose carriers to either familial, adult- onset diabetes or hypoglycemia (low blood glucose). Curiously, S64F MAFA-associated diabetes is much more prevalent in men while women tend to present with hypoglycemia. To better understand the sex- dependent effects of this variant, we generated a mouse model harboring this mutation. This model shows the expected sex-dependent effects seen in humans, suggesting similar mechanisms between mice and humans. Male S64F MAFA mice were hyperglycemic due to widespread, premature b-cell aging and senescence, while female S64F MAFA mice were hypoglycemic by a mechanism which is not yet clearly defined. However, our preliminary studies suggest that S64F MAFA creates different b-cell subtypes in females, one of which is hyperfunctional. Taken together, these results suggest that S64F MAFA can incur diverse b-cell responses to produce sex-dependent diseases: diabetes (b-cell hypofunction) and hypoglycemia (b-cell hyperfunction). This investigation will identify and compare the diverse molecular responses to S64F MAFA in male and female b-cells across mice and humans to understand the sex-dependent, b-cell responses unique to human b-cells. We will first use the penetrant, proof-of-principle S64F MAFA mouse model which mimics several aspects of human disease to identify the diverse b-cell populations by single cell transcriptomics. For example, diversity in premature aging signatures will be related to the dysfunction seen in senescent, male S64F MAFA b-cells. We will then investigate the molecular and functional responses to the S64F MAFA protein in genetically modified, male and female human b-cells using novel pseudoislet technology to identify targets unique to human b-cell function. In sum, our work will advance fundamental understanding of sex-dependent b-cell responses in humans. Mechanisms underlying a relative male vulnerability and female resistance to diabetes in this model can be harnessed to develop therapies tailored to the individual.


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 = $158,436 )
2026	2026	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/19/2026	NON-COMPETING CONTINUATION	$158,436
														Subtotal = $158,436

Issue Date FY: 2025 ( Subtotal = $158,436 )
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/9/2025	NON-COMPETING CONTINUATION	$158,436
														Subtotal = $158,436

Issue Date FY: 2024 ( Subtotal = $158,436 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/24/2024	NON-COMPETING CONTINUATION	$158,436
														Subtotal = $158,436

Issue Date FY: 2023 ( Subtotal = $158,436 )
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/5/2023	NON-COMPETING CONTINUATION	$158,436
														Subtotal = $158,436

Issue Date FY: 2022 ( Subtotal = $158,316 )
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/9/2022	NEW	$158,316
														Subtotal = $158,316

Grand Total All Awards = $792,060

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Examining how the novel S64F MAFA variant produces glucose intolerance or hypoglycemia in a sex-dependent manner

Award Number: K08DK132507

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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