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Control of insulin secretion by mitochondrial fusion

Award Number: R01DK135268
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: 08/23/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Control of insulin secretion by mitochondrial fusion - ABSTRACT Diabetes results from insufficient functional β-cell mass to meet peripheral insulin demands. β-cells rely upon mitochondrial respiration to generate the energy necessary for insulin biosynthesis, processing, and secretion. Indeed, defects in mitochondrial structure and function have been reported in the β-cells of patients with type 2 diabetes (T2D). Defects in mitochondrial structure and function are characteristic of impairments in mitochondrial dynamics, the balance of fusion and fission of mitochondrial networks. Mitochondrial fusion is governed by several dynamin-like GTPases, including Mitofusins 1 and 2 (Mfn1 and 2). Expression of Mfn1 and/or Mfn2 are reduced in human T2D islets, mouse models of T2D, and following the deposition of toxic islet amyloid polypeptide oligomers. However, the functions of Mfn1 and Mfn2 in β-cells in vivo, and their role in T2D pathogenesis are unclear. Therefore, our goal is to dissect the mechanistic and physiologic regulation of mitochondrial fusion in β-cells to elucidate its contribution to diabetes pathogenesis. The central hypothesis to be tested is that Mfn1 and 2 regulate insulin secretion and islet β-cell connectivity through control of mitochondrial DNA and network stability, and their dysregulation contribute to β-cell failure in T2D. We will test this hypothesis by the following approach: Specific Aim 1 will directly assess the mechanistic implications of loss of mitochondrial fusion on control of mitochondrial DNA copy number. Specific Aim 2 will delineate the mechanisms by which incretins restore insulin secretion following impairments in mitochondrial fusion. Specific Aim 3 will investigate the importance of mitofusins within human β-cells. We anticipate obtaining a clear understanding of the importance and translational relevance of mitochondrial fusion in β-cell function from an evaluation of the central effectors crucial to the maintenance of mitochondrial structure. These results should advance the field of β-cell biology by defining the role of mitochondrial fusion in T2D pathogenesis and could open new horizons for therapies for patients with 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: 2025 ( Subtotal = $602,644 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	8/20/2025	NON-COMPETING CONTINUATION	$602,644
														Subtotal = $602,644

Issue Date FY: 2024 ( Subtotal = $585,042 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/4/2024	NON-COMPETING CONTINUATION	$585,042
														Subtotal = $585,042

Issue Date FY: 2023 ( Subtotal = $637,870 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/22/2023	NEW	$637,870
														Subtotal = $637,870

Grand Total All Awards = $1,825,556

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Control of insulin secretion by mitochondrial fusion

Award Number: R01DK135268

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: 08/23/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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