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Mechanisms of Fatigability and the Protective Effects of Exercise in People with Diabetes

Award Number: R01AG077688
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Mechanisms of Fatigability and the Protective Effects of Exercise in People with Diabetes - ABSTRACT Pre-diabetes (Pre-D) is characterized by elevated glycated hemoglobin and plasma glucose and is a clinical precursor to type 2 diabetes mellitus (T2D). Pre-D currently affects ~90 million Americans. Both Pre-D and T2D are highly associated with cardiovascular disease and among the top five causes of mortality worldwide. Exercise is the cornerstone of management and is most efficacious during the Pre-D stage when glycemia is below the diabetic threshold. However, excessive fatigability during exercise (i.e., exercise induced reductions in force or power of the limb muscles) limits exercise performance in people with Pre-D. Our laboratory demonstrated that (1) across the diabetic spectrum, people with Pre-D and T2D have greater fatigability of limb muscles than controls due to mechanisms within the muscle, and (2) fatigability in people with T2D was associated with a reduced blood flow to the exercising muscle. It is unknown, however, if people with Pre-D have impaired vascular function and oxygen delivery that leads to an increased fatigability. Our central hypothesis is that impaired vascular function impedes blood flow and blunts subsequent oxygen delivery to skeletal muscle during exercise, resulting in excessive fatigability of limb muscles in people with Pre-D. A unique and translational aspect of this proposal is the quantification of the vascular responses (macro- and micro-vasculature) to fatiguing exercise and exercising training at different sites along the vascular tree, including, in feed arteries (doppler ultrasonography), isolated skeletal muscle arterioles (extracted from muscle biopsy), capillary perfusion (near infrared spectroscopy, NIRS) and capillary density (from muscle biopsies). Aim 1 will determine if vascular dysfunction is a mechanism for excessive fatigability in people with Pre-D. Aim 1.1 will compare leg blood flow and skeletal muscle oxygenation in response to dynamic fatiguing exercise between people with Pre-D, healthy controls and T2D. Groups will be matched for age, sex, body mass index and physical activity levels to determine disease- related vascular function and fatigability rather than inactivity-related changes across the diabetic spectrum. Skeletal muscle blood flow through the femoral artery will be quantified with ultrasonography and skeletal muscle oxygenation with NIRS during a dynamic fatiguing knee extension exercise. Aim 1.2 will determine endothelial vascular function at macro- and micro-vascular levels in people with Pre-D and T2D. Flow-mediated dilation will be assessed in vivo in the femoral artery using ultrasonography and in isolated arterioles extracted from the vastus lateralis muscle biopsies. Aim 2 is a clinical trial that will determine the effectiveness of resistance exercise training coupled with blood flow restriction to improve fatigability and vascular function in people with diabetes. People with Pre-D and T2D will perform 8 weeks of unilateral resistance training in which one leg is exercised with freely perfused conditions and the other leg with blood flow restriction. Thus, blood flow restriction and resistance training will be used as a probe to further understand the mechanisms of fatigability along the vascular tree in people with Pre-D and T2D, and test training strategies to improve fatigability in this population.


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	2024	MARQUETTE UNIVERSITY	313 N 13TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Aging Research	000	3	1/26/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	MARQUETTE UNIVERSITY	313 N 13TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Aging Research	000	3	9/19/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $609,795 )
2024	2024	MARQUETTE UNIVERSITY	313 N 13TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Aging Research	000	3	8/5/2024	NON-COMPETING CONTINUATION	$609,795
														Subtotal = $609,795

Issue Date FY: 2023 ( Subtotal = $616,309 )
2023	2023	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Aging Research	001	2	8/23/2023	NON-COMPETING CONTINUATION	$616,309
2023	2022	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Aging Research	000	1	11/22/2022	NEW	$0
														Subtotal = $616,309

Issue Date FY: 2022 ( Subtotal = $631,134 )
2022	2022	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Aging Research	000	1	9/15/2022	NEW	$631,134
														Subtotal = $631,134

Grand Total All Awards = $1,857,238

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Mechanisms of Fatigability and the Protective Effects of Exercise in People with Diabetes

Award Number: R01AG077688

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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