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Insulin-resistant Leanness and Insulin-Sensitive Obesity in Humans: Role of Skeletal Muscle Phosphoproteome and O-GlcNAc Glycoproteome

Award Number: RC2DK142611
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: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Insulin-resistant Leanness and Insulin-Sensitive Obesity in Humans: Role of Skeletal Muscle Phosphoproteome and O-GlcNAc Glycoproteome - Insulin resistance in skeletal muscle is considered to be a primary contributor to the development of T2D1-8. Mechanisms underlying insulin resistance in skeletal muscle are incompletely understood, limiting effective strategies for preventing and treating T2D. For example, it is estimated that 30% of lean individuals are metabolically unhealthy and have reduced insulin sensitivity, with insulin activity similar to obese, insulin-resistant individuals9-11. Similarly, an estimated 30% of individuals with obesity are metabolically healthy with functional insulin sensitivity12-15. The factors that confer promotion of insulin resistance in certain lean subjects or protection from insulin resistance in certain obese subjects remain elusive, which constitutes a significant unmet medical need. An underexplored factor in insulin resistance is the crosstalk between reversible phosphorylation and O-linked N-acetylglucosamine (O-GlcNAc) protein modifications, each of which is known to play fundamental roles in insulin signaling. Examples of phosphorylation/O-GlcNAc cross-talk have been observed at the same Ser/Thr sites on proteins directly involved in insulin signaling, including Akt and Foxo121,22. The main goal of this RC2 proposal is to determine the role of protein phosphorylation and O-GlcNAc glycosylation cross-talk in skeletal muscle insulin resistance, by establishing a database of phosphorylation and O-GlcNAc differences between insulin-sensitive vs. insulin-resistant human individuals. This unique resource will drive unbiased discovery across the metabolic disease field. To the best of our knowledge, no peer-reviewed publications have reported (1) Phosphorylation/O-GlcNAc cross-talk in skeletal muscle tissue in any species; (2) Phosphorylation/O-GlcNAc cross-talk in lean insulin sensitive (LIS), lean insulin resistant (LIR), obese insulin sensitive (OIS) and obese insulin resistant (OIR) human participants; and (3) Differential phosphoproteomics and O-GlcNAc glycoproteomics studies on skeletal muscle from the same LIS, LIR, OIS and OIR participants. In this proposal, we aim to generate a research resource for the NIDDK community: a comprehensive metabolic disease-relevant database of protein phosphorylation and O-GlcNAc glycosylation sites in skeletal muscle tissue from LIS, LIR, OIS and OIR participants. This new knowledge may facilitate re-purposing of FDA-approved kinase inhibitor drugs, and rationalize O-GlcNAc transferase (OGT) inhibitors for T2D therapies. We will work with dkNET to connect this resource to the greater research community.


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 = $1,137,052 )
2026	2026	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/26/2026	NEW	$1,137,052
														Subtotal = $1,137,052

Grand Total All Awards = $1,137,052

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Insulin-resistant Leanness and Insulin-Sensitive Obesity in Humans: Role of Skeletal Muscle Phosphoproteome and O-GlcNAc Glycoproteome

Award Number: RC2DK142611

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: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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