DETROIT – A Wayne State University research team was awarded a $5.7 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health focused on discovering the biological mechanisms that may help explain why some lean people develop insulin resistance while some people with obesity remain sensitive to insulin. The interdisciplinary project is co-led by Dr. Zhengping Yi, professor of pharmaceutical sciences in the Eugene Applebaum College of Pharmacy and Health Sciences, and Dr. Charlie Fehl, associate professor of chemistry in the College of Liberal Arts and Sciences, and includes co-investigators Dr. Berhane Seyoum and Dr. Seongho Kim of the Wayne State University School of Medicine.
The five-year project, “Insulin-resistant Leanness and Insulin-Sensitive Obesity in Humans: Role of Skeletal Muscle Phosphoproteome and O-GlcNAc Glycoproteome,” will support research examining molecular mechanisms in skeletal muscle that may contribute to insulin resistance, an important risk factor for type 2 diabetes. Insulin is a hormone that helps regulate blood sugar by allowing cells to absorb glucose and use it for energy. When a person develops insulin resistance, cells do not respond to insulin as effectively as they should. Over time, this can contribute to elevated blood sugar and the development of type 2 diabetes. These higher blood sugar levels redirect cellular processes, which this project seeks to reveal and exploit as therapeutic targets to prevent at-risk individuals from progressing to diabetes.
Yi and Fehl and their collaborators will study skeletal muscle tissue from four groups: lean people who are insulin sensitive, lean people who are insulin resistant, people with obesity who are insulin sensitive and people with obesity who are insulin resistant. Comparing these groups will allow the researchers to investigate molecular differences associated with insulin resistance separately from those associated with body weight. The study will recruit volunteers from metro Detroit, positioned to directly promote health within the local community.
The researchers will focus on two types of chemical changes to proteins, known as phosphorylation and O-GlcNAc glycosylation. These modifications can affect how proteins function and communicate within cells. By examining them on a large scale, the team aims to identify biological pathways that distinguish insulin-sensitive muscle from insulin-resistant muscle.
A major goal of the project is to create a comprehensive database of these protein modifications in human skeletal muscle from the four groups. The resource is intended to support the broader research community in studying insulin resistance, obesity, type 2 diabetes and related metabolic disease.
“This project is an excellent example of the important work our researchers are conducting that aims to impact the health and well-being of our local community and beyond,” said Dr. Ezemenari M. Obasi, vice president for research & innovation at Wayne State University. “Dr. Yi and Fehl are bringing together teams of researchers across our campus that will combine their expertise to accelerate discoveries beyond a single lab. I look forward to the new knowledge and data they will provide to the broader scientific community to improve the health of many.”
The findings could also help researchers identify potential therapeutic strategies. The team will examine whether its findings could support repurposing U.S. Food and Drug Administration-approved kinase inhibitor drugs and provide a scientific rationale for further study of inhibitors targeting O-GlcNAc transferase, or OGT, as a potential approach to insulin resistance and type 2 diabetes.
Additional research, including clinical trials, would be necessary to determine whether therapeutic approaches emerging from this work are safe and effective in people.
“Dr. Yi’s research highlights the kind of collaborative, forward-looking science we strive to advance,” said Dr. Christine Rabinak, associate dean for research for WSU Applebaum. “By bringing together expertise from across Wayne State to better understand the complex biology of insulin resistance, this project has the potential to advance our knowledge to guide future approaches to preventing and treating type 2 diabetes.”
Yi’s research focuses on insulin signaling, insulin resistance, obesity, type 2 diabetes, and proteomics and the large-scale study of proteins. His work combines clinical, biological, biochemical, proteomic and bioinformatic approaches. He joined Wayne State in 2011 and is director of the Department of Pharmaceutical Sciences graduate program and the Proteomics Research Laboratory.
Fehl’s research focuses on how O-GlcNAc glycosylation levels modulate cell behavior in hyperglycemia versus normoglycemic settings. His group designs chemical systems to track and treat these sugar levels in diseases like diabetes. He joined Wayne State in 2018.
Acknowledgment and Disclaimer: Research cited in this article was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award number RC2DK142611. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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