Scientists at the University of Pittsburgh School of Medicine discovered a surprising new way the body can fight insulin resistance and diabetes – by boosting a special type of "good" immune cell in fat tissue.
Announced today in Nature Communications , the preclinical findings pave the path to develop a medication to treat and prevent type 2 diabetes , potentially replacing or supplementing GLP-1 weight maintenance drugs that lose effectiveness over time.
"One-third of our population is obese or overweight – over the next decade or so, obesity will drive increasing rates of many chronic diseases, including diabetes," said senior author Partha Dutta, Ph.D., D.V.M. , cardiology professor and director of the Center for Cardiovascular Inflammation in Pitt's Department of Medicine. "Our discovery could be the key to reversing insulin resistance and curing type 2 diabetes."
Inflammation driven by immune signals given off by excess fat surrounding abdominal organs has long been known to trigger the insulin resistance that leads to type 2 diabetes. Dutta and his team at Pitt's Vascular Medicine Institute sought to better understand that process through research on mice and human tissue.
"What we found is that there is a subset of immune cells in our fat tissue that are actually helpful," Dutta said. "Although they're immune cells, they're not inflammatory – rather, they actually suppress the inflammation that causes insulin resistance."
This subset of immune cells – called resident macrophages – clean up dead cells, fight infections and keep tissues healthy. SerpinB2 is a protein that helps resident macrophages survive. When too much visceral fat accumulates – which occurs when someone is overweight or obese – inflammation increases and SerpinB2 levels plummet. This causes resident macrophages to die out, which allows fat tissue to grow larger and become more inflamed. Ultimately, the body can't respond as well to insulin, which controls blood sugar, and the person develops diabetes.
When overweight mice with insulin-resistance were given antioxidant supplements, their levels of resident macrophages increased and their insulin sensitivity improved.
Dutta's team is now working to replicate this in humans by identifying a small molecule that improves SerpinB2 levels and can be given as a medication in clinical trials. That should protect resident macrophages and stop the runaway fat accumulation and inflammation that gives rise to type 2 diabetes. He also expects that it would be helpful in reversing the process in people who already have type 2 diabetes, particularly when given with GLP-1 weight maintenance medications.
"Studies are showing that people who have been on GLP-1 medications for a long time develop 'GLP-1 resistance' and they plateau," Dutta said. "Our goal is to develop a drug that will stop and reverse the process that leads to bad fat accumulation and insulin-resistance by protecting and boosting the good immune cells that keep fat tissues healthy."
Additional authors on this research include Sathish Babu Vasamsetti, Ph.D., Samreen Sadaf, Ph.D., Mohammad A Uddin, Ph.D., Jixing Shen, M.S., Ebin Johny, Ph.D., Awishi Mondal, M.S., Jonathan Florentin, Ph.D., Liqun Lei, Ph.D., Aleef Mannan, Krithika Sudhakar Rao, Ph.D., John Sembrat, M.S., Ian Sipula, Jake Kastroll, Ph.D., Michael J Jurczak, Ph.D., Sruti Shiva, Ph.D., Robert M. O'Doherty, Ph.D., and Vijay Yechoor, M.D., all of Pitt; and Mauricio Rojas, M.D., of The Ohio State University .
This research was supported by the National Institutes of Health (R00HL121076-03, R01HL14262, R01HL143967, R01AG069399 and R01DK129339) and the American Heart Association (19TPA34910142, 19IPLOI34760566, IA-629694 and 20POST35210088).
