Beta cell failure during weight cycling as a driver of cardiometabolic disease
Description: Type 2 diabetes (T2D) affects over 500 million people worldwide and is a leading cause of cardiovascular disease (CVD), the primary source of morbidity and mortality in diabetes. Beta cells regulate glucose homeostasis by secreting insulin in response to elevations in blood glucose levels. Loss of identity factors, such as MafA, and impaired insulin release drive beta cell failure and T2D onset. Preserving beta cell function is therefore critical to reducing cardiometabolic risk. Calorie restriction (CR) and CR-mimicking therapies, such as GLP-1 receptor agonists (GLP1RA), improve glucose metabolism and promote weight loss. However, weight regain after CR or treatment discontinuation leads to “weight cycling,” which may impair beta cell plasticity. My preliminary data show that CR beta cells fail to proliferate under high-fat diet (HFD) stress, resulting in disproportionate workload and functional decline. These findings suggest that weight cycling accelerates beta cell dysfunction and increases CVD risk. I hypothesize that weight regain after CR disrupts beta cell Ca² homeostasis and activates ER stress, ultimately leading to beta cell failure. To test this, I will combine in vivo metabolic phenotyping, live Ca² imaging of acute pancreatic slices, and single-nucleus sequencing in CR- and GLP1RA-treated mice before and after HFD-induced weight gain. Aim 1 will define how weight cycling impairs beta cell function and identity. Aim 2 will investigate MafA-dependent transcription as a regulator of beta cell plasticity. This work directly supports AHA's mission to prevent cardiovascular disease by uncovering mechanisms linking weight cycling to beta cell failure and cardiometabolic disease.
Funder: American Heart Association
Amount: $159,200
Funding type: fellowship
Funder scheme: Postdoctoral Fellowship
Start date: 2026-01-01
End date: 2027-12-31
Investigators: Amanda Coelho, Amanda Coelho
Institution: Vanderbilt University
Funded outputs count: 2
Funder award ID: 26POST1571444
OpenAlex ID: G848463812