Our research aims to understand the role of glucoregulatory hormone signaling in the pathogenesis of obesity, type II diabetes mellitus, and aging. We investigate mechanisms in mouse and cell culture models and translate these findings through our collaborations with clinicians. Our goal is to apply our findings to improve the prevention and treatment of diabetes and age-related metabolic disorders.
Caloric Restriction and Exercise in Preventing Age-Related Disease:
More than 25% of the U.S. population greater than 65 years old has type II diabetes mellitus, representing the highest prevalence of diabetes of any age group. Most research aimed at understanding the consequences of obesity in aging have focused on insulin and downstream signaling cascades, overlooking a potential role for the hormone glucagon. Given that many prominent diabetes treatments target glucagon or glucagon signaling pathways, it is essential to understand the role of glucagon in aging. Our research examines 1) the role of glucagon signaling in obesity-accelerated aging, 2) the role of glucagon signaling in healthspan extension promoted by calorie restriction, and 3) the role of glucagon signaling in exercise-mediated improvements in metabolic and physical function. This work will close a significant gap in our understanding of how glucagon alters aging, while allowing us to assess the potential risks associated with inhibition of glucagon signaling.
Glucagon Signaling in Obesity and Type II Diabetes:
Insulin resistance and elevated insulin are key to the metabolic disturbances in type II diabetes mellitus. Yet, elevated glucagon, common to diabetes, may be equally important in the metabolic abnormalities in diabetes. We have shown that nutritional state differentially affects glucagon secretion in obesity. In turn, the glucagon:insulin ratio is dysregulated in obesity. Current Stern lab research aims to understand the metabolic consequences of a dysregulated glucagon response to fasting and re-feeding.
Obesity and Liver Cancer
Obesity is the leading cause of multiple solid cancers. In particular, the risk of developing hepatocellular carcinoma (HCC) is more than doubled in obese people with Type II diabetes. To identify new drug targets to treat HCC, the Stern lab applies a chemical model of accelerated hepatocellular carcinoma. We use this to examine the effects of hepatic lipid accumulation and dysregulated glucoregulatory hormone signaling on HCC development and progression.