A clinical research team at UT Health San Antonio, the academic health center of The University of Texas at San Antonio, has been awarded a five-year, nearly $4 million grant from the National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases to explore the many roles the hormone glucagon plays in human metabolism. The first-of-its-kind study will examine how glucagon contributes to insulin secretion, glucose regulation and energy balance in people with obesity who have or have not undergone bariatric surgery.
Shifting views in drug development
“We are beginning to understand that individual peptide signals will be key to building more effective therapies,” said the study’s principal investigator Marzieh Salehi, MD, MS, FACP, professor of medicine in the university’s Joe R. and Teresa Lozano Long School of Medicine and medical director of the Bartter Research Unit at Audie L. Murphy Memorial Veterans’ Hospital. “Our work is designed to define glucagon’s role in this new three-legged approach.”
Glucagon was historically seen only as insulin’s counterbalance, raising blood sugar during periods when it was low, called hypoglycemia. Now it is recognized as influencing a much broader range of processes, including stimulating insulin release in the pancreas and enhancing insulin’s action after eating.
More recently, glucagon-like peptide 1 (GLP-1) receptor agonists and dual-acting GLP-1/glucose-dependent insulinotropic polypeptide (GIP) drugs have transformed obesity and diabetes treatment. Yet glucagon, as part of the three-legged approach in multi-agonist therapies, is less understood.
The rise of peptide therapies and rediscovery of glucagon
For decades, diabetes care focused on insulin replacement and oral glucose-lowering agents such as metformin, which controlled blood sugar but did little to address obesity, fatty liver, kidney disease or cardiovascular complications.
The discovery of GLP-1 receptor agonists about two decades ago changed that. GLP-1 receptor agonists revolutionized care by lowering glucose, promoting weight loss and improving cardiovascular outcomes.
More recently, dual-acting GLP-1/GIP receptor agonists such as tirzepatide have delivered even greater benefits, igniting interest in a three-legged approach with triple-agonist therapies that combine GLP-1, GIP and glucagon activity.
“We know that GLP-1 and GIP work together in beneficial ways, and now glucagon is re-entering the conversation,” Salehi said.
Once considered a metabolic “villain” because it raises blood sugar, glucagon is being reexamined.
“While studies in animal models of obesity and diabetes suggest the peptide may also perform important functions such as enhancing insulin secretion in the pancreas or improving insulin sensitivity, we still don’t fully understand its role in glucose control or weight loss in humans,” she said.
Salehi explained that a better mechanistic understanding of glucagon is needed, especially in human populations, to elucidate how these processes function in the body and inform more effective drug development.
Methodology
The research team will recruit approximately 150 non-diabetic participants with obesity in the San Antonio area for the study. Two groups will be composed of individuals who have undergone either gastric bypass surgery or sleeve gastrectomy. A subgroup will be post-surgery individuals who developed hypoglycemia. Another group will be individuals with obesity who have not had bariatric surgery.
Bariatric surgery, Salehi said, provides a natural model to study the role of glucagon. Unlike in people who have not undergone surgery, glucagon levels rise after meals, creating a unique opportunity to test its actions.
Participants will undergo comprehensive metabolic testing, including measurement of glucose production, insulin release, and energy expenditure, under both fasting and after-meal conditions.
Early hypotheses
The research team will test whether:
- Glucagon acts as a key stimulus for insulin secretion in the after-meal, or prandial, state. After bariatric surgery, this effect is exaggerated, contributing to the beneficial glycemic impact of surgery — diabetes remission — in most patients, while leading to detrimental post-meal hypoglycemia for others.
- Glucagon is vital to rescue from insulin-induced hypoglycemia. This protective effect may be blunted after bariatric surgery due to gut rerouting.
- The effect of nutrient ingestion on energy balance and food intake is partially mediated by prandial glucagon concentrations. This role may be important in individuals who have undergone bariatric surgery.
Implications for drug development
Current multi-agonist drugs mix GLP-1, GIP and glucagon activity in varying amounts, but without clear evidence to guide the “recipe.” Some formulations minimize glucagon’s contribution over concerns about elevated blood sugar, while others highlight its potential for weight loss and liver health.
“This study will provide the mechanistic evidence needed to move beyond trial-and-error drug design,” Salehi said. “By understanding how glucagon functions across different patient groups, we can refine therapies to more precisely target fatty liver disease, hypoglycemia and hyperglycemia, cardiovascular risk or obesity.”
Looking ahead
The five-year project represents a step toward a better understanding of how these peptides — and potentially many more — interact to regulate human metabolism. As obesity and Type 2 diabetes continue to rise worldwide, clarifying glucagon’s role could have far-reaching clinical and therapeutic impact for millions of people.