UT Health San Antonio leads study on glucagon hormone’s role in human metabolism

A clinical research team at UT Health San Antonio, the academic health centre 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 for a first-of-its-kind study to explore the many roles glucagon plays in human metabolism.

Glucagon historically was seen only as insulin’s counterbalance, raising blood sugar during periods when it was low, a condition called hypoglycemia. Now, it is recognised as influencing a much broader range of processes, including stimulating insulin release in the pancreas and enhancing insulin’s action after eating.

The research team will recruit approximately 150 non-diabetic participants with obesity in the San Antonio area for the new study, with important implications for new drug development. 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.

More recently, glucagon-like peptide 1 (GLP-1) receptor agonists and dual-acting GLP-1/glucose-dependent insulinotropic polypeptide (GIP) drugs – medications that mimic naturally occurring hormones to help manage blood sugar and promote weight loss –have transformed obesity and diabetes treatment. Yet glucagon, as part of a “three-legged approach” with those two drugs, is less understood.

“We are beginning to understand that individual peptide signals will be key to building more effective therapies,” said the study’s principal investigator, Dr Marzieh Salehi, 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.”

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 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. “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.”

Salehi said that a better mechanistic understanding of glucagon is needed, especially in human populations, to reveal how these processes function in the body and inform more effective drug development.

Of the roughly 150 non-diabetic participants to be recruited in San Antonio for the new 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 include 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.

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 glycaemic 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.

Current multi-agonist drugs mix GLP-1, GIP and glucagon activity in varying amounts, but without clear evidence to guide the “recipe.” Some formulations minimise 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 added. “By understanding how glucagon functions across different patient groups, we can refine therapies to more precisely target fatty liver disease, hypoglycemia and hyperglycaemia, cardiovascular risk or obesity.”

The five-year project represents a step toward a better understanding of how these peptides – and potentially many more – interact to regulate human metabolism.