Kirk Habegger, Ph.D.Kirk Habegger, Ph.D., Professor of Medicine in the UAB Department of Medicine Division of Endocrinology, Diabetes and Metabolism, has received funding from Eli Lilly and Company to continue investigation of glucagon receptor activation in incretin-based obesity therapies.

The new 12-month project extends a prior two-year award for which Habegger studied mechanisms of glucagon, Glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) and how they reduce body weight and influence glucose homeostasis in mouse models of obesity.

GLP-1 receptor agonists and GIP receptor agonists have revolutionized Type 2 diabetes (T2D) treatment. They work by mimicking the body’s natural incretin hormones, GLP-1 and GIP, which stimulate insulin release, improve the body’s sensitivity to insulin, reduce food intake, and lead to significant weight loss. 

Glucagon (GCG) is a pancreatic hormone that regulates glucose and lipid metabolism. Stimulating the glucagon receptor (GCGR) increases energy expenditure while reducing food intake, thus regulating whole-body energy balance. As such, manipulating glucagon receptor (GCGR) activity has been a key addition to the development of GLP-1/GIP therapies for T2D and now obesity.

The cutting-edge peptide chemistry behind these therapies includes single-molecule co-agonists (Semagludtide/GLP1), single-molecule multi-agonists (Tirzepatide/GIP/GLP), and now for the first time a combination of all three receptor agonists, with the addition of glucagon, into a single-molecule tri-agonist called Retatrutide (GIP/GLP/GCG). Semaglutide and Tirzepatide are FDA-approved treatments, while Retatrutide is in Phase 3 clinical trials with Eli Lilly.

“Preclinical and clinical data from these compounds suggest superior performance that may again transform T2D and obesity therapy. However, the target tissue(s) and mechanisms of action for these dramatic enhancements have yet to be elucidated,” said Habegger, a scientist in the UAB Comprehensive Diabetes Center (UCDC) and the UAB Nutrition Obesity Research Center. 

Habegger’s team will compare Retatrutide to mono- and dual-agonists Semaglutide and Tirzepatide in the context of obesity treatment using diet-induced obese mice.

“We are trying to solidify what adding glucagon-receptor agonism does to the therapeutic attributes of Tirzepaptide—what does it add or impair? Those are the questions we are addressing. And the big difference between this and the prior study is that we are using clinically relevant peptides as opposed to analogs,” Habegger said

People with diabetes generally have elevated glucagon, which leads to high blood glucose. Giving glucagon to someone with diabetes would initially seem counterproductive as it would raise blood sugar even higher. However, as research grows in this area, Habegger said this expectation oversimplifies glucagon’s complex physiological actions. Moreover, glucagon’s potential to elicit effects like significant weight loss and increased energy expenditure are being examined more closely in a cost-benefit type way.

“Our specific work, and that of others, has provided more nuance to the role of glucagon in glucose regulation,” Habegger said. “That is, it’s not always the case that glucagon receptor signaling will result in diabetes. So, now there is a lot more openness to the idea of adding glucagon and the benefits we know it has, while we also take a more detailed look at its potential negative effects on glucose.”

In addition to effects on obesity, Habegger’s team will look at glucagon’s effects on the liver discovered in their previous collaborations with Lilly. Glucagon, unlike GLP-1 and GIP, signals directly to the liver, therefore investigators saw its potential to enhance the anti-MASLD and MASH effects of Tirzepatide. MASLD, formerly known as fatty liver disease, is the most common chronic liver disease in the U.S.

Habegger’s team also saw effects on reducing liver fibrosis, a buildup of scar tissue in the liver that can lead to cirrhosis, liver failure, and even cancer.

“We hypothesize we will also see in Retatrutide, as opposed to GLP-1 alone or GIP plus GLP-1, a significant reduction of fibrosis when you add glucagon,” Habegger said.

Overall, the purpose of the latest Habegger-Lilly project will be to reveal mechanisms for the potentially counterintuitive effects of long-acting glucagon receptor activation and assess anti-obesity therapies at the same level of weight loss. The goal is to uncover those biological processes that are directly attributable to each treatment and those that are secondary to reduced obesity, Habegger said.