Scientists at the University of Alabama at Birmingham (UAB) Comprehensive Diabetes Center have characterized a molecular tool that will allow researchers to further study long-term glucagon action and glucagon receptor signaling.
Kirk Habegger, Ph.D., and collaborators published their research article, “Characterization of LY3324954 a long-acting glucagon-receptor agonist” in the peer-reviewed journal Molecular Metabolism.
Habegger, the study’s corresponding author, is Associate Professor of Medicine in the UAB Division of Endocrinology, Diabetes and Metabolism and a scientist in the UAB Comprehensive Diabetes Center (UCDC) and UAB Nutrition Obesity Research Center who studies glucagon biology. Studies reported in the article were conducted in collaboration with Lilly Research Laboratories in Indiana.
Glucagon is a pancreatic hormone that is a crucial regulator of glucose and lipid metabolism as well as whole-body energy balance. Therefore, modulation of glucagon receptor (GCGR) activity has become an emerging therapeutic target against obesity and obesity-associated metabolic dysfunction.
To better understand the role of GCGR-signaling when paired with incretin receptor signaling or on its own, Lilly scientists developed LY3324954, a long-acting glucagon-like molecule with improved potency and selectivity as compared to the native glucagon peptide. LY3324954, for instance, is more soluble, stays in the bloodstream longer, and can be delivered less frequently.
Researchers administered biweekly treatments of LY3324954 in lean and obese mice to characterize the molecule’s effects on glucose homeostasis and energy balance.
“What we learned was that glucagon causes these obese animals to lose weight—mostly fat mass, and presumably from the adipose tissue,” Habegger said.
Scientists also looked at what happens both immediately after the injection of the molecule in terms of glucose and what happens to the ability of the body to deal with a glucose load after multiple doses. They found obese animals seemed to have a less pronounced glucose response over multiple doses and were surprisingly more glucose tolerant as compared to untreated control animals.
Characterization of LY3324954 now opens doors for other researchers to further explore the actions of glucagon, which Habegger said until recently had been regarded as only doing “the opposite of insulin.”
“We’ve been working hard as a group to try to understand all of the things that glucagon does and when it works not just against insulin but with insulin and what its therapeutic applications might be,” Habegger said. “Papers like this one and the tools that they characterize are important to understand the mechanisms that will lead to the next generation of treatments.”
Future studies using LY3324954 could reinforce understanding of why or when it may be beneficial to add GCGR agonism to therapeutics for conditions such as obesity, diabetes, and fatty liver, Habegger said.
Authors from the Habegger lab included Teayoun Kim, Shelly Nason, Jasmin Hernandez-Alamillo and Saidharshana Dhantu.
Other study authors included first author William Roell, Tamer Coskun, Libbey O’Farrell, Jennifer A. Martin, Daniel J. Drucker, Kyle W. Sloop, James P. Steele, and Jorge Alsina-Fernandez.