Dual agonists of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have taken center stage in the treatment of obesity and type 2 diabetes.

The symposium Weight-Reducing Mechanisms of GLP-1–Based Therapies—New Insights from Animal Studies will take place on Sunday, June 23, from 4:30 p.m. – 6:00 p.m. ET in Room W415B, the Valencia Ballroom, of the Orange County Convention Center. This session will explore GLP-1/GIP-mediated energy metabolism and approaches for mitigating side effects of GLP-1–based therapies. The session will be livestreamed on the virtual meeting platform for registered meeting participants and will be available on-demand following the 84^th Scientific Sessions.

Timo D. Müller, PhD, Director of the Institute for Diabetes and Obesity and W3 Professor at Ludwig Maximilian University of Munich, Germany, will focus on the role of G1P signaling.

“We have, along with Richard DiMarchi and Matthias Tschӧp, developed agonists that coactivate GLP-1 and GIP receptors. These dual agonists have conceptionally advanced to the drug tirzepatide, which was recently approved for treating obesity and diabetes,” Dr. Müller said. “While the GLP-1 signaling component of these drugs is intuitive, the mechanistic role of GIP in obesity modulation is largely unknown.”

Dr. Müller and colleagues previously showed that GIP-mediated weight loss and food intake reduction is dependent on the GLP-1 receptor in the brain, particularly in certain inhibitory GABAergic neurons.

“We have now developed a series of additional conditional knockout animals to answer the question: What are these GABAergic neurons through which GIP acts in the brain, specifically the hindbrain and hypothalamus, to decrease body weight and food intake?” Dr. Müller said.

In addition to presenting these new GIP data, he will explore an enigma in this field—weight loss and food intake modulation through activation as well as inactivation of the GLP-1 receptor.

 “We have witnessed a renaissance in GIP biology in recent years,” Dr. Müller noted, adding that the induction of a greater weight loss via dual agonism of GLP/GIP, compared to GLP alone, has revived interest in GIP as a therapeutic target in diabetes and obesity.

Stefan Trapp, PhD, University College London, United Kingdom, will explore insights into different physiologic GLP-1 networks.

“We have at least two different systems or sources of GLP-1 in the body—from the gut, where GLP-1 is released post-prandially, and from a population of neurons in the brain, particularly the lower brain stem,” Dr. Trapp said.

The projections from these neurons impinge on many parts of the brain, including regions involved in regulation of food intake.

Dr. Trapp said that with the expanded and prolonged therapeutic use of GLP-1 receptor agonists, it is important to understand whether these agents exclusively mimic gut GLP-1 or if they also interact with the brain GLP-1 system.  

“We need to be aware that there are these two physiologic GLP-1 systems that are separate, and the same level of separation seems true for pharmacologic targeting with GLP-1 receptor agonists,” he said.

While systemically administered GLP-1 receptor agonists, acting on the gut system, have yielded clinical success, additive effects on weight loss may be possible in the future by targeting the brain system as well, he noted.

Tito Borner, PhD, Assistant Professor of Biological Sciences at the University of Southern California, will review new insights on ways to mitigate nausea and emesis associated with GLP-1 receptor agonists.

 “As drug interventions for diabetes and obesity management, GLP-1 receptor agonists have yielded almost two decades of exceptional outcomes in both weight management and glucose control,” Dr. Borner said. “The long-acting GLP-1 analog semaglutide, for instance, consistently shows double-digit weight loss in overweight and obese patients. However, despite its remarkable success, semaglutide—like all its GLP-1-based therapeutic predecessors—causes nausea and vomiting in a significant percentage of patients.”

He added that these side effects can limit the use of higher therapeutic dosages and lead to treatment discontinuation.

Dr. Borner said that GLP-1/GIP dual analogs (twin-cretins) have yielded superior results in enhancing glycemic control and weight management compared to GLP-1 receptor agonism alone.

“Intriguingly, GIP receptor agonism appears to induce anti-emetic effects,” he noted. “I will share data collected using different pre-clinical models and paradigms, demonstrating that GIP receptor agonism blocks emesis and attenuates other malaise-indicative behaviors elicited by GLP-1 receptor activation, while maintaining reduced food intake, body weight loss, and improved glucose tolerance.’”

Dr. Borner will also highlight recent advances in the development of promising GLP‐1 receptor agonist‐based approaches to tackle side effects. Specifically, he will discuss a novel GLP-1 receptor agonist conjugated to vitamin B12 with modified brain penetrance that enhances GLP-1 receptor-mediated glycemic control without inducing vomiting.

Karolina P. Skibicka, PhD, Pennsylvania State University College of Health and Human Development, will speak about the neural circuits underlying GLP-1/GLP-1 analog-mediated food intake and body weight regulation.