A pioneering investigator credited with reshaping the understanding and treatment of obesity and diabetes through his foundational insights into central nervous system glucose-dependent insulinotropic polypeptide (GIP) receptor biology was honored with the Outstanding Scientific Achievement Award by the American Diabetes Association® (ADA) at the 2026 Scientific Sessions.
Timo D. Müller, PhD, accepted the award and shared his insights on hormonal control of metabolism by GIP and next-generation incretin-based polyagonists during the Monday, June 8 session, National Scientific & Health Care Achievement Awards Presentation, Outstanding Scientific Achievement Award Lecture and Outstanding Educator in Diabetes Award Lecture.
“Most monotherapies show very limited efficacy to decrease body weight at tolerable doses. And when thinking about what it takes to make a better obesity drug, we have to note that energy metabolism is not regulated by a single gut hormone. It’s the combination of different peripheral hormones that synergistically act together to unlock central mechanisms to regulate hunger and satiety,” Dr. Müller explained. “Accordingly, it is quite likely that an optimized obesity drug requires targeting of multiple key mechanisms.”
On-demand access to recorded presentations, including Dr. Müller’s lecture, will be available to registered participants of the 2026 Scientific Sessions through August 10.
Hormonal Control of Metabolism by GIP
Dr. Müller has been involved in the development of novel unimolecular therapies for the treatment of obesity and diabetes since 2013, when he was a postdoctoral fellow in the lab of Matthias H. Tschöp, MD, at the University of Cincinnati’s Metabolic Disease Institute. The initial breakthrough in combining GIP and glucagon-like peptide-1 (GLP-1) receptor agonism was published in 2013. This concept was clinically validated a few years later in the form of tirzepatide, which has demonstrated superiority to semaglutide in decreasing weight among non-diabetic individuals living with obesity.
To understand why this was, Dr. Müller set out to determine what makes GIP/GLP-1 receptor co-agonism superior to single GLP-1 receptor agonism, and how GIP contributes to the metabolic efficacy of the co-agonist.
Working with GIP receptor and GLP receptor knockout mice, Dr. Müller’s lab found that GIP decreases body weight, and it does so via the GIP receptor, but not via the GLP-1 receptor. In an effort to elucidate whether GIP acts centrally to decrease body weight and food intake, administration of GIP was made into the lateral ventricle of diet-induced obese mice. Results demonstrated that a single central administration of GIP could decrease body weight and food intake. However, GIP did not decrease body weight in mice with neuronal loss of the GIP receptor, indicating that GIP decreases body weight and food intake via the brain GIP receptor.
Dr. Müller then asked how important GIP was to the metabolic efficacy of GLP-1/GIP receptor co-agonism. Notably, tirzepatide is not suitable to assess the mode of action of GLP-1/GIP receptor co-agonism in mice because it is 75.7-fold less potent at the mouse GIP receptor than at the human receptor. The team found that GLP-1/GIP receptor co-agonism decreased body weight via both receptors and that the additional GIP effects were mediated through the GIP receptor. Additional studies were conducted to determine which neurons mediated the effect of GIP and revealed that GIP decreases body weight and food intake via GABAergic GIP receptor neurons.
Next-Generation Incretin-based Polyagonists
Lately, Dr. Müller has been working to improve GLP-1/GIP receptor co-agonists.
“An interesting concept that we developed with materials more than a decade ago is to covalently link nuclear-acting hormones to a peptide,” he said. “The principle of this concept is that the nuclear hormone is sitting on the shoulders of the peptide hormone and is naturally internalized via the peptide receptor, thereby restricting the action of the nuclear hormone to only cells that express the peptide receptor.”
The selected nuclear hormone class was the peroxisome proliferator-activated receptors (PPARs). Targeting these receptors yields very strong insulin-sensitizing and anti-inflammatory effects, but with the downside that current drugs targeting PPARs cause body weight gain, anemia, and renal impairment. The basic idea behind this work was to retain the beneficial effects of PPAR agonists while avoiding adverse events.
Following optimization, lanifibranor, a nuclear-acting small-molecule triple agonist of PPARα, PPARγ, and PPARδ, was chosen to evaluate this concept.
“When delivering the lanifibranor via GLP-1, the weight loss of the drug was still underwhelming, but when delivering the PPAR via a GLP-1/GIP co-agonist, the molecule all of a sudden achieved remarkable weight loss,” Dr. Müller said.
In terms of body weight and glucose, GLP-1/GIP/lanifibranor further improved insulin sensitivity and reduced hepatic glucose production compared with GLP-1/GIP.
Overall, these findings indicate that the efficacy of GIPR/GLP-1 receptor co-agonism is further enhanced by GLP-1R–GIPR–PPARα/γ/δ quintuple agonism.
Save the date
Make plans to join us June 18–21, 2027, for the 2027 Scientific Sessions at the Walter E. Washington Convention Center in Washington, DC. Registration will open in January.
