Diabetes journal weighs blocking or activating the GIP receptor that tirzepatide targets

On June 16, 2025, the journal Diabetes published two articles arguing opposite positions on whether obesity drugs should switch the GIP receptor on or off, plus a commentary by Jonathan E. Campbell of the Duke Molecular Physiology Institute and Daniel J. Drucker of the Lunenfeld-Tanenbaum Research Institute in Toronto that tries to explain how both strategies can lower body weight ^[1][2].

The articles appeared in the August 2025 issue, volume 74, issue 8, at pages 1320–1325 and 1334–1338 ^[1][2].

The case for activating the receptor leans on tirzepatide, sold as Mounjaro and Zepbound, which activates both the GIP receptor and the GLP-1 receptor ^[1]. The commentary says that approach is supported by the drug's clinical results and by GIP's effects on insulin secretion, insulin sensitivity and inflammation in fat tissue, along with brain effects that reduce food intake and blunt aversive responses ^[1]. GIP receptor monoagonism reduces food intake and body weight in animals and in humans, and the weight-lowering effect in mice requires GIP receptors inside the central nervous system ^[1].

The case for blocking the receptor, written by Mette Marie Rosenkilde, Jyothis Thomas George, Murielle M. Véniant and Jens Juul Holst, rests partly on human genetics ^[2]. Three missense GIP receptor variants with impaired function — Arg190Gln (rs139215588), Glu288Gly (rs143430880) and Glu354Gln (rs1800437) — have been linked to lower BMI ^[2]. Whole-body and central nervous system knockout of GIP receptors both protect mice on a high-fat diet from obesity and insulin resistance, the authors write ^[2]. In humans, GIP infusion increases lipid deposition in fat tissue in lean people and raises fat-tissue triglycerides in people with obesity and type 2 diabetes, effects blocked by the GIP receptor antagonist GIP(3–30)NH2 ^[2]. A phase 1 study offers proof of principle in humans that GIP receptor antagonism adds to GLP-1 effects, and in nonhuman primates the antagonist AT-7687 combined with GLP-1 receptor agonism produced additive weight reduction compared with either alone ^[2].

Why two opposite approaches lead to weight loss is still not settled. The commentary describes one leading idea: hindbrain neurons that carry GIP receptors appear to dampen GLP-1 satiety signaling in mice, and deleting the GIP receptor in those neurons enhances the effect of GLP-1 receptor agonism on food intake and body weight ^[1]. Campbell and Drucker conclude there is no current evidence that tirzepatide reduces activity in the GIP-receptor-positive neurons that regulate food intake, which weakens the idea that desensitization of those neurons explains the paradox ^[1]. They add that it remains unclear where in the brain the key GIP receptor signals occur, listing the hypothalamus, hindbrain and nonneuronal cell populations as candidates ^[1].

Why it matters for patients

The disagreement is about mechanism, not about whether the drugs work. The argument for GIP agonism is built on tirzepatide's clinical efficacy, and the argument for antagonism on genetics and early human data ^[1][2]. Nothing in these papers changes what is currently prescribed, and no dose or treatment recommendation appears in either article.

The debate matters most for what gets developed next. Rosenkilde and colleagues argue more options are needed because many people do not reach their weight goals on GLP-1 receptor agonists alone, weight is often regained after those drugs are stopped, and some people have persistent gastrointestinal side effects ^[2]. They also note that dosing frequency has fallen from twice daily to once weekly as the field has advanced, and that longer-acting agents are desirable ^[2].

One open question is how a GIP-blocking drug would affect tolerability. The commentary says the hypothesis that GIP receptor antagonism might reduce the tolerability of simultaneous GLP-1 receptor agonism is being examined in clinical trials of maritide (maridebart cafraglutide), an antibody that blocks the GIP receptor joined to two GLP-1 peptide agonists ^[1]. Whether that hypothesis holds has not been reported.

What happens next

Both articles point to clinical trials as the way to settle which approach works better, and for whom ^[1][2]. Results from the maridebart cafraglutide trials, including the tolerability question, have not been disclosed, and no dates for those results appear in the papers ^[1]. The commentary states that answering the remaining questions about where GIP receptor signals act in the brain will require additional experiments as well as forthcoming trial results ^[1].