Diabetes runs a point-counterpoint on agonizing versus antagonizing GIP

The journal Diabetes published paired point-counterpoint articles on June 16, 2025, debating whether drugs should activate or block the GIP receptor to treat obesity, along with a commentary from researchers Jonathan Campbell and Daniel Drucker trying to make sense of the contradiction ^[1][2].

The puzzle is this: tirzepatide, sold as Mounjaro and Zepbound, works partly by activating the GIP receptor alongside the GLP-1 receptor ^[1]. But a different experimental drug called maridebart cafraglutide, or MariTide, blocks the GIP receptor while also activating GLP-1 receptors, and early data suggest it also produces weight loss ^[2]. Researchers on both sides agree that both approaches seem to work, though the reasons remain unclear ^[1][2].

The case for activating the GIP receptor rests on evidence that it can improve insulin secretion, insulin sensitivity, and reduce inflammation in fat tissue, plus effects in the brain that reduce food intake and dial down feelings of nausea or aversion tied to GLP-1 drugs ^[1]. The case for blocking it points to human genetics: three specific GIP receptor gene variants with reduced function are linked to lower body mass index ^[2]. Mice lacking the GIP receptor entirely, or just in the brain, are protected from diet-induced obesity ^[1][2]. In monkeys, combining a GIP receptor blocker called AT-7687 with a GLP-1 drug produced more weight loss than either drug alone, and a phase 1 human study offered early support that blocking the receptor can help too ^[2].

One theory for reconciling the two approaches focuses on a group of brain cells called GABAergic neurons in the hindbrain. GIP receptor activation in these cells appears to dampen the nausea-inducing and aversive effects tied to GLP-1 signaling, but it may also blunt some of the appetite-suppressing benefits of GLP-1 ^[1]. If that inhibitory brake could instead be removed through GIP receptor blockade, it might make GLP-1 signaling more effective at reducing food intake, which is one reason bispecific drugs like MariTide pair GIP blockade with GLP-1 activation ^[1][2].

But Campbell and Drucker's commentary complicates a simpler explanation some researchers had floated: that tirzepatide's benefits stem from desensitizing, or dialing down, the very same GIP receptor-positive neurons that control food intake, making agonism functionally similar to antagonism. The commentary states there is currently no evidence that tirzepatide actually reduces activity in these specific neurons, weakening that explanation ^[1].

Why it matters for patients

This debate is about basic biology, not a new approval or a change in how current drugs are used. For people taking tirzepatide (Mounjaro, Zepbound) or considering a future GIP-blocking drug like MariTide, the science shows that different, even opposite, ways of interacting with the same hormone receptor may both lead to weight loss, though researchers do not yet agree on exactly why ^[1][2]. Understanding this mechanism could eventually help explain why some people respond differently to these medications, or why side effect patterns differ between drug classes, but that link is not yet established in the sources reviewed here.

The unmet needs highlighted by these researchers, including rapid weight regain after stopping current drugs and persistent gastrointestinal side effects for some patients, are part of why scientists are exploring GIP receptor blockade as a possible complement to GLP-1 drugs ^[2].

What happens next

The authors say resolving the paradox will require further experiments to pinpoint exactly where in the brain GIP receptor signaling controls appetite, as well as results from ongoing clinical trials testing GIP receptor blockade combined with GLP-1 agonism, including studies of MariTide ^[1][2]. No specific trial completion dates were given in these sources.