Twelve people had their entire pancreas removed. When researchers infused two gut hormones into them after a meal, the hormones still worked, and the way they split the labor says something about how the newest weight-loss drugs act on the body.
The hormones are GLP-1 ↗ and GIP ↗, the two incretins the gut releases after eating. Both are usually explained through the pancreas. They tell it to release insulin. That is also how the blockbuster drugs built on them are usually explained. Tirzepatide ↗, sold as Mounjaro and Zepbound, switches on both the GLP-1 receptor ↗ and the GIP receptor ↗ at once. But the pancreas cannot be the whole story, because these hormones do things insulin does not.
Remove the organ, keep the question
To separate the pancreatic effects from everything else, a team studied people who no longer have a pancreas at all. Writing online June 1 in Diabetes, Obesity and Metabolism ↗, they gave 12 totally pancreatectomised adults four liquid meals on four separate days, each paired with a 270-minute infusion of one of four things: GLP-1 alone, GIP alone, both together, or salt water as a placebo. The design was randomised and double-blind, so neither the participants nor the people measuring them knew which infusion was running. Everyone stayed on their background insulin and skipped mealtime insulin from the night before.
GLP-1 ran glucose. GIP ran bone and blood pressure.
GLP-1 did its familiar work. It cut the post-meal rise in blood sugar by 45 percent (p=0.005) and slowed the stomach's emptying by about a third, measured by how fast a marker drug was absorbed. With no pancreas in the loop, those effects cannot be coming through insulin. The hormone is acting on the gut and the rest of the body directly.
GIP told a different story. On blood sugar it did nothing that the placebo did not do. But it raised heart rate by 10 beats per minute (p=0.004), lowered diastolic blood pressure by about 9 mmHg (p=0.002), and cut post-meal bone breakdown by 65 percent (p=0.003), tracked by a collagen fragment that climbs when bone is being dismantled. GLP-1 left that bone marker alone.
So the two hormones that drug companies bundle into a single injection turn out to run separate programs. One works on glucose and stomach emptying. The other works on bone and the cardiovascular system. Given together, the two cut how much the participants ate at a free buffet by 31 percent (p=0.018), but that was no better than GLP-1 alone, so the appetite effect belonged to GLP-1.
Why the dual agonists should care
The headline is independence. The authors conclude that the physiological actions of both hormones survive the loss of the pancreas, which means a large share of what incretin drugs do is built to happen outside it.
That reframes the dual agonists. If GIP's contribution to a drug like tirzepatide is partly about bone density and blood pressure rather than insulin, then the benefit-and-harm ledger for the whole class has line items that no glucose curve will ever show. A faster heart rate is not free. Slower bone loss may be a quiet benefit nobody was counting. Neither shows up if you only watch blood sugar.
It also matters for the people this study actually enrolled. Total pancreatectomy leaves a person with a brittle, hard-to-manage form of diabetes and a raised risk of fracture. If the gut hormones, and the drugs that copy them, still reach bone and the heart in those patients, they may do more than steady blood sugar. That is a small population, but it is one with few good options, and this is a direct measurement rather than a guess.