Type 2 diabetes is not all about beta cells and insulin secretion. Two hormones—the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)—are major players in insulin secretion and sensitivity, glucose and glucagon levels, appetite, and eating. And both are produced primarily in the gut rather than the pancreas.

“The gut was the very first organ and gut hormones existed before the gut itself. Islets and the pancreas itself developed from the gut and they remain connected by gut hormones,” said Jens Juul Holst, MD, DrMedSci, who was awarded the Banting Medal for Outstanding Achievement for his trailblazing incretin research.

Dr. Holst delivered the annual Banting lecture Sunday, June 27, at the Scientific Sessions. The lecture, In the Beginning Was the Gut—And Then Something Happened—A Story about the Incretins, can be viewed by registered meeting attendees at ADA2021.org through September 29, 2021. If you haven’t registered for the Virtual 81st Scientific Sessions, register today to access all of the valuable meeting content.

GIP was identified in the 1970s and observed to have dramatic effects on insulin secretion. But the path from its discovery to the current round of phase 3 clinical trials of tirzepatide, the first dual GIP/GLP-1 co-agonist, was far from direct, explained Dr. Holst, Professor at the Panum Institute, University of Copenhagen, Denmark.

It was clear to researchers that the incretin effect maintains blood glucose levels within physiologically acceptable parameters, but the mechanism was unknown, he continued. Neutralizing GIP did not entirely block incretin activity. And in patients with intestinal resection, the incretin effect correlated with the length of the remaining distal small intestine, but not with GIP. There had to be another incretin.

It was first identified in 1986 in the pancreas, part of the large proglucagon molecule. Working with anglerfish and hamster models, researchers characterized not just the glucagon sequence but two related peptides, GLP-1 and GLP-2.

“To our surprise and disappointment, neither of the GLPs had any effect in the pancreas,” Dr. Holst said.

It turned out that food intake stimulates secretion of GIP and GLP-1, and both contribute to postprandial insulin secretion glucose levels. But GLP-1 also inhibits glucagon secretion. A peptide that acts on both insulin and glucagon secretion has a double effect on glucose levels.

In healthy individuals, three molecules affect postprandial insulin secretion, Dr. Holst said. Glucose is responsible for about 26% of the total effect, GIP 45%, and GLP-1 29%.

If GLP-1 has a relatively small impact on insulin secretion, what is its more important function?

It was clear to researchers that GLP-1 inhibits food intake, but it wasn’t clear how, Dr. Holst said. The hormone is secreted in the small intestine and is quickly cleaved and inactivated by dipeptidyl peptidase-4 (DPP-4). And endogenous GLP-1 in circulation has a half-life of just one to two minutes—only 10% to 15% ever reaches the pancreas, but most survives long enough to activate GLP-1 receptors in the small intestine that connect to the vagus nerve. The vagal system connects to the area postrema and the nucleus tractus solitarius in the hypothalamus—areas that control appetite.

This gut-brain connection explains the dramatic effects of Roux-en-Y gastric bypass surgery. The bypass shunts copious quantities of nutrients directly to the distal small intestine, stimulating exaggerated release of GLP-1 and peptide YY. The increased GLP-1 secretion causes an equally dramatic increase in insulin secretion and appetite suppression, which can lead to resolution of diabetes in about half of individuals following gastric bypass.

“We called GLP-1 the diabetologists dream, but the snake in the grass was DPP-4, which makes it impossible to use GLP-1 for therapy. Just a few percent survive in circulation,” Dr. Holst said. “DPP-4 inhibition works, not just by protecting GLP-1 activity, but by enhancing insulin secretion. The pharmaceutical industry soon picked up on our work and you know the rest of the story.”