Chapter 44
Obesity and Diabetes — 3
So, we lost twenty years in the advance of public health by not noticing that the same drugs that could help people with diabetes could help those with obesity. A couple of decades might not seem much, given that obesity has been a growing problem in human health since the late eighteenth century. Apart from all the advances in medical science and human biology over those centuries, a key enigma was the role of hormones in weight gain, particularly the incretins, a family of hormones sending signals from the gut. When I finished medical school around 1980, we weren’t taught that the gut could make hormones.
Incretin hormones, which include GLP-1 made from the cells lining the gut, are distinct from insulin and glucagon manufactured and released by the pancreas. Some of the signals discovered among the incretins run in a short-term system between the gut and brain, going in both directions. This information network is always busy sensing and regulating the calories we ingest. Other incretin hormones make up a long-term system regulating energy expenditure and the mass of fat tissue. This system assures that our fat tissue mass, our principal site of energy storage, is maintained. As a result, overeating or caloric restriction for a period is unlikely to induce a durable change in fat tissue mass. That’s why so many diets have yo-yo results, because it’s hard to override this tight regulation of our physiology—it’s like the sodium or potassium levels in our blood, or core body temperature. The two systems, long and short term, are highly integrated. Discovering and observing how the gut-related hormones—such as ghrelin produced in the stomach, leptin from adipose tissue, amylin made in the pancreas, cholecystokinin and peptide Y from the intestine—operate in our bodies has dramatically changed our perspective.
When we eat sugar, insulin levels go much higher than if sugar is injected into our bloodstream. This had to be explained by something in the gut, but it was elusive. The first incretin hormone discovered was GIP in 1970, but its role in stimulating insulin secretion was not immediately obvious. Svetlana Mojsov, a Yugoslavian chemist who ran the Massachusetts General Hospital in Boston core facility, made the shortened GLP-1 (7-37) peptide, and proved that it triggered insulin secretion, unlike the full GLP-1 peptide. Subsequently, in 1986, Mojsov and Habener published a paper that showed this form of the peptide occurred naturally in gut tissue. Svetlana Mojsov’s story is another example of a long history of female scientists getting sidelined, such as Rosalind Franklin’s pivotal participation in the discovery of the DNA double helix in the 1950s. In the case of GLP-1, Mojsov, after waging a legal battle to be listed as a co-inventor on key patents, ultimately prevailed in 2006. But that was long after many international prizes were awarded to Habener and collaborators.
Iwas involved in another related GLP-1 recognition—the Mani Bhaumik Breakthrough of the Year Award. In 2024, I served on a committee of the American Association for Advancement of Science to determine who was responsible for pushing these drugs into obesity clinical trials, despite the skeptics. After many interviews, much digging, and reviewing many documents translated from Danish, our committee recognized Lotte Bjerre Knudsen, chief scientific adviser in Research and Early Development at Novo Nordisk, and Richard DiMarchi, distinguished professor of biochemistry at Indiana University, as the two key players. Had it not been for them, we might still not know about GLP-1’s pronounced impact on obesity.