Satiety hormone may have role in treating diabetes

With a name that derives from the Greek word for “thin,” the leptin hormone regulates the amount of fat stored in the body by controlling the feeling of hunger. It was discovered in 1994, with high hopes that it would provide a groundbreaking treatment for a growing national epidemic of obesity. After an extensive clinical trial, those hopes were dashed.

Since that first study, the “satiety hormone,” as leptin is known, has proved useful in other ways. A team led by Gerald I. Shulman, M.D., Ph.D., the George Cowgill Professor of Medicine (Endocrinology), professor of cellular and molecular physiology, and a Howard Hughes Medical Institute investigator, found that leptin could treat lipodystrophy, a condition common in HIV patients. The disease redistributes body fat in atypical ways, removing it from such areas as the arms, legs, and face and depositing it in the abdomen or the back of the neck. Leptin gained FDA approval for treatment of lipodystrophy in April of this year.

Now, on the 20th anniversary of the discovery of leptin, Shulman and colleagues have found another potential use for the hormone. In a study published in June in the advance online publication of Nature Medicine, the team reported that treatment with leptin reverses hyperglycemia, or high blood sugar, in rats with poorly controlled type 1 and type 2 diabetes.

Like obesity, diabetes is one of the most common chronic conditions in the United States, affecting nearly 30 million Americans. Despite currently available treatments, many patients still struggle to control the high blood sugar levels that characterize the disease and result in complications, including heart disease and blindness. According to Shulman, previous studies had shown that leptin lowered plasma glucagon, a hormone that raises sugar levels in the bloodstream, producing the opposite effect of insulin. Using methods including noninvasive nuclear magnetic resonance (NMR) spectroscopy, a technique pioneered by Shulman in the study of diabetes, his team studied why this was happening. “We came to a very different conclusion,” Shulman said.

The team showed that instead of having its effect mostly through plasma glucagon, leptin reduced blood sugar in the rats by inhibiting a major neuroendocrine pathway, the hypothalamic-pituitary-adrenal axis. This interaction of three glands controls the body’s reaction to stress and regulates other body processes including digestion, energy storage, and metabolism. Further, the team found that leptin did in fact reduce plasma glucagon, but much later in the course of the treatment than through the newly discovered pathway.

Shulman, who is also co-director of the Yale Diabetes Research Center, noted that though typical cases of diabetes can be successfully treated with insulin, “some cases are still difficult to control, and it may be in that subset that leptin therapy might be useful.”

Leptin treatment for lipodystrophy made a very successful leap from rodent to human, said Shulman, who hopes the same is true in the case of diabetes treatment. “Clearly, leptin has been shown to be efficacious in patients with severe lipodystrophy and has made a great improvement in quality of life,” he said, “and now the question is whether it might be beneficial in patients with poorly controlled type 1 and type 2 diabetes.” Shulman and his team are currently working to develop a clinical trial of leptin in human diabetes patients.

Though these are “still early days,” Shulman said, “we are very excited about the data.”