Appetite Suppressor Could Be an Alternative to Insulin

In 1922, a Toronto teenager with diabetes became the first person to be saved by insulin treatment, and since then injections have sustained millions of diabetics, who don’t make their own hormone. But are there alternatives to a lifetime of insulin therapy? A new study suggests that an appetite-suppressing hormone called leptin is just as effective as insulin at controlling diabetes in mice.

The discovery of insulin transformed type 1 diabetes from a fatal to a chronic disease. In this type of diabetes, the body destroys insulin-producing cells in the pancreas, resulting in high blood glucose levels. (The more common form of diabetes, type 2, occurs when the body doesn’t respond properly to its own insulin.) But insulin treatment isn’t perfect. Getting the dose of insulin just right is difficult, and despite their best efforts to manage their disease, many people with diabetes suffer severe complications, including kidney failure, blindness, and limb amputation.

Diabetes researchers are considering various replacements for insulin injections: Transplanting new pancreatic islet cells that make insulin, coaxing the patient’s own islets to regenerate, or treating diabetics early in the disease with immune-suppressing therapies to prevent their body from destroying the rest of their pancreatic islets. Some studies have also considered leptin; like insulin, this hormone helps the body reduce glucose levels. Last year, researchers reported that mice with a form of diabetes recovered after receiving leptin gene therapy directly into the brain.

Diabetes researcher Roger Unger of the University of Texas Southwestern Medical Center at Dallas became interested in leptin by happenstance. He was performing islet transplants on diabetic rodents and found that treating the animals with leptin helped make the transplants more effective. Unger and his colleagues then tried giving leptin solo—and the animals’ blood glucose levels returned to normal, just as if they’d gotten new islets. “We didn’t believe it at first,” he says.

To study the effect in more detail, Unger’s group took 15 diabetic mice and implanted a pump near their shoulder blades that would deliver high levels of leptin for 12 days. They compared those animals with ones treated only with insulin pumps. Glucose levels returned to normal in both groups, the researchers report online today in the Proceedings of the National Academy of Sciences.

Unger and his colleagues found that leptin curbs production of glucagon, a hormone that essentially does the opposite of insulin. Glucagon spurs the liver to release glucose into the bloodstream. Suppressing glucagon with leptin had the same effect on mice as making insulin: it reduced blood levels of glucose.

“It’s substitute insulin,” agrees Satya Kalra, a neuroscientist at the University of Florida in Gainesville who did the earlier gene therapy work with leptin. “In type 1 diabetes, if you have a lot more leptin, it should help.” Unger believes that leptin actually has advantages over insulin because it appears to reduce the fluctuations in blood sugar that people with diabetes struggle with.

The effectiveness of leptin at battling diabetes in these animals may have been due to the high doses given, says Laura McCabe, a physiologist at Michigan State University in East Lansing. In research published last year with one of her graduate students, Katherine Motyl, she tested whether leptin could help mice avert the bone loss that can accompany type 1 diabetes. It didn’t. But they found that doses much lower than those Unger used caused glucose levels to drop, though not back to normal. Unger, however, points out that he had success with lower doses, too.

McCabe and Kalra agree that leptin, which has been used as a treatment for some rare metabolic diseases, probably wouldn’t have serious side effects, although weight loss is a concern: Leptin significantly dampens appetite, and Unger’s mice ate 50% less than normal. (Long-term, Unger says, the leptin mice are no lighter than those who get insulin, though they have more lean body mass and less body fat.) It’s also not clear whether leptin has immune effects. Unger’s team and some colleagues are now preparing to test a combination of leptin and insulin in a clinical trial to determine whether people with diabetes do as well as his mice.