In early studies, a single compound that activates receptors for two separate hormones improves blood sugar control and stimulates weight loss.
Researchers have designed a new compound that targets not one, but two, hormone receptors involved in diabetes and obesity. Although final approval of the drug is still years away, early studies have already shown that the dual-acting molecule can control blood sugar levels and stimulate weight loss, without the severe side-effects of similar drugs.
“Our thesis is that the pharmacology is best when it replicates physiology,” says Richard DiMarchi, Ph.D., a lead author of a new study released today in Science Translational Medicine. “Nature uses multiple hormones to control metabolism, and therefore if we could come closer to replicating nature, we could create greater efficacy and greater safety.”
In this case, the new compound targets the receptors for two hormones the body produces naturally—GLP and GIP. When the compound binds to the receptor for these incretins, as they are called, it mimics their activity.
Previous studies have looked at the role incretins play in obesity and diabetes. Other drugs have already been tested that activate the GLP-1 receptor in order to control the level of glucose, or sugar, in the blood. These medications, however, tend to have limited long-term benefit for diabetics and are also harsh on the stomach and intestines, causing nausea and vomiting.
As for the other hormone, GIP, it’s usefulness for controlling diabetes and obesity has caused heated debate. Some studies in rats have hinted that increasing levels of the hormone might lead to the opposite of the desired effect—weight gain.
It turns out, though, that GIP is more beneficial than it first appeared—as long as it’s used in the right context. DiMarchi, Matthias Tscöhp, Ph.D., and their colleagues found that combining the action of both hormones—GLP and GIP—into one molecule provided better results, without the harsh side effects.
“Our results clearly indicate that when [GIP is] appropriately combined with GLP, there’s a beneficial response,” says DiMarchi.
Normally, the body releases both GLP and GIP when you eat food, signaling to the pancreas that you’ve started a meal. The pancreas, in turn, produces and releases insulin, which helps the body use or store the sugar found in food.
It was no surprise to the researchers, then, that the dual-acting compound improves blood sugar control. It’s effect on obesity, however, was an added benefit.
“These compounds were designed primarily for their glycemic benefit,” says DiMarchi. “What we saw was this highly effective lowering of body weight in these rodent models, which is consistent across the species and different models that we’ve looked at.”
Although GLP-1 has also been found to suppress appetite—which can potentially lead to weight loss—just how the dual-acting molecule improves obesity is less clear.
DiMarchi says that GIP may make its own contribution to weight loss, or it may turbo-charge the well-known ability of GLP-1 to suppress appetite and lower body weight.
The researchers have had some success testing the new compound in people. In early clinical studies, people with type 2 diabetes who were given the new drug showed improved blood sugar levels, an important step in managing the disease.
The subjects also experienced modest weight loss, even though the study wasn’t designed to look at that specifically. Weight studies, in general, run longer than the six week span of the current trial.
More importantly, combining the activity of the two hormones reduced harsh side effects for patients.
“The real beauty of this [study],” says DiMarchi, “is that it documents GIP’s function and how you can use it in concert with GLP to generate a very effective medication that is of minimal adverse character.”