Mechanisms of Weight Loss from Diabetes Drug Still Unknown

Some diabetes drugs are thought to cause weight loss through the hypothalamus, but other parts of the brain may be involved.

Weight loss is a side effect of certain diabetes medications that may not be a negative occurrence, but how these drugs spur this effect is currently unknown. Improved understanding of how these drugs work in the body could potentially be harnessed to create novel drugs that promote weight loss.

According to a new study published by Diabetes, glucagon-like peptide-1 receptor antagonists (GLP-1RAs) may promote weight loss through involving a different part of the brain than researchers previously speculated.

"GLP-1RAs cause people to eat less, and their weight loss effects were thought to rely on the hypothalamus, a part of the brain that controls appetite," said senior study author Julio Ayala, Ph.D. "There was some evidence to support this notion, but it hadn't been directly tested. In this study, we show that it's not the case -- other regions of the brain must be involved in weight loss caused by GLP-1RAs."

While interest in weight loss medications is high, there have been few drugs to show efficacy in this area. One GLP-1RA drug was recently approved by the FDA to treat obesity in patients without diabetes, but the drug only causes a small amount of weight less. Unfortunately, these drugs are administered via injection twice per day, which may present a barrier for some patients, and could potentially increase the risk of pancreatitis.

"Better treatments for obesity would make a huge impact on public health," Dr Ayala said. "GLP-1RAs are a tool towards that end -- if we can understand how they lead to weight loss, we may be able to design drugs that act on just the right parts of the brain, or modify GLP-1RAs to be more effective."

Approved GLP-1RAs include liraglutide (Victoza), exenatide (Byetta), and albiglutide (Tanzeum). These drugs mimic the GLP-1 hormone that is released after a meal. The drugs have been found to trigger the release of insulin and lower blood sugar in the stomach to slow digestion, and on the brain to reduce food intake, according to the study.

The study included mice that lacked GLP-1 receptors in the hypothalamus to determine whether the hypothalamus was essential for weight loss resulting from GLP-1RAs. The researchers discovered that the GLP-1RAs still reduced body mass and food intake in the mice models.

These findings indicate that the hypothalamus may not play as large of a role in the drug’s weight loss effects, the study concluded.

"Our findings show that we still have work to do to understand what GLP-1RAs are doing in the brain," Dr Ayala said. "But we know where to start. We're already looking at their effects on brain regions that are involved in the reward associated with eating, such as the ventral tegmental area and the nucleus accumbens."

The researchers plan to continue their research, and focus on multiple different pathways that may be involved with GLP-1RA effects on weight. By doing so, new findings could potentially lead to more effective weight loss drugs.

"Though the idea that the hypothalamus was central to GLP-1RAs' effects on eating had become accepted in the field, in a way it's not surprising that it turns out to be more complicated," Dr Ayala concluded. "Feeding is a complex behavior that's controlled by a complex organ, so these drugs likely modulate more than just one brain region -- they probably impact entire circuits. That's where our research is headed."