GLP-1 Receptor Agonists and Brain Glucose Metabolism

Glucagon-like peptide (GLP) 1 receptor agonists may have a “major effect” on the regulation of brain glucose metabolism in the absorptive state in patients with mild postprandial hyperglycemia, according to the results of a small study published in Diabetes.

“Our results demonstrate that, following glucose ingestion, exenatide exerts a profound effect on glucose metabolism in multiple brain areas involved in regulation of glucose homeostasis and the reward system,” wrote Amalia Gastaldelli, director of the Cardiometabolic Risk Laboratory at the Institute of Clinical Physiology, Pisa, Italy, and colleagues.

For example, these brain areas control satiety and food intake, according to the study, which may, in part, explain the appetite-suppressant effect of this class of drugs. 

The study included 15 men with a mean HbA1c level of 5.7%. All participants were randomly assigned to  5 mcg exenatide or placebo 30 minutes before an oral glucose tolerance test. The researchers then measured cerebral glucose metabolic rate using positron emission tomography followed by an 18F-FDG injection before the glucose test and used stable isotope tracers to measure the rate of glucose absorption and disposal.

Overall, assignment to exenatide was associated with reduced rate of glucose absorption between zero and 60 minutes (4.6 vs. 13.1), and a decreased rise in mean glucose (107 vs. 138) and insulin from zero to 60 minutes (17.3 vs. 24.7).

In addition, the researchers found that cerebral glucose metabolic rate in total gray matter, total cortex and collectively in brain areas associated with glucose homeostasis regulation and good reward system was significantly increased during the oral glucose tolerance test among those patients assigned exenatide compared with placebo. This increase was seen despite lower plasma insulin concentrations.

“In normal glucose tolerant subjects, some studies have failed to show any effect of insulin on brain glucose metabolism, while other studies have demonstrated that insulin increases cerebral glucose metabolic rate,” the researchers wrote. “However, in our study, the rise in both plasma insulin and glucose concentrations following exenatide was reduced compared to placebo making this an unlikely explanation for the increase in cerebral glucose metabolic rate.”

Reference: Daniele G, Iozzo P, Molina-Carrion M, et al. Exenatide regulates cerebral glucose metabolism in brain areas associated with glucose homeostasis and reward system.  Diabetes. 2015 Jun 26.