A new study published in the journal Diabetes demonstrates that a glucagon-like peptide-1 receptor (GLP-1R) agonist, a member of a class of drugs used to treat Type 2 diabetes and obesity, can lead to a rapid improvement in insulin sensitivity.
Insulin sensitivity is how well cells respond to insulin, a key hormone that controls blood glucose levels. Increasing insulin sensitivity means that insulin can lower blood glucose more effectively. Reduced insulin sensitivity or insulin resistance is a hallmark of type 2 diabetes. Thus, improved insulin sensitivity can reduce the risk of developing type 2 diabetes or improve its treatment.
GLP-1R agonists are drugs that affect metabolism, such as lowering blood sugar levels by promoting insulin secretion. Dipeptidyl peptidase 4 (DPP-4) inhibitors block the degradation of the body’s own endogenous GLP-1, as well as other peptide hormones such as glucose-dependent insulinotropic peptide (GIP).
“We know that GLP-1R agonists promote weight loss, but we were surprised to find that the GLP-1R agonist liraglutide also has rapid effects on insulin sensitivity, independent of weight loss,” said Mona Mashayekhi MD, PhD, assistant professor Medicine. in the Department of Diabetes, Endocrinology and Metabolism. “This effect requires activation of the GLP-1 receptor, but increasing the body’s own endogenous GLP-1 through the use of the DPP4 inhibitor sitagliptin does not achieve similar effects.”
“Our research shows that liraglutide, and possibly other GLP-1R agonists, have important metabolic effects in a manner distinct from increasing endogenous GLP-1 levels, even though they use the same receptor. Future research will focus on possible mechanisms for how GLP-1R agonists improve insulin sensitivity independent of weight loss.”
Eighty-eight subjects with obesity and prediabetes were randomized for 14 weeks to receive the GLP-1R agonist liraglutide, the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin, or unmedicated weight loss using a low-calorie diet.
To further investigate the GLP-1R-dependent effects of the treatments, the GLP-1R antagonist exendin and a placebo were administered in a two-by-two crossover study during mixed meal trials. Cross-over studies allow one subject’s response to treatment A to be compared with the same person’s response to treatment B.
Liraglutide was shown to rapidly improve insulin sensitivity as well as lower blood glucose within two weeks of starting treatment and before any weight loss.
“GLP-1R agonists are an exciting class of drugs given their potent glucose-lowering effects combined with tremendous benefits for weight loss, and have changed the way diabetes and obesity are managed in the clinic,” said Mashayekhi. “As the number of drugs in this class expands rapidly, a deeper understanding of the mechanisms of benefit is crucial so that we can design the right drugs for the desired outcomes in the right patients.”
The researchers’ previous research showed that liraglutide, but not sitagliptin or diet, improved measures of heart disease and inflammation. This matches the clinical findings of reduced CVD with GLP-1R agonist treatment.
Future studies will continue to investigate receptor-dependent effects of GLP-1R agonists and weight loss in humans.
This research was supported by the American Heart Association (17SFRN33520017), the National Center for Advancing Translational Sciences (5UL1TR002243), and the National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007061). is funded by grant DK020593 from the National Institute of Diabetes and Digestive and Kidney Diseases. Novo Nordisk provided liraglutide and matching placebo.