New drug mixture improves blood glucose manipulate and weight reduction in mice

Overview

• Post By : Kumar Jeetendra


• Source: eLife


• Date: 23 Dec,2020

Scientists have demonstrated that adding an experimental cancer drug to a widely used diabetes treatment improves blood glucose control and weight loss in mice, according to a study published today in eLife.

The results pave the way for clinical trials of this new drug combination as a more successful long-term remedy for countless individuals with diabetes and obesity.

Glucagon-like peptide 1 agonists (GLP-1 analogs) are a relatively new class of drugs that reduce blood sugar levels and lower body weight. They partly operate by binding to the glucagon-like peptide 1 receptor on pancreatic beta cells, which leads the cells to produce insulin. However, not all patients achieve normalization of blood sugar control with GLP-1 medications, and very few achieve full reversal of obesity.

We have previously shown that prolonged association of the GLP-1 agonists with the glucagon-like peptide 1 receptor supports insulin secretion in pancreatic beta cells. This led us to see whether we could enhance the effects of GLP-1 agonism on regulating glucose levels with a complementary therapy.”

Dr. Prasenjit Mitra, Project Team Leader, Dr. Reddy’s Institute of Life Sciences

The team started with a library of potential drugs and tested them in pancreatic beta cells to determine whether they improved the effects of a GLP-1 drug on incretin receptor activity, by measuring a second messenger molecule called cAMP. They discovered four molecules that improved GLP-1 drug activity. The best one, MS-275 (also referred to as entinostat), generated 3.5 times the cAMP levels compared to GLP-1 drug alone.

Considering that the synergistic effect of these medication in pancreatic beta cells, the team analyzed whether their findings would hold true in obese mice, fed a high-fat diet. Shilpak Bele, the graduate student under Dr. Mitra’s management, along with other team members discovered that mice treated with the combination of GLP-1 agonist and MS-275 had a considerably lower fasting glucose level than control mice that were sustained with repeat dosing. Where a high-fat diet increased fasting blood sugar in the untreated mice, the mice on the combination treatment stayed in control.

Given these effects on blood sugar, the group explored whether the combination therapy also exerts weight gain. Mice given the combination treatment had a significant and sustained reduction in their food intake, which caused weight loss. When therapy was interrupted, the mice regained weight.

“GLP-1 drugs have emerged in the past decade as unique medicines that offer substantial improvements in glycemic control and body weightnonetheless, they rarely achieve full metabolic healing or help treat associated comorbidities such as body weight,” Dr. Mitra explains. “Our results imply that the course 1 HDAC inhibitor MS-275 can significantly enhance the action of GLP-1 drugs, more efficiently normalising blood glucose and reducing weight reduction. This lays the foundation for clinical studies of combinations of GLP-1/HDAC inhibitors to the long term management of obesity and diabetes in humans.”