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Scientists have shown that adding an experimental cancer drug to a widely used diabetes treatment improves blood sugar control and weight loss in mice, according to a study published today in eLife.
The results pave the way for clinical studies of the new drug combination as a more effective long-term treatment for millions of people with diabetes and obesity.
Glucagon-like peptide 1 agonists (GLP-1 analogs) are a relatively new class of drugs that reduce blood sugar and body weight. They work partially by binding to the glucagon-like peptide 1 receptor on pancreatic beta cells, which causes the cells to produce insulin. But not all patients achieve normalization of blood sugar control with GLP-1 drugs, and very few achieve a complete reversal of obesity.
We have previously shown that a prolonged association of GLP-1 agonists with the glucagon-like peptide 1 receptor promotes insulin secretion in pancreatic beta cells. This led us to see if we could improve the effects of GLP-1 agonism on the regulation of glucose levels with complementary therapy. “
Dr Prasenjit Mitra, Project Team Leader, Dr Reddy Institute for Life Sciences
The team started with a library of potential drugs and tested them in pancreatic beta cells to see if they enhanced the effects of a GLP-1 drug on incretin receptor activity, by measuring a second messenger molecule. called AMPc. They found four molecules that enhanced the activity of the GLP-1 drug. The most effective, MS-275 (also called entinostat), generated 3.5 times the levels of cAMP than the drug GLP-1 alone. MS-275 is one of a family of drugs called Class 1 HDAC inhibitors which are being studied as treatments for other diseases, including cancer.
Given the drugs’ synergistic effect on pancreatic beta cells, the team tested whether their results would be valid in obese mice, fed a high-fat diet. Shilpak Bele, the graduate student under the supervision of Dr. Mitra, and other members of the team found that mice treated with the combination of the GLP-1 agonist and MS-275 had lower glucose levels. fasting much lower than control mice which were maintained with repeated doses. When a high-fat diet increased fasting blood sugar in untreated mice, mice on combination therapy remained under control.
Given these effects on blood sugar, the team looked at whether the combination treatment also minimized weight gain. The mice given the combination treatment had a significant and lasting reduction in their food intake, which resulted in weight loss. When the treatment was stopped, the mice gained weight. Once the treatment was resumed, only the mice receiving the combination treatment again showed significant weight loss.
“GLP-1 drugs have emerged over the past decade as unique drugs that provide substantial improvements in blood sugar control and body weight; however, they rarely achieve full metabolic recovery or help treat associated co-morbidities such as body weight, ”says Dr Mitra. “Our results suggest that the HDAC class 1 inhibitor MS-275 can significantly improve the action of GLP-1 drugs, more effectively normalizing blood sugar levels and reducing weight gain. This lays the groundwork for clinical studies of combinations of GLP-1 / HDAC inhibitors for the long-term management of diabetes and obesity in humans. “
Source:
Journal reference:
Bele, S., et al. (2020) MS-275, a class 1 histone deacetylase inhibitor increases agonism of the glucagon-like peptide-1 receptor to improve glycemic control and reduce obesity in obese food-induced mice. eLife. doi.org/10.7554/eLife.52212.
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