Scientists have shown that adding experimental cancer drugs to the treatment of diabetes is widely used to improve blood glucose control and weight loss in mice, according to a study published in today in eLife.
The findings 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 type of drug that reduces blood sugar levels and lower body weight. They work in part by binding to the glucagon-like peptide receptor 1 on pancreatic beta cells, which causes the cells to make insulin. However, not all patients achieve normal blood glucose control with GLP-1 drugs, and very few achieve full obesity.
We have previously shown that prolonged binding of the GLP-1 agonists with the glucagon-like peptide 1 receptor supports insulin secretion in pancreatic beta cells. This has led us to see if we can strengthen the effect of GLP-1 agonism on the regulation of glucose levels by complementary therapy. “
Dr. Dr. Prasenjit Mitra, Project Team Leader, Institute of Life Sciences. Reddy
The team started with a library of potential drugs and tested them in pancreatic beta cells to see if they improved the effect of GLP-1 drug on incretin receptor activity, by measuring a second messenger molecule to the called cAMP. They found four molecules that improved the activity of GLP-1 drugs. The most effective one, MS-275 (also known as entinostat), generated 3.5 times higher cAMP levels than the drug GLP-1 alone. MS-275 is a member of a family of drugs called class 1 HDAC inhibitors that are being studied as treatments for other diseases including cancer.
Given the synergistic effect of the drugs in pancreatic beta cells, the team tested whether their findings would be true in obese mice, fed a high-fat diet. Shilpak Bele, the graduate student led by Dr. Mitra, and other team members found that mice treated with the combination of agonist GLP-1 and MS-275 had a rapidly lower glucose level than previously controlled mice. maintained with repeated doses. Where a high-fat diet increased blood sugar rapidly in the untreated mice, the treated mice were controlled by mixing.
Given these effects on blood sugar, the team investigated whether the combination treatment also reduced weight gain. Mice that received the combination treatment had a significant and sustained reduction in their diet, which led to weight loss. When treatment was discontinued, the mice regained weight. Once the treatment was restarted, only the mice receiving the combination treatment showed significant weight loss again.
“GLP-1 drugs have emerged in the last decade as specific drugs that provide significant improvements in glycemic control and body weight; however, they rarely receive full metabolic therapy or ‘helps treat related comorbidities such as body weight,’ ‘Dr Mitra explains. “Our findings suggest that the HDAC inhibitor class 1 MS-275 may significantly increase GLP-1 drug activity, normalize blood glucose more efficiently and reduce weight. This lays the foundation for studies clinical combination of GLP-1 / HDAC inhibitors for the long-term management of diabetes and obesity in humans. “
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Magazine Reference:
Bele, S., et al. (2020) MS-275, a class 1 histone deacetylase inhibitor enhances glucagon-like peptide-1 receptor agonism to improve glycemic control and reduce obesity in diet-induced obese mice. eLife. doi.org/10.7554/eLife.52212.