Targeting a MicroRNA Shows Potential to Enhance Effectiveness of Diabetes Drugs


 

Over the past 15 years, UAB endocrinologist Anath Shalev, MD has unraveled a crucial biological pathway that malfunctions in diabetes.

Her latest discovery in this beta-cell pathway, published in the journal Diabetes, shows the potential to enhance the effectiveness of existing diabetes drugs.

In 2013, the UAB researchers found that either diabetes or elevated production of the protein TXNIP induced beta-cell expression of microRNA-204, or miR-204, and this microRNA, in turn, blocked insulin production.

The Shalev group has now found another vital role for miR-204 -- regulating the cell surface receptor that is the target of many of the newer type 2 diabetes drugs. This drug target is the glucagon-like peptide 1 receptor, or GLP1R. Activation of GLP1R with these drugs helps the beta cell produce and secrete more insulin.

Shalev's new work was performed in rat beta cells, genetically modified mice, mouse pancreatic islets and human pancreatic islets. Healthy beta cells, which are found in the pancreatic islets, produce insulin to control blood sugar levels; in diabetes the beta cells are impaired and dysfunctional, and have lower GLP1R levels.

Shalev and colleagues found that overexpression of miR-204 decreased expression of GLP1R in rat beta cells and in mouse and human pancreatic islets. Conversely, knock-down of miR-204 increased expression of GLP1R in those cells and pancreatic islets.

Greater GLP1R expression is beneficial because it helps transfer a signal to the beta cell to secrete more insulin, such as after a meal. Also, many of the newer diabetes drugs act as agonists to activate GLP1R. Higher expression can allow use of a lower-drug dose to treat diabetes, thus reducing dose-dependent side effects.

In mice, the UAB researchers found that a deletion of miR-204 caused enhanced GLP1R expression, and also better insulin secretion and glucose control. Furthermore, the knockout mice were more responsive to a GLP1R agonist in glucose tolerance tests. When the GLP1R knockout mice were used in a model of diabetes, where beta cells are damaged by low doses of the toxin streptozotocin, the diabetic mice showed improved glucose control and increased serum insulin levels.

These results suggest that downregulating miR-204, now revealed as an upstream regulator of GLP1R, could lead to better treatment of diabetes.

 
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