New gene therapy improves insulin sensitivity and diabetes markers in mice

Camille Bienvenu
Tue, 18 Jul 2017
New gene therapy improves insulin sensitivity and diabetes markers in mice
New research presented at the last American Heart Association's Scientific Sessions suggests that a therapy called Urocortin 2 gene transfer raises insulin sensitivity in mice.

Urocortin 2 (Ucn2), from the corticotropin releasing factor (CRF) family of peptides, binds to and activates a receptor called CRF in insulin resistant cells.

The experimental therapy was designed by UCSD Professor of Medicine, Kirk Hammond, who is also co-founder of the biotechnology company delivering it, Renova Therapeutics.

Those kind of gene and peptide-based treatments are being tested since 2009 or so for use in prevention of cardiovascular disease as well as metabolic problems like type 2 diabetes.

Previously, Hammond and his team have found that Urocortin 3 (Ucn3) gene transfer, a similar therapy to Ucn2, increases heart function in heart failure.

Here, Hammond presented new datasets showing targeting Ucn2 benefits insulin resistant mice, which serves as evidence for moving to human clinical trials in type 2 diabetes.

Back in 2006, it has been first shown that Ucn2 interfered with glucose control in skeletal muscle - a major site of insulin resistance in the body.

They now found that higher CRFR2 expression in muscle cells is closely related to insulin sensitivity whereby high Ucn2 increases insulin resistance.

What happens is that the stimulation of Ucn2 inhibits the effect of insulin on glucose uptake in muscle cells. In contrast, mice lacking Ucn2 have increased insulin sensitivity and lower fat accumulation.

Body composition measurements of mice without Ucn2 on an unhealthy diet demonstrated, for example, decreases in fat and increases in lean muscle tissue.

Ucn2 constitutes an attractive target for insulin resistance as it also enables something called paracrine activity.

This refers to the ability for cell-to-cell communication in which a cell produces a signal to induce the same changes (in this case lowering insulin resistance) in nearby cells.

The latest results show that targeting CRFR2 with Ucn2 and/or Ucn3 is associated with significant and long-lasting beneficial effects on heart function, glucose control, weight loss and reduction in liver fat.

Interestingly, in 2015, scientists learned that a well-studied potential longevity compound, called rapamycin, reversed this inhibitory effect of CRFR2 stimulation on insulin signalling.

This again reinforces the idea that blood sugar control is the name of the game for reducing complications in type 2 diabetes and improving lifespan.
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