Evidence for a Liver-Derived Alpha Cell Growth Factor Uncovered

The recent observations that alpha cells can be converted into beta cells has spurred interest in harnessing this process with novel therapies to restore beta cell numbers in individuals with T1D. A potential therapeutic approach that combines agents to promote the conversion of alpha cells into beta cells with agents to stimulate the expansion of alpha cells could, in theory, be able to restore normal beta cell function while maintaining a normal alpha cell mass and glucagon response in an individual with T1D. Previous studies showed that lowering glucagon levels or blocking glucagon signaling resulted in the expansion of alpha cell numbers. However, it was not clear how this effect was controlled or if it was the result of a direct action on the alpha cells or occurred through an intermediate effect on another tissue. To better understand the mechanisms regulating alpha cell expansion, Dr. Powers and Dr. Drucker undertook a collaborative research program combining genetic studies with transplant studies to determine the source of the alpha cell growth signal. Through these experiments, the team discovered that elimination of glucagon receptor signaling in the liver resulted in expression of a liver-derived growth factor capable of promoting the expansion of alpha cells. The team is now working to identify the details of the liver-derived signaling process in order to identify factors or drug targets that could then be manipulated with novel drugs.

Ramifications for Individuals with T1D:
This early stage exploratory research helps to map out the mechanisms that promote the expansion of alpha cells in individuals. This knowledge will be used to guide the discovery of factors and potential drug targets and ultimately novel drugs to promote alpha cell expansion for the conversion into and restoration of beta cell numbers in individuals with T1D, thus restoring their insulin independence.

JDRF Involvement:
This work was supported, in part, by a JDRF Innovative Grant to Dr. Powers.

Investigators and Institutions:
This work represents a collaboration between Dr. Al Powers’ laboratory at Vanderbilt University and Dr. Daniel Drucker’s laboratory at the University of Toronto.

Reference:
Longuet, C, Robledo, AM, Dean, ED, Dai, C, Ali, S, McGuinness, I, de Chavez, V, Vuguin, PM, Charron, MJ, Powers, AC and Drucker, DJ. (2012) Liver-Specific Disruption of the Murine Glucagon Receptor Produces Beta Cell Hyperplasia: Evidence for a Circulating Beta Cell Growth Factor. Diabetes. Apr;62(4):1196-205. doi: 10.2337/db11-1605. Epub 2012 Nov 16.