Clinical issue

Diabetes exacts one of the highest annual costs for treatment of any disease in the world and is the seventh leading cause of death in the USA. Most cases of both type 1 and type 2 diabetes involve the actual or functional loss of insulin-producing pancreatic β-cells. Although β-cells can replicate, little is known about how the process is regulated and available therapies for diabetes cannot specifically stimulate β-cell regeneration. There is hope that understanding the signals that control islet cell proliferation and differentiation will help generate targeted β-cell regenerative therapies for diabetic patients.

Results

This study shows that two members of the gene family regulators of G protein signaling (RGS), Rgs8 and Rgs16, coordinate β-cell expansion with metabolic need. Rgs8 and Rgs16 are expressed during islet development and in mouse models of type 1 and type 2 diabetes. Exendin-4, a Glp-1/incretin mimetic that stimulates β-cell expansion in diabetics, also promotes the expression of Rgs16::GFP in pancreatic ductal-associated cells and islet β-cells in mice. As the name implies, RGS members regulate the frequency and duration of G protein-coupled receptor (GPCR) signaling. Since GPCR pathways are also associated with β-cell expansion, this suggests that RGS proteins serve as sensitive and early beacons of G protein signaling in β-cell progenitor expansion and regeneration during development and in metabolically stressed adults.

Implications and future directions

This study indicates that the RGS proteins Rgs8 and Rgs16 coordinate GPCR signaling with islet development and, later in life, with metabolic stress. The early response of these proteins to metabolic changes suggests that they may be useful screening indicators. Furthermore, understanding the mechanisms that regulate GPCR induction of pancreatic β-cell proliferation may provide a crucial inroad to diabetes therapy. Future work should determine the potential of RGS proteins to promote β-cell development and islet regeneration.