[HTML][HTML] Chronic activation of a designer Gq-coupled receptor improves β cell function

S Jain, IR de Azua, H Lu, MF White… - The Journal of …, 2013 - Am Soc Clin Investig
S Jain, IR de Azua, H Lu, MF White, JM Guettier, J Wess
The Journal of clinical investigation, 2013Am Soc Clin Investig
Type 2 diabetes (T2D) has emerged as a major threat to human health in most parts of the
world. Therapeutic strategies aimed at improving pancreatic β cell function are predicted to
prove beneficial for the treatment of T2D. In the present study, we demonstrate that drug-
mediated, chronic, and selective activation of β cell G q signaling greatly improve β cell
function and glucose homeostasis in mice. These beneficial metabolic effects were
accompanied by the enhanced expression of many genes critical for β cell function …
Type 2 diabetes (T2D) has emerged as a major threat to human health in most parts of the world. Therapeutic strategies aimed at improving pancreatic β cell function are predicted to prove beneficial for the treatment of T2D. In the present study, we demonstrate that drug-mediated, chronic, and selective activation of β cell G q signaling greatly improve β cell function and glucose homeostasis in mice. These beneficial metabolic effects were accompanied by the enhanced expression of many genes critical for β cell function, maintenance, and differentiation. By employing a combination of in vivo and in vitro approaches, we identified a novel β cell pathway through which receptor-activated G q leads to the sequential activation of ERK1/2 and IRS2 signaling, thus triggering a series of events that greatly improve β cell function. Importantly, we found that chronic stimulation of a designer G q-coupled receptor selectively expressed in β cells prevented both streptozotocin-induced diabetes and the metabolic deficits associated with the consumption of a high-fat diet in mice. Since β cells are endowed with numerous receptors that mediate their cellular effects via activation of G q-type G proteins, our findings provide a rational basis for the development of novel antidiabetic drugs targeting this class of receptors.
The Journal of Clinical Investigation