The G(q)/G(11)-mediated signaling pathway is critical for autocrine potentiation of insulin secretion in mice

A variety of neurotransmitters, gastrointestinal hormones, and metabolic signals are known to potentiate insulin secretion through GPCRs. We show here that beta cell-specific inactivation of the genes encoding the G protein alpha-subunits G alpha(q) and G alpha(11) resulted in impaired glucose tolerance and insulin secretion in mice. Interestingly, the defects observed in G alpha(q)/G alpha(11)-deficient beta cells were not restricted to loss of muscarinic or metabolic potentiation of insulin release; the response to glucose per se was also diminished. Electrophysiological recordings revealed that glucose-induced depolarization of isolated beta cells was impaired in the absence of G alpha(q)/G alpha(11), and closure of K-ATP channels was inhibited. We provide evidence that this reduced excitability was due to a loss of beta cell-autonomous potentiation of insulin secretion through factors cosecreted with insulin. We identified as autocrine mediators involved in this process extracellular nucleotides such as uridine diphosphate acting through the G(q)/G(11)-coupled P2Y6 receptor and extracellular calcium acting through the calcium-sensing receptor. Thus, the G(q)/G(11)-mediated signaling pathway potentiates insulin secretion in response to glucose by integrating systemic as well as autocrine/paracrine mediators.