A variety of neurotransmitters, gastrointestinal hormones, and metabolic signals are known to potentiate insulin secretion through GPCRs. We show here that β cell–specific inactivation of the genes encoding the G protein α-subunits Gα_q and Gα₁₁ resulted in impaired glucose tolerance and insulin secretion in mice. Interestingly, the defects observed in Gα_q/Gα₁₁-deficient β 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 β cells was impaired in the absence of Gα_q/Gα₁₁, and closure of K_ATP channels was inhibited. We provide evidence that this reduced excitability was due to a loss of β 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/G₁₁-coupled P2Y6 receptor and extracellular calcium acting through the calcium-sensing receptor. Thus, the G_q/G₁₁-mediated signaling pathway potentiates insulin secretion in response to glucose by integrating systemic as well as autocrine/paracrine mediators.