The insulin-producing b cells of pancreatic islets play a major role in the physiological regulation of blood glucose, and in the development of most forms of diabetes. We have shown that these cells are coupled by channels made of Cx36. Loss of this protein results in the disappearance of b cell gap junctions, of the normal intercellular synchronization of the Ca²⁺ transients which are elicited by glucose stimulation, and of the intercellular diffusion of depolarizing and hyperpolarizing electrotonic currents. As a result, basal insulin secretion increases, glucose-induced stimulation is prevented, the release of insulin is no more oscillatory, nor is it rapidly turn off when the nutrient stimulus is withdrawn. Cx36-null mice also became more hyperglycaemic than wild type or heterozygous littermates when treated with drugs selectively killing b cells, and the apoptosis of their b cells was much increased after exposure to cytokines thought to be involved at the onset of type 1 diabetes. In contrast, transgenic mice over expressing Cx36 in b cells were fully protected against these conditions. A similar pattern of Cx36 expression and coupling was observed between the b cells of multi-organ donors. In these human islets, Cx36 expression correlated with that of insulin, as the 2 cognate genes were found controlled by similar transcription factors. Screening of populations of type 2 diabetics revealed a single nucleotide polymorphism in the coding region of Cx36, which is highly associated to the disease. The data provide evidence that Cx36-dependent signaling is required for the proper physiological functioning of the insulin-producing b cells, and is altered in diabetes-like conditions.