ATP-sensitive potassium (K_ATP) channels are unique combinations of potassium inward rectifiers (K_IR6.x) and sulfonylurea receptors (SURs), members of the ATP-binding cassette superfamily. In pancreatic β-cells, K_ATP channels couple metabolism to membrane electrical activity and regulate insulin secretion by modulating the β-cell resting membrane potential and thus the activity of voltage-gated Ca²⁺ channels. Early studies defined the stoichiometry of the β-cell channel as SUR1/K_IR6.x)₄; more recent work has centred on defining functionally important domains and interactions within the channel, for example, for drug binding and regulation of gating. Work done in the mid-1990s identified mutations in human SUR1 or K_IR6.2 genes that altered or abolished K_ATP channel activity, producing mild or severe recessive forms of persistent hyperinsulinaemic hypoglycaemia of infancy, PHHI. Point mutations that affect regulation by ADP/ATP are known, while nonsense and splice site mutations in SUR1 remove a critical C-terminal signal required for surface expression. In contrast to the severe hypoglycaemia observed in PHHI, SUR1KO mice, like their K_IR6.2KO counterparts, are normoglycaemic although their electrophysiological profile is the same as PHHI β-cells – no K_ATP currents, higher resting membrane potential, spontaneous Ca²⁺-dependent action potentials, and elevated, oscillating [Ca²⁺]_i in low glucose. These mice are a novel system in which to study K_ATP-independent regulation of [Ca²⁺]_i oscillations, insulin secretion, and other cellular functions. Unexpectedly, islets from SUR1KO mice are refractory to GLP-1 and GIP, gastrointestinal peptides known to potentiate glucose-induced insulin secretion by elevating cAMP. The normal potentiation of secretion by cAMP is not affected by PKA inhibitors, thus the results argue K_ATP channels participate in cAMP sensing in β-cells, possibly via direct interactions with the recently discovered guanine nucleotide exchange proteins activated by cAMP, termed Epacs or cAMP-GEFs, and which interact with Rab3 and Rim proteins. Thus although K_ATP channels are missing and [Ca²⁺]_i is elevated, disrupting the enteroinsular axis removes a major stimulus for insulin release, allowing K_ATPKO mice to remain normoglycaemic.

All animals experiments were conducted in accordance with NIH guidelines and all animal protocols were reviewed and accepted by the Animal Research Committee of the Baylor College of Medicine.