Loss of β-cell KATP reduces Ca2+ sensitivity of insulin secretion and Trpm5 expression

Loss-of-function (LOF) mutations in KATP channels cause hyperexcitability and insulin hypersecretion, resulting in congenital hyperinsulinism (CHI). Paradoxically, despite the initial insulin hypersecretion, many CHI cases, as well as KATP knockout (KO) animals, eventually 'crossover' to undersecretion and even diabetes. Here we confirm that Sur1 KO islets exhibit higher intracellular [Ca2+] ([Ca2+]i) at all [glucose], but show decreased glucose-stimulated insulin secretion. However, when [Ca2+]i is artificially elevated by increasing extracellular [Ca2+], insulin secretion from Sur1 KO islets increases to the same levels as WT islets. This indicates that a right-shift in [Ca2+]i-dependence of insulin secretion, rather than loss of insulin content or intrinsic secretability, is the primary cause for the crossover. Chronic pharmacological inhibition of KATP channel activity by slow release of glibenclamide in pellet-implanted mice causes a very similar 'crossover' to glucose intolerance and impaired insulin secretion to that seen in Sur1 KO animals. Whole islet and single cell transcriptomic analysis reveal markedly reduced Trpm5 in both conditions. Glibenclamide pellet-implanted Trpm5 KO mice also exhibited significant glucose intolerance. However, this was not as severe as in WT animals, which suggests that decreased expression of Trpm5 may play a small role in the disruption of insulin secretion with KATP loss.