Loss of β-Cell K_atp Reduces Ca²⁺ Sensitivity of Insulin Secretion and Trpm5 Expression

Loss-of-function mutations in ATP-sensitive potassium (K_ATP) channels cause hyperexcitability and insulin hypersecretion, resulting in congenital hyperinsulinism (CHI). Paradoxically, despite the initial insulin hypersecretion, many CHI cases, as well as K_ATP knockout (KO) animals, eventually “crossover” to undersecretion and even diabetes. Here, we confirm that Sur1 KO islets exhibit higher intracellular concentration of calcium ion ([Ca²⁺]_i) at all concentrations of 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 in wild-type (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 K_ATP channel activity by slowrelease of glibenclamide in pellet-implanted mice causes a very similar crossover to glucose intolerance and impaired insulin secretion 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 decreased expression of Trpm5may play a small role in the disruption of insulin secretionwith K_ATP loss.