Loss of β-Cell KATP Reduces Ca2+ Sensitivity of Insulin Secretion and <i>Trpm5</i> Expression

Congenital hyperinsulinism caused by loss of ATP-sensitive potassium (KATP) channels crosses over to unexplained undersecretion. Why does loss of β-cell KATP channel activity result in undersecretion of insulin and glucose tolerance, despite elevated intracellular concentration of calcium ion ([Ca2+]i) levels? Superelevation of [Ca2+]i in supraphysiological extracellular [Ca2+] boosted secretion from Sur1 knockout (KO) islets to the same levels as WT, indicating a right-shift in [Ca2+]i dependence of secretion. Transcriptomic analysis revealed markedly reduced β-cell Trpm5 in the absence of KATP. KATP inhibition in Trpm5 KO mice still caused significant glucose intolerance, but slightly less severe than in WT animals. Right-shifted [Ca2+]i dependence of secretion explains crossover. Downregulation of Trpm5 may be involved.