Chronic KATP inhibition in vivo results in decreased Ca2+ sensitivity of insulin secretion

Acute inhibition of KATP channels in pancreatic β-cells causes depolarization, Ca2+ influx, and insulin secretion. Accordingly, loss of KATP results in congenital hyperinsulinism (CI) in humans. Interestingly, many patients with CI caused by KATP LOF mutations gradually remit or even progress to a diabetic state, and adult Kir6.2- or SUR1-subunit knockout mice exhibit reduced insulin secretion and glucose-intolerance. Causal mechanism(s) for this counterintuitive crossover from hypersecretion to undersecretion remain unknown.