Acute inhibition of K ATP channels in pancreatic β-cells causes depolarization, Ca 2+ influx, and insulin secretion. Accordingly, loss of K ATP results in congenital hyperinsulinism (CI) in humans. Interestingly, many patients with CI caused by K ATP 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, reflecting a right-shifted Cai-dependence of secretion. Causal mechanism(s) for this counterintuitive crossover from hypersecretion to undersecretion remain unknown. cAMP, produced by adenylyl cyclase (AC), is a key component in the “amplifying pathway” of insulin secretion, and elevated Ca 2+ has previously been shown to decrease AC activity. Here, we assessed the impact of the AC activator forskolin (FSK) on insulin secretion in SUR1 KO islets. In the presence of FSK, insulin secretion was significantly increased at 2.8 mM glucose in SUR1 KO islets but not in WT islets. FSK treatment had no effect on intracellular Ca 2+ levels, suggesting that increased production of cAMP can normalize Ca 2+ i-dependence. Another key component of the amplifying pathway, CAMKII, is acutely activated by autophosphorylation in response to elevated Ca 2+ and amplifies Ca 2+ influx and insulin secretion. Here, we observe reduced total CAMKII, but markedly reduced phosphor-CAMKII in SUR1KO islets, suggesting reduced activity of this important component of the amplifying pathway. Intriguingly, treatment of islets with a low dose of the CAMKII inhibitor KN93 (1μM) blocks FSK potentiation of insulin secretion in SUR1KO but not WT islets, and FSK treatment results in a moderate increase in CAMKII phosphorylation. These data suggest that impaired insulin secretion in SUR1 KO mice may be the result of lower cAMP production and reduced phospho-CAMKII action, leading to suppression of the amplifying pathway of insulin secretion.
York et al. (Sun,) studied this question.