Abstract
The cause of insulin insufficiency remains unknown in many diabetic cases. Up to 50% adult patients with cystic fibrosis (CF), a disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), develop CF-related diabetes (CFRD) with most patients exhibiting insulin insufficiency. Here we show that CFTR is a regulator of glucose-dependent electrical acitivities and insulin secretion in β-cells. We demonstrate that glucose elicited whole-cell currents, membrane depolarization, electrical bursts or action potentials, Ca2+ oscillations and insulin secretion are abolished or reduced by inhibitors or knockdown of CFTR in primary mouse β-cells or RINm5F β-cell line, or significantly attenuated in CFTR mutant (DF508) mice compared with wild-type mice. VX-809, a newly discovered corrector of DF508 mutation, successfully rescues the defects in DF508 β-cells. Our results reveal a role of CFTR in glucose-induced electrical activities and insulin secretion in β-cells, shed light on the pathogenesis of CFRD and possibly other idiopathic diabetes, and present a potential treatment strategy.
Highlights
The cause of insulin insufficiency remains unknown in many diabetic cases
As CFTR is a cAMP/PKA-dependent Cl À channel[13] known to be gated by intracellular ATP14–16, which is metabolized from glucose taken up by the cell[17], its expression in b-cells prompted us to hypothesize that CFTR might be sensitive to glucose and its activation by glucose could contribute to the glucoseinduced electrical activities required for insulin secretion in the b-cell
The results show that glucose-induced whole-cell currents, membrane depolarization, electrical bursts or action potentials, Ca2 þ oscillations and insulin secretion in b-cells are dependent on CFTR, indicating a previously unrecognized essential role of CFTR in the regulation of insulin secretion
Summary
The cause of insulin insufficiency remains unknown in many diabetic cases. Up to 50% adult patients with cystic fibrosis (CF), a disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), develop CF-related diabetes (CFRD) with most patients exhibiting insulin insufficiency. Our results reveal a role of CFTR in glucose-induced electrical activities and insulin secretion in b-cells, shed light on the pathogenesis of CFRD and possibly other idiopathic diabetes, and present a potential treatment strategy. Whereas most CFRD cases exhibit insulin insufficiency[4,5], the exact cause remains elusive destruction of the insulin-secreting pancreatic islets secondary to the obstruction of the pancreatic duct due to defective CFTR has long been considered the underlying cause[6,7]. The results show that glucose-induced whole-cell currents, membrane depolarization, electrical bursts or action potentials, Ca2 þ oscillations and insulin secretion in b-cells are dependent on CFTR, indicating a previously unrecognized essential role of CFTR in the regulation of insulin secretion
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