Electrogenic sodium bicarbonate cotransporter NBCe1 regulates pancreatic ß cell function in type 2 diabetes.

ABSTRACT

Pancreatic ß cell failure in type 2 diabetes mellitus (T2DM) is attributed to perturbations of the ß cell's transcriptional landscape resulting in impaired glucose-stimulated insulin secretion. Recent studies identified SLC4A4 (a gene encoding an electrogenic Na+-coupled HCO3- cotransporter and intracellular pH regulator, NBCe1) as one of the misexpressed genes in ß cells of patients with T2DM. Thus, in the current study, we set out to test the hypothesis that misexpression of SLC4A4/NBCe1 in T2DM ß cells contributes to ß cell dysfunction and impaired glucose homeostasis. To address this hypothesis, we first confirmed induction of SLC4A4/NBCe1 expression in ß cells of patients with T2DM and demonstrated that its expression was associated with loss of ß cell transcriptional identity, intracellular alkalinization, and ß cell dysfunction. In addition, we generated a ß cell-selective Slc4a4/NBCe1-KO mouse model and found that these mice were protected from diet-induced metabolic stress and ß cell dysfunction. Importantly, improved glucose tolerance and enhanced ß cell function in Slc4a4/NBCe1-deficient mice were due to augmented mitochondrial function and increased expression of genes regulating ß cell identity and function. These results suggest that increased ß cell expression of SLC4A4/NBCe1 in T2DM plays a contributory role in promotion of ß cell failure and should be considered as a potential therapeutic target.