Electrogenic sodium bicarbonate cotransporter NBCe1 regulates pancreatic β cell function in type 2 diabetes
Matthew R. Brown, Heather Holmes, Kuntol Rakshit, Naureen Javeed, Tracy K. Her, Alison A. Stiller, Satish Sen, Gary E. Shull, Y.S. Prakash, Michael F. Romero, Aleksey V. Matveyenko
Matthew R. Brown, Heather Holmes, Kuntol Rakshit, Naureen Javeed, Tracy K. Her, Alison A. Stiller, Satish Sen, Gary E. Shull, Y.S. Prakash, Michael F. Romero, Aleksey V. Matveyenko
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Research Article Cell biology Endocrinology

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

Abstract

Pancreatic β cell failure in type 2 diabetes mellitus (T2DM) is attributed to perturbations of the β 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 β cells of patients with T2DM. Thus, in the current study, we set out to test the hypothesis that misexpression of SLC4A4/NBCe1 in T2DM β cells contributes to β cell dysfunction and impaired glucose homeostasis. To address this hypothesis, we first confirmed induction of SLC4A4/NBCe1 expression in β cells of patients with T2DM and demonstrated that its expression was associated with loss of β cell transcriptional identity, intracellular alkalinization, and β cell dysfunction. In addition, we generated a β cell–selective Slc4a4/NBCe1-KO mouse model and found that these mice were protected from diet-induced metabolic stress and β cell dysfunction. Importantly, improved glucose tolerance and enhanced β cell function in Slc4a4/NBCe1-deficient mice were due to augmented mitochondrial function and increased expression of genes regulating β cell identity and function. These results suggest that increased β cell expression of SLC4A4/NBCe1 in T2DM plays a contributory role in promotion of β cell failure and should be considered as a potential therapeutic target.

Authors

Matthew R. Brown, Heather Holmes, Kuntol Rakshit, Naureen Javeed, Tracy K. Her, Alison A. Stiller, Satish Sen, Gary E. Shull, Y.S. Prakash, Michael F. Romero, Aleksey V. Matveyenko

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Figure 6

Selective deletion of Slc4a4 in β cells enhances β cell function.

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Selective deletion of Slc4a4 in β cells enhances β cell function. (A) Gl...
(A) Glucose-stimulated insulin secretion (GSIS) at 16 mM and 4 mM glucose concentrations in islets from β-Slc4a4+/+ (Slc4a4fl/fl+/+) and β-Slc4a4–/– (Slc4a4fl/flIns2Cre/+) mice exposed to 8 weeks of chow or HFD. *P < 0.05 denotes statistical significance (1-way ANOVA with Tukey’s method for multiple comparisons; n = 5–9 independent experiments from 3–5 mice). (B) Fold change in insulin secretion (16 mM vs. 4 mM glucose) (left) and insulin content (right) in β-Slc4a4+/+ (Slc4a4fl/fl+/+) and β-Slc4a4–/– (Slc4a4fl/flIns2Cre/+) chow and HFD islets. *P < 0.05, **P < 0.01, ***P < 0.001 (1-way ANOVA with Tukey’s method for multiple comparisons; n = 5–9 independent experiments from 3–5 mice). (C) Slc4a4 expression in islets isolated from β-Slc4a4+/+ (Slc4a4fl/fl+/+) mice exposed to 8 weeks of HFD after knockdown of Slc4a4. Islets were infected (96 hours) with control human adenovirus expressing eGFP (Ad5eGFP) or Ad5eGFP and Cre recombinase (Ad5Cre-eGFP). *P < 0.05 denotes statistical significance (unpaired, 2-tailed t test; n = 3 independent experiments from 3 mice). (D) Assessment of GSIS in Slc4a4fl/fl+/+ HFD islets infected with Ad5eGFP or Ad5Cre-eGFP; *P < 0.05 (unpaired, 2-tailed t test; n = 5 independent experiments from 3 mice). (E) Fold change in insulin secretion (16 mM vs. 4 mM glucose) (left) and insulin content (right) in Slc4a4fl/fl+/+ HFD islets infected with Ad5eGFP or Ad5Cre-eGFP. *P < 0.05 (unpaired, 2-tailed t test; n = 5 independent experiments from 3 mice) (F) β Cell mass (left) and α cell mass (right) in β-Slc4a4+/+ (Slc4a4fl/fl+/+) and β-Slc4a4–/– (Slc4a4fl/flIns2Cre/+) mice exposed to chow or HFD. *P < 0.05 (unpaired, 2-tailed t test; n = 4–6 mice per group). (G) β Cell proliferation (left) and apoptosis (right) in β-Slc4a4+/+ (Slc4a4fl/fl+/+) and β-Slc4a4–/– (Slc4a4fl/flIns2Cre/+) mice exposed to chow or HFD. *P < 0.05 (unpaired, 2-tailed t test; n = 4–6 independent experiments). Values represented as mean ± SEM.