Deletion of SLC4A4 in Pancreatic ß Cells Protects from High-Fat Diet–Induced Glucose Intolerance and ß-Cell Dysfunction

Abstract

Islet failure in type 2 diabetes (T2DM) is characterised by loss of glucose-stimulated insulin secretion (GSIS) attributed in part to β-cell dedifferentiation (e.g., mis-expression of alpha cell-specific genes). Recent single cell transcriptomics studies identified SLC4A4 (a gene encoding an electrogenic Na+-nHCO3- cotransporter, NBCe1) as one of the mis-expressed genes in β-cells of patients with T2DM. Thus, we set out to test the hypothesis that mis-expression of SLC4A4 in β-cells contributes to loss of GSIS and impaired glucose homeostasis in T2DM. To address this hypothesis, we first confirmed induction of robust SLC4A4 protein expression in β-cells of patients with T2DM utilizing immunofluorescence staining of autopsy-derived human pancreas specimens. We next generated β-cell-specific slc4a4 knockout (β-slc4a4-/-) and corresponding control (β-slc4a4+/+) mice through crossing of slc4a4 loxP/loxP and Ins2-Cre mouse models. Adult (3 month old) β-slc4a4-/- mice displayed normal body weight, glycaemia, glucose tolerance and insulin sensitivity under standard chow fed conditions (p>0.vs. β-slc4a4+/+). In contrast, β-slc4a4-/- mice exhibited enhanced glucose tolerance and in vivo glucose-stimulated insulin response under conditions of metabolic stress induced by ad libitum intake of 60% high fat diet (HFD) for 8 weeks (p<0.vs. β-slc4a4+/+ HFD). Interestingly, improved glucose tolerance in β-slc4a4-/-mice was also associated with a tendency for expansion of β-cells mass (82%, p=0.09 vs. β-slc4a4+/+ HFD) and increased β-cells proliferation (26%, p=0.11 vs. β-slc4a4+/+ HFD). These results suggest that β-cell mis-expression of the Na+-nHCO3- cotransporter encoded by SLC4A4 contributes to induction of β-cell failure under conditions of metabolic stress and T2DM. Disclosure M. Brown: None. H.L. Holmes: None. K. Rakshit: None. M.F. Romero: None. A. Matveyenko: None.