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Electrogenic Na+-coupled HCO3- cotransporter NBCe1 regulates pancreatic beta cell function in type 2 diabetes

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

ORGANISM(S): Mus musculus

PROVIDER: GSE179284 | GEO | 2021/08/11

REPOSITORIES: GEO

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Project description:The NF-κB pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. While canonical NF-κB signaling is well studied, there is little information on the divergent non-canonical NF-κB pathway in the context of pancreatic islet dysfunction in diabetes. Here, we demonstrate that pharmacological activation of the non-canonical NF-κB inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. Further, we identify NIK as a critical negative regulator of beta cell function as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of non-canonical NF-κB components p100 to p52, and accumulation of RelB. Tumor necrosis factor α (TNFα) and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive beta cell intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the non-canonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to beta cell failure. These studies reveal that NIK contributes a central mechanism for beta cell failure in diet-induced obesity. We identify a role for Nuclear Factor inducing κB (NIK) in pancreatic beta cell failure. NIK activation disrupts glucose homeostasis in zebrafish in vivo and impairs glucose-stimulated insulin secretion in mouse and human islets in vitro. NIK activation also perturbs beta cell insulin secretion in a diet-induced obesity mouse model. These studies reveal that NIK contributes a central mechanism for beta cell failure in obesity. To uncover the role of NIK in pancreatic beta cells, we performed a gene expression microarray analysis comparing pancreatic islets with constitutive beta cell intrinsicNIK activation from the 16 week old mice (beta cell specific TRAF2 and TRAF2 knockout mice) to their controls (n=3 per group).

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Electrogenic Na+-coupled HCO3- cotransporter NBCe1 regulates pancreatic beta cell function in type 2 diabetes

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