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Regulation of Pancreatic Beta Cell Function by Ankyrin‐B
Author(s) -
Lorenzo Damaris N,
Hostettler Janell,
Bennett Vann
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.893.5
Subject(s) - medicine , endocrinology , beta cell , islet , insulin , biology , ankyrin , insulin resistance , pancreas , lipotoxicity , endoplasmic reticulum , glucose homeostasis , type 2 diabetes , microbiology and biotechnology , diabetes mellitus , biochemistry , gene
Functional variants of the cytoskeletal protein ankyrin‐B (AnkB) have been implicated in human hereditary cardiac arrhythmia and type 2 diabetes (T2D).1–3 We recently showed that knock‐in mice expressing human AnkB variants p.R1788W (present in 0.2% Caucasians and associated with T2D) or p.L1622I (present in 7.5% of African Americans), exhibit a metabolic syndrome that combines deficits in insulin secretion with age‐ and diet‐dependent adiposity, and insulin resistance.3 Here, we demonstrate that beta cell‐specific depletion of AnkB is sufficient to promote alterations in pancreatic islet morphology, reduction in insulin secretion, abnormal glucose tolerance, and the onset of diabetes in mice. We found that AnkB, through multiple structural and signaling functions, is a critical player in pancreatic islet biology. Biochemical and proximity ligation assays show that AnkB interacts with the inositol‐1,4,5‐triphosphate receptor (InsP 3 R) and with the Kir6.2 subunit of the ATP‐sensitive potassium channel. Expression of T2D‐associated AnkB mutations or loss of AnkB altered the level and localization of the InsP 3 R and Kir6.2 in beta cells, which, in turn, resulted in decreased insulin secretion in response to glucose and carbachol stimulation in vivo and in isolated islets, and hyperglycemia in mice. Immunohistochemistry of the pancreas revealed reduction in beta‐cell area, along with increase in apoptosis and endoplasmic reticulum stress markers. These morphological and metabolic deficits are exacerbated with age or following a high‐fat diet. These results show that Ank‐B is a critical regulator of pancreatic beta cell function in a cell‐autonomous fashion, and its deficits might cause diabetes. Support or Funding Information Howard Hughes Medical Institute