Ankyrin-B metabolic syndrome combines age-dependent adiposity with pancreatic β cell insufficiency
Damaris N. Lorenzo, … , Mingjie Zhang, Vann Bennett
Damaris N. Lorenzo, … , Mingjie Zhang, Vann Bennett
Published July 13, 2015
Citation Information: J Clin Invest. 2015;125(8):3087-3102. https://doi.org/10.1172/JCI81317.
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Research Article Endocrinology

Ankyrin-B metabolic syndrome combines age-dependent adiposity with pancreatic β cell insufficiency

Abstract

Rare functional variants of ankyrin-B have been implicated in human disease, including hereditary cardiac arrhythmia and type 2 diabetes (T2D). Here, we developed murine models to evaluate the metabolic consequences of these alterations in vivo. Specifically, we generated knockin mice that express either the human ankyrin-B variant R1788W, which is present in 0.3% of North Americans of mixed European descent and is associated with T2D, or L1622I, which is present in 7.5% of African Americans. Young AnkbR1788W/R1788W mice displayed primary pancreatic β cell insufficiency that was characterized by reduced insulin secretion in response to muscarinic agonists, combined with increased peripheral glucose uptake and concomitantly increased plasma membrane localization of glucose transporter 4 (GLUT4) in skeletal muscle and adipocytes. In contrast, older AnkbR1788W/R1788W and AnkbL1622I/L1622I mice developed increased adiposity, a phenotype that was reproduced in cultured adipocytes, and insulin resistance. GLUT4 trafficking was altered in animals expressing mutant forms of ankyrin-B, and we propose that increased cell surface expression of GLUT4 in skeletal muscle and fatty tissue of AnkbR1788W/R1788W mice leads to the observed age-dependent adiposity. Together, our data suggest that ankyrin-B deficiency results in a metabolic syndrome that combines primary pancreatic β cell insufficiency with peripheral insulin resistance and is directly relevant to the nearly one million North Americans bearing the R1788W ankyrin-B variant.

Authors

Damaris N. Lorenzo, Jane A. Healy, Janell Hostettler, Jonathan Davis, Jiayu Yang, Chao Wang, Hans Ewald Hohmeier, Mingjie Zhang, Vann Bennett

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Figure 4

Increased GLUT4 association with plasma membranes of mutant AnkB adipocytes caused by reduced GLUT4 internalization rates.

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Increased GLUT4 association with plasma membranes of mutant AnkB adipocy...
(A) 2-DG uptake in differentiated adipocytes before and after stimulation with 100 nM insulin. Data represent mean ± SEM of values from one 6-well plate per genotype for 1 of 3 repeats. (B) Coimmunoprecipitation from control mouse skeletal muscle homogenates. (C) Diagram of a GLUT4 construct with extracellular Myc and C-terminal GFP epitopes (Myc-GLUT4-GFP) used for assessing GLUT4 distribution in differentiated adipocytes. The position of the F5QQI motif is indicated. (D) GLUT4 localization in differentiated adipocytes under basal conditions or following insulin stimulation and internalization at 37°C. Scale bar: 10 μm. (E) Quantification of GLUT4 association with plasma membranes of differentiated adipocytes either at rest or at indicated times following treatment with 100 nM insulin and internalization at 37°C. (F) Coimmunoprecipitation from HEK293 cells expressing either wild-type HA-GLUT4 or F5QQI8-A5AAA8 HA-GLUT4 and GFP-AnkB proteins. Data is representative of 3 independent experiments. Data represent mean ± SEM for 1 of 3 independent determinations (n = 30 cells per genotype and per condition). *P < 0.05, **P < 0.01, ***P < 0.001, 1-way ANOVA with post-hoc Tukey test.