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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

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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 1

Human AnkB variants cause tissue-specific AnkB reduction.

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Human AnkB variants cause tissue-specific AnkB reduction.
(A) Variant fr...
(A) Variant frequency (per 100 individuals) for the most common ANKB variants in North Americans of European and African descent. Allele frequencies were compiled from the NHLBI GO Exome Sequencing Project. Asterisks indicate undetected variants. (B) Frequency of the p.R1788W ANKB variant in European Americans and Hispanics from the GENNID cohort of noninsulin-dependent diabetic patients (control and T2D cases) and from individuals of the same ethnicity sequenced as part of the entire GENNID cohort, the NHLBI GO Exome Sequencing Project, and the 1000 Genomes Project. Asterisks indicate undetected variants. (C) Model of AnkB structure, with domains indicated, showing the localization of L1622 and R1788 sites within AnkB’s unstructured C-terminal domain. (D) Evolutionary conservation of L1622 and R1788 sites. (E) Sequencing chromatograms of brain cDNA from Ankb+/+ and Ankb knockin mice. (F) Quantitative analysis of AnkB protein levels for the indicated tissues as a percentage of control (Ankb+/+). (G) Quantification of 220-kDa Ankb transcript levels by qPCR. GAPDH was used for normalization of mRNA and protein levels. Data represent mean ± SEM (n = 5 males, 10-weeks-old). Results are representative of 3 independent experiments. ***P < 0.001, 2-tailed t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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