Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 125, Issue 8, Pages 3087-3102Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI81317
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Funding
- Research Grant Council of Hong Kong [663812, AoE/M09/12]
- Yale MMPC grant [U24 DK-059635]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [U24DK059635] Funding Source: NIH RePORTER
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Rare functional variants of ankyrin-B have been implicated in human disease, including hereditary cardiac arrhythmia and type 2 diabetes (120). 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 120, or L1622I, which is present in 7.5% of African Americans. Young Ankb(R1788W/R1788W) mice displayed primary pancreatic beta 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 Ankb(R1788W/R1788W) and Ankb(L16221/L16221) 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 Ankb(R1788W/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 beta cell insufficiency with peripheral insulin resistance and is directly relevant to the nearly one million North Americans bearing the R1788W ankyrin-B variant.
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