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

J Clin Invest. 2015 Aug 3;125(8):3087-102. doi: 10.1172/JCI81317. Epub 2015 Jul 13.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiposity / genetics*
  • Aging* / genetics
  • Aging* / metabolism
  • Aging* / pathology
  • Amino Acid Substitution
  • Animals
  • Ankyrins* / genetics
  • Ankyrins* / metabolism
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism
  • Humans
  • Insulin / genetics
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells* / metabolism
  • Insulin-Secreting Cells* / pathology
  • Male
  • Metabolic Syndrome* / genetics
  • Metabolic Syndrome* / metabolism
  • Metabolic Syndrome* / pathology
  • Mice
  • Mice, Mutant Strains
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Mutation, Missense*


  • Ank2 protein, mouse
  • Ankyrins
  • Glucose Transporter Type 4
  • Insulin
  • Slc2a4 protein, mouse