title: 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.forename: Damaris N
authors.initials: DN
authors.lastname: Lorenzo
authors.forename: Jane A
authors.initials: JA
authors.lastname: Healy
authors.forename: Janell
authors.initials: J
authors.lastname: Hostettler
authors.forename: Jonathan
authors.initials: J
authors.lastname: Davis
authors.forename: Jiayu
authors.initials: J
authors.lastname: Yang
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Hans Ewald
authors.initials: HE
authors.lastname: Hohmeier
authors.forename: Mingjie
authors.initials: M
authors.lastname: Zhang
authors.forename: Vann
authors.initials: V
authors.lastname: Bennett
mesh_terms: D050154:Adiposity / Q000235:genetics*; D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019943:Amino Acid Substitution; D000818:Animals; D017487:Ankyrins / Q000235:genetics / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense
chemical_list: C498995:Ank2 protein, mouse; D017487:Ankyrins; D051275:Glucose Transporter Type 4; D007328:Insulin; C495693:Slc2a4 protein, mouse