| First Author | Lorenzo DN | Year | 2015 |
| Journal | J Clin Invest | Volume | 125 |
| Issue | 8 | Pages | 3087-102 |
| PubMed ID | 26168218 | Mgi Jnum | J:222913 |
| Mgi Id | MGI:5646030 | Doi | 10.1172/JCI81317 |
| Citation | Lorenzo DN, et al. (2015) Ankyrin-B metabolic syndrome combines age-dependent adiposity with pancreatic beta cell insufficiency. J Clin Invest 125(8):3087-3102 |
| abstractText | 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 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 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 beta cell insufficiency with peripheral insulin resistance and is directly relevant to the nearly one million North Americans bearing the R1788W ankyrin-B variant. |
