Integrin-Linked Kinase in Muscle Is Necessary for the Development of Insulin Resistance in Diet-Induced Obese Mice

Li Kang, Shilpa Mokshagundam, Bradley Reuter, Daniel S Lark, Claire C Sneddon, Chandani Hennayake, Ashley S Williams, Deanna P Bracy, Freyja D James, Ambra Pozzi, Roy Zent, David H Wasserman

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

Diet-induced muscle insulin resistance is associated with expansion of extracellular matrix (ECM) components, such as collagens, and the expression of collagen-binding integrin, α2β1. Integrins transduce signals from ECM via their cytoplasmic domains, which bind to intracellular integrin-binding proteins. The integrin-linked kinase (ILK)-PINCH-parvin (IPP) complex interacts with the cytoplasmic domain of β-integrin subunits and is critical for integrin signaling. In this study we defined the role of ILK, a key component of the IPP complex, in diet-induced muscle insulin resistance. Wild-type (ILK(lox/lox)) and muscle-specific ILK-deficient (ILK(lox/lox)HSAcre) mice were fed chow or a high-fat (HF) diet for 16 weeks. Body weight was not different between ILK(lox/lox) and ILK(lox/lox)HSAcre mice. However, HF-fed ILK(lox/lox)HSAcre mice had improved muscle insulin sensitivity relative to HF-fed ILK(lox/lox) mice, as shown by increased rates of glucose infusion, glucose disappearance, and muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. Improved muscle insulin action in the HF-fed ILK(lox/lox)HSAcre mice was associated with increased insulin-stimulated phosphorylation of Akt and increased muscle capillarization. These results suggest that ILK expression in muscle is a critical component of diet-induced insulin resistance, which possibly acts by impairing insulin signaling and insulin perfusion through capillaries.

Original languageEnglish
Pages (from-to)1590-600
Number of pages11
JournalDiabetes
Volume65
Issue number6
DOIs
Publication statusPublished - Jun 2016

Keywords

  • Animals
  • Diet, High-Fat
  • Extracellular Matrix/metabolism
  • Glucose/metabolism
  • Glucose Clamp Technique
  • Insulin/metabolism
  • Insulin Resistance
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Muscle, Skeletal/metabolism
  • Obesity/etiology
  • Protein Serine-Threonine Kinases/metabolism
  • Signal Transduction

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