Journal
DIABETES
Volume 66, Issue 2, Pages 325-334Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db16-0484
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01 DK095761, R01 DK083187, R01 DK075594, R01 DK069221, R37 DK050277, R01 DK054902, U24 DK059637]
- Veterans Affairs Merit Review, Center for Integrated Healthcare, U.S. Department of Veterans Affairs [1I01BX002025-01, 1I01BX002196]
- NIDDK (the Diabetes Research and Training Center) [DK20593]
- Molecular Endocrinology Training Program at Vanderbilt University
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The liver extracellular matrix (ECM) expands with high fat (HF) feeding. This finding led us to address whether receptors for the ECM, integrins, are key to the development of diet-induced hepatic insulin resistance. Integrin-linked kinase (ILK) is a downstream integrin signaling molecule involved in multiple hepatic processes, including those related to differentiation, wound healing, and metabolism. We tested the hypothesis that deletion of ILK in mice on an HF diet would disrupt the ECM-integrin signaling axis, thereby preventing the transformation into the insulin-resistant liver. To determine the role of ILK in hepatic insulin action in vivo, male C57BL/6J ILKlox/lox mice were crossed with Albcre mice to produce a hepatocyte-specific ILK deletion (ILK(lox/lox)Albcre). Results from this study show that hepatic ILK deletion has no effect on insulin action in lean mice but sensitizes the liver to insulin during the challenge of HF feeding. This effect corresponds to changes in the expression and activation of key insulin signaling pathways as well as a greater capacity for hepatic mitochondria! glucose oxidation. This demonstrates that ILK contributes to hepatic insulin resistance and highlights the previously undefined role of integrin signaling in the pathogenesis of diet-induced hepatic insulin resistance.
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