CD44 contributes to hyaluronan-mediated insulin resistance in skeletal muscle of high fat-fed C57BL/6 mice

Annie Hasib, Chandani Hennayake, Deanna P. Bracy, Aimee-Rose Bugler-Lamb, Louise Lantier, Faisel Khan, Michael Ashford, Rory McCrimmon, David H. Wasserman, Li Kang (Lead / Corresponding author)

Research output: Contribution to journalArticle

Abstract

Extracellular matrix hyaluronan is increased in skeletal muscle of high-fat-fed insulin-resistant mice, and reduction of hyaluronan by PEGPH20 hyaluronidase ameliorates diet-induced insulin resistance (IR). CD44, the main hyaluronan receptor, is positively correlated with type 2 diabetes. This study determines the role of CD44 in skeletal muscle IR. Global CD44-deficient (cd44-/-) mice and wild-type littermates (cd44+/+) were fed a chow diet or 60% high-fat diet for 16 wk. High-fat-fed cd44-/- mice were also treated with PEGPH20 to evaluate its CD44-dependent action. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp (ICv). High-fat feeding increased muscle CD44 protein expression. In the absence of differences in body weight and composition, despite lower clamp insulin during ICv, the cd44-/- mice had sustained glucose infusion rate (GIR) regardless of diet. High-fat diet-induced muscle IR as evidenced by decreased muscle glucose uptake (Rg) was exhibited in cd44+/+ mice but absent in cd44-/- mice. Moreover, gastrocnemius Rg remained unchanged between genotypes on chow diet but was increased in high-fat-fed cd44-/- compared with cd44+/+ when normalized to clamp insulin concentrations. Ameliorated muscle IR in high-fat-fed cd44-/- mice was associated with increased vascularization. In contrast to previously observed increases in wild-type mice, PEGPH20 treatment in high-fat-fed cd44-/- mice did not change GIR or muscle Rg during ICv, suggesting a CD44-dependent action. In conclusion, genetic CD44 deletion improves muscle IR, and the beneficial effects of PEGPH20 are CD44-dependent. These results suggest a critical role of CD44 in promoting hyaluronan-mediated muscle IR, therefore representing a potential therapeutic target for diabetes.

Original languageEnglish
Pages (from-to)E973-E983
Number of pages11
JournalAmerican Journal of Physiology, Endocrinology and Metabolism
Volume317
Issue number6
Early online date24 Sep 2019
DOIs
Publication statusPublished - 1 Dec 2019

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Keywords

  • Extracellular matrix
  • hyaluronan
  • insulin resistance
  • extracellular matrix

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