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Publication
CD44 contributes to hyaluronan-mediated insulin resistance in skeletal muscle of
high-fat-fed C57BL/6 mice.
Authors Hasib A, Hennayake CK, Bracy DP, Bugler-Lamb AR, Lantier L, Khan F, Ashford MLJ,
McCrimmon RJ, Wasserman DH, Kang L
Submitted By Submitted Externally on 1/14/2020
Status Published
Journal American journal of physiology. Endocrinology and metabolism
Year 2019
Date Published 12/1/2019
Volume : Pages 317 : E973 - E983
PubMed Reference 31550181
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.




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