Hyaluronan accumulates with high-fat feeding and contributes to insulin resistance.

Kang L, Lantier L, Kennedy A, Bonner JS, Mayes WH, Bracy DP, Bookbinder LH, Hasty AH, Thompson CB, Wasserman DH
Diabetes. 2013 62 (6): 1888-96

PMID: 23349492 · PMCID: PMC3661617 · DOI:10.2337/db12-1502

Increased deposition of specific extracellular matrix (ECM) components is a characteristic of insulin-resistant skeletal muscle. Hyaluronan (HA) is a major constituent of the ECM. The hypotheses that 1) HA content is increased in the ECM of insulin-resistant skeletal muscle and 2) reduction of HA in the muscle ECM by long-acting pegylated human recombinant PH20 hyaluronidase (PEGPH20) reverses high-fat (HF) diet-induced muscle insulin resistance were tested. We show that muscle HA was increased in HF diet-induced obese (DIO) mice and that treatment of PEGPH20, which dose-dependently reduced HA in muscle ECM, decreased fat mass, adipocyte size, and hepatic and muscle insulin resistance in DIO mice at 10 mg/kg. Reduced muscle insulin resistance was associated with increased insulin signaling, muscle vascularization, and percent cardiac output to muscle rather than insulin sensitization of muscle per se. Dose-response studies revealed that PEGPH20 dose-dependently increased insulin sensitivity in DIO mice with a minimally effective dose of 0.01 mg/kg. PEGPH20 at doses of 0.1 and 1 mg/kg reduced muscle HA to levels seen in chow-fed mice, decreased fat mass, and increased muscle glucose uptake. These findings suggest that ECM HA is a target for treatment of insulin resistance.

MeSH Terms (14)

Animals Cell Adhesion Molecules Diet, High-Fat Hyaluronic Acid Hyaluronoglucosaminidase Immunoblotting Immunohistochemistry Immunoprecipitation Insulin Resistance Male Mice Mice, Inbred C57BL Muscle, Skeletal Obesity

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