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Diabetes. 2013 Jun;62(6):1888-96. doi: 10.2337/db12-1502. Epub 2013 Jan 24.

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

Author information

1
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA. li.kang@vanderbilt.edu

Abstract

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.

PMID:
23349492
PMCID:
PMC3661617
DOI:
10.2337/db12-1502
[Indexed for MEDLINE]
Free PMC Article
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