Hyaluronan Accumulates With High-Fat Feeding and Contributes to Insulin Resistance
Open accessAbstract
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.
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The glycosaminoglycan hyaluronan is increased in tissues of prediabetic animals.
“The glycosaminoglycan hyaluronan is increased in tissues of prediabetic animals”
From The Vasculature in Prediabetes (2018) · cites this paper as [173]
A reduction of hyaluronan using PEGylated hyaluronidase in high fat-fed mice improves insulin action.
“A reduction of hyaluronan using PEGylated hyaluronidase in high fat-fed mice improves insulin action.”
From The Vasculature in Prediabetes (2018) · cites this paper as [173]
ECM remodeling causes changes in signaling via cell surface receptors that sense the extracellular microenvironment.
“ECM remodeling170, 172, 173, 178 causes changes in signaling via cell surface receptors that sense the extracellular microenvironment.162, 179-181”
From The Vasculature in Prediabetes (2018) · cites this paper as [173]
Treatments that improve insulin action in rodent models of prediabetes normalize collagen levels and increase muscle capillaries.
“Treatments that improve insulin action in rodent models of prediabetes normalize collagen levels and increase muscle capillaries.”
From The Vasculature in Prediabetes (2018) · cites this paper as [173]
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- Authors
- Kang, L., Lantier, L., Kennedy, A., Bonner, J. S., Mayes, W. H., Bracy, D. P., Bookbinder, L. H., Hasty, A. H., Thompson, C. B., & Wasserman, D. H.
- Affiliations
- Vanderbilt University (US)
- Halozyme Therapeutics (United States) (US)
- Corresponding author
- Kang, Li
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2013-05-17
- Volume
- 62
- Issue
- 6
- Pages
- 1888-1896
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3661617
- OpenAlex
- W2127235850
- Cited by
- 133
- References
- 49
- Citations by year
- 2026: 3 · 2025: 13 · 2024: 11 · 2023: 13 · 2022: 9 · 2021: 4 · 2020: 14 · 2019: 12 · 2018: 10 · 2017: 11 · 2016: 9 · 2015: 12 · 2014: 7 · 2013: 5
- FWCI
- 6.38
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Funders
- National Institutes of Health (5p60dk020593-31)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 020593, P60-DK020593, U24DK059637, DK-054902, DK 059637, R01DK054902, R56DK054902, T32DK007563, P30DK020593)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- hyaluronic acid, insulin resistance, skeletal muscle, extracellular matrix, high-fat diet, obesity, PEGPH20, hyaluronidase, muscle glucose uptake, adipocyte size, fat mass, insulin signaling, muscle vascularization, cardiac output
- MeSH terms
- Animals, Hyaluronic Acid, Hyaluronoglucosaminidase, Immunohistochemistry, Insulin Resistance, Male, Mice, Inbred C57BL, Obesity, Immunoblotting, Cell Adhesion Molecules, Muscle, Skeletal, Immunoprecipitation, Mice, Diet, High-Fat
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