Novel link between inflammation and impaired glucose transport during equine insulin resistance.
Abstract: Although insulin resistance (IR) has been increasingly recognized in horses, a clear understanding of its pathophysiology is lacking. The purpose of the present study was to determine the early pathologic changes in IR horses by characterizing alterations in proteins that play key roles in innate immunological responses and inflammatory pathways, and by identifying potential links with glucose transport and insulin signaling. Visceral (VIS) and subcutaneous (SC) adipose tissue and skeletal muscle (SM) biopsies were collected from horses, which were classified as insulin-sensitive (IS) or IR based on the results of an insulin-modified frequently sampled intravenous glucose tolerance test. Protein expression of Toll-like receptor 4 (TLR-4), suppressor of cytokine signaling 3 (SOCS-3) and tumor necrosis factor alpha (TNF-α) were quantified by Western blotting in VIS and SC adipose depots and SM, as well as insulin receptor substrate 1 (IRS-1). To better characterize the potential relationship between inflammation, IR and impaired glucose transport, we correlated active cell surface glucose transporter 4 (GLUT-4) content (measured by a cell surface biotinylated assay) with individual- and tissue-specific data related to inflammation. IR was associated with a significantly increased expression of TLR-4 and SOCS-3 in SM and VIS tissue, without a significant change in SC site. We also observed a significant increase in TNF-α in VIS, but not in SC, tissue of IR vs. IS horses. There was no difference in total content or serine phosphorylation of IRS-1 for any sampling site in IR compared to IS horses. We further observed a significant positive correlation between TLR-4 content and SOCS-3, as well as a significant negative correlation between SOCS-3 content and GLUT-4 trafficking. Taken together, the data suggested a pro-inflammatory state in SM and VIS, but not SC, adipose depot during compensated IR. In addition, SOCS-3 appears to be a novel link between inflammation and dysregulated glucose metabolism and insulin sensitivity during the early pathogenesis of insulin resistance.
Copyright © 2012 Elsevier B.V. All rights reserved.
Publication Date: 2012-07-20 PubMed ID: 22871576DOI: 10.1016/j.vetimm.2012.07.003Google Scholar: Lookup
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- Journal Article
- Research Support
- N.I.H.
- Extramural
- Research Support
- Non-U.S. Gov't
Summary
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This research investigates the early changes that occur in insulin-resistant (IR) horses by studying alterations in key proteins involved in immune responses and inflammation. The results suggest a heightened state of inflammation in certain tissues in IR horses and identify a protein (SOCS-3) as a potential link between inflammation and impaired glucose metabolism, furthering our understanding of the pathology of insulin resistance in these animals.
About the Study
- This research investigates the early pathological changes that occur in horses with insulin resistance (IR)—a condition where the body’s cells do not respond properly to insulin, leading to elevated blood glucose levels.
- Researchers traced changes in proteins that are crucial to immune responses and inflammation, and searched for links relating those proteins to glucose transport and insulin signaling.
- The study involved visceral and subcutaneous adipose tissue, as well as skeletal muscle biopsies from horses categorized as either insulin-sensitive or IR.
Key Findings
- The study found that there was significant overexpression of Toll-like receptor 4 (TLR-4) and suppressor of cytokine signaling 3 (SOCS-3) in the skeletal muscle and visceral tissue of IR horses. This difference was not found in the subcutaneous adipose tissue.
- Increased levels of tumor necrosis factor alpha (TNF-α) were observed in the visceral tissue, but not the subcutaneous tissue, of the IR horses compared to the insulin-sensitive ones.
- No difference was observed in the total content or the phosphorylation state of insulin receptor substrate 1 (IRS-1) for any of the sites examined.
- A strong correlation was found between the levels of TLR-4 and SOCS-3, as well as between the amounts of SOCS-3 and the activity of glucose transporter 4 (GLUT-4).
Interpretation and Implications
- The data suggests that a heightened state of inflammation occurs in the skeletal muscle and visceral, but not subcutaneous, adipose tissue during compensatory IR.
- Notably, the protein SOCS-3 was proposed as a new connection between inflammation and the disrupted glucose metabolism seen in the onset of insulin resistance.
- These findings further our understanding of the pathology of insulin resistance in horses, potentially providing a basis for future research in ways to prevent and manage this condition.
Cite This Article
APA
Waller AP, Huettner L, Kohler K, Lacombe VA.
(2012).
Novel link between inflammation and impaired glucose transport during equine insulin resistance.
Vet Immunol Immunopathol, 149(3-4), 208-215.
https://doi.org/10.1016/j.vetimm.2012.07.003 Publication
Researcher Affiliations
- College of Pharmacy, 500W. 12th Avenue, The Ohio State University, Columbus, OH 43210, USA.
MeSH Terms
- Animals
- Biological Transport
- Biopsy / veterinary
- Female
- Glucose / metabolism
- Glucose Tolerance Test / veterinary
- Glucose Transporter Type 4 / immunology
- Glucose Transporter Type 4 / metabolism
- Horse Diseases / immunology
- Horse Diseases / metabolism
- Horses
- Inflammation / immunology
- Inflammation / metabolism
- Insulin Receptor Substrate Proteins / blood
- Insulin Resistance / immunology
- Intra-Abdominal Fat / immunology
- Intra-Abdominal Fat / metabolism
- Linear Models
- Muscle, Skeletal / immunology
- Muscle, Skeletal / metabolism
- Subcutaneous Fat / immunology
- Subcutaneous Fat / metabolism
- Suppressor of Cytokine Signaling Proteins / blood
- Toll-Like Receptor 4 / blood
- Tumor Necrosis Factor-alpha / blood
Grant Funding
- K01 RR023083 / NCRR NIH HHS
- K01RR023083-01 / NCRR NIH HHS
Citations
This article has been cited 10 times.- Delarocque J, Frers F, Feige K, Huber K, Jung K, Warnken T. Metabolic changes induced by oral glucose tests in horses and their diagnostic use.. J Vet Intern Med 2021 Jan;35(1):597-605.
- Campolo A, Frantz MW, de Laat MA, Hartson SD, Furr MO, Lacombe VA. Differential Proteomic Expression of Equine Cardiac and Lamellar Tissue During Insulin-Induced Laminitis.. Front Vet Sci 2020;7:308.
- Blaue D, Schedlbauer C, Starzonek J, Gittel C, Brehm W, Blüher M, Pfeffer M, Vervuert I. The influence of equine body weight gain on inflammatory cytokine expressions of adipose tissue in response to endotoxin challenge.. Acta Vet Scand 2020 Apr 22;62(1):17.
- Durham AE, Frank N, McGowan CM, Menzies-Gow NJ, Roelfsema E, Vervuert I, Feige K, Fey K. ECEIM consensus statement on equine metabolic syndrome.. J Vet Intern Med 2019 Mar;33(2):335-349.
- Feng XT, Tang SY, Jiang YX, Zhao W. ANTI-DIABETIC EFFECTS OF ZHUODUQING FORMULA, A CHINESE HERBAL DECOCTION, ON A RAT MODEL OF TYPE 2 DIABETES.. Afr J Tradit Complement Altern Med 2017;14(3):42-50.
- Banse HE, Holbrook TC, Frank N, McFarlane D. Relationship of skeletal muscle inflammation with obesity and obesity-associated hyperinsulinemia in horses.. Can J Vet Res 2016 Jul;80(3):217-24.
- Jackson EE, Rendina-Ruedy E, Smith BJ, Lacombe VA. Loss of Toll-Like Receptor 4 Function Partially Protects against Peripheral and Cardiac Glucose Metabolic Derangements During a Long-Term High-Fat Diet.. PLoS One 2015;10(11):e0142077.
- de Laat MA, Gruntmeir KJ, Pollitt CC, McGowan CM, Sillence MN, Lacombe VA. Hyperinsulinemia Down-Regulates TLR4 Expression in the Mammalian Heart.. Front Endocrinol (Lausanne) 2014;5:120.
- Lacombe VA. Expression and regulation of facilitative glucose transporters in equine insulin-sensitive tissue: from physiology to pathology.. ISRN Vet Sci 2014;2014:409547.
- Ertelt A, Barton AK, Schmitz RR, Gehlen H. Metabolic syndrome: is equine disease comparable to what we know in humans?. Endocr Connect 2014 Sep;3(3):R81-93.
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