• 1. Treiber KH, Kronfeld DS, Geor RJ. Insulin resistance in equids: possible role in laminitis. J Nutr 2006; 136: 2094S2098S.

  • 2. Treiber KH, Kronfeld DS, Hess TM, et al. Evaluation of genetic and metabolic predispositions and nutritional risk factors for pasture-associated laminitis in ponies. J Am Vet Med Assoc 2006; 228: 15381545.

    • Search Google Scholar
    • Export Citation
  • 3. Carter RA, Treiber KH, Geor RJ, et al. Prediction of incipient pasture-associated laminitis from hyperinsulinaemia, hyperleptinaemia and generalised and localised obesity in a cohort of ponies. Equine Vet J 2009; 41: 171178.

    • Search Google Scholar
    • Export Citation
  • 4. Frank N, Geor RJ, Bailey SR, et al. Equine metabolic syndrome. J Vet Intern Med 2010; 24: 467475.

  • 5. Fulop T, Tessier D, Carpentier A. The metabolic syndrome. Pathol Biol (Paris) 2006; 54: 375386.

  • 6. Cersosimo E, DeFronzo RA. Insulin resistance and endothelial dysfunction: the road map to cardiovascular diseases. Diabetes Metab Res Rev 2006; 22: 423436.

    • Search Google Scholar
    • Export Citation
  • 7. Burns TA, Watts MR, Weber PS, et al. Distribution of insulin receptor and insulin-like growth factor-1 receptor in the digital laminae of mixed-breed ponies: an immunohistochemical study 2013;45:326332.

    • Search Google Scholar
    • Export Citation
  • 8. Knowles EJ, Withers JM, Mair TS. Increased plasma fructosamine concentrations in laminitic horses. Equine Vet J 2012; 44: 226229.

  • 9. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414: 813820.

  • 10. Johnson PJ, Wiedmeyer CE, LaCarrubba A, et al. Laminitis and the equine metabolic syndrome. Vet Clin North Am Equine Pract 2010; 26: 239255.

    • Search Google Scholar
    • Export Citation
  • 11. Coutinho M, Gerstein HC, Wang Y, et al. The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care 1999; 22: 233240.

    • Search Google Scholar
    • Export Citation
  • 12. Title LM, Cummings PM, Giddens K, et al. Oral glucose loading acutely attenuates endothelium-dependent vasodilation in healthy adults without diabetes: an effect prevented by vitamins C and E. J Am Coll Cardiol 2000; 36: 21852191.

    • Search Google Scholar
    • Export Citation
  • 13. Geor RJ. Current concepts on the pathophysiology of pasture-associated laminitis. Vet Clin North Am Equine Pract 2010; 26: 265276.

    • Search Google Scholar
    • Export Citation
  • 14. Marik PE, Raghavan M. Stress-hyperglycemia, insulin and immunomodulation in sepsis. Intensive Care Med 2004; 30: 748756.

  • 15. Gearhart MM, Parbhoo SK. Hyperglycemia in the critically ill patient. AACN Clin Issues 2006; 17: 5055.

  • 16. Tóth F, Frank N, Elliott SB, et al. Effects of an intravenous endotoxin challenge on glucose and insulin dynamics in horses. Am J Vet Res 2008; 69: 8288.

    • Search Google Scholar
    • Export Citation
  • 17. Tóth F, Frank N, Geor RJ, et al. Effects of pretreatment with dexamethasone or levothyroxine sodium on endotoxin-induced alterations in glucose and insulin dynamics in horses. Am J Vet Res 2010; 71: 6068.

    • Search Google Scholar
    • Export Citation
  • 18. Vick MM, Murphy BA, Sessions DR, et al. Effects of systemic inflammation on insulin sensitivity in horses and inflammatory cytokine expression in adipose tissue. Am J Vet Res 2008; 69: 130139.

    • Search Google Scholar
    • Export Citation
  • 19. Vachharajani V, Vital S. Obesity and sepsis. J Intensive Care Med 2006; 21: 287295.

  • 20. Bercault N, Boulain T, Kuteifan K, et al. Obesity-related excess mortality rate in an adult intensive care unit: a risk-adjusted matched cohort study. Crit Care Med 2004; 32: 9981003.

    • Search Google Scholar
    • Export Citation
  • 21. Mizock BA. Alterations in fuel metabolism in critical illness: hyperglycaemia. Best Pract Res Clin Endocrinol Metab 2001; 15: 533551.

    • Search Google Scholar
    • Export Citation
  • 22. Belknap JK, Moore JN, Crouser EC. Sepsis—from human organ failure to laminar failure. Vet Immunol Immunopathol 2009; 129: 155157.

    • Search Google Scholar
    • Export Citation
  • 23. Moore RM, Eades SC, Stokes AM. Evidence for vascular and enzymatic events in the pathophysiology of acute laminitis: which pathway is responsible for initiation of this process in horses? Equine Vet J 2004; 36: 204209.

    • Search Google Scholar
    • Export Citation
  • 24. Singer G, Granger DN. Inflammatory responses underlying the microvascular dysfunction associated with obesity and insulin resistance. Microcirculation 2007; 14: 375387.

    • Search Google Scholar
    • Export Citation
  • 25. Tadros EM, Frank N, Donnell RL. Effects of equine metabolic syndrome on inflammatory responses of horses to intravenous lipopolysaccharide infusion. Am J Vet Res 2013; 74: 10101019.

    • Search Google Scholar
    • Export Citation
  • 26. Hoffman RM, Boston RC, Stefanovski D, et al. Obesity and diet affect glucose dynamics and insulin sensitivity in Thoroughbred geldings. J Anim Sci 2003; 81: 23332342.

    • Search Google Scholar
    • Export Citation
  • 27. Tóth F, Frank N, Elliott SB, et al. Optimisation of the frequently sampled intravenous glucose tolerance test to reduce urinary glucose spilling in horses. Equine Vet J 2009; 41: 844851.

    • Search Google Scholar
    • Export Citation
  • 28. Freestone JF, Wolfsheimer KJ, Kamerling SG, et al. Exercise induced hormonal and metabolic changes in Thoroughbred horses: effects of conditioning and acepromazine. Equine Vet J 1991; 23: 219223.

    • Search Google Scholar
    • Export Citation
  • 29. Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest 1981; 68: 14561467.

    • Search Google Scholar
    • Export Citation
  • 30. Boston RC, Stefanovski D, Moate PJ, et al. MINMOD Millennium: a computer program to calculate glucose effectiveness and insulin sensitivity from the frequently sampled intravenous glucose tolerance test. Diabetes Technol Ther 2003; 5: 10031015.

    • Search Google Scholar
    • Export Citation
  • 31. Frank N, Elliott SB, Brandt LE, et al. Physical characteristics, blood hormone concentrations, and plasma lipid concentrations in obese horses with insulin resistance. J Am Vet Med Assoc 2006; 228: 13831390.

    • Search Google Scholar
    • Export Citation
  • 32. Bergman RN, Ider YZ, Bowden CR, et al. Quantitative estimation of insulin sensitivity. Am J Physiol 1979; 236: E667E677.

  • 33. Best JD, Kahn SE, Ader M, et al. Role of glucose effectiveness in the determination of glucose tolerance. Diabetes Care 1996; 19: 10181030.

    • Search Google Scholar
    • Export Citation
  • 34. Ader M, Pacini G, Yang YJ, et al. Importance of glucose per se to intravenous glucose tolerance. Comparison of the minimal-model prediction with direct measurements. Diabetes 1985; 34: 10921103.

    • Search Google Scholar
    • Export Citation
  • 35. Bergman RN. Minimal model: perspective from 2005. Horm Res 2005; 64(suppl 3):815.

  • 36. Carter RA, McCutcheon LJ, George LA, et al. Effects of diet-induced weight gain on insulin sensitivity and plasma hormone and lipid concentrations in horses. Am J Vet Res 2009; 70: 12501258.

    • Search Google Scholar
    • Export Citation
  • 37. Vick MM, Sessions DR, Murphy BA, et al. Obesity is associated with altered metabolic and reproductive activity in the mare: effects of metformin on insulin sensitivity and reproductive cyclicity. Reprod Fertil Dev 2006; 18: 609617.

    • Search Google Scholar
    • Export Citation
  • 38. Freestone JF, Beadle R, Shoemaker K, et al. Improved insulin sensitivity in hyperinsulinaemic ponies through physical conditioning and controlled feed intake. Equine Vet J 1992; 24: 187190.

    • Search Google Scholar
    • Export Citation
  • 39. Treiber KH, Kronfeld DS, Hess TM, et al. Use of proxies and reference quintiles obtained from minimal model analysis for determination of insulin sensitivity and pancreatic beta-cell responsiveness in horses. Am J Vet Res 2005; 66: 21142121.

    • Search Google Scholar
    • Export Citation
  • 40. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005; 115: 11111119.

  • 41. Burén J, Liu HX, Jensen J, et al. Dexamethasone impairs insulin signalling and glucose transport by depletion of insulin receptor substrate-1, phosphatidylinositol 3-kinase and protein kinase B in primary cultured rat adipocytes. Eur J Endocrinol 2002; 146: 419429.

    • Search Google Scholar
    • Export Citation
  • 42. Hunt DG, Ivy JL. Epinephrine inhibits insulin-stimulated muscle glucose transport. J Appl Physiol 2002; 93: 16381643.

  • 43. van der Crabben SN, Blumer RM, Stegenga ME, et al. Early endotoxemia increases peripheral and hepatic insulin sensitivity in healthy humans. J Clin Endocrinol Metab 2009; 94: 463468.

    • Search Google Scholar
    • Export Citation
  • 44. Agwunobi AO, Reid C, Maycock P, et al. Insulin resistance and substrate utilization in human endotoxemia. J Clin Endocrinol Metab 2000; 85: 37703778.

    • Search Google Scholar
    • Export Citation
  • 45. Hagiwara S, Iwasaka H, Shingu C, et al. Heat shock protein 72 protects insulin-secreting beta cells from lipopolysaccharide-induced endoplasmic reticulum stress. Int J Hyperthermia 2009; 25: 626633.

    • Search Google Scholar
    • Export Citation
  • 46. Martin IK, Weber KM, Boston RC, et al. Effects of epinephrine infusion on determinants of intravenous glucose tolerance in dogs. Am J Physiol 1988; 255: E668E673.

    • Search Google Scholar
    • Export Citation
  • 47. Zenni GC, McLane M P, Law WR, et al. Hepatic insulin resistance during chronic hyperdynamic sepsis. Circ Shock 1992; 37: 198208.

  • 48. Tóth F, Frank N, Martin-Jimenez T, et al. Measurement of C-peptide concentrations and responses to somatostatin, glucose infusion, and insulin resistance in horses. Equine Vet J 2010; 42: 149155.

    • Search Google Scholar
    • Export Citation
  • 49. Channon KM, Guzik TJ. Mechanisms of superoxide production in human blood vessels: relationship to endothelial dysfunction, clinical and genetic risk factors. J Physiol Pharmacol 2002; 53: 515524.

    • Search Google Scholar
    • Export Citation
  • 50. Yu WK, Li WQ, Li N, et al. Influence of acute hyperglycemia in human sepsis on inflammatory cytokine and counterregulatory hormone concentrations. World J Gastroenterol 2003; 9: 18241827.

    • Search Google Scholar
    • Export Citation
  • 51. Death AK, Fisher EJ, McGrath KC, et al. High glucose alters matrix metalloproteinase expression in two key vascular cells: potential impact on atherosclerosis in diabetes. Atherosclerosis 2003; 168: 263269.

    • Search Google Scholar
    • Export Citation
  • 52. Asplin KE, Sillence MN, Pollitt CC, et al. Induction of laminitis by prolonged hyperinsulinaemia in clinically normal ponies. Vet J 2007; 174: 530535.

    • Search Google Scholar
    • Export Citation
  • 53. de Laat MA, McGowan CM, Sillence MN, et al. Equine laminitis: induced by 48 h hyperinsulinaemia in Standardbred horses. Equine Vet J 2010; 42: 129135.

    • Search Google Scholar
    • Export Citation
  • 54. de Laat MA, Sillence MN, McGowan CM, et al. Continuous intravenous infusion of glucose induces endogenous hyperinsulinaemia and lamellar histopathology in Standardbred horses. Vet J 2012; 191: 317322.

    • Search Google Scholar
    • Export Citation
  • 55. Kronfeld DS, Treiber KH, Hess TM, et al. Metabolic syndrome in healthy ponies facilitates nutritional countermeasures against pasture laminitis. J Nutr 2006; 136: 2090S2093S.

    • Search Google Scholar
    • Export Citation
  • 56. Bailey SR, Habershon-Butcher JL, Ransom KJ, et al. Hypertension and insulin resistance in a mixed-breed population of ponies predisposed to laminitis. Am J Vet Res 2008; 69: 122129.

    • Search Google Scholar
    • Export Citation
  • 57. Bailey SR, Menzies-Gow NJ, Harris PA, et al. Effect of dietary fructans and dexamethasone administration on the insulin response of ponies predisposed to laminitis. J Am Vet Med Assoc 2007; 231: 13651373.

    • Search Google Scholar
    • Export Citation

Advertisement

Effects of intravenous lipopolysaccharide infusion on glucose and insulin dynamics in horses with equine metabolic syndrome

View More View Less
  • 1 Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996.
  • | 2 Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996.
  • | 3 Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996.
  • | 4 Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA 19348.

Abstract

Objective—To test the hypothesis that glucose and insulin dynamics during endotoxemia differ between healthy horses and horses with equine metabolic syndrome (EMS).

Animals—6 healthy adult mares and 6 horses with EMS.

Procedures—Each horse randomly received an IV infusion of lipopolysaccharide (20 ng/kg [in 60 mL of sterile saline {0.9% NaCl} solution]) or saline solution, followed by the other treatment after a 7-day washout period. Baseline insulin-modified frequently sampled IV glucose tolerance tests were performed 27 hours before and then repeated at 0.5 and 21 hours after infusion. Results were assessed via minimal model analysis and area under the curve values for plasma glucose and serum insulin concentrations.

Results—Lipopolysaccharide infusion decreased insulin sensitivity and increased area under the serum insulin concentration curve (treatment × time) in both healthy and EMS-affected horses, compared with findings following saline solution administration. The magnitude of increase in area under the plasma glucose curve following LPS administration was greater for the EMS-affected horses than it was for the healthy horses. Horses with EMS that received LPS or saline solution infusions had decreased insulin sensitivity over time.

Conclusions and Clinical Relevance—Glucose and insulin responses to endotoxemia differed between healthy horses and horses with EMS, with greater loss of glycemic control in EMS-affected horses. Horses with EMS also had greater derangements in glucose and insulin homeostasis that were potentially stress induced. It may therefore be helpful to avoid exposure of these horses to stressful situations.

Contributor Notes

Dr. Tadros’ present address is Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.

Dr. Frank's present address is Department of Clinical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536.

Supported by the University of Tennessee Center of Excellence in Livestock Diseases and Human Health, the Charles and Julie Wharton Fellowship, and the Wells Graduate Student Fellowship.

Presented in part at the American College of Veterinary Internal Medicine Forum, Denver, June 2011.

The authors thank Dr. Arnold Saxton for statistical advice and Sarah Elliott for technical assistance.

Address correspondence to Dr. Frank (nicholas.frank@tufts.edu).