Skip to main content
SpringerLink
Log in

Alterations in the Vascular Actions of Insulin in the Pathogenesis of Insulin Resistance and Hypertension

  • Chapter
Diabetes and Cardiovascular Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 498))

  • 345 Accesses

Abstract

Resistance to the metabolic effects of insulin (insulin resistance) and hyperinsulinemia have been suggested to contribute to a cluster of abnormalities including diabetes, hypertension, obesity, hyperlipidemia, atherosclerosis, coronary artery disease and polycystic ovary syndrome.1–5 One of our primary interests has been the role of insulin resistance and hyperinsulinemia in the pathogenesis of hypertension independent of obesity and diabetes. In a series of studies we have demonstrated that drugs that specifically improve insulin sensitivity (counter insulin resistance) and decrease plasma insulin levels both prevent and reverse hypertension in experimental models of high blood pressure (BP).3,4,6–12 These data lend credence to the notion that insulin resistance and hyperinsulinemia may play an important role in the final expression of high BP. Following these observations, we focussed our efforts towards elucidating the mechanisms through which insulin resistance and hyperinsulinemia lead to hypertension in these models. Our studies have focussed on the interaction of insulin with endothelium derived relaxing and contracting factors. A growing body of evidence suggests that insulin exerts direct effects on vascular tone through stimulation of endothelium derived nitric oxide (NO). This has led to the suggestion that changes in the actions of insulin (in states of insulin resistance) may be important in modulating the expression of both cardiovascular and metabolic endpoints. For example, resistance to the vasodilatory action of insulin (vascular insulin resistance) has been documented in the insulin resistant states of diabetes, obesity and hypertension.13–16 Vascular insulin resistance may sensitize/predispose the vasculature to the effects of pressors and lead to an increased vascular smooth muscle (VSM) tone and reactivity. As the vasodilatory actions of insulin contribute significantly to whole body glucose disposal, vasoconstriction (secondary to vascular insulin resistance) may play a role in the development and/or reinforcement of skeletal muscle/whole body insulin resistance. In this paper, we briefly discuss the relationship between insulin resistance and hypertension from a pharmacological and mechanistic standpoint. We then present some data from our laboratory that suggest that the vascular actions of insulin are altered in insulin resistant hypertensive rats and that these effects may antedate the development of high BP. For a general discussion of insulin resistance in cardiovascular regulation, the reader is referred to several comprehensive reviews.1,3,4,17

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Reaven GM. Role of insulin resistance in human disease. Diabetes. 1988; 37:1595–1607.

    Article  PubMed  CAS  Google Scholar 

  2. DeFronzo RA. Insulin resistance, hyperinsulinemia and coronary artery disease: a complex metabolic web. J Cardiovasc Pharmacol. 1992; 20:S1–S16.

    Article  PubMed  Google Scholar 

  3. Bhanot S, and McNeill JH. Insulin and hypertension: a causal relationship? Cardiovasc. Res. 1996; 31:212–221.

    PubMed  CAS  Google Scholar 

  4. Verma S and McNeill JH. Insulin resistance and hypertension: pharmacological and mechanistic studies. Can J Diab Care (in press).

    Google Scholar 

  5. Verma S, MatherK, Dumont A and Anderson TJ. Pharmacological modulation of insulin resistance and hyperinsulinemia in polycystic ovary syndrome: the emerging role. The Endocrinologist 1998; 8: 418–424.

    Article  Google Scholar 

  6. Bhanot S, McNeill JH. Vanadyl sulfate lowers plasma insulin levels and blood pressure in spontaneously hypertensive rats. Hypertension. 1994; 24:625–632.

    Article  PubMed  CAS  Google Scholar 

  7. Bhanot S, Bryer-Ash M, Cheung A, McNeill JH. Bis(maltolato)oxovanadium(IV) attenuates hyperinsulinemia and hypertension in spontaneously hypertensive rats. Diabetes. 1994; 43:857–861.

    Article  PubMed  CAS  Google Scholar 

  8. Bhanot S, Bryer-Ash M, Nichoulas A, McNeill JH. Pioglitazone attenuates hyperinsulinemia and lowers systolic blood pressure in spontaneously hypertensive rats.(abstract) Can. J. Physiol. Pharmacol. 1994; 72(Suppl. 1):P1.9.29.

    Google Scholar 

  9. Verma S, Bhanot S and McNeill, JH. Metformin decreases plasma insulin levels and blood pressure in spontaneously hypertensive rats. Am. J. Physiol. 1994; 36:H1250–H1253.

    Google Scholar 

  10. Bhanot S, McNeill H and Bryer-Ash M. Vanadyl sulfate prevents fructose induced hyperinsulinemia and hypertension in rats. Hypertension. 1994; 23:308–12.

    Article  PubMed  CAS  Google Scholar 

  11. Bhanot S, Verma S, Michoulas A, McNeill JH. Drugs that attenuate hyperinsulinemia in spontaneously hypertensive rats cause concurrent decreases in systolic blood pressure (abstract). Diabetes 1994; 43(Suppl 1):40A.

    Google Scholar 

  12. Verma S, Bhanot S and McNeill JH. Antihypertensive effects of metformin in fructose-fed hyperinsulinemic, hypertensive rats. J. Pharmacol. Exp. Therap. 1994; 271:1334–1337.

    CAS  Google Scholar 

  13. Baron AD. Cardiovascular actions of insulin in humans. Implications for insulin sensitivity and vascular tone. Baillere’s Clin Endocrinol Metab 1993; 7: 961–987.

    Article  CAS  Google Scholar 

  14. Laakso M, Edelman SV, Brechtel G and Baron AD. Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM. Diabetes 1992; 41: 1076–1083.

    Article  PubMed  CAS  Google Scholar 

  15. Laakso M, Edelman SV, Brechtel G and Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese men. J Clin Invest 1990; 85: 1844–1852.

    Article  PubMed  CAS  Google Scholar 

  16. Verma S, Bhanot S, Yao L and McNeill JH. Vascular insulin resistance in fructose hypertensive rats. Eur J Pharmacol 1997; 322:R1–R2.

    Article  PubMed  CAS  Google Scholar 

  17. Reaven GM. Syndrome X: 6 years later. J. Intern Med. 1994; 236(Suppl 736): 13–22.

    Google Scholar 

  18. Textor SC. Pathogenesis of hypertension. In: Primer on Kidney Diseases (Ed Greenberg A) 2“d edition, National Kidney Foundation, Academic Press, 1998; pp491–495.

    Google Scholar 

  19. Brands MW, Mizelle HL, Gaillard CA, Hildebrandt DA, Hall JE. The hemodynamic response to chronic hyperinsulinemia in conscious dogs. Am. J. Hypertens. 1991; 4:164–168.

    Article  PubMed  CAS  Google Scholar 

  20. Dela F, Larsen JJ, Mikines KJ and Galbo H. Normal effect of insulin to stimulate leg blood flow in NIDDM. Diabetes. 1995; 44:221–226.

    Article  PubMed  CAS  Google Scholar 

  21. Egan BM and Stepnaikowski K. Compensatory hyperinsulinemia and the forearm vasodilator response during an oral glucose tolerance test in obese hypertensives. J. Hypertens. 1994; 12:1061–1067.

    Article  PubMed  CAS  Google Scholar 

  22. Baron AD, Brechtel G. Insulin differentially regulates systemic and skeletal muscle vascular resistance. Am. J. Physiol. 1993; 265:E61–E67.

    PubMed  CAS  Google Scholar 

  23. Baron AD. Hemodynamic actions of insulin. Am. J. Physiol. 1994; 267:E187–E202.

    PubMed  CAS  Google Scholar 

  24. Baron AD, Steinberg HO, Chaker I., Learning R, Johnson A and Brechtel G. Insulin-mediated skeletal muscle vasodilation contributes to both insulin sensitivity and responsiveness in lean humans. J. Clin. Invest. 1995; 96:786–792.

    Article  PubMed  CAS  Google Scholar 

  25. Baron AD, Laakso M, Brechtel G and Edelman SV. Mechanism of insulin resistance in insulin-dependent diabetes mellitus: a major role for reduced skeletal muscle blood flow. J. Clin. Endo. Metab. 1991; 73:637–643.

    Article  CAS  Google Scholar 

  26. Richter EA, Mikines KG, Galbo H and Kiens B. Effect of exercise on insulin action in human skeletal muscle. J. Appl. Physiol. 1989; 66:876–885.

    PubMed  CAS  Google Scholar 

  27. Bennett WM, Connacher AA, Scrimgeour CM, Jung RT and Rennie MJ. Euglycemic hyperinsulinemia augments amino acid uptake by human leg tissue during hyperaminoacidemia. Am. J. Physiol. 1990; 259:E185–E194.

    Google Scholar 

  28. Edelman SV, Marco M, Wallace P, Buchtel J, Olefsky JL and Baron AD. Kinetics of insulin-mediated and non-insulin mediated glucose uptake in humans. Diabetes. 1990; 39:955–964.

    Article  PubMed  CAS  Google Scholar 

  29. Vollenweider P, Tappy L, Randin D, Schneiter P, Jequier E, Nicod P and Scherrer U. Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans. J. Clin. Invest. 1993; 92:147–154.

    Article  PubMed  CAS  Google Scholar 

  30. Boden G, De Santis R, Chen X, Morris M and Badoza F. Glucose metabolism and leg blood flow after pancreas/kidney transplantation. J. Clin. Endocrinol. Metabol. 1993; 76:1229–1233.

    Article  CAS  Google Scholar 

  31. Anderson EA, Hoffmann RP, Balon TW, Sinkey CA and Mark AL. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J. Clin. Invest. 1991; 87:22462252.

    Google Scholar 

  32. Baron AD and Steinberg HO. Vascular actions of insulin in health and disease. In: Endocrinology of the vasculature, Sowers JR Editor, Humana Press, Totowa, New Jersey. 1996; pp95–107.

    Google Scholar 

  33. Baron AD. The coupling of glucose metabolism and perfusion in human skeletal muscle. The potential role of endothelium-derived nitric oxide. Diabetes. 1996; 45 (Suppl. 1):S105–5109.

    PubMed  CAS  Google Scholar 

  34. Baron AD, Brechtel G, Johnson A, Fineberg N, Henry DP, Steinberg HO. Interactions between insulin and norepinephrine on blood pressure and insulin sensitivity: studies in lean and obese men. J. Clin. Invest. 1994; 93:2453–2462.

    Article  PubMed  CAS  Google Scholar 

  35. Verma S, Arikawa E, Yao L, Laher I and McNeill JH. Insulin induced vasodilation is dependent upon tetrahydrobiopterin synthesis. Metabolism. 1998; 47: 1037–1039.

    Article  PubMed  CAS  Google Scholar 

  36. Steinberg HO, Brechtel G, Johnson A, Fineberg N and Baron AD. Insulin-mediated skeletal muscle blood flow is nitric oxide dependent. J. Clin. Invest. 1994; 94:1172–1179.

    Article  PubMed  CAS  Google Scholar 

  37. Juncos LA and Hito S. Disparate effect of insulin on isolated rabbit afferent and efferent arterioles. J. Clin. Invest. 1993; 92:1981–1985.

    Article  PubMed  CAS  Google Scholar 

  38. Yanagisawa-Miwa A, Ito H and Sugimot T. Effects of insulin on vasoconstriction induced by thromboxane A2 in porcine coronay artery. Circulation. 1990; 81:1654–1659.

    Article  PubMed  CAS  Google Scholar 

  39. Wu H, Jeng YY, Yue C, Chye KY, Hsueh WA and Chan TM. Endothelium derived vascular effects of insulin and insulin-like growth factor 1 in the perfused mesenteric artery and aortic ring. Diabetes. 1994; 43:1027–1032.

    Article  PubMed  CAS  Google Scholar 

  40. Townsend RR, Yamamoto R, Nickols M, Dipette DJ and Nickols GA. Insulin enhances pressor responses to norepinephrine in rat mesenteric vasculature. Hypertension. 1992; 19 (Suppl. II):II105-II-110.

    Article  PubMed  CAS  Google Scholar 

  41. Walker AB, Savage MW, Dores J and Williams G. Insulin-induced attenuation of noradrenalinemediated vasoconstriction in resistance arteries from Wistar rats is nitric oxide dependent. Clin. Sci. 1997; 92:147–152.

    PubMed  CAS  Google Scholar 

  42. Alexander WE and Oake RJ. The effect of insulin on vascular reactivity to norepinephrine. Diabetes. 1977; 26:611–614.

    Article  PubMed  CAS  Google Scholar 

  43. Yagi S, Takata S, Kiyokawa H, Yamamoto M, Noto Y, Ikeda T and Hattori N. Effects of insulin on vasoconstrictive responses to norepinephrine and angiotensin II in rabbit femoral artery and vein. Diabetes. 1988; 37:1064–1067.

    Article  PubMed  CAS  Google Scholar 

  44. Wambach GK and Liu D. Insulin attenuates vasoconstriction by noradrenaline, serotonin and potassium chloride in rat mesenteric arterioles. Clin. Exp. Hyper. 1992; A14(4):733–740.

    Article  CAS  Google Scholar 

  45. Oliver FJ, De la Rubia G, Feener EP et al. Stimulation of endothelin-1 gene expression by insulin in endothelial cells. J. Biol. Chem. 1991; 266:23251–23526.

    PubMed  CAS  Google Scholar 

  46. Frank HJL, Levin ER, Hu RM and Pedram A. Insulin stimulates endothelin binding and action on cultured vascular smooth muscle cells. Endocrinology. 1993; 133:1092–1097.

    Article  PubMed  CAS  Google Scholar 

  47. Hu R-M, Levin ER, Pedram A and Frank HJL. Insulin stimulates production and secretion of endothelin from bovine endothelial cells. Diabetes. 1993; 42:351–358.

    Article  PubMed  CAS  Google Scholar 

  48. Hattori Y, Kasai K, Nakamura T, Emoto T, Shimoda S-I. Effect of glucose and insulin on immunoreactive endothelin-1 release from cultured porcine aortic endothelial cells. Metabolism 1991; 40:165–169.

    Article  PubMed  CAS  Google Scholar 

  49. Takahashi K, Gathei MA, Lam HC, O’Halloran DJ and Bloom SR. Elevated plasma endothelin in patients with diabetes mellitus. Diabetologia. 1990; 33:306–310.

    Article  PubMed  CAS  Google Scholar 

  50. Hopfner RL, Misurski D, Wilson TW, McNeill JR and Gopalakrishnan V. Insulin and vanadate restore decreased plasma endothelin concentrations and exaggerated vascular responses to normal in the streptozotocin diabetic rat. Diabetologia. 1998; 41:1233–1240.

    Article  PubMed  CAS  Google Scholar 

  51. Verma S. Mechanisms of hypertension in hyperinsulinemic and insulin resistant fructose hypertensive rats. PhD Thesis. 1997; The University of British Columbia, Canada.

    Google Scholar 

  52. Verma S, Bhanot S and McNeill JH. Effect of chronic endothelin blockade in hyperinsulinemic hypertensive rats. Am. J. Physiol. 1995; 269:H2017–H2021.

    CAS  Google Scholar 

  53. Verma S, Skarsgard P, Bhanot S, Yao L, Laher I and McNeill JH. Reactivity of mesenteric arteries from fructose-hypertensive rats to endothelin-1. Am. J. Hypertens. 1997; 10: 1010–1019.

    Article  CAS  Google Scholar 

  54. Verma S, Bhanot S, Hicke A and McNeill JH. Chronic T-type calcium channel blockade in hyperinsulinemic, hypertensive rats. Cardiovasc. Res. 1997; 34:121–128.

    Article  PubMed  CAS  Google Scholar 

  55. Verma S, Bhanot S, Arikawa E, Yao L and McNeill JH. Direct vasodepressor effects of pioglitazone in spontaneously hypertension rats. Pharmacol. 1998; 56:7–16.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Division of Cardiology Faculty of Medicine, University of Calgary, Canada

    Subodh Verma

  2. The Division of Pharmacology and Toxicology Faculty of Pharmaceutical Sciences, The University of British Columbia, Canada

    John H. McNeill

Authors
  1. Subodh Verma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John H. McNeill
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Diabetes Research and Treatment Centre, Winnipeg, Canada

    Aubie Angel

  2. St. Boniface Research Centre, Winnipeg, Canada

    Naranjan Dhalla , Grant Pierce  & Pawan Singal ,  & 

Rights and permissions

Reprints and permissions

Copyright information

© 2001 Springer Science+Business Media New York

About this chapter

Cite this chapter

Verma, S., McNeill, J.H. (2001). Alterations in the Vascular Actions of Insulin in the Pathogenesis of Insulin Resistance and Hypertension. In: Angel, A., Dhalla, N., Pierce, G., Singal, P. (eds) Diabetes and Cardiovascular Disease. Advances in Experimental Medicine and Biology, vol 498. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1321-6_18

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-1321-6_18

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-5496-3

  • Online ISBN: 978-1-4615-1321-6

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation