Current Hypertension Reports

, Volume 6, Issue 1, pp 60–65 | Cite as

Mechanisms for early microvascular injury in obesity and type II diabetes

  • H. Glenn Bohlen
Article

Abstract

Obesity in the absence of hyperglycemia carries a low risk for microvascular disease compared with type II diabetes. The occurrence of hyperglycemia seems to be an important, if not the most important, distinction between obesity and obesity plus diabetes mellitus for microvascular disease. In vitro and in vivo human and animal studies of the early microvascular consequences of hyperglycemia indicate an immediate detrimental suppression of vasodilatory microvascular mechanisms that might be even worse with pre-existing obesity. The overall concept emerging from a very large research base is that hyperglycemia activates protein kinase C, increases oxidant formation, elevates constrictor prostanoid species to the detriment of beneficial prostanoids, and suppresses flow-mediated regulation with the nitric oxide generated by endothelial cells. The end result is decreased blood flow and loss of microvascular reactivity to endothelial-dependent vasodilatory stimuli that persists for 3 to 6 hours.

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References and Recommended Reading

  1. 1.
    Bohlen HG, Lash JM: Topical hyperglycemia rapidly suppresses EDRF-mediated vasodilation of normal rat arterioles. Am J Physiol 1993, 265:H219-H225.PubMedGoogle Scholar
  2. 2.
    Bohlen HG, Nase GP, Jin J-S: Multiple mechanisms of early hyperglycaemic injury of the rat intestinal microcirculation. Clin Exp Pharmacol Physiol 2002, 29:138–142.PubMedCrossRefGoogle Scholar
  3. 3.
    Jin J-S, Bohlen HG: Non-insulin-dependent diabetes and hyperglycemia impair rat intestinal flow-mediated regulation. Am J Physiol 1997, 272:H728-H734.PubMedGoogle Scholar
  4. 4.
    Lash JM, Nase GP, Bohlen HG: Acute hyperglycemia depresses arteriolar NO formation in skeletal muscle. Am J Physiol 1980, 277:H1513-H1520.Google Scholar
  5. 5.
    Mayhan WG, Patel KP: Acute effects of glucose on reactivity of cerebral microcirculation: role of activation of protein kinase C. Am J Physiol 1995, 269:H1297-H1302.PubMedGoogle Scholar
  6. 6.
    Ihlemann N, Rask-Madsen C, Perner A, et al.: Tetrahydrobiopterin restores endothelial dysfunction induced by an oral glucose challenge in healthy subjects. Am J Physiol Heart Circ Physiol 2003, 285:H875-H882. This study illustrates that in normal humans, systemic hyperglycemia impairs endothelial-dependent vasodilation. This problem is negated by supplemental administration of tetrahydrobiopterin.PubMedGoogle Scholar
  7. 7.
    Beckman JA, Goldfine AB, Gordon MB, et al.: Inhibition of protein kinase C beta prevents impaired endotheliumdependent vasodilation caused by hyperglycemia in humans. Circ Res 2002, 90:107–111. This study demonstrates that endothelial-dependent vasodilation in humans is suppressed by acute hyperglycemia but, if pretreated to block protein kinase C beta, can avoid endothelial acute dysfunction.PubMedCrossRefGoogle Scholar
  8. 8.
    Dorner GT, Garhofer G, Huemer KH, et al.: Hyperglycemia affects flicker-induced vasodilation in the retina of healthy subjects. Vision Res 2003, 43:1495–1500.PubMedCrossRefGoogle Scholar
  9. 9.
    Title LM, Cummings PM, Giddens K, Nassar BA: 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, 36:2185–2191.PubMedCrossRefGoogle Scholar
  10. 10.
    Bohlen HG, Nase GP: Obesity lowers hyperglycemic threshold for impaired in vivo endothelial nitric oxide function. Am J Physiol Heart Circ Physiol 2002, 283:H391-H397. This study in Zucker obese rats found that obesity lowered the glucose concentration required to inhibit nitric oxide production by endothelial cells to 200 mg/dL, the mechanism caused by excessive activation of PKC IIβ.PubMedGoogle Scholar
  11. 11.
    King GL, Kunisaki M, Nishio Y, et al.: Vitamin E normalizes diacylglycerol-protein kinase C activation induced by hyperglycemia in rat vascular tissues. Diabetes 1996, 45S:S117-S119.Google Scholar
  12. 12.
    Matsubara M, Hayashi N, Jing T, Titani K: Regulation of endothelial nitric oxide synthase by protein kinase C. J Biochem (Tokyo) 2003, 133:773–781. This is an excellent review of the interplay of protein kinase C with eNOS, which is likely a key issue in diabetes and obesity.Google Scholar
  13. 13.
    Inoguchi T, Sonta T, Tsubouchi H, et al.: Protein kinase C-dependent increase in reactive oxygen species (ROS) production in vascular tissues of diabetes: role of vascular NAD(P)H oxidase. J Am Soc Nephrol 2003, 14:S227-S232.PubMedCrossRefGoogle Scholar
  14. 14.
    Inoguchi T, Li P, Umeda F, et al.: High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 2000, 49:1939–1945.PubMedCrossRefGoogle Scholar
  15. 15.
    Kowluru RA: Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress in diabetic rats. Diabetes 2003, 52:818–823.PubMedCrossRefGoogle Scholar
  16. 16.
    Boden G: Effects of free fatty acids (FFA) on glucose metabolism: significance for insulin resistance and type 2 diabetes. Exp Clin Endocrinol Diabetes 2003, 111:121–124.PubMedCrossRefGoogle Scholar
  17. 17.
    Way KJ, Katai N, King GL: Protein kinase C and the development of diabetic vascular complications. Diabet Med 2001, 18:945–959. This review illustrates the biochemical and functional evidence that PKC activation is a major problem in diabetic vascular regulation and the pharmacologic approaches that have proven useful in animal models of diabetes.PubMedCrossRefGoogle Scholar
  18. 18.
    Schmitz-Peiffer C: Protein kinase C and the development of diabetic vascular complications. Diabet Med 2001, 18:945–959.CrossRefGoogle Scholar
  19. 19.
    Koller A, Kaley G: Prostaglandins mediate arteriolar dilation to increased blood flow velocity in skeletal muscle microcirculation. Circ Res 1990, 67:529–534.PubMedGoogle Scholar
  20. 20.
    Cosentino F, Eto M, De Paolis P, et al.: High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species. Circulation 2003, 107:1017–1023.PubMedCrossRefGoogle Scholar
  21. 21.
    Bohlen HG, Nase GP: Arteriolar nitric oxide concentration is decreased during hyperglycemia-induced beta II PKC activation. Am J Physiol Heart Circ Physiol 2001, 280:H621-H627.PubMedGoogle Scholar
  22. 22.
    Gupta S, Chough E, Daley J, et al.: Hyperglycemia increases endothelial superoxide that impairs smooth muscle cell Na+-K+-ATPase activity. Am J Physiol Cell Physiol 2002, 282:C560-C566.PubMedGoogle Scholar
  23. 23.
    Frisbee JC: Impaired dilation of skeletal muscle microvessels to reduced oxygen tension in diabetic obese Zucker rats. Am J Physiol Heart Circ Physiol 2001, 281:H1568-H157.PubMedGoogle Scholar
  24. 24.
    Nase GP, Tuttle J, Bohlen HG: Reduced perivascular PO2 increases nitric oxide release from endothelial cells. Am J Physiol Heart Circ Physiol 2003, 285:H507-H515.PubMedGoogle Scholar
  25. 25.
    Ammar RF Jr, Gutterman DD, Brooks LA, Dellsperger KC:Impaired dilation of coronary arterioles during increases in myocardial O(2) consumption with hyperglycemia. Am J Physiol Endocrinol Metab 2000, 279:E868-E874.PubMedGoogle Scholar
  26. 26.
    Sheetz MJ, King GL: Molecular understanding of hyperglycemia’s adverse effects for diabetic complications. JAMA 2002, 288:2579–2588. In this review, the four major mechanisms thought to impair cells during hyperglycemia and the pharmacologic approaches to suppress the mechanisms are considered.PubMedCrossRefGoogle Scholar
  27. 27.
    Lee IK, Kim HS, Bae JH: Endothelial dysfunction: its relationship with acute hyperglycaemia and hyperlipidemia. Int J Clin Pract Suppl 2002, 129:59–64.PubMedGoogle Scholar
  28. 28.
    Huang A, Vita JA, Venema RC, Keaney JF Jr: Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. J Biol Chem 2000, 275:17399–17406. This study found that a large part of the beneficial effect of vitamin C to improve NO physiology is through increasing a cofactor for eNOS, tetrahydrobiopterin. This cofactor is likely suppressed by hyperglycemia.PubMedCrossRefGoogle Scholar
  29. 29.
    Kunisaki M, Bursell SE, Clermont AC, et al.: Vitamin E prevents diabetes-induced abnormal retinal blood flow via the diacylglycerol-protein kinase C pathway. Am J Physiol 1995, 269:E239-E246.PubMedGoogle Scholar
  30. 30.
    Buerk DG, Riva CE, Cranstoun SD: Nitric oxide has a vasodilatory role in cat optic nerve head during flicker stimuli. Microvas Res 1996, 52:13–26.CrossRefGoogle Scholar
  31. 31.
    Thom SR, Fisher D, Zhang J, et al.: Stimulation of perivascular nitric oxide synthesis by oxygen. Am J Physiol Heart Circ Physiol 2003, 284:H1230-H1239.PubMedGoogle Scholar
  32. 32.
    Bohlen HG, Nase GP: Dependence of intestinal arteriolar regulation on flow-mediated nitric oxide formation. Am J Physiol Heart Circ Physiol 2000, 279:H2249-H2258.PubMedGoogle Scholar
  33. 33.
    Huang M, Manning RD Jr, LeBlanc MH, Hester RL: Overall hemodynamic studies after the chronic inhibition of endothelial-derived nitric oxide in rats. Am J Hypertension 1995, 8:358–364.CrossRefGoogle Scholar
  34. 34.
    Nilius B, Droogmans G: Ion channels and their functional role in vascular endothelium. Physiol Rev 2001, 81:1415–1459.PubMedGoogle Scholar
  35. 35.
    Koller A: Signaling pathways of mechanotransduction in arteriolar endothelium and smooth muscle cells in hypertension. Microcirculation 2002, 9:277–294.PubMedCrossRefGoogle Scholar
  36. 36.
    Borders JL, Granger HJ: Power dissipation as a measure of peripheral resistance in vascular networks. Hypertension 1986, 8:184–191.PubMedGoogle Scholar
  37. 37.
    Bohlen HG: Determinants of resting and passive intestinal vascular pressures in rat and rabbit. Am J Physiol 1987, 253:G587-G595.PubMedGoogle Scholar

Copyright information

© Current Science Inc 2004

Authors and Affiliations

  • H. Glenn Bohlen
    • 1
  1. 1.Department of Cellular and Integrative PhysiologyIndiana University Medical SchoolIndianapolisUSA

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