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Hypertension Management and Microvascular Insulin Resistance in Diabetes

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Abstract

Type 2 diabetes is in essence a vascular disease and is frequently associated with hypertension, macrovascular events, and microvascular complications. Microvascular dysfunction, including impaired recruitment and capillary rarefaction, has been implicated in the pathogenesis of diabetic complications. Microvascular insulin resistance and renin-angiotensin system upregulation are present in diabetes, and each contributes to the development of hypertension and microvascular dysfunction. In the insulin-sensitive state, insulin increases microvascular perfusion by increasing endothelial nitric oxide production, but this effect is abolished by insulin resistance. Angiotensin II, acting via the type 1 receptors, induces inflammation and oxidative stress, leading to impaired insulin signaling, reduced nitric oxide availability, and vasoconstriction. Conversely, it acts on the type 2 receptors to cause vasodilatation. Because substrate and hormonal exchanges occur in the microvasculature, antihypertensive agents targeted to improve microvascular insulin sensitivity and function may have beneficial effects beyond their capacity to lower blood pressure in patients with diabetes.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. •• Barrett E, Eggleston E, Inyard A, et al.: The vascular actions of insulin control its delivery to muscle and regulate the rate-limiting step in skeletal muscle insulin action. Diabetologia 2009, 52:752–764. This comprehensive review examined insulin’s microvascular actions and the three discrete steps by which insulin acts to enhance its own delivery to muscle and thus its metabolic actions: relaxation of resistance vessels to increase total blood flow, relaxation of precapillary arterioles to increase the microvascular exchange surface area, and the transendothelial transport of insulin.

    Article  CAS  PubMed  Google Scholar 

  2. Liu Z, Liu J, Jahn LA, et al.: Infusing lipid raises plasma free fatty acids and induces insulin resistance in muscle microvasculature. J Clin Endocrinol Metab 2009, 94:3543–3549.

    Article  CAS  PubMed  Google Scholar 

  3. Liu Z: Insulin at physiological concentrations increases microvascular perfusion in human myocardium. Am J Physiol Endocrinol Metab 2007, 293:E1250–E1255.

    Article  CAS  PubMed  Google Scholar 

  4. Clerk LH, Vincent MA, Jahn LA, et al.: Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle. Diabetes 2006, 55:1436–1442.

    Article  CAS  PubMed  Google Scholar 

  5. Kim JA, Montagnani M, Koh KK, et al.: Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 2006, 113:1888–1904.

    Article  PubMed  Google Scholar 

  6. Baron AD, Steinberg H, Brechtel G, et al.: Skeletal muscle blood flow independently modulates insulin-mediated glucose uptake. Am J Physiol Endocrinol Metab 1994, 266:E248–E253.

    CAS  Google Scholar 

  7. Vincent MA, Barrett EJ, Lindner JR, et al.: Inhibiting NOS blocks microvascular recruitment and blunts muscle glucose uptake in response to insulin. Am J Physiol Endocrinol Metab 2003, 285:E123–E129.

    CAS  PubMed  Google Scholar 

  8. Vincent MA, Clerk LH, Lindner JR, et al.: Microvascular recruitment is an early insulin effect that regulates skeletal muscle glucose uptake in vivo. Diabetes 2004, 53:1418–1423.

    Article  CAS  PubMed  Google Scholar 

  9. Clerk LH, Rattigan S, Clark MG: Lipid infusion impairs physiologic insulin-mediated capillary recruitment and muscle glucose uptake in vivo. Diabetes 2002, 51:1138–1145.

    Article  CAS  PubMed  Google Scholar 

  10. Kim JA, Koh KK, Quon MJ: The union of vascular and metabolic actions of insulin in sickness and in health. Arterioscler Thromb Vasc Biol 2005, 25:889–891.

    Article  CAS  PubMed  Google Scholar 

  11. Potenza MA, Marasciulo FL, Chieppa DM, et al.: Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production. Am J Physiol Heart Circ Physiol 2005, 289:H813–H822.

    Article  CAS  PubMed  Google Scholar 

  12. Eringa EC, Stehouwer CDA, Merlijn T, et al.: Physiological concentrations of insulin induce endothelin-mediated vasoconstriction during inhibition of NOS or PI3-kinase in skeletal muscle arterioles. Cardiovasc Res 2002, 56:464–471.

    Article  CAS  PubMed  Google Scholar 

  13. • Clerk LH, Vincent MA, Barrett EJ, et al.: Skeletal muscle capillary responses to insulin are abnormal in late-stage diabetes and are restored by angiotensin-converting enzyme inhibition. Am J Physiol Endocrinol Metab 2007, 293:E1804–E1809. Using contrast-enhanced ultrasound, the authors found that insulin-mediated capillary recruitment in skeletal muscle, which participates in glucose utilization, is impaired in an animal model of type 2 diabetes but can be partially reversed by chronic ACE inhibitor therapy.

    Article  CAS  PubMed  Google Scholar 

  14. Wallis MG, Wheatley CM, Rattigan S, et al.: Insulin-mediated hemodynamic changes are impaired in muscle of Zucker obese rats. Diabetes 2002, 51:3492–3498.

    Article  CAS  PubMed  Google Scholar 

  15. Scognamiglio R, Negut C, De Kreutzenberg SV, et al.: Postprandial myocardial perfusion in healthy subjects and in type 2 diabetic patients. Circulation 2005, 112:179–184.

    Article  PubMed  Google Scholar 

  16. Li G, Barrett EJ, Barrett MO, et al.: Tumor necrosis factor-α induces insulin resistance in endothelial cells via a p38 mitogen-activated protein kinase-dependent pathway. Endocrinology 2007, 148:3356–3363.

    Article  CAS  PubMed  Google Scholar 

  17. Youd JM, Rattigan S, Clark MG: Acute impairment of insulin-mediated capillary recruitment and glucose uptake in rat skeletal muscle in vivo by TNF-α. Diabetes 2000, 49:1904–1909.

    Article  CAS  PubMed  Google Scholar 

  18. Tripathy D, Mohanty P, Dhindsa S, et al.: Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes 2003, 52:2882–2887.

    Article  CAS  PubMed  Google Scholar 

  19. Steinberg HO, Paradisi G, Hook G, et al.: Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production. Diabetes 2000, 49:1231–1238.

    Article  CAS  PubMed  Google Scholar 

  20. Kim F, Tysseling KA, Rice J, et al.: Free fatty acid impairment of nitric oxide production in endothelial cells is mediated by IKKβ. Arterioscler Thromb Vasc Biol 2005, 25:989–994.

    Article  CAS  PubMed  Google Scholar 

  21. Liu Z: The renin-angiotensin system and insulin resistance. Curr Diab Rep 2007, 7:34–42.

    Article  PubMed  Google Scholar 

  22. de Jongh RT, Serne EH, Ijzerman RG, et al.: Impaired microvascular function in obesity: implications for obesity-associated microangiopathy, hypertension, and insulin resistance. Circulation 2004, 109:2529–2535.

    Article  PubMed  Google Scholar 

  23. Panza JA, Quyyumi AA, Brush JE Jr, et al.: Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990, 323:22–27.

    CAS  PubMed  Google Scholar 

  24. Farkas K, Kolossvary E, Jarai Z, et al.: Non-invasive assessment of microvascular endothelial function by laser Doppler flowmetry in patients with essential hypertension. Atherosclerosis 2004, 173:97–102.

    Article  CAS  PubMed  Google Scholar 

  25. Carey RM, Siragy HM: Newly recognized components of the renin-angiotensin system: potential roles in cardiovascular and renal regulation. Endocr Rev 2003, 24:261–271.

    Article  CAS  PubMed  Google Scholar 

  26. Paul M, Poyan Mehr A, Kreutz R: Physiology of local renin-angiotensin systems. Physiol Rev 2006, 86:747–803.

    Article  CAS  PubMed  Google Scholar 

  27. Carey RM: Cardiovascular and renal regulation by the angiotensin type 2 receptor: The AT2 receptor comes of age. Hypertension 2005, 45:840–844.

    Article  CAS  PubMed  Google Scholar 

  28. • Chai W, Wang W, Liu J, et al.: Angiotensin II type 1 and type 2 receptors regulate basal skeletal muscle microvascular volume and glucose use. Hypertension 2010, 55:523–530. Using contrast-enhanced ultrasound, the authors found that basal AT 1 R tone restricts muscle microvascular blood volume and glucose extraction, whereas basal AT 2 R activity increases muscle microvascular blood volume and glucose uptake.

    Article  CAS  PubMed  Google Scholar 

  29. Lim HS, MacFadyen RJ, Lip GYH: Diabetes mellitus, the renin-angiotensin aldosterone system, and the heart. Arch Intern Med 2004, 164:1737–1748.

    Article  CAS  PubMed  Google Scholar 

  30. Velloso LA, Folli F, Sun XJ, et al.: Cross-talk between the insulin and angiotensin signaling systems. PNAS 1996, 93:12490–12495.

    Article  CAS  PubMed  Google Scholar 

  31. Folli F, Kahn CR, Hansen H, et al.: Angiotensin II inhibits insulin signaling in aortic smooth muscle cells at multiple levels. A potential role for serine phosphorylation in insulin/angiotensin II crosstalk. J Clin Invest 1997, 100:2158–2169.

    Article  CAS  PubMed  Google Scholar 

  32. Andreozzi F, Laratta E, Sciacqua A, et al.: Angiotensin II impairs the insulin signaling pathway promoting production of nitric oxide by inducing phosphorylation of insulin receptor substrate-1 on Ser312 and Ser616 in human umbilical vein endothelial cells. Circ Res 2004, 94:1211–1218.

    Article  CAS  PubMed  Google Scholar 

  33. Shinozaki K, Ayajiki K, Nishio Y, et al.: Evidence for a causal role of the renin-angiotensin system in vascular dysfunction associated with insulin resistance. Hypertension 2004, 43:255–262.

    Article  CAS  PubMed  Google Scholar 

  34. Zhang C, Hein TW, Wang W, et al.: Divergent roles of angiotensin II AT1 and AT2 receptors in modulating coronary microvascular function. Circ Res 2003, 92:322–329.

    Article  CAS  PubMed  Google Scholar 

  35. Thai H, Wollmuth J, Goldman S, et al.: Angiotensin subtype 1 receptor (AT1) blockade improves vasorelaxation in heart failure by up-regulation of endothelial nitric-oxide synthase via activation of the AT2 receptor. J Pharmacol Exp Ther 2003, 307:1171–1178.

    Article  CAS  PubMed  Google Scholar 

  36. Batenburg WW, Garrelds IM, Bernasconi CC, et al.: Angiotensin II type 2 receptor-mediated vasodilation in human coronary microarteries. Circulation 2004, 109:2296–2301.

    Article  CAS  PubMed  Google Scholar 

  37. Carey RM: Angiotensin type-2 receptors and cardiovascular function: Are angiotensin type-2 receptors protective? Curr Opin Cardiol 2005, 20:264–269.

    Article  PubMed  Google Scholar 

  38. •• Holman RR, Paul SK, Bethel MA, et al.: Long-term follow-up after tight control of blood pressure in type 2 diabetes. N Engl J Med 2008, 359:1565–1576. This study showed that early improvement in blood pressure control in patients with both type 2 diabetes and hypertension was associated with a reduced risk of cardiovascular complications, but these benefits were not sustained when between-group differences in blood pressure were lost. It emphasizes the importance of continued tight blood pressure control in patients with diabetes to maintain the cardiovascular benefits.

    Article  CAS  PubMed  Google Scholar 

  39. Schiffrin EL, Park JB, Intengan HD, et al.: Correction of arterial structure and endothelial dysfunction in human essential hypertension by the angiotensin receptor antagonist losartan. Circulation 2000, 101:1653–1659.

    CAS  PubMed  Google Scholar 

  40. Klingbeil AU, John S, Schneider MP, et al.: Effect of AT1 receptor blockade on endothelial function in essential hypertension. Am J Hypertens 2003, 16:123–128.

    Article  CAS  PubMed  Google Scholar 

  41. Bosch J, Lonn E, Pogue J, et al.; HOPE/HOPE-TOO Study Investigators: Long-term effects of ramipril on cardiovascular events and on diabetes: results of the HOPE study extension. Circulation 2005, 112:1339–1346.

    Article  PubMed  Google Scholar 

  42. Hansson L, Lindholm LH, Ekbom T, et al.: Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 1999, 354:1751–1756.

    Article  CAS  PubMed  Google Scholar 

  43. DREAM Trial Investigators, Bosch J, Yusuf S, et al.: Effect of ramipril on the incidence of diabetes. N Engl J Med 2006, 355:1551–1562.

    Article  PubMed  Google Scholar 

  44. Mogensen CE, Neldam S, Tikkanen I, et al.: Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 2000, 321:1440–1444.

    Article  CAS  PubMed  Google Scholar 

  45. The ONTARGET Investigators: Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008, 358:1547–1559.

    Article  Google Scholar 

  46. Parving H-H, Persson F, Lewis JB, et al.: Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008, 358:2433–2446.

    Article  CAS  PubMed  Google Scholar 

  47. Feldman DL, Jin L, Xuan H, et al.: Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mRen-2)27 rats. Hypertension 2008, 52:130–136.

    Article  CAS  PubMed  Google Scholar 

  48. Lambers Heerspink HJ, Perkovic V, et al.: Renal and cardio-protective effects of direct renin inhibition: a systematic literature review. J Hypertens 2009, 27:2321–2331.

    Article  CAS  PubMed  Google Scholar 

  49. Fisher NDL, Hollenberg NK: Renin inhibition: what are the therapeutic opportunities? J Am Soc Nephrol 2005, 16:592–599.

    Article  CAS  PubMed  Google Scholar 

  50. Nguyen G, Danser AH: Prorenin and (pro)renin receptor: a review of available data from in vitro studies and experimental models in rodents. Exp Physiol 2008, 93:557–563.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by American Diabetes Association grants 7-07-CR-34 and 9-09-NOVO-11 (to Z.L.), and by the National Institutes of Health grants R01HL094722 (to Z.L.) and RR-00847 (to the University of Virginia General Clinical Research Center).

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No potential conflicts of interest relevant to this article were reported.

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Authors and Affiliations

  1. Division of Endocrinology & Metabolism, Department of Internal Medicine, University of Virginia Health System, PO Box 801410, Charlottesville, VA, 22908-1410, USA

    Seung-Hyun Ko & Zhenqi Liu

  2. Endocrine Biology Program, The Hamner Institutes for Health Sciences, Research Triangle Park, NC, USA

    Wenhong Cao

  3. Division of Endocrinology and Metabolism, Department of Medicine, The Catholic University of Korea, Seoul, Korea

    Seung-Hyun Ko

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  1. Seung-Hyun Ko
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  2. Wenhong Cao
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Correspondence to Zhenqi Liu.

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Ko, SH., Cao, W. & Liu, Z. Hypertension Management and Microvascular Insulin Resistance in Diabetes. Curr Hypertens Rep 12, 243–251 (2010). https://doi.org/10.1007/s11906-010-0114-6

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