Diabetes Metab J.  2012 Apr;36(2):83-89. 10.4093/dmj.2012.36.2.83.

Regulation of Muscle Microcirculation in Health and Diabetes

• Liu Z
• Ko SH
• Chai W
• Cao W

• KMID: 2281409
• DOI: http://doi.org/10.4093/dmj.2012.36.2.83

Abstract

Insulin increases microvascular perfusion and substrate exchange surface area in muscle, which is pivotal for hormone action and substrate exchange, by activating insulin signaling cascade in the endothelial cells to produce nitric oxide. This action of insulin is closely coupled with its metabolic action and type 2 diabetes is associated with both metabolic and microvascular insulin resistance. Muscle microvascular perfusion/volume can be assessed by 1-methylxanthine metabolism, contrast-enhanced ultrasound and positron emission tomography. In addition to insulin, several factors have been shown to recruit muscle microvasculature, including exercise or muscle contraction, mixed meals, glucagon-like peptide 1 and angiotensin II type 1 receptor (AT1R) blocker. On the other hand, factors that cause metabolic insulin resistance, such as inflammatory cytokines, free fatty acids, and selective activation of the AT1R, are capable of causing microvascular insulin resistance. Therapies targeting microvascular insulin resistance may help prevent or control diabetes and decrease the associated cardiovascular morbidity and mortality.

Keyword

Endothelium; Insulin; Microvasculature; Muscle; Nitric oxide; Vasoconstriction; Vasorelaxation

MeSH Terms

Cytokines
Endothelial Cells
Endothelium
Fatty Acids, Nonesterified
Glucagon-Like Peptide 1
Hand
Insulin
Insulin Resistance
Meals
Microcirculation
Microvessels
Muscle Contraction
Muscles
Nitric Oxide
Perfusion
Positron-Emission Tomography
Receptor, Angiotensin, Type 1
Vasoconstriction
Vasodilation
Xanthines
Cytokines
Fatty Acids, Nonesterified
Glucagon-Like Peptide 1
Insulin
Nitric Oxide
Receptor, Angiotensin, Type 1
Xanthines

Figure

• 

  Fig. 1 Schematic diagram illustrating the regulation of microvasculature in muscle. AT1R, angiotensin II type 1 receptor; GLP-1, glucagon-like peptide 1; FFAs, free fatty acids.

Reference

1. Barrett EJ, Wang H, Upchurch CT, Liu Z. Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature. Am J Physiol Endocrinol Metab. 2011. 301:E252–E263.

2. Barrett EJ, Eggleston EM, Inyard AC, Wang H, Li G, Chai W, Liu Z. 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.

3. Clark MG, Wallis MG, Barrett EJ, Vincent MA, Richards SM, Clerk LH, Rattigan S. Blood flow and muscle metabolism: a focus on insulin action. Am J Physiol Endocrinol Metab. 2003. 284:E241–E258.

4. Honig CR, Odoroff CL, Frierson JL. Active and passive capillary control in red muscle at rest and in exercise. Am J Physiol. 1982. 243:H196–H206.

5. Baron AD. Hemodynamic actions of insulin. Am J Physiol. 1994. 267(2 Pt 1):E187–E202.

6. Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Invest. 1994. 94:1172–1179.

7. Rattigan S, Clark MG, Barrett EJ. Hemodynamic actions of insulin in rat skeletal muscle: evidence for capillary recruitment. Diabetes. 1997. 46:1381–1388.

8. Wei K, Jayaweera AR, Firoozan S, Linka A, Skyba DM, Kaul S. Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. Circulation. 1998. 97:473–483.

9. Wei K, Kaul S. Recent advances in myocardial contrast echocardiography. Curr Opin Cardiol. 1997. 12:539–546.

10. Wei K, Skyba DM, Firschke C, Jayaweera AR, Lindner JR, Kaul S. Interactions between microbubbles and ultrasound: in vitro and in vivo observations. J Am Coll Cardiol. 1997. 29:1081–1088.

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

12. Vincent MA, Clerk LH, Lindner JR, Klibanov AL, Clark MG, Rattigan S, Barrett EJ. Microvascular recruitment is an early insulin effect that regulates skeletal muscle glucose uptake in vivo. Diabetes. 2004. 53:1418–1423.

13. Vincent MA, Dawson D, Clark AD, Lindner JR, Rattigan S, Clark MG, Barrett EJ. Skeletal muscle microvascular recruitment by physiological hyperinsulinemia precedes increases in total blood flow. Diabetes. 2002. 51:42–48.

14. Chai W, Wang W, Dong Z, Cao W, Liu Z. Angiotensin II receptors modulate muscle microvascular and metabolic responses to insulin in vivo. Diabetes. 2011. 60:2939–2946.

15. Liu Z, Liu J, Jahn LA, Fowler DE, Barrett EJ. Infusing lipid raises plasma free fatty acids and induces insulin resistance in muscle microvasculature. J Clin Endocrinol Metab. 2009. 94:3543–3549.

16. Chai W, Liu J, Jahn LA, Fowler DE, Barrett EJ, Liu Z. Salsalate attenuates free fatty acid-induced microvascular and metabolic insulin resistance in humans. Diabetes Care. 2011. 34:1634–1638.

17. Ruotsalainen U, Raitakari M, Nuutila P, Oikonen V, Sipila H, Teras M, Knuuti MJ, Bloomfield PM, Iida H. Quantitative blood flow measurement of skeletal muscle using oxygen-15-water and PET. J Nucl Med. 1997. 38:314–319.

18. Laine H, Knuuti MJ, Ruotsalainen U, Raitakari M, Iida H, Kapanen J, Kirvela O, Haaparanta M, Yki-Jarvinen H, Nuutila P. Insulin resistance in essential hypertension is characterized by impaired insulin stimulation of blood flow in skeletal muscle. J Hypertens. 1998. 16:211–219.

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

20. Clerk LH, Vincent MA, Jahn LA, Liu Z, Lindner JR, Barrett EJ. Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle. Diabetes. 2006. 55:1436–1442.

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

22. Baron AD, Steinberg H, Brechtel G, Johnson A. Skeletal muscle blood flow independently modulates insulin-mediated glucose uptake. Am J Physiol. 1994. 266(2 Pt 1):E248–E253.

23. 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.

24. Eringa EC, Stehouwer CD, van Nieuw Amerongen GP, Ouwehand L, Westerhof N, Sipkema P. Vasoconstrictor effects of insulin in skeletal muscle arterioles are mediated by ERK1/2 activation in endothelium. Am J Physiol Heart Circ Physiol. 2004. 287:H2043–H2048.

25. Eringa EC, Stehouwer CD, Merlijn T, Westerhof N, Sipkema P. 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.

26. Vincent MA, Clerk LH, Lindner JR, Price WJ, Jahn LA, Leong-Poi H, Barrett EJ. Mixed meal and light exercise each recruit muscle capillaries in healthy humans. Am J Physiol Endocrinol Metab. 2006. 290:E1191–E1197.

27. Inyard AC, Chong DG, Klibanov AL, Barrett EJ. Muscle contraction, but not insulin, increases microvascular blood volume in the presence of free fatty acid-induced insulin resistance. Diabetes. 2009. 58:2457–2463.

28. Inyard AC, Clerk LH, Vincent MA, Barrett EJ. Contraction stimulates nitric oxide independent microvascular recruitment and increases muscle insulin uptake. Diabetes. 2007. 56:2194–2200.

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

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

31. Chai W, Wang W, Liu J, Barrett EJ, Carey RM, Cao W, Liu Z. Angiotensin II type 1 and type 2 receptors regulate basal skeletal muscle microvascular volume and glucose use. Hypertension. 2010. 55:523–530.

32. Keske MA, Clerk LH, Price WJ, Jahn LA, Barrett EJ. Obesity blunts microvascular recruitment in human forearm muscle after a mixed meal. Diabetes Care. 2009. 32:1672–1677.

33. Chai W, Dong Z, Wang N, Wang W, Tao L, Cao W, Liu Z. Glucagon-like peptide 1 recruits microvasculature and increases glucose use in muscle via a nitric oxide-dependent mechanism. Diabetes. 2012. 61:888–896.

34. Clerk LH, Vincent MA, Barrett EJ, Lankford MF, Lindner JR. 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.

35. Wallis MG, Wheatley CM, Rattigan S, Barrett EJ, Clark AD, Clark MG. Insulin-mediated hemodynamic changes are impaired in muscle of Zucker obese rats. Diabetes. 2002. 51:3492–3498.

36. 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.

37. Eringa EC, Stehouwer CD, Roos MH, Westerhof N, Sipkema P. Selective resistance to vasoactive effects of insulin in muscle resistance arteries of obese Zucker (fa/fa) rats. Am J Physiol Endocrinol Metab. 2007. 293:E1134–E1139.

38. Potenza MA, Marasciulo FL, Chieppa DM, Brigiani GS, Formoso G, Quon MJ, Montagnani M. 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.

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

40. Li G, Barrett EJ, Barrett MO, Cao W, Liu Z. Tumor necrosis factor-alpha induces insulin resistance in endothelial cells via a p38 mitogen-activated protein kinase-dependent pathway. Endocrinology. 2007. 148:3356–3363.

41. Tripathy D, Mohanty P, Dhindsa S, Syed T, Ghanim H, Aljada A, Dandona P. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes. 2003. 52:2882–2887.

42. Steinberg HO, Paradisi G, Hook G, Crowder K, Cronin J, Baron AD. Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production. Diabetes. 2000. 49:1231–1238.

43. Kim F, Tysseling KA, Rice J, Pham M, Haji L, Gallis BM, Baas AS, Paramsothy P, Giachelli CM, Corson MA, Raines EW. Free fatty acid impairment of nitric oxide production in endothelial cells is mediated by IKKbeta. Arterioscler Thromb Vasc Biol. 2005. 25:989–994.

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

45. Ko SH, Cao W, Liu Z. Hypertension management and microvascular insulin resistance in diabetes. Curr Hypertens Rep. 2010. 12:243–251.

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

47. Velloso LA, Folli F, Sun XJ, White MF, Saad MJ, Kahn CR. Cross-talk between the insulin and angiotensin signaling systems. Proc Natl Acad Sci U S A. 1996. 93:12490–12495.

48. Folli F, Kahn CR, Hansen H, Bouchie JL, Feener EP. 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.

49. Andreozzi F, Laratta E, Sciacqua A, Perticone F, Sesti G. 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.

50. 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.