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Semin Vasc Med 2002; 2(1): 021-032
DOI: 10.1055/s-2002-23506
DOI: 10.1055/s-2002-23506
The Microvasculature in Insulin Resistance and Type 2 Diabetes
Further Information
Publication History
Publication Date:
25 March 2002 (online)
ABSTRACT
Insulin resistance of muscle has been attributed to impairment of elements of insulin signaling, glucose transport, and/or metabolism within the muscle cells. This article explores the notion that a component of insulin resistance in vivo may result from impaired hemodynamic effects of this hormone to facilitate access to the muscle cells for itself and other nutrients, including glucose. In chronic situations this may manifest as a decreased capillary density of muscle, but in the acute, there may be impaired mechanisms for increasing total limb blood flow or for achieving optimal microvascular perfusion. Newly developed techniques show that insulin acts to recruit muscle capillary flow to enhance microvascular perfusion in animals and humans. This microvascular effect of insulin correlates closely with muscle glucose uptake, is independent of increases in bulk blood flow, and is impaired in obese insulin-resistant patients. Similarly, there are impaired vasodilatory responses in the skin of diabetic subjects.
KEYWORD
Insulin action - insulin resistance - capillary recruitment - muscle - skin
REFERENCES
- 1 Lillioja S, Young A A, Culter C L. Skeletal muscle capillary density and fiber type are possible determinants of in vivo insulin resistance in man. J Clin Invest . 1987; 80 415-424
- 2 Hedman A, Berglund L, Essen-Gustavsson B, Reneland R, Lithell H. Relationships between muscle morphology and insulin sensitivity are improved after adjustment for intra-individual variability in 70-year-old men. Acta Physiol Scand . 2000; 169(2) 125-132
- 3 Egan B M. Neurohumoral, hemodynamic and microvascular changes as mechanisms of insulin resistance in hypertension: a provocative but partial picture. Int J Obes . 1991; 15 133-139
- 4 Julius S, Gudbrandsson T, Jamerson K, Andersson O. The interconnection between sympathetics, microcirculation, and insulin resistance in hypertension. Blood Pressure . 1992; 1 9-19
- 5 DeFronzo R A, Bonadonna R C, Ferrannini E. Pathogenesis of NIDDM. A balanced overview. Diabetes Care . 1992; 15(3) 318-368
- 6 Krotkiewski M. Role of muscle capillarization and morphology in the development of insulin resistance and metabolic syndrome. Presse Med . 1994; 23 1353-1356
- 7 Cleland S J, Petrie J R, Ueda S, Elliott H L, Connell J M. Insulin as a vascular hormone: implications for the pathophysiology of cardiovascular disease. Clin Exp Pharmacol Physiol . 1998; 25(3-4) 175-184
- 8 Hedman A, Reneland R, Lithell H O. Alterations in skeletal muscle morphology in glucose-tolerant elderly hypertensive men: relationship to development of hypertension and heart rate. J Hypertens . 2000; 18(5) 559-565
- 9 Hepple R T, Mackinnon S L, Goodman J M, Thomas S G, Plyley M J. Resistance and aerobic training in older men: effects on VO2peak and the capillary supply to skeletal muscle. J Appl Physiol . 1997; 82(4) 1305-1310
- 10 Jaap A J, Shore A C, Stockman A J, Tooke J E. Skin capillary density in subjects with impaired glucose tolerance and patients with type 2 diabetes. Diabet Med . 1996; 13(2) 160-164
- 11 Serné E H, Gans R O, ter Maaten C J, ter Wee M P, Donker A J, Stehouwer C D. Capillary recruitment is impaired in essential hypertension and relates to insulin's metabolic and vascular actions. Cardiovasc Res . 2001; 49(1) 161-168
- 12 Abramson D I, Schkloven N, Margolis M N, Mirsky I A. Influence of massive doses of insulin on peripheral blood flow in man. Am J Physiol . 1939; 128 124-132
- 13 Ernstene A C, Altschule M D. The effect of insulin hypoglycemia on the circulation. J Clin Invest . 1931; 10 521-528
- 14 Dosekun F O, Grayson J, Mendel D. The measurement of metabolic and vascular responses in liver and muscle with observations on their responses to insulin and glucose. J Physiol (Lond). 1960; 150 581-606
- 15 French E B, Kilpatrick R. The role of adrenaline in hypoglycaemic reactions in man. Clin Sci . 1955; 14 639-651
- 16 Ginsburg J, Paton A. Effects of insulin after adrenalectomy. Lancet . 1956; 271 491-494
- 17 Pereda S A, Eckstein J W, Abboud F M. Cardiovascular responses to insulin in the absence of hypoglycemia. Am J Physiol . 1962; 202 249-252
- 18 James D E, Burleigh K M, Storlien L H, Bennett S P, Kraegen E W. Heterogeneity of insulin action in muscle: influence of blood flow. Am J Physiol . 1986; 251 E422-E430
- 19 Liang C S, Doherty J U, Faillace R. Insulin infusion in conscious dogs. J Clin Invest . 1982; 69 1321-1336
- 20 Fisher B M, Gillen G, Dargie H J, Inglis G C, Frier B M. The effects of insulin-induced hypoglycemia on cardiovascular function in normal man: studies using radionuclide ventriculography. Diabetologia . 1987; 30 841-845
- 21 Gelfand R A, Barrett E J. Effects of physiologic hyperinsulinemia on skeletal muscle protein synthesis and breakdown in man. J Clin Invest . 1987; 80 1-6
- 22 Creager M A, Liang C S, Coffman J D. Beta adrenergic-mediated vasodilator response to insulin in the human forearm. J Pharmacol Exp Ther . 1985; 235 709-714
- 23 Richter E A, Mikines K J, Galbo H, Kiens B. Effect of exercise on insulin action in human skeletal muscle. J Appl Physiol . 1989; 66 876-885
- 24 Defronzo R A, Jacot E, Jequier E, Maeder E, Wahren J, Felber J P. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes . 1981; 30 1000-1007
- 25 Defronzo R A, Ferrannini E, Hendler R, Felig P, Wahren J. Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in man. Diabetes . 1983; 32 35-45
- 26 Jackson R A, Roshania R D, Hawa M I, Sim B M, DiSilvio L. Impact of glucose ingestion on hepatic and peripheral glucose metabolism in man: an analysis based on simultaneous use of the forearm and double isotope techniques. J Clin Endocrinol Metab . 1986; 63(3) 541-549
- 27 Jackson R A, Hamling J B, Blix P M. The influence of graded hyperglycemia with and without physiological hyperinsulinemia on forearm glucose uptake and other metabolic responses in man. J Clin Endocrinol Metab . 1986; 63(3) 594-604
- 28 Yki-Jarvinen H, Young A A, Lamkin C, Foley J E. Kinetics of glucose disposal in whole body and across the forearm in man. J Clin Invest . 1987; 79(6) 1713-1719
- 29 Yki-Jarvinen H, Utriainen T. Insulin-induced vasodilatation: physiology or pharmacology?. Diabetologia . 1998; 41(4) 369-379
- 30 Scherrer U, Randin D, Vollenweider P, Vollenweider L, Nicod P. Nitric oxide release accounts for insulin's vascular effects in humans. J Clin Invest . 1994; 94(6) 2511-2515
- 31 Natali A, Bonadonna R, Santoro D. Insulin resistance and vasodilation in essential hypertension. Studies with adenosine. J Clin Invest . 1994; 94(4) 1570-1576
- 32 Natali A, Quinones G A, Pecori N, Sanna G, Toschi E, Ferrannini E. Vasodilation with sodium nitroprusside does not improve insulin action in essential hypertension. Hypertension . 1998; 31(2) 632-636
- 33 Laine H, Yki-Jarvinen H, Kirvela O. Insulin resistance of glucose uptake in skeletal muscle cannot be ameliorated by enhancing endothelium-dependent blood flow in obesity. J Clin Invest . 1998; 101(5) 1156-1162
- 34 Laakso M, Edelman S V, Brechtel G, Baron A D. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. J Clin Invest . 1990; 85 1844-1852
- 35 Yang Y J, Hope I D, Ader M, Bergman R N. Insulin transport across capillaries is rate limiting for insulin action in dogs. J Clin Invest . 1989; 84 1620-1628
- 36 Bergman R N. New concepts in extracellular signaling for insulin action: the single gateway hypothesis. Recent Prog Horm Res . 1997; 52 359-387
- 37 Jansson P A, Fowelin J P, von Schenck P H, Smith U P, Lonnroth P N. Measurement by microdialysis of the insulin concentration in subcutaneous interstitial fluid. Importance of the endothelial barrier for insulin. Diabetes . 1993; 42(10) 1469-1473
- 38 Scherrer U, Vollenweider P, Randin D, Jequier E, Nicod P, Tappy L. Suppression of insulin-induced sympathetic activation and vasodilation by dexamethasone in humans. Circulation . 1993; 88(2) 388-394
- 39 Tappy L, Randin D, Vollenweider P. Mechanisms of dexamethasone-induced insulin resistance in healthy humans. J Clin Endocrinol Metab . 1994; 79 1063-1069
- 40 Vollenweider L, Tappy L, Owlya R, Jequier E, Nicod P, Scherrer U. Insulin-induced sympathetic activation and vasodilation in skeletal muscle. Effects of insulin resistance in lean subjects. Diabetes . 1995; 44 641-645
- 41 Steinberg H O, Paradisi G, Hook G, Crowder K, Cronin J, Baron A D. Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production. Diabetes . 2000; 49(7) 1231-1238
- 42 Stallknecht B, Larsen J J, Mikines K J, Simonsen L, Bulow J, Galbo H. Effect of training on insulin sensitivity of glucose uptake and lipolysis in human adipose tissue. Am J Physiol Endocrinol Metab . 2000; 279(2) E376-E385
- 43 Baron A D, 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
- 44 Allwood M J, Hensel H, Papenberg J. Muscle and skin blood flow in the human forearm during insulin hypoglycaemia. J Physiol (Lond). 1959; 147 269-273
- 45 Renaudin C, Michoud E, Rapin J R, Lagarde M, Wiernsperger N. Hyperglycaemia modifies the reaction of microvessels to insulin in rat skeletal muscle. Diabetologia . 1998; 41(1) 26-33
- 46 Scherrer U, Sartori C. Insulin as a vascular and sympathoexcitatory hormone: implications for blood pressure regulation, insulin sensitivity, and cardiovascular morbidity. Circulation . 1997; 96(11) 4104-4113
- 47 Natali A. Skeletal muscle blood flow and insulin action. Nutr Metab Cardiovas Dis . 1997; 7 105-109
- 48 Ahlborg G, Wahren J, Felig P. Splanchnic and peripheral glucose and lactate metabolism during and after prolonged arm exercise. J Clin Invest . 1986; 77(3) 690-699
- 49 Honig C R, Odoroff C L, Frierson J L. Active and passive capillary control in red muscle at rest and in exercise. Am J Physiol . 1982; 243 H196-H206
- 50 Bonadonna R C, Saccomani M P, Del Prato S, Bonora E, Defronzo R A, Cobelli C. Role of tissue-specific blood flow and tissue recruitment in insulin-mediated glucose uptake of human skeletal muscle. Circulation . 1998; 98(3) 234-241
- 51 Raitakari M, Knuuti M J, Ruotsalainen U. Insulin increases blood volume in human skeletal muscle: studies using [15O]CO and positron emission tomography. Am J Physiol . 1995; 269 E1000-E1005
- 52 Rattigan S, Clark M G, Barrett E J. Hemodynamic actions of insulin in rat skeletal muscle: evidence for capillary recruitment. Diabetes . 1997; 46(9) 1381-1388
- 53 Coggins M P, Fasy E, Lindner J, Jahn L, Kaul S, Barrett E J. Physiologic hyperinsulinemia increases skeletal muscle microvascular blood volume in healthy humans [abstract]. Diabetes . 1999; A220
- 54 Jarasch E D, Bruder G, Heid H W. Significance of xanthine oxidase in capillary endothelial cells. Acta Physiol Scand . 1986; 548 39-46
- 55 Rattigan S, Appleby G J, Miller K A. Serotonin inhibition of 1-methylxanthine metabolism parallels its vasoconstrictor activity and inhibition of oxygen uptake in perfused rat hindlimb. Acta Physiol Scand . 1997; 161(2) 161-169
- 56 Clark M G, Rattigan S, Clerk L H. Nutritive and non-nutritive blood flow: rest and exercise. Acta Physiol Scand . 2000; 168(4) 519-530
- 57 Clark A DH, Barrett E J, Rattigan S, Wallis M G, Clark M G. Insulin stimulates laser Doppler signal by rat muscle in vivo consistent with nutritive flow recruitment. Clin Sci . 2001; 100 283-290
- 58 Vincent M A, Dawson D, Clark A DH. Skeletal muscle microvascular recruitment by hyperinsulinemia precedes increases in total blood flow. Diabetes In press.
- 59 Clark A DH, Youd J M, Rattigan S, Barrett E J, Clark M G. Heterogeneity of laser Doppler flowmetry in perfused muscle indicative of nutritive and nonnutritive flow. Am J Physiol . 2001; 280(3) H1324-H1333
- 60 Goodyear L J, Kahn B B. Exercise, glucose transport, and insulin sensitivity. Annu Rev Med . 1998; 49 235-261
- 61 Vincent M A, Dawson D, Clark A D. Physiologic hyperinsulinemia mimics the capillary recruitment induced by exercise in skeletal muscle in vivo [abstract]. Diabetes . 2000; 49(Suppl 1) LB-15
- 62 Goetze S, Kintscher U, Kawano H. Tumor necrosis factor alpha inhibits insulin-induced mitogenic signaling in vascular smooth muscle cells. J Biol Chem . 2000; 275(24) 18279-18283
- 63 Murata H, Hruz P W, Mueckler M. The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem . 2000; 275(27) 20251-20254
- 64 Fryer L G, Hajduch E, Rencurel F. Activation of glucose transport by AMP-activated protein kinase via stimulation of nitric oxide synthase. Diabetes . 2000; 49(12) 1978-1985
- 65 Bradley S J, Kingwell B A, McConell G K. Nitric oxide synthase inhibition reduces leg glucose uptake but not blood flow during dynamic exercise in humans. Diabetes . 1999; 48(9) 1815-1821
- 66 Balon T W, Nadler J L. Evidence that nitric oxide increases glucose transport in skeletal muscle. J Appl Physiol . 1997; 82 359-363
- 67 Jaap A J, Shore A C, Tooke J E. Relationship of insulin resistance to microvascular dysfunction in subjects with fasting hyperglycaemia. Diabetologia . 1997; 40(2) 238-243
- 68 Caballero A E, Arora S, Saouaf R. Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes . 1999; 48(9) 1856-1862
- 69 Serné E H, Stehouwer C D, ter Maaten C J. Microvascular function relates to insulin sensitivity and blood pressure in normal subjects. Circulation . 1999; 99(7) 896-902
- 70 Utriainen T, Malmstrom R, Makimattila S, Yki-Jarvinen H. Methodological aspects, dose-response characteristics and causes of interindividual variation in insulin stimulation of limb blood flow in normal subjects. Diabetologia . 1995; 38(5) 555-564
- 71 Forst T, Kunt T, Pohlmann T. Microvascular skin blood flow following the ingestion of 75 g glucose in healthy individuals [In Process Citation]. Exp Clin Endocrinol Diabetes . 1998; 106(6) 454-459
- 72 Laakso M, Edelman S V, Brechtel G, Baron A D. Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM. Diabetes . 1992; 41 1076-1083
- 73 Baron A D, Laakso M, Brechtel G, Edelman S V. Mechanism of insulin resistance in insulin-dependent diabetes mellitus: a major role for reduced skeletal muscle blood flow. J Clin Endocrinol Metab . 1991; 73 637-643
- 74 Laine H, Knuuti M J, Ruotsalainen U. Insulin resistance in essential hypertension is characterized by impaired insulin stimulation of blood flow in skeletal muscle. J Hypertens . 1998; 16(2) 211-219
- 75 Paolisso G, Tagliamonte M R, Gambardella A. Losartan mediated improvement in insulin action is mainly due to an increase in non-oxidative glucose metabolism and blood flow in insulin-resistant hypertensive patients. J Hum Hypertens . 1997; 11(5) 307-312
- 76 Tack C J, Ong M K, Lutterman J A, Smits P. Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone. Diabetologia . 1998; 41(5) 569-576
- 77 Meneilly G S, Elliot T, Bryer-Ash M, Floras J S. Insulin-mediated increase in blood flow is impaired in the elderly. J Clin Endocrinol Metab . 1995; 80(6) 1899-1903
- 78 Hogikyan R V, Galecki A T, Pitt B, Halter J B, Greene D A, Supiano M A. Specific impairment of endothelium-dependent vasodilation in subjects with type 2 diabetes independent of obesity. J Clin Endocrinol Metab . 1998; 83(6) 1946-1952
- 79 Vollenweider P, Randin D, Tappy L, Jequier E, Nicod P, Scherrer U. Impaired insulin-induced sympathetic neural activation and vasodilation in skeletal muscle in obese humans. J Clin Invest . 1994; 93 2365-2371
- 80 Sarabi M, Lind L, Millgard J. Local vasodilatation with metacholine, but not with nitroprusside, increases forearm glucose uptake. Physiol Res . 1999; 48(4) 291-295
- 81 Newman J M, Clark M G. Stimulation and inhibition of resting muscle thermogenesis by vasoconstrictors in perfused rat hind limb. Can J Physiol Pharmacol . 1998; 76(9) 867-872
- 82 Rattigan S, Clark M G, Barrett E J. Acute vasoconstriction-induced insulin resistance in rat muscle in vivo. Diabetes . 1999; 48(3) 564-569
- 83 Youd J M, Rattigan S, Clark M G. Acute impairment of insulin-mediated capillary recruitment and glucose uptake in rat skeletal muscle in vivo by TNFα. Diabetes . 2000; 49(11) 1904-1909
- 84 Coggins M, Fasy E, Lindner J, Jahn L, Kaul S, Barrett E J. Obesity blunts insulin's action to recruit capillaries in human skeletal muscle. Diabetes . 2000; A237