The Microvasculature in Insulin Resistance and Type 2 Diabetes

 

 Buy Article Permissions and Reprints

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.

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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 5 DeFronzo R A, Bonadonna R C, Ferrannini E. Pathogenesis of NIDDM. A balanced overview.  Diabetes Care . 1992;  15(3) 318-368
  CrossrefPubMedGoogle Scholar
• 6 Krotkiewski M. Role of muscle capillarization and morphology in the development of insulin resistance and metabolic syndrome.  Presse Med . 1994;  23 1353-1356
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 13 Ernstene A C, Altschule M D. The effect of insulin hypoglycemia on the circulation.  J Clin Invest . 1931;  10 521-528
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 15 French E B, Kilpatrick R. The role of adrenaline in hypoglycaemic reactions in man.  Clin Sci . 1955;  14 639-651
  PubMedGoogle Scholar
• 16 Ginsburg J, Paton A. Effects of insulin after adrenalectomy.  Lancet . 1956;  271 491-494
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 19 Liang C S, Doherty J U, Faillace R. Insulin infusion in conscious dogs.  J Clin Invest . 1982;  69 1321-1336
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 29 Yki-Jarvinen H, Utriainen T. Insulin-induced vasodilatation: physiology or pharmacology?.  Diabetologia . 1998;  41(4) 369-379
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 36 Bergman R N. New concepts in extracellular signaling for insulin action: the single gateway hypothesis.  Recent Prog Horm Res . 1997;  52 359-387
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 39 Tappy L, Randin D, Vollenweider P. Mechanisms of dexamethasone-induced insulin resistance in healthy humans.  J Clin Endocrinol Metab . 1994;  79 1063-1069
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 47 Natali A. Skeletal muscle blood flow and insulin action.  Nutr Metab Cardiovas Dis . 1997;  7 105-109
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 54 Jarasch E D, Bruder G, Heid H W. Significance of xanthine oxidase in capillary endothelial cells.  Acta Physiol Scand . 1986;  548 39-46
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 58 Vincent M A, Dawson D, Clark A DH. Skeletal muscle microvascular recruitment by hyperinsulinemia precedes increases in total blood flow.  Diabetes In press.
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 60 Goodyear L J, Kahn B B. Exercise, glucose transport, and insulin sensitivity.  Annu Rev Med . 1998;  49 235-261
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 66 Balon T W, Nadler J L. Evidence that nitric oxide increases glucose transport in skeletal muscle.  J Appl Physiol . 1997;  82 359-363
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar