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. 1998 Mar 1;101(5):1156–1162. doi: 10.1172/JCI1065

Insulin resistance of glucose uptake in skeletal muscle cannot be ameliorated by enhancing endothelium-dependent blood flow in obesity.

H Laine 1, H Yki-Jarvinen 1, O Kirvela 1, T Tolvanen 1, M Raitakari 1, O Solin 1, M Haaparanta 1, J Knuuti 1, P Nuutila 1
PMCID: PMC508668  PMID: 9486987

Abstract

We tested the hypothesis that endothelium-dependent vasodilatation is a determinant of insulin resistance of skeletal muscle glucose uptake in human obesity. Eight obese (age 26+/-1 yr, body mass index 37+/-1 kg/m2) and seven nonobese males (25+/-2 yr, 23+/-1 kg/m2) received an infusion of bradykinin into the femoral artery of one leg under intravenously maintained normoglycemic hyperinsulinemic conditions. Blood flow was measured simultaneously in the bradykinin and insulin- and the insulin-infused leg before and during hyperinsulinemia using [15O]-labeled water ([15O]H2O) and positron emission tomography (PET). Glucose uptake was quantitated immediately thereafter in both legs using [18F]- fluoro-deoxy-glucose ([18F]FDG) and PET. Whole body insulin-stimulated glucose uptake was lower in the obese (507+/-47 mumol/m2 . min) than the nonobese (1205+/-97 micromol/m2 . min, P < 0.001) subjects. Muscle glucose uptake in the insulin-infused leg was 66% lower in the obese (19+/-4 micromol/kg muscle . min) than in the nonobese (56+/-9 micromol/kg muscle . min, P < 0.005) subjects. Bradykinin increased blood flow during hyperinsulinemia in the obese subjects by 75% from 16+/-1 to 28+/-4 ml/kg muscle . min (P < 0.05), and in the normal subjects by 65% from 23+/-3 to 38+/-9 ml/kg muscle . min (P < 0.05). However, this flow increase required twice as much bradykinin in the obese (51+/-3 microg over 100 min) than in the normal (25+/-1 mug, P < 0.001) subjects. In the obese subjects, blood flow in the bradykinin and insulin-infused leg (28+/-4 ml/kg muscle . min) was comparable to that in the insulin-infused leg in the normal subjects during hyperinsulinemia (24+/-5 ml/kg muscle . min). Despite this, insulin-stimulated glucose uptake remained unchanged in the bradykinin and insulin-infused leg (18+/-4 mumol/kg . min) compared with the insulin-infused leg (19+/-4 micromol/kg muscle . min) in the obese subjects. Insulin-stimulated glucose uptake also was unaffected by bradykinin in the normal subjects (58+/-10 vs. 56+/-9 micromol/kg . min, bradykinin and insulin versus insulin leg). These data demonstrate that obesity is characterized by two distinct defects in skeletal muscle: insulin resistance of cellular glucose extraction and impaired endothelium-dependent vasodilatation. Since a 75% increase in blood flow does not alter glucose uptake, insulin resistance in obesity cannot be overcome by normalizing muscle blood flow.

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Selected References

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  1. Balon T. W., Nadler J. L. Evidence that nitric oxide increases glucose transport in skeletal muscle. J Appl Physiol (1985) 1997 Jan;82(1):359–363. doi: 10.1152/jappl.1997.82.1.359. [DOI] [PubMed] [Google Scholar]
  2. Balon T. W., Nadler J. L. Nitric oxide release is present from incubated skeletal muscle preparations. J Appl Physiol (1985) 1994 Dec;77(6):2519–2521. doi: 10.1152/jappl.1994.77.6.2519. [DOI] [PubMed] [Google Scholar]
  3. Baron A. D., Steinberg H. O., Chaker H., Leaming R., Johnson A., Brechtel G. Insulin-mediated skeletal muscle vasodilation contributes to both insulin sensitivity and responsiveness in lean humans. J Clin Invest. 1995 Aug;96(2):786–792. doi: 10.1172/JCI118124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baron A. D., Steinberg H., Brechtel G., Johnson A. Skeletal muscle blood flow independently modulates insulin-mediated glucose uptake. Am J Physiol. 1994 Feb;266(2 Pt 1):E248–E253. doi: 10.1152/ajpendo.1994.266.2.E248. [DOI] [PubMed] [Google Scholar]
  5. Bonadonna R. C., Saccomani M. P., Seely L., Zych K. S., Ferrannini E., Cobelli C., DeFronzo R. A. Glucose transport in human skeletal muscle. The in vivo response to insulin. Diabetes. 1993 Jan;42(1):191–198. doi: 10.2337/diab.42.1.191. [DOI] [PubMed] [Google Scholar]
  6. Buchanan T. A., Thawani H., Kades W., Modrall J. G., Weaver F. A., Laurel C., Poppiti R., Xiang A., Hsueh W. Angiotensin II increases glucose utilization during acute hyperinsulinemia via a hemodynamic mechanism. J Clin Invest. 1993 Aug;92(2):720–726. doi: 10.1172/JCI116642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Castillo C., Bogardus C., Bergman R., Thuillez P., Lillioja S. Interstitial insulin concentrations determine glucose uptake rates but not insulin resistance in lean and obese men. J Clin Invest. 1994 Jan;93(1):10–16. doi: 10.1172/JCI116932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cockcroft J. R., Chowienczyk P. J., Brett S. E., Ritter J. M. Effect of NG-monomethyl-L-arginine on kinin-induced vasodilation in the human forearm. Br J Clin Pharmacol. 1994 Oct;38(4):307–310. doi: 10.1111/j.1365-2125.1994.tb04358.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. D'Orléans-Juste P., Dion S., Mizrahi J., Regoli D. Effects of peptides and non-peptides on isolated arterial smooth muscles: role of endothelium. Eur J Pharmacol. 1985 Aug 7;114(1):9–21. doi: 10.1016/0014-2999(85)90515-1. [DOI] [PubMed] [Google Scholar]
  10. 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 Jan;32(1):35–45. doi: 10.2337/diab.32.1.35. [DOI] [PubMed] [Google Scholar]
  11. 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 Dec;30(12):1000–1007. doi: 10.2337/diab.30.12.1000. [DOI] [PubMed] [Google Scholar]
  12. DeFronzo R. A., Soman V., Sherwin R. S., Hendler R., Felig P. Insulin binding to monocytes and insulin action in human obesity, starvation, and refeeding. J Clin Invest. 1978 Jul;62(1):204–213. doi: 10.1172/JCI109108. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  13. DeFronzo R. A., Tobin J. D., Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979 Sep;237(3):E214–E223. doi: 10.1152/ajpendo.1979.237.3.E214. [DOI] [PubMed] [Google Scholar]
  14. Dinerman J. L., Lowenstein C. J., Snyder S. H. Molecular mechanisms of nitric oxide regulation. Potential relevance to cardiovascular disease. Circ Res. 1993 Aug;73(2):217–222. doi: 10.1161/01.res.73.2.217. [DOI] [PubMed] [Google Scholar]
  15. Dohm G. L., Tapscott E. B., Pories W. J., Dabbs D. J., Flickinger E. G., Meelheim D., Fushiki T., Atkinson S. M., Elton C. W., Caro J. F. An in vitro human muscle preparation suitable for metabolic studies. Decreased insulin stimulation of glucose transport in muscle from morbidly obese and diabetic subjects. J Clin Invest. 1988 Aug;82(2):486–494. doi: 10.1172/JCI113622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gambhir S. S., Schwaiger M., Huang S. C., Krivokapich J., Schelbert H. R., Nienaber C. A., Phelps M. E. Simple noninvasive quantification method for measuring myocardial glucose utilization in humans employing positron emission tomography and fluorine-18 deoxyglucose. J Nucl Med. 1989 Mar;30(3):359–366. [PubMed] [Google Scholar]
  17. Goodyear L. J., Giorgino F., Sherman L. A., Carey J., Smith R. J., Dohm G. L. Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. J Clin Invest. 1995 May;95(5):2195–2204. doi: 10.1172/JCI117909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hamacher K., Coenen H. H., Stöcklin G. Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-D-glucose using aminopolyether supported nucleophilic substitution. J Nucl Med. 1986 Feb;27(2):235–238. [PubMed] [Google Scholar]
  19. Howard B. E., Ginsberg M. D., Hassel W. R., Lockwood A. H., Freed P. On the uniqueness of cerebral blood flow measured by the in vivo autoradiographic strategy and positron emission tomography. J Cereb Blood Flow Metab. 1983 Dec;3(4):432–441. doi: 10.1038/jcbfm.1983.69. [DOI] [PubMed] [Google Scholar]
  20. Iida H., Kanno I., Miura S., Murakami M., Takahashi K., Uemura K. Error analysis of a quantitative cerebral blood flow measurement using H2(15)O autoradiography and positron emission tomography, with respect to the dispersion of the input function. J Cereb Blood Flow Metab. 1986 Oct;6(5):536–545. doi: 10.1038/jcbfm.1986.99. [DOI] [PubMed] [Google Scholar]
  21. Jackson R. A., Peters N., Advani U., Perry G., Rogers J., Brough W. H., Pilkington T. R. Forearm glucose uptake during the oral glucose tolerance test in normal subjects. Diabetes. 1973 Jun;22(6):442–458. doi: 10.2337/diab.22.6.442. [DOI] [PubMed] [Google Scholar]
  22. Jamerson K. A., Nesbitt S. D., Amerena J. V., Grant E., Julius S. Angiotensin mediates forearm glucose uptake by hemodynamic rather than direct effects. Hypertension. 1996 Apr;27(4):854–858. doi: 10.1161/01.hyp.27.4.854. [DOI] [PubMed] [Google Scholar]
  23. Kelley D., Mitrakou A., Marsh H., Schwenk F., Benn J., Sonnenberg G., Arcangeli M., Aoki T., Sorensen J., Berger M. Skeletal muscle glycolysis, oxidation, and storage of an oral glucose load. J Clin Invest. 1988 May;81(5):1563–1571. doi: 10.1172/JCI113489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kuzuya H., Blix P. M., Horwitz D. L., Steiner D. F., Rubenstein A. H. Determination of free and total insulin and C-peptide in insulin-treated diabetics. Diabetes. 1977 Jan;26(1):22–29. doi: 10.2337/diab.26.1.22. [DOI] [PubMed] [Google Scholar]
  25. Laakso M., Edelman S. V., Brechtel G., Baron A. D. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. J Clin Invest. 1990 Jun;85(6):1844–1852. doi: 10.1172/JCI114644. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Laakso M., Edelman S. V., Olefsky J. M., Brechtel G., Wallace P., Baron A. D. Kinetics of in vivo muscle insulin-mediated glucose uptake in human obesity. Diabetes. 1990 Aug;39(8):965–974. doi: 10.2337/diab.39.8.965. [DOI] [PubMed] [Google Scholar]
  27. Lillioja S., Bogardus C., Mott D. M., Kennedy A. L., Knowler W. C., Howard B. V. Relationship between insulin-mediated glucose disposal and lipid metabolism in man. J Clin Invest. 1985 Apr;75(4):1106–1115. doi: 10.1172/JCI111804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Mandarino L. J., Consoli A., Jain A., Kelley D. E. Interaction of carbohydrate and fat fuels in human skeletal muscle: impact of obesity and NIDDM. Am J Physiol. 1996 Mar;270(3 Pt 1):E463–E470. doi: 10.1152/ajpendo.1996.270.3.E463. [DOI] [PubMed] [Google Scholar]
  29. Nagasaka Y., Kaku K., Nakamura K., Kaneko T. The new oral hypoglycemic agent, CS-045, inhibits the lipid peroxidation of human plasma low density lipoprotein in vitro. Biochem Pharmacol. 1995 Sep 28;50(7):1109–1111. doi: 10.1016/0006-2952(95)00235-r. [DOI] [PubMed] [Google Scholar]
  30. Nakane M., Schmidt H. H., Pollock J. S., Förstermann U., Murad F. Cloned human brain nitric oxide synthase is highly expressed in skeletal muscle. FEBS Lett. 1993 Jan 25;316(2):175–180. doi: 10.1016/0014-5793(93)81210-q. [DOI] [PubMed] [Google Scholar]
  31. Natali A., Bonadonna R., Santoro D., Galvan A. Q., Baldi S., Frascerra S., Palombo C., Ghione S., Ferrannini E. Insulin resistance and vasodilation in essential hypertension. Studies with adenosine. J Clin Invest. 1994 Oct;94(4):1570–1576. doi: 10.1172/JCI117498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Noguchi N., Sakai H., Kato Y., Tsuchiya J., Yamamoto Y., Niki E., Horikoshi H., Kodama T. Inhibition of oxidation of low density lipoprotein by troglitazone. Atherosclerosis. 1996 Jun;123(1-2):227–234. doi: 10.1016/0021-9150(96)05811-x. [DOI] [PubMed] [Google Scholar]
  33. Nuutila P., Koivisto V. A., Knuuti J., Ruotsalainen U., Teräs M., Haaparanta M., Bergman J., Solin O., Voipio-Pulkki L. M., Wegelius U. Glucose-free fatty acid cycle operates in human heart and skeletal muscle in vivo. J Clin Invest. 1992 Jun;89(6):1767–1774. doi: 10.1172/JCI115780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Nuutila P., Raitakari M., Laine H., Kirvelä O., Takala T., Utriainen T., Mäkimattila S., Pitkänen O. P., Ruotsalainen U., Iida H. Role of blood flow in regulating insulin-stimulated glucose uptake in humans. Studies using bradykinin, [15O]water, and [18F]fluoro-deoxy-glucose and positron emission tomography. J Clin Invest. 1996 Apr 1;97(7):1741–1747. doi: 10.1172/JCI118601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Patlak C. S., Blasberg R. G. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab. 1985 Dec;5(4):584–590. doi: 10.1038/jcbfm.1985.87. [DOI] [PubMed] [Google Scholar]
  36. Pyöräla K. Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: results from two population studies in Finland. Diabetes Care. 1979 Mar-Apr;2(2):131–141. doi: 10.2337/diacare.2.2.131. [DOI] [PubMed] [Google Scholar]
  37. RABINOWITZ D., ZIERLER K. L. Forearm metabolism in obesity and its response to intra-arterial insulin. Characterization of insulin resistance and evidence for adaptive hyperinsulinism. J Clin Invest. 1962 Dec;41:2173–2181. doi: 10.1172/JCI104676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Regoli D., Barabé J. Pharmacology of bradykinin and related kinins. Pharmacol Rev. 1980 Mar;32(1):1–46. [PubMed] [Google Scholar]
  39. Ruotsalainen U., Raitakari M., Nuutila P., Oikonen V., Sipilä H., Teräs M., Knuuti M. J., Bloomfield P. M., Iida H. Quantitative blood flow measurement of skeletal muscle using oxygen-15-water and PET. J Nucl Med. 1997 Feb;38(2):314–319. [PubMed] [Google Scholar]
  40. Rösen P., Eckel J., Reinauer H. Influence of bradykinin on glucose uptake and metabolism studied in isolated cardiac myocytes and isolated perfused rat hearts. Hoppe Seylers Z Physiol Chem. 1983 Oct;364(10):1431–1438. doi: 10.1515/bchm2.1983.364.2.1431. [DOI] [PubMed] [Google Scholar]
  41. 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 Dec;94(6):2511–2515. doi: 10.1172/JCI117621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Shimojo N., Pickens T. G., Margolius H. S., Mayfield R. K. Tissue kallikrein and bradykinin do not have direct insulin-like actions on skeletal muscle glucose utilization. Biol Chem Hoppe Seyler. 1987 Oct;368(10):1355–1361. doi: 10.1515/bchm3.1987.368.2.1355. [DOI] [PubMed] [Google Scholar]
  43. Sokoloff L., Reivich M., Kennedy C., Des Rosiers M. H., Patlak C. S., Pettigrew K. D., Sakurada O., Shinohara M. The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem. 1977 May;28(5):897–916. doi: 10.1111/j.1471-4159.1977.tb10649.x. [DOI] [PubMed] [Google Scholar]
  44. Steinberg H. O., Brechtel G., Johnson A., Fineberg N., Baron A. D. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J Clin Invest. 1994 Sep;94(3):1172–1179. doi: 10.1172/JCI117433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Steinberg H. O., Chaker H., Leaming R., Johnson A., Brechtel G., Baron A. D. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest. 1996 Jun 1;97(11):2601–2610. doi: 10.1172/JCI118709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Utriainen T., Malmström R., Mäkimattila S., Yki-Järvinen H. Methodological aspects, dose-response characteristics and causes of interindividual variation in insulin stimulation of limb blood flow in normal subjects. Diabetologia. 1995 May;38(5):555–564. doi: 10.1007/BF00400724. [DOI] [PubMed] [Google Scholar]
  47. Vallance P., Collier J., Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet. 1989 Oct 28;2(8670):997–1000. doi: 10.1016/s0140-6736(89)91013-1. [DOI] [PubMed] [Google Scholar]
  48. Welborn T. A., Wearne K. Coronary heart disease incidence and cardiovascular mortality in Busselton with reference to glucose and insulin concentrations. Diabetes Care. 1979 Mar-Apr;2(2):154–160. doi: 10.2337/diacare.2.2.154. [DOI] [PubMed] [Google Scholar]
  49. Yki-Järvinen H., Koivisto V. A., Karonen S. L. Influence of body composition on insulin clearance. Clin Physiol. 1985 Feb;5(1):45–52. doi: 10.1111/j.1475-097x.1985.tb00745.x. [DOI] [PubMed] [Google Scholar]
  50. Yki-Järvinen 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 Jun;79(6):1713–1719. doi: 10.1172/JCI113011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Zhang B., Berger J., Zhou G., Elbrecht A., Biswas S., White-Carrington S., Szalkowski D., Moller D. E. Insulin- and mitogen-activated protein kinase-mediated phosphorylation and activation of peroxisome proliferator-activated receptor gamma. J Biol Chem. 1996 Dec 13;271(50):31771–31774. doi: 10.1074/jbc.271.50.31771. [DOI] [PubMed] [Google Scholar]

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