Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Apr 1;97(7):1741–1747. doi: 10.1172/JCI118601

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.

P Nuutila 1, M Raitakari 1, H Laine 1, O Kirvelä 1, T Takala 1, T Utriainen 1, S Mäkimattila 1, O P Pitkänen 1, U Ruotsalainen 1, H Iida 1, J Knuuti 1, H Yki-Järvinen 1
PMCID: PMC507239  PMID: 8601640

Abstract

Defects in insulin stimulation of blood flow have been used suggested to contribute to insulin resistance. To directly test whether glucose uptake can be altered by changing blood flow, we infused bradykinin (27 microgram over 100 min), an endothelium-dependent vasodilator, into the femoral artery of 12 normal subjects (age 25+/-1 yr, body mass index 22+/-1 kg/m2) after an overnight fast (n = 5) and during normoglycemic hyperinsulinemic (n = 7) conditions (serum insulin 465+/-11 pmol/liter, 0-100 min). Blood flow was measured simultaneously in both femoral regions using [15O]-labeled water ([15O]H2O) and positron emission tomography (PET), before and during (50 min) the bradykinin infusion. Glucose uptake was measured immediately after the blood flow measurement simultaneously in both femoral regions using [18F]-fluoro-deoxy-glucose ([18F]FDG) and PET. During hyperinsulinemia, muscle blood flow was 58% higher in the bradykinin-infused (38+/-9 ml/kg muscle x min) than in the control leg (24+/-5, P<0.01). Femoral muscle glucose uptake was identical in both legs (60.6+/-9.5 vs. 58.7+/-9.0 micromol/kg x min, bradykinin-infused vs control leg, NS). Glucose extraction by skeletal muscle was 44% higher in the control (2.6+/-0.2 mmol/liter) than the bradykinin-infused leg (1.8+/-0.2 mmol/liter, P<0.01). When bradykinin was infused in the basal state, flow was 98% higher in the bradykinin-infused (58+/-12 ml/kg muscle x min) than the control leg (28+/-6 ml/kg muscle x min, P<0.01) but rates of muscle glucose uptake were identical in both legs (10.1+/-0.9 vs. 10.6+/-0.8 micromol/kg x min). We conclude that bradykinin increases skeletal muscle blood flow but not muscle glucose uptake in vivo. These data provide direct evidence against the hypothesis that blood flow is an independent regulator of insulin-stimulated glucose uptake in humans.

Full Text

The Full Text of this article is available as a PDF (344.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson E. A., Hoffman R. P., Balon T. W., Sinkey C. A., Mark A. L. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest. 1991 Jun;87(6):2246–2252. doi: 10.1172/JCI115260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baron A. D., Brechtel-Hook G., Johnson A., Hardin D. Skeletal muscle blood flow. A possible link between insulin resistance and blood pressure. Hypertension. 1993 Feb;21(2):129–135. doi: 10.1161/01.hyp.21.2.129. [DOI] [PubMed] [Google Scholar]
  3. Baron A. D., Brechtel G., Johnson A., Fineberg N., Henry D. P., Steinberg H. O. Interactions between insulin and norepinephrine on blood pressure and insulin sensitivity. Studies in lean and obese men. J Clin Invest. 1994 Jun;93(6):2453–2462. doi: 10.1172/JCI117254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baron A. D. Hemodynamic actions of insulin. Am J Physiol. 1994 Aug;267(2 Pt 1):E187–E202. doi: 10.1152/ajpendo.1994.267.2.E187. [DOI] [PubMed] [Google Scholar]
  5. 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 Sep;73(3):637–643. doi: 10.1210/jcem-73-3-637. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Biral D., Betto R., Danieli-Betto D., Salviati G. Myosin heavy chain composition of single fibres from normal human muscle. Biochem J. 1988 Feb 15;250(1):307–308. doi: 10.1042/bj2500307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. 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]
  9. 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]
  10. Cockcroft J. R., Chowienczyk P. J., Brett S. E., Bender N., Ritter J. M. Inhibition of bradykinin-induced vasodilation in human forearm vasculature by icatibant, a potent B2-receptor antagonist. Br J Clin Pharmacol. 1994 Oct;38(4):317–321. doi: 10.1111/j.1365-2125.1994.tb04360.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Dachman W. D., Ford G. A., Blaschke T. F., Hoffman B. B. Mechanism of bradykinin-induced venodilation in humans. J Cardiovasc Pharmacol. 1993 Feb;21(2):241–248. doi: 10.1097/00005344-199302000-00009. [DOI] [PubMed] [Google Scholar]
  13. DeFronzo R. A., Gunnarsson R., Björkman O., Olsson M., Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest. 1985 Jul;76(1):149–155. doi: 10.1172/JCI111938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. 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]
  16. Dela F., Larsen J. J., Mikines K. J., Galbo H. Normal effect of insulin to stimulate leg blood flow in NIDDM. Diabetes. 1995 Feb;44(2):221–226. doi: 10.2337/diab.44.2.221. [DOI] [PubMed] [Google Scholar]
  17. Depairon M., Depresseux J. C., Petermans J., Zicot M. Assessment of flow and oxygen delivery to the lower extremity in arterial insufficiency: a PET-scan study comparison with other methods. Angiology. 1991 Oct;42(10):788–795. doi: 10.1177/000331979104201003. [DOI] [PubMed] [Google Scholar]
  18. Durán W. N., Renkin E. M. Oxygen consumption and blood flow in resting mammalian skeletal muscle. Am J Physiol. 1974 Jan;226(1):173–177. doi: 10.1152/ajplegacy.1974.226.1.173. [DOI] [PubMed] [Google Scholar]
  19. Farhy R. D., Carretero O. A., Ho K. L., Scicli A. G. Role of kinins and nitric oxide in the effects of angiotensin converting enzyme inhibitors on neointima formation. Circ Res. 1993 Jun;72(6):1202–1210. doi: 10.1161/01.res.72.6.1202. [DOI] [PubMed] [Google Scholar]
  20. Farhy R. D., Ho K. L., Carretero O. A., Scicli A. G. Kinins mediate the antiproliferative effect of ramipril in rat carotid artery. Biochem Biophys Res Commun. 1992 Jan 15;182(1):283–288. doi: 10.1016/s0006-291x(05)80142-1. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. 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]
  23. 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]
  24. 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]
  25. Jauch K. W., Günther B., Hartl W., Rett K., Wicklmayr M., Dietze G. Improvement of impaired postoperative insulin action by bradykinin. Biol Chem Hoppe Seyler. 1986 Mar;367(3):207–210. doi: 10.1515/bchm3.1986.367.1.207. [DOI] [PubMed] [Google Scholar]
  26. Jauch K. W., Hartl W., Guenther B., Wicklmayr M., Rett K., Dietze G. Captopril enhances insulin responsiveness of forearm muscle tissue in non-insulin-dependent diabetes mellitus. Eur J Clin Invest. 1987 Oct;17(5):448–454. doi: 10.1111/j.1365-2362.1987.tb01141.x. [DOI] [PubMed] [Google Scholar]
  27. Kelley D. E., Mandarino L. J. Hyperglycemia normalizes insulin-stimulated skeletal muscle glucose oxidation and storage in noninsulin-dependent diabetes mellitus. J Clin Invest. 1990 Dec;86(6):1999–2007. doi: 10.1172/JCI114935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kelley D. E., Reilly J. P., Veneman T., Mandarino L. J. Effects of insulin on skeletal muscle glucose storage, oxidation, and glycolysis in humans. Am J Physiol. 1990 Jun;258(6 Pt 1):E923–E929. doi: 10.1152/ajpendo.1990.258.6.E923. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. 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]
  31. Laakso M., Edelman S. V., Brechtel G., Baron A. D. Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM. Diabetes. 1992 Sep;41(9):1076–1083. doi: 10.2337/diab.41.9.1076. [DOI] [PubMed] [Google Scholar]
  32. Lillioja S., Young A. A., Culter C. L., Ivy J. L., Abbott W. G., Zawadzki J. K., Yki-Järvinen H., Christin L., Secomb T. W., Bogardus C. Skeletal muscle capillary density and fiber type are possible determinants of in vivo insulin resistance in man. J Clin Invest. 1987 Aug;80(2):415–424. doi: 10.1172/JCI113088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Morris A. D., Petrie J. R., Ueda S., Connell J. M., Elliott H. L., Small M., Donnelly R. Pressor and subpressor doses of angiotensin II increase insulin sensitivity in NIDDM. Dissociation of metabolic and blood pressure effects. Diabetes. 1994 Dec;43(12):1445–1449. doi: 10.2337/diab.43.12.1445. [DOI] [PubMed] [Google Scholar]
  34. 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]
  35. Nuutila P., Knuuti J., Ruotsalainen U., Koivisto V. A., Eronen E., Teräs M., Bergman J., Haaparanta M., Voipio-Pulkki L. M., Viikari J. Insulin resistance is localized to skeletal but not heart muscle in type 1 diabetes. Am J Physiol. 1993 May;264(5 Pt 1):E756–E762. doi: 10.1152/ajpendo.1993.264.5.E756. [DOI] [PubMed] [Google Scholar]
  36. Nuutila P., Knuuti M. J., Mäki M., Laine H., Ruotsalainen U., Teräs M., Haaparanta M., Solin O., Yki-Järvinen H. Gender and insulin sensitivity in the heart and in skeletal muscles. Studies using positron emission tomography. Diabetes. 1995 Jan;44(1):31–36. doi: 10.2337/diab.44.1.31. [DOI] [PubMed] [Google Scholar]
  37. Nuutila P., Knuuti M. J., Raitakari M., Ruotsalainen U., Teräs M., Voipio-Pulkki L. M., Haaparanta M., Solin O., Wegelius U., Yki-Järvinen H. Effect of antilipolysis on heart and skeletal muscle glucose uptake in overnight fasted humans. Am J Physiol. 1994 Dec;267(6 Pt 1):E941–E946. doi: 10.1152/ajpendo.1994.267.6.E941. [DOI] [PubMed] [Google Scholar]
  38. 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]
  39. Nuutila P., Mäki M., Laine H., Knuuti M. J., Ruotsalainen U., Luotolahti M., Haaparanta M., Solin O., Jula A., Koivisto V. A. Insulin action on heart and skeletal muscle glucose uptake in essential hypertension. J Clin Invest. 1995 Aug;96(2):1003–1009. doi: 10.1172/JCI118085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. 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]
  41. Phelps M. E., Huang S. C., Hoffman E. J., Selin C., Sokoloff L., Kuhl D. E. Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-D-glucose: validation of method. Ann Neurol. 1979 Nov;6(5):371–388. doi: 10.1002/ana.410060502. [DOI] [PubMed] [Google Scholar]
  42. Pirrelli A. M., Ricci S., Vulpis V. Effect of cilazapril on isomyosin pattern in the spontaneously hypertensive rat. Am J Med. 1993 Apr 23;94(4A):50S–51S. [PubMed] [Google Scholar]
  43. Pollare T., Lithell H., Berne C. A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl J Med. 1989 Sep 28;321(13):868–873. doi: 10.1056/NEJM198909283211305. [DOI] [PubMed] [Google Scholar]
  44. Pollare T., Lithell H., Selinus I., Berne C. Application of prazosin is associated with an increase of insulin sensitivity in obese patients with hypertension. Diabetologia. 1988 Jul;31(7):415–420. doi: 10.1007/BF00271585. [DOI] [PubMed] [Google Scholar]
  45. Regoli D., Barabé J. Pharmacology of bradykinin and related kinins. Pharmacol Rev. 1980 Mar;32(1):1–46. [PubMed] [Google Scholar]
  46. 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]
  47. 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]
  48. 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]
  49. 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]
  50. 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]
  51. Tomiyama H., Kushiro T., Abeta H., Ishii T., Takahashi A., Furukawa L., Asagami T., Hino T., Saito F., Otsuka Y. Kinins contribute to the improvement of insulin sensitivity during treatment with angiotensin converting enzyme inhibitor. Hypertension. 1994 Apr;23(4):450–455. doi: 10.1161/01.hyp.23.4.450. [DOI] [PubMed] [Google Scholar]
  52. Torlone E., Britta M., Rambotti A. M., Perriello G., Santeusanio F., Brunetti P., Bolli G. B. Improved insulin action and glycemic control after long-term angiotensin-converting enzyme inhibition in subjects with arterial hypertension and type II diabetes. Diabetes Care. 1993 Oct;16(10):1347–1355. doi: 10.2337/diacare.16.10.1347. [DOI] [PubMed] [Google Scholar]
  53. 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]
  54. Vallance P., Collier J., Moncada S. Nitric oxide synthesised from L-arginine mediates endothelium dependent dilatation in human veins in vivo. Cardiovasc Res. 1989 Dec;23(12):1053–1057. doi: 10.1093/cvr/23.12.1053. [DOI] [PubMed] [Google Scholar]
  55. Vollenweider P., Tappy L., Randin D., Schneiter P., Jéquier E., Nicod P., Scherrer U. Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans. J Clin Invest. 1993 Jul;92(1):147–154. doi: 10.1172/JCI116542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Vuorinen-Markkola H., Yki-Järvinen H. Antihypertensive therapy with enalapril improves glucose storage and insulin sensitivity in hypertensive patients with non-insulin-dependent diabetes mellitus. Metabolism. 1995 Jan;44(1):85–89. doi: 10.1016/0026-0495(95)90293-7. [DOI] [PubMed] [Google Scholar]
  57. WHITNEY R. J. The measurement of volume changes in human limbs. J Physiol. 1953 Jul;121(1):1–27. doi: 10.1113/jphysiol.1953.sp004926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Yki-Järvinen H., Mott D., Young A. A., Stone K., Bogardus C. Regulation of glycogen synthase and phosphorylase activities by glucose and insulin in human skeletal muscle. J Clin Invest. 1987 Jul;80(1):95–100. doi: 10.1172/JCI113069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. 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]
  60. Zierler K. L. THEORY OF THE USE OF ARTERIOVENOUS CONCENTRATION DIFFERENCES FOR MEASURING METABOLISM IN STEADY AND NON-STEADY STATES. J Clin Invest. 1961 Dec;40(12):2111–2125. doi: 10.1172/JCI104437. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES