Summary
To resolve some of the controversy regarding insulin regulation of blood flow, we performed in 20 normal subjects a) a reproducibility study of plethysmographic, Doppler ultrasound and laser Doppler blood flow measurements (n=7), b) a sequential insulin dose-response study with measurement of forearm (plethysmography), leg (Doppler ultrasound) and skin (laser Doppler) blood flow (n=12), and c) a sequential insulin dose-response study with comparison of forearm (plethysmography) and calf (plethysmography) blood flow (n=8). We also searched for factors which might explain the interindividual variation in the blood flow response to insulin. During sequential insulin infusions (2 h each, 61±2, 139±6, 462±15 mU/l), forearm blood flow increased by 17±6, 50±14 and 113±17% (p<0.05 or less between steps), respectively. The increase at the 61±2 mU/l insulin concentration barely exceeded methodological variation (13±2%). In contrast to the continuous increase in blood flow, the glucose arterio venous difference reached its maximum (1.7±0.2 mmol/l) at the lowest 61±2 mU/l insulin concentration and remained constant thereafter. Forearm and calf blood flow responses to insulin were virtually identical when determined with plethysmography. In contrast, only a 27% increase was detected in femoral flow index as determined by Doppler ultrasound. Forearm blood flow (per forearm volume) was highly correlated with the relative forearm muscle content (mean 59±5%, range 24–81%) both basally (r=0.86, p<0.001, n=12) and at all insulin concentrations (r=0.85–0.92, p<0.001) indicating that the percent of forearm that is muscle explains 70–85% of interindividual variation in blood flow. In conclusion 1) physiological insulin concentrations stimulate glucose uptake mainly by increasing glucose extraction while supraphysiological insulin concentrations increase forearm glucose uptake predominantly via increases in blood flow. 2) The dose-response characteristics of insulin stimulation of forearm and calf blood flow are similar when determined with strain-gauge plethysmography. 3) Relative forearm muscle content is a key factor in determining both basal forearm blood flow and the interindividual variation in its response to insulin in normal subjects.
Article PDF
Similar content being viewed by others
References
Zierler KL (1961) Theory of the use of arteriovenous concentration differences for measuring metabolism in steady and non-steady states. J Clin Invest 40: 2111–2125
Laakso M, Edelman SV, Brechtel G, Baron AD (1990) Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. J Clin Invest 85: 1844–1852
Baron AD, Brechtel-Hook G, Johnson A, Hardin D (1993) Skeletal muscle blood flow. A possible link between insulin resistance and blood pressure. Hypertension 21: 129–135
Baron AD, Laakso M, Brechtel G, Edelman SV (1991) Mechanism of insulin resistance in insulin-dependent diabetes mellitus: A major role for reduced skeletal muscle blood flow. J Clin Endocrinol Metab 73: 637–643
Laakso M, Edelman SV, Brechtel G, Baron AD (1992) Impaired insulin mediated skeletal muscle blood flow in patients with NIDDM. Diabetes 41: 1076–1083
Baron AD, Steinberg H, Brechtel G, Johnson A (1994) Skeletal muscle blood flow independently modulates insulin-mediated glucose uptake. Am J Phys 266: E248-E253
Baron AD, Brechtel G (1993) Insulin differentially regulates systemic and skeletal muscle vascular resistance. Am J Physiol 265: E61-E67
Jackson RA, Hamling JB, Blix PM et al. (1986) The influence of graded hyperglycemia with and without physiological hyperinsulinemia on forearm glucose uptake and other metabolic responses in man. J Clin Endocrinol Metab 63: 594–604
Yki-JÄrvinen H, Young AA, Lamkin C, Foley JE (1987) Kinetics of glucose disposal in whole body and across the forearm in man. J Clin Invest 79: 1713–1719
Kelley DE, Reilly JP, Veneman T, Mandarino LJ (1990) Effects of insulin on skeletal muscle storage, oxidation, and glycolysis in humans. Am J Physiol 258: E923-E929
Yki-JÄrvinen H, Sahlin K, Ren JM, Koivisto VA (1990) Localization of rate-limiting defect for glucose disposal in skeletal muscle of insulin-resistant type I diabetic patients. Diabetes 39: 157–167
Capaldo B, Napoli R, Di Bonito P, Albano G, Sacca L (1991) Dual mechanism of insulin action on human skeletal muscle: identification of an indirect component not mediated by FFA. Am J Physiol 260: E389-E394
Bonadonna RC, Prato SD, Saccomani MP et al. (1993) Transmembrane glucose transport in skeletal muscle of patients with non-insulin-dependent diabetes. J Clin Invest 92: 486–494
Ebeling P, Bourey R, Koranyi L et al. (1993) Mechanism of enhanced insulin sensitivity in athletes. Increased blood flow, muscle glucose transport protein (GLUT-4) concentration, and glycogen synthase activity. J Clin Invest 92: 1623–1631
Bennet WM, Connacher AA, Scrimgeour CM, Jung RT, Rennie MJ (1990) Euglycemic hyperinsulinemia augments amino acid uptake by human leg tissues during hyperaminoacidemia. Am J Physiol 259: E185-E194
Anderson EA, Hoffmann RP, Balon TW, Sinkey CA, Mark AL (1991) Hyperinsulinemia produces both sympathetic neural activation and vasodilatation in normal humans. J Clin Invest 87: 2246–2252
Bonadonna RC, Saccomani MP, Seely L et al. (1993) Glucose transport in human skeletal muscle. The in vivo response to insulin. Diabetes 42: 191–198
Vollenweider P, Tappy L, Randin D et al. (1993) Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans. J Clin Invest 92: 147–154
Gallen IW, MacDonald IA (1990) Effects of blood glucose concentration on thermogenesis and glucose disposal during hyperinsulinemia. Clin Sci 79: 279–285
Dela F, Mikines KJ, von Linstow M, Secher NH, Galbo H (1992) Effect of training on insulin-mediated glucose uptake in human muscle. Am J Phys 263: E1134-E1143
Richter EA, Mikines KJ, Galbo H, Kiens B (1989) Effect of exercise on insulin action in human skeletal muscle. J Appl Physiol 66: 876–885
Yki-JÄrvinen H, Koivisto VA (1983) Effects of body composition on insulin sensitivity. Diabetes 32: 965–969
DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237: E214-E223
Rizza RA, Mandarino LJ, Gerich JE (1981) Dose-response characteristics for effects of insulin on production and utilization of glucose in man. Am J Physiol 240: E630-E639
DeFronzo RA, Ferrannini E, Hendler R, Feiig P, Wahren J (1983) Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in man. Diabetes 32: 35–45
Yki-JÄrvinen H, Consoli A, Nurjhan N, Young AA, Gerich JE (1989) Mechanism for underestimation of isotopically determined glucose disposal. Diabetes 38: 744–751
Dillon RS (1965) Importance of hematocrit in interpretation of blood sugar. Diabetes 14: 672–674
Clarke RSJ, Hellon RF (1957) Venous collection in forearm and hand measured by the strain-gauge and volume plethysmograph. Clin Sci 16: 103–117
Gill RW (1985) Measurement of blood flow by ultrasound: accuracy and sources of error. Ultrasound Med Biol 11: 625–641
Maughan RJ, Watson JS, Weir J (1984) The relative proportions of fat, muscle and bone in the normal human forearm as determined by computed tomography. Clin Sci 66: 683–689
Kadish AH, Little RL, Sternberg JC (1968) A new and rapid method for the determination of glucose by measurement of rate of oxygen consumption. Clin Chem 14: 116–131
Desbuquois B, Aurbach DG (1971) Use of polyethylene glycol to separate free and antibody-bound peptide hormones in radioimmunoassays. J Clin Endocrinol Metab 33: 732–738
Buchanan TA, Thawani H, Kades W et al. (1993) Angiotensin II increases glucose utilization during acute hyperinsulinemia via a hemodynamic mechanism. J Clin Invest 92: 720–726
Lundgren F, Edén E, Arfvidsson B, Lundholm K (1991) Insulin time-dependent effects on the leg exchange of glucose and amino acids in man. Eur J Clin Inv 21: 421–429
Elia M, Kurpad A (1993) What is the blood flow to resting human muscle? Clin Sci 84: 559–563
Nuutila P, Ruotsalainen U, SipilÄ H et al. (1994) Simultaneous quantitation of insulin induced increases in glucose uptake and blood flow in skeletal muscle using 15O-water, 18FDG and PET. Diabetes 43 [Suppl 1]: 72A, (Abstract)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Utriainen, T., Malmström, R., MÄkimattila, S. et al. Methodological aspects, dose-response characteristics and causes of interindividual variation in insulin stimulation of limb blood flow in normal subjects. Diabetologia 38, 555–564 (1995). https://doi.org/10.1007/BF00400724
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00400724