Metformin Increases Blood Flow and Forearm Glucose Uptake in a Group of Non-obese Type 2 Diabetes Patients

Abstract

The present study was designed to determine the effects of metformin on the forearm glucose uptake and blood flow after an oral glucose challenge. Eleven normal subjects, and ten non-obese type 2 diabetes patients without medication of anti-hyperglycemic drug and with medication of metformin for four weeks, were studied after an overnight fast (12-14 h) and 3 hours after ingestion of 75 g of glucose. Peripheral glucose metabolism was analyzed by the forearm technique combined with indirect calorimetry. The forearm glucose uptake increased in diabetes patients taking metformin (63.5±9.1 vs. 39.1±5.3 mg/100 ml FA. 3 h). The increase of forearm glucose uptake was due to increase of blood flow. The glucose oxidation was greater in the group treated with metformin, compared to the same group without anti-hyperglycemic drug (19.3±2.6 vs. 7.7±2.6 mg/100 ml FA. 3 hrs). The free fatty acids were higher in diabetes patients, which normalized after taking metformin. In conclusion, it was found that in these participants metformin acts in insulin resistance; it increases glucose muscle uptake and blood flow. The enhancement of blood flow and lower free fatty acids, not described yet, could be direct effects of the drug or due to reduced glucose toxicity. These positive effects must be responsible for the improvement in vascular function.

Key words

Metformin - blood flow - free fatty acids - glucose uptake - muscle metabolism - forearm technique

References

• 1 De Fronzo RA. Pharmacological therapy for type 2 diabetes mellitus.  Ann Intern Med. 1999;  131 281-303
• 2 Wiernsperger NF, Bailey CJ. The antihyperglycaemic effect of metformin: therapeutic and cellular mechanism.  Drugs. 1999;  58 ((Suppl 1)) 31-39
• 3 Ikeda T, Iwata K, Murakanu H. Inhibitory effect of metformin on intestinal glucose absorption in the perfused rat intestine.  Biochem Pharmacol. 2000;  59 887-890
• 4 Wollen N, Bailey CJ. Inhibition of hepatic gluconeogenesis by metformin. Synergism with insulin.  Biochem Pharmacol. 1988;  15 4353-4358
• 5 Bailey CJ, Puha J. Effect of metformin on glucose metabolism in mouse soleus muscle.  Diabetes Metab. 1986;  12 212-218
• 6 Mithieux G, Guignot L, Bordet JC, Wiernsperger N. Intrahepatic mechanisms underlying the effect of metformin in decreasing basal production in rats fed a high-fat diet.  Diabetes. 2002;  51 139-143
• 7 Jacobs DB, Hayes GR, Truglia JA, Lockwood DH. Effects of metformin on insulin receptor tyrosine kinase activity in rat adipocites.  Diabetologia. 1986;  29 798-801
• 8 Galuska D, Zierath J, Thorne A, Sonnenfeld T, Wallberg-Henriksson H. Metformin increases insulin-stimulated glucose transport in insulin-resistant human skeletal muscle.  Diabetes Metab. 1991;  17 159-163
• 9 He G, Pedersen SB, Bruun JM, Lihn AS, Richelsen B. Metformin, but not Thiazolidinediones, Inhibits Plasminogen Activator Inhibitor-1 Production in Human Adipose Tissue in vitro.  Horm Metab Res. 2003;  35 18-23
• 10 Herrmann BL, Berg C, Vogel E, Nowak T, Renzing-Koehler K, Mann K, Saller B. Effects of a Combination of Recombinant Human Growth Hormone with Metformin on Glucose Metabolism and Body Composition in Patients with Metabolic Syndrome.  Horm Metab Res. 2004;  36 54-61
• 11 Prager R, Schernthaner G, Graf H. Effect of metformin on peripheral insulin sensitivity in non insulin dependent diabetes mellitus.  Diabetes Metab. 1986;  12 346-350
• 12 Nosadini R, Avogado A, Trevisan R, Valerio A, Tessari P, Duner E, Tiengo A, Velussi M, Del Prato S, De Kreutzenberg S, Muggeo M, Crepaldi G. Effect of metformin on insulin-stimulated glucose turnover and insulin binding to receptors in type II diabetes.  Diabetes Care. 1987;  10 62-67
• 13 Hother-Nielsen O, Schmitz O, Andersen PH, Beck-Nielsen H, Pedersen O. Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes.  Acta Endocrinol (Copenh). 1989;  120 257-265
• 14 Marena S, Tagliaferro V, Montegrosso G, Pagano A, Scaglione L, Pagano G. Metabolic effects of metformin addition to chronic glibenclamide treatment in type 2 diabetes.  Diabetes Metab. 1994;  20 15-19
• 15 Rossetti L, De Fronzo RA, Gherzi R, Stein P, Andraghetti G, Falzetti G, Shulman GI, Klein-Robbenhaar E, Cordera R. Effect of metformin treatment on insulin action in diabetic rats: in vivo and in vitro correlations.  Metabolism. 1990;  39 425-435
• 16 Borst SE, Sneller HG Lai HL. Metformin treatment enhances insulin-stimulated glucose transport in skeletal muscle of Sprague-Dawley rats.  Life Sci. 2000;  67 165-174
• 17 Kemmer FW, Berger M, Herberg L, Gries FA. Effects of metformin on glucose metabolism of isolated rat skeletal muscle.  Drug Res. 1977;  27 1573-1576
• 18 Jackson RA, Hawa MI, Jaspan JB Sim BM, Silvio L, Featherbe D, Kurtz AB. Mechanisms of metformin action in non-insulin-dependent diabetes.  Diabetes. 1987;  36 632-640
• 19 Wu MS, Johnston P, Sheu WHH, Hollenbeck CB, Jeng CY, Goldfine ID, Chen YDI, Reaven GM. Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients.  Diabetes Care. 1990;  13 1-8
• 20 De Fronzo RA, Barlizai N, Simonson C. Mechanism of metformin action in obese and lean non-insulin-dependent diabetic subjects.  J Clin Endocrin Metab. 1991;  73 1294-1301
• 21 The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus . Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.  Diabetes Care. 1997;  20 1183-1197
• 22 Foss MC, Saad MJA, Paccola GMGF, Paula FJA, Piccinato CE. Peripheral Glucose Metabolism in Patients with Insulin Resistance and Acanthosis Nigricans.  Horm Metab Res. 1992;  24 26-30
• 23 Paula FJA, Foss MC. Muscle Uptake of Inorganic Phosphorus During Oral Glucose Challenge.  Horm Metab Res. 1990;  22 506-507
• 24 Norton J, Burt ME, Brennan MF. Capacitance plethysmography: validation in an ex vivo human limb model.  J Surg Res. 1982;  32 127-129
• 25 Huggett ASC, Nixon DA. Use of glucose oxidase, peroxidase and O-diamisidine in determination of blood and urinary glucose.  Lancet. 1957;  2 368-370
• 26 Novak M. Colorimetric ultramicro-method for the determination of free fatty acids.  J Lip Res. 1965;  6 431-433
• 27 Gutmann I, Wahlefeld AW. Methods of enzymatic analysis.  New York: Academic Press. 1974;  3 1464
• 28 Van Slyke DD, Neill JM. The determination of gases in blood and other solutions by vacuum extraction and manometric measurement.  J Biol Chem. 1924;  61 523-573
• 29 Vieira JGH, Russo EMK, Germek AO, Chacra AR. Desenvolvimento de um radioimunoensaio heterólogo para a dosagem de insulina humana no soro.  Rev Bras Pat Clin. 1980;  16 108-114
• 30 Dillon RS. Importance of hematocrit in the interpretation of blood sugar.  Diabetes. 1965;  14 672-674
• 31 Lusk G. Animal calorimetry-Analysis of the oxidation of mixtures of carbohydrate and fat.  J Biol Chem. 1924;  59 41-42
• 32 Allison DB, Paultre E, Maggio C, Mezzitis N, Pi-Sunyer FX. The use of area under curves in diabetes research.  Diabetes Care. 1995;  18 245-250
• 33 Arango HG. Bioestatística-Teórica e Computacional 2nd ed. Rio de Janeiro, Guanabara Koogan 2005
• 34 Baron AD, Laakso M, Brechtel G, Hoit B, Watt C, Eldman SV. Reduced postprandial skeletal muscle blood flow contributes to glucose intolerance in human obesity.  J Clin Endocrinol Metab. 1990;  70 1525-1533
• 35 Laakso M, Edelman SV, Brechtel G, Baron AD. Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM.  Diabetes. 1992;  41 1076-1083
• 36 Kingwell BA, Formosa M, Muhglmann M, Bradley S, McConell GK. Type 2 diabetic individuals impaired leg blood flow response to exercise.  Diabetes Care. 2003;  26 899-904
• 37 Katakam PV, Ujhelyi MR, Hoenig M, Miller AW. Metformin improves vascular function in insulin-resistant rats.  Hypertension. 2000;  35 108-112
• 38 Kosegawa I, Chen S, Awata T, Negishi K, Katayama S. Troglitazone and metformin, but not glibenclamide, decrease blood pressure in Otsuka Long Evans Tokushima Fatty rats.  Clin Exp Hypertens. 1999;  21 199-211
• 39 Bhalla RC, Toth KF, Tan E, Bhatty RA, Mathias E, Sharma RV. Vascular effects of metformin. Possible mechanism for its antihypertensive action in the spontaneously hypertensive rat.  Am J Hypertens. 1996;  9 570-576
• 40 Sundaresan P, Lykos D, Daher A, Diamond T, Morris R, Howes LG. Comparative effects of glibenclamide and metformin on ambulatory blood pressure and cardiovascular reactivity in NIDDM.  Diabetes Care. 1997;  20 692-697
• 41 Landin K, Tengborn L, Smith U. Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factors.  J Intern Med. 1991;  229 181-187
• 42 Radziuk J, Zhang Z, Wiernsperger N, Pye S. Effects of metformin on lactate uptake and gluconeogenesis in the peripheral rat liver.  Diabetes. 1997;  46 1406-1413
• 43 Wyne KL. Free fatty acids and type 2 diabetes mellitus.  Am J Med. 2003;  ((Suppl 8A)) 29S-36S
• 44 Riemens SC, Sluiter WJ, Dullaart RP. Enhanced escape of non-esterified fatty acids from tissue uptake: its role in impaired insulin-induced lowering of total rate of appearance in obesity and Type II diabetes mellitus.  Diabetologia. 2000;  43 416-426

Correspondence