Summary
Metformin has been demonstrated to lower blood glucose in vivo by a mechanism which increases peripheral glucose uptake. Furthermore, the therapeutic concentration of metformin has been estimated to be in the order of 0.01 mmol/l. We investigated the effect of metformin on insulin-stimulated 3-0-methylglucose transport in isolated skeletal muscle obtained from seven patients with non-insulin-dependent diabetes mellitus (NIDDM) and from eight healthy subjects. Whole body insulin-mediated glucose utilization was decreased by 45% (p<0.05) in the diabetic subjects when studied at 8 mmol/l glucose, compared to the healthy subjects studied at 5 mmol/l glucose. Metformin, at concentrations of 0.1 and 0.01 mmol/l, had no effect on basal or insulin-stimulated (100 ΜU/ml) glucose transport in muscle strips from either of the groups. However, the two control subjects and three patients with NIDDM which displayed a low rate of insulin-mediated glucose utilization (<20 Μmol·kg−1·min−1), as well as in vitro insulin resistance, demonstrated increased insulin-stimulated glucose transport in the presence of metformin at 0.1 mmol/l (p<0.05). In conclusion, the concentration of metformin resulting in a potentiating effect on insulin-stimulated glucose transport in insulin-resistant human skeletal muscle is 10-fold higher than the therapeutic concentrations administered to patients with NIDDM. Thus, it is conceivable that the hypoglycaemic effect of metformin in vivo may be due to an accumulation of the drug in the extracellular space of skeletal muscle, or to an effect of the drug distal to the glucose transport step.
Article PDF
Similar content being viewed by others
Abbreviations
- NIDDM:
-
Non-insulin-dependent diabetes mellitus
- KHB:
-
Krebs-Henseleit's bicarbonate buffer
- HEPES:
-
N-2, hydroxyethyl-piperazine-N'-2-ethanesulfonic acid
- BSA:
-
bovine serum albumin
- RIA:
-
radioimmunoassay
- HbA1c :
-
glycated haemoglobin A1c
- BMI:
-
body mass index (kg/m2)
- GLUT 1:
-
HepG2/erythrocyte
- GLUT 4:
-
insulin-regulatable glucose transporter
References
Bell GI, Kayano T, Buse JB et al. (1990) Molecular biology of mammalian glucose transporters. Diabetes Care 13: 198–208
Klip A, Pâquet MR (1990) Glucose transport and glucose transporters in muscle and their metabolic regulation. Diabetes Care 13: 228–243
Wallberg-Henriksson H (1987) Glucose transport into skeletal muscle. Influence of contractile activity, insulin, catecholamines and diabetes mellitus. Acta Physiol Scand 131 [Suppl 564]: 1–80
Ziel FH, Venkatesan N, Davidson MB (1988) Glucose transport is rate limiting for skeletal muscle glucose metabolism in normal and STZ-induced diabetic rats. Diabetes 37: 885–890
Olefsky JM, Garvey WT, Henry RR, Brillon D, Mathaei S, Freidenberg GR (1988) Cellular mechanisms of insulin resistance in non-insulin-dependent (type II) diabetes. Am J Med 85 [Suppl 5A]: 86–105
Caro JF, Dohm LG, Pories WJ, Sindha MK (1989) Cellular alterations in liver, skeletal muscle and adipose tissue responsible for insulin resistance in obesity and type II diabetes. Diabetes Metab Rev 5: 665–689
Andreasson K, Galuska D, Thörne A, Sonnenfeld T, Wallberg-Henriksson H (1991) Decreased insulin-stimulated 3- 0-methylglucose transport in in vitro incubated muscle strips from type II diabetic subjects. Acta Physiol Scand 142: 255–260
Dohm GL, Trapscot EB, Pories WJ et al. (1988) An in vitro muscle preparation suitable for metabolic studies. J Clin Invest 82: 486–494
Herman LS (1979) Metformin: a review of its pharmacological properties and therapeutic use. Diabete Metab 5: 233–245
Hother-Nielsen O, Schmitz O, Andersen PH, Beck-Nielsen H, Pedersen O (1989) Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes. Acta Endocrinol 120: 257–265
Jackson RA, Hawa MI, Jaspan JB et al. (1987) Mechanism of metformin action in non-insulin-dependent diabetes. Diabetes 36: 632–640
Wu MS, Johnston P, Sheu VHH et al. (1990) Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care 13: 1–8
Sterne J (1969) Pharmacology and mode of action of hypoglycaemic guanidine derivatives. In: Campell GD (ed) Oral hypoglycaemic agents. Academic Press, London, UK, pp 193–245
Galuska G, Zierath JR, Thörne A, Sonnenfeld T, Wallberg-Henriksson H (1991) Metformin increases insulin-stimulated glucose transport in insulin resistant human skeletal muscle. Diabete Metab 17: 59–63
Bailey CJ (1992) Biguanides and NIDDM. Diabetes Care 15: 755–772
Zierath JR, Galuska D, Engström å et al. (1992) Human islet amyloid polypeptide at pharmacological levels inhibits insulin and phorbol-ester-stimulated glucose transport in in vitro incubated human muscle strips. Diabetologia 35: 26–31
Argyraki M, Wright PD, Venables CW, Proud G, Taylor R (1989) In vitro study of human skeletal muscle strips: effect of nonesterified fatty acid supply on glucose storage. Metabolism 38: 1183–1187
Krebs HA, Henseleit K (1932) Untersuchungen über die Harnstoffbildung im Tierkörper. Hoppe-Steyler's Z Physiol Chem 210: 33–66
Wallberg-Henriksson H, Zetan N, Henriksson J (1987) Reversibility of decreased insulin-stimulated glucose transport capacity in diabetic muscle with in vitro incubation. J Biol Chem 262: 7665–7671
De Fronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 173: E214-E223
Pedersen O, Bak JF, Andersen PH et al. (1990) Evidence against altered expression of GLUT 1 and GLUT 4 in skeletal muscle of patients with obesity or NIDDM. Diabetes 39: 865–870
Vogt B, Mühlbacher C, Carrascossa J et al. (1992) Sub-cellular distribution of Glut 4 in skeletal muscle of lean type 2 (non-insulin-dependent) diabetic patients in the basal state. Diabetologia 35: 456–463
Handberg A, Kayser L, Hoyer PE, Voldstedlund M, Hansen HP, Vinten J (1993) Metformin ameliorates diabetes but does not normalize the decreased GLUT 4 content in skeletal muscle of obese (fa/fa) Zucker rats. Diabetologia 36: 481–486
Matthaei S, Hamann A, Klein HH, Benecke H, Kreymann G, Flier JS, Greten H (1991) Association of metformin's effect to increase insulin-stimulated glucose transport with potentiation of insulin-induced translocation of glucose transporters from an intracellular pool to plasma membrane in rat adipocytes. Diabetes 40: 850–857
Kozzka IJ, Holman GD (1993) Metformin blocks down-regulation of cell surface GLUT 4 caused by chronic insulin treatment of adipocytes. Diabetes 42: 1159–1165
Garvey WT (1989) Insulin resistance and noninsulin-dependent diabetes mellitus: which horse is pulling the cart? Diabetes Metab Rev 5: 727–742
Beck-Nielsen H, Vaag A, Damsbo P et al. (1992) Insulin resistance in skeletal muscles in patients with NIDDM. Diabetes Care 15: 418–429
Bailey CJ, Puah JA (1986) Effect of metformin on glucose metabolism in mouse soleus muscle. Diabete Metab 12: 212–218
Lord JM, Puah JA, Atkins TW, Bailey CJ (1985) Post-receptor effect of metformin on insulin action in mice. J Pharm Pharmacol 37: 821–823
Yki-JÄrvinen H (1992) Glucose toxicity. Endocr Rev 13: 415–431
Henry RR, Gumbiner B, Flynn T, Thorburn AW (1990) Metabolic effects of hyperglycemia and hyperinsulinemia on the fate of intracellular glucose in NIDDM. Diabetes 39: 149–156
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Galuska, D., Nolte, L.A., Zierath, J.R. et al. Effect of metformin on insulin-stimulated glucose transport in isolated skeletal muscle obtained from patients with NIDDM. Diabetologia 37, 826–832 (1994). https://doi.org/10.1007/BF00404340
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00404340