Dose-dependent relationship between serum metformin levels and glycemic control, insulin resistance and leptin levels in females newly diagnosed with type 2 diabetes mellitus


Despite the extensive clinical experience with the use of metformin worldwide, no formal dose-ranging study has been conducted because the current dosing strategy of metformin was determined empirically, rather than by an understanding of its dose-response relationship in patients with type 2 diabetes. The present study was designed to evaluate the correlation between serum metformin levels and glycemic control, insulin resistance and leptin levels in females newly diagnosed with type 2 diabetes. Sixty type 2 diabetic females were recruited for the study and were allocated into 3 groups; each receiving metformin 1000, 1500 and 2000 mg/day respectively for 3 months. Blood samples withdrawn from each patient at zero time and after 3 months is used to evaluate serum levels of HbA1c, glucose, leptin and insulin, in addition, the measurement of serum level of metformin in blood after 3 months by HPLC. The results demonstrated that all the treated groups with different doses of metformin showed significant improve in all parameters; the use of increased metformin doses was only correlated with plasma leptin levels in the highest dose. In conclusion, serum metformin levels are not good predictors for correlating improvement in clinical and biochemical parameters with increasing the dose in newly diagnosed non-insulin resistant females with type 2 diabetes.

Share and Cite:

Ali Kadhim, K. , Khalil Ismael, D. , Hoshi Khalaf, B. , Ibrahim Hussein, K. , Hashim Zalzala, M. and Abdulrahman Hussain, S. (2012) Dose-dependent relationship between serum metformin levels and glycemic control, insulin resistance and leptin levels in females newly diagnosed with type 2 diabetes mellitus. Journal of Diabetes Mellitus, 2, 179-185. doi: 10.4236/jdm.2012.22028.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Kirpichnikov, D., McFarlane, S.I. and Sowers, J.R. (2002) Metformin: An update. Annals of International Medicine, 137, 25-33.
[2] Kahn, S.E., Haffner, S.M., Heise, M.A., Herman, W.H., Holman, R.R., Jones, N.P., et al. (2006) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. The New England Journal of Medicine, 355, 2427-2443. doi:10.1056/NEJMoa066224
[3] Scheen, A.J. (1996) Clinical pharmacokinetics of metformin. Clinical Pharmacokinetics, 30, 359-371. doi:10.2165/00003088-199630050-00003
[4] Kay, J.P., Alemzadeh, R., Langley, G., D’Angelo, L., Smith, P. and Holshouser, S. (2001) Beneficial effects of metformin in normoglycemic morbidly obese adolescents. Metabolism, 50, 1457-1461. doi:10.1053/meta.2001.28078
[5] Glueck, C.J., Fontaine, R.N., Wang, P., Subbiah, M.T.R., Weber, K., Illig, E., et al. (2001) Metformin reduces weight, centropedal obesity, insulin, leptin, and low-density lipoprotein cholesterol in non-diabetic, morbidly obese subjects with body mass index greater than 30. Metabolism, 50, 856-861. doi:10.1053/meta.2001.24192
[6] Fruehwald-Schultes, B., Oltmanns, K.M., Toschek, B., Sopke, S., Kern, W., Born, J., et al. (2002) Short-term treatment with metformin decreases serum leptin concentration without affecting body weight and body fat content in normal-weight healthy men. Metabolism, 51, 531-536. doi:10.1053/meta.2002.31332
[7] Pentikainen, P.J., Neuvonen, P.J. and Penttila, A. (1979) Pharmacokinetics of metformin after intravenous and oral administration to man. European Journal of Clinical Pharmacology, 16, 195-202. doi:10.1007/BF00562061
[8] Graham, G.G., Punt, J., Arora, M., Day, R.O., Doogue, M.P., Duong, J.K., et al. (2011) Clinical pharmacokinetics of metformin. Clinical Pharmacokinetics, 50, 81-98. doi:10.2165/11534750-000000000-00000
[9] Sambol, N.C., Chiang, J., O’Conner, M., Liu, C.Y., Lin, E.T., Goodman, A.M., et al. (1996) Pharmacokinetics and pharmacodynamics of metformin in healthy subjects and patients with noninsulin-dependent diabetes mellitus. The Journal of Clinical Pharmacology, 36, 1012-1021. doi:10.1177/009127009603601105
[10] Hong, Y., Rohatagi, S., Habtemariam, B., et al. (2008) Population exposure-response modeling of metformin in patients with type 2 diabetes mellitus. The Journal of Clinical Pharmacology, 48, 696-707. doi:10.1177/0091270008316884
[11] Schwartz, S., Fonseca, V., Berner, B., et al. (2006) Efficacy, tolerability, and safety of a novel once-daily extended-release metformin in patients with type 2 diabetes. Diabetes Care, 29, 759-764. doi:10.2337/diacare.29.04.06.dc05-1967
[12] American Diabetic Association. (2008) Diagnosis and classification of diabetes mellitus. Diabetes Care, 31, S55-S60. doi:10.2337/dc08-S055
[13] Barham, D. and Trinder, P. (1972) An improved color reagent for the determination of blood glucose by the oxidative system. Analyst, 97, 142-145. doi:10.1039/an9729700142
[14] Abraham, E.C., Huff, T.A., Cope, N.D., Wilson, J.B., Bransome, E.D. and Huisman, T.H. (1978) Determination of the glycosylated hemoglobin (HbA1c) with a new micro column procedure, suitability of the technique for assessing the clinical management of diabetes mellitus. Diabetes, 27, 931.
[15] Guillaume, M. and Bjorntorp, P. (1996) Obesity in children: Environmental and genetic aspects. Hormone and Metabolic Research, 28, 573-581. doi:10.1055/s-2007-979856
[16] Flier, J.S., Kahn, C.R. and Roth, J. (1979) Receptor, antireceptor antibodies and mechanisms of insulin resistance. The New England Journal of Medicine, 300, 413-419. doi:10.1056/NEJM197902223000808
[17] Cheng, C.L. and Chou, C.H. (2011) Determination of metformin in human plasma by high-performance liquid chromatography with spectrophotometric detection. Journal of Chromatography, 762, 51-58.
[18] Choi, Y.H., Lee, M.G. and Lee, I. (2008) Effects of diabetes mellitus induced by alloxan on the pharmacokinetics of metformin in rats: Restoration of pharmacokinetic parameters to the control state by insulin treatment. Journal of Pharmacy Pharmaceutical Sciences, 11, 88-103.
[19] UK Prospective Diabetes Study (UKPDS) Group. (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes. The Lancet, 352, 854-865. doi:10.1016/S0140-6736(98)07037-8
[20] Christensen, M.M., Brasch-Andersen, C., Green, H., Nielsen, F., Damkier, P., Beck-Nielsen, H. and Brosen, K. (2011) The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c. Pharmacogenetics and Genomics, 21, 837-850. doi:10.1097/FPC.0b013e32834c0010
[21] Yasmin, E., Glanville, J., Barth, J. and Balen, A.H. (2011) Effect of dose escalation of metformin on clinical features, insulin sensitivity and androgen profile in polycystic ovary syndrome. European Journal of Obstetrics and Gynecology and Reproductive Biology, 156, 67-71. doi:10.1016/j.ejogrb.2010.12.041
[22] Frid, A., Sterner, G.N., Londahl, M., Wiklander, C., Cato, A., Vinge, E. and Andersson, A. (2010) Novel assay of metformin levels in patients with type 2 diabetes and varying levels of renal function. Diabetes Care, 33, 1291-1293. doi:10.2337/dc09-1284
[23] Leabman, M.K. and Giacomini, K.M. (2003) Estimating the contribution of genes and environment to variation in renal drug clearance. Pharmacogenetics, 13, 581-584. doi:10.1097/00008571-200309000-00007
[24] Santos, R.F., Nomizo, R., Wajhenberg, B.L., Reaven, G.M. and Azhar, S. (1995) Changes in insulin receptor tyrosine kinase activity associated with metformin treatment of type 2 diabetes. Diabetes and Metabolism, 21, 274-280.
[25] Harborne, L.R., Sattar, N., Norman, J.E. and Fleming, R. (2005) Metformin and weight loss in obese women with polycystic ovary syndrome: Comparison of doses. The Journal of Clinical Endocrinology and Metabolism, 90, 4593-4598. doi:10.1210/jc.2004-2283
[26] Lalau, J.D. and Lacroix, C. (2003) Measurement of metformin concentration in erythrocytes: Clinical implications. Diabetes, Obesity and Metabolism, 5, 93-98. doi:10.1046/j.1463-1326.2003.00241.x
[27] Marchetti, P., Benzi, L., Cecchetti, P., Giannarelli, R., Boni, C., Ciociaro, D., Ciccarone, A.M., Di Cianni, G., Zappella, A. and Navalesi, R. (1987) Plasma biguanide levels are correlated with metabolic effects in diabetic patients. Clinical Pharmacology and Therapeutics, 41, 450-454. doi:10.1038/clpt.1987.55
[28] Bruno, R.V., de Avilla, M.A., Neves, F.B., Nardi, A.E., Crespo, C.M. and Sobrinho, A.T. (2007) Comparison of two doses of metformin (2.5 and 1.5 g/day) for the treatment of polycystic ovary syndrome and their effect on body mass index and waist circumference. Fertility and Sterility, 88, 510-512. doi:10.1016/j.fertnstert.2006.11.133
[29] Tang, T., Lord, J.M., Norman, R.J., Yasmin, E. and Balen, A.H. (2010) Insulin-sensitizing drugs (metformin, rosiglitazone, pioglitazone, d-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database of Systematic Reviews, 1. doi:10.1002/14651858
[30] Morin-Papunen, L.C., Koivunen, R.M., Tomas, C., Ruokonen, A. and Martikanian, H.K. (1998) Decreased serum leptin concentrations during metformin therapy in obese with PCOS. The Journal of Clinical Endocrinology and Metabolism, 83, 2566-2568. doi:10.1210/jc.83.7.2566
[31] Paolisso, G., Amato, L., Eccellente, R., et al. (1998) Effect of metformin on food intake in obese subjects. European Journal of Clinical Investigation, 28, 441-446. doi:10.1046/j.1365-2362.1998.00304.x

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.