Can metformin limit weight gain in the obese with pregnancy?

Eman Ali Abd El Fattah


Background: Maternal overweight and obesity is associated with many obstetric complications.  Obesity is linked to insulin resistance. Improving insulin sensitivity may therefore account for weight reduction. Metformin was found to be effective in type 2 diabetes and polycystic ovarian syndrome through improving insulin sensitivity. Several studies proved its efficacy in the obese non- pregnants, but its role during pregnancy is not yet well-established. In this study, we are testing the ability of metformin to limit weight gain with pregnancy and therefore reducing complications as gestational Diabetes and hypertension.

Methods: A prospective study was conducted in Alexandria, Egypt. The study was registered in the South African Cochrane Centre under an identification number PACTR201505001142202. Two Hundreds participants with a BMI of ≥35 Kg/m2, pregnant in the early second trimester, were equally divided into two groups; in which group 1 will receive metformin 500 mg twice a day and group 2 will receive placebo. Prior to inclusion, 75 g oral glucose tolerance test, fasting insulin, fasting blood glucose, 1 h and 2 h glucose blood and HbA1C were measured .Both groups were followed up monthly for weight and for pregnancy complications namely gestational diabetes and pre-eclampsia till 36 weeks of pregnancy.

Results: There was a significant difference in the weight gain and the one hour blood sugar measurement between the two groups, but not in the occurrence of pregnancy complications namely gestational diabetes and hypertension.

Conclusions: Metformin succeeded to limit weight gain the obese with pregnancy.


Pregnancy, Weight gain, Metformin

Full Text:



Catalano PM. Increasing maternal obesity and weight gain during pregnancy: the obstetric problems of plentitude. Obstet Gynecol. 2007;110:743-4

Sidebottom AC, Brown JE, Jacobs DR Jr. Pregnancy-related changes in body fat. Eur J Obstet Gynecol Reprod Biol. 2001;94:216-23.

Soltani H, Fraser RB. A longitudinal study of maternal anthropometric changes in normal weight, overweight, and obese women during pregnancy and postpartum. Br J Nutr. 2000;84:95-101.

Dabelea D, Hanson RL, Lindsay RS, Pettitt DJ, Imperatore G, Gabir MM et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes 2000;49:2208-11.

Dabelea D. The predisposition to obesity and diabetes in offspring of diabetic mothers. Diabet Care. 2007;30(2):S169-74.

Dyer JS, Rosenfeld CR, Rice J, Rice M, Hardin DS. Insulin resistance in hispanic large-for-gestational-age neonates at birth. J Clin Endocrinol Metabol. 2007;92:3836-43.

Rowan JA, Rush EC, Obolonkin V, Battin M, Wouldes T, Hague WM. Metformin in Gestational diabetes: The offspring follow-up (MiG TOFU): body composition at 2 years of age. Diabet Care. 2011;34:2279-84.

Ali AT, Ferris WF, Naran NH, Crowther NJ. Insulin resistance in the control of body fat distribution: a new hypothesis. Horm Metab Res. 2011;43:77-80.

Silverman BL, Metzger BE, Cho NH, Loeb CA Impaired glucose tolerance in adolescent offspring of diabetic mothers: relationship to fetal hyperinsulinism. Diabetes Care. 1995;18:611-7.

Catalano PM, Nizielski SE, Shao J, Preston L, Qiao L, Friedman JE. Down regulated IRS-1 and PPAR gamma in obese women with gestational diabetes: relationship to FFA during pregnancy. Am J Physiol Endocrinol Metab. 2002;282:E522-33.

Friedman JE, Ishizuka T, Shao J, Huston L, Highman T, Catalano P. Impaired glucose transport and insulin receptor tyrosine phosphorylation in skeletal muscle from obese women with gestational diabetes. Diabetes. 1999;48:1807-14.

Catalano PM, Huston L, Amini SB, Kalhan SC. Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus. Am J Obstet Gynecol. 1999;180:903-16.

Homko CJ, Sivan E, Reece EA, Boden G. Fuel metabolism during pregnancy. Semin Reprod Endocrinol. 1999;17:119-25.

Cho NH, Roston SM, Radvany R. Pre-pregnancy weight and antepartum insulin secretion predict glucose tolerance five years after gestational diabetes mellitus. Diabet Care. 1993;16:1598-605.

Buchanan TA, Xiang AH, Kjos SL, Trigo E, Lee WP, Peters RK. Antepartum predictors of the development of type 2 diabetes in Latino women 11-26 months after pregnancies complicated by gestational diabetes. Diabetes. 1999;48:2430-6.

Handwerger S, Freemark M. The roles of placental growth hormone and placental lactogen in the regulation of human fetal growth and development. J Pediatr Endocrinol Metab. 2000;13:343-56.

Kirwan JP, Hauguel-De Mouzon S, Lepercq J, Challier JC, Huston-Presley L, Friedman JE, Kalhan SC, Catalano PM. TNF-alpha is a predictor of insulin resistance in human pregnancy. Diabetes. 2002;51:2207-13.

Hotamisligil GS, Spiegelman BM. Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes. 1994;43:1271-8.

Peraldi P, Hotamisligil GS, Buurman WA, White MF, Spiegelman BM. Tumor necrosis factor (TNF)-alpha inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase. J Biol Chem. 1996;271:13018-22.

Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha and obesity-induced insulin resistance. Science. 1996;271:665-8.

Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA: Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab. 2001;86:1930-5.

Worda C, Leipold H, Gruber C, Kautzky-Willer A, Knofler M, Bancher-Todesca D. Decreased plasma adiponectin concentrations in women with gestational diabetes mellitus. Am J Obstet Gynecol. 2004;191:2120-4.

Cseh K, Baranyi E, Melczer Z, Kaszas E, Palik E, Winkler G. Plasma adiponectin and pregnancy-induced insulin resistance. Diabetes Care. 2004;27:274-5.

Catalano PM, Hoegh M, Minium J, Huston-Presley L, Bernard S, Kalhan S, Hauguel-De Mouzon S. Adiponectin in human pregnancy: implications for regulation of glucose and lipid metabolism. Diabetologia. 2006;49:1677-85.

Hara K, Yamauchi T, Kadowaki T. Adiponectin: an adipokine linking adipocytes and type 2 diabetes in humans. Curr Diab Rep. 2005;5:136-40.

Winzer C, Wagner O, Festa A, Schneider B, Roden M, Bancher-Todesca D, Pacini G, Funahashi T, Kautzky-Willer A. Plasma adiponectin, insulin sensitivity, and subclinical inflammation in women with prior gestational diabetes mellitus. Diabetes Care. 2004;27:1721-7.

Heitritter SM, Solomon CG, Mitchell GF, Skali-Ounis N, Seely EW. Subclinical inflammation and vascular dysfunction in women with previous gestational diabetes mellitus. J Clin Endocrinol Metab. 2005;90:3983-8.

Williams MA, Qiu C, Muy-Rivera M, Vadachkoria S, Song T, Luthy DA. Plasma adiponectin concentrations in early pregnancy and subsequent risk of gestational diabetes mellitus. J Clin Endocrinol Metab. 2004;89:2306-11.

Ranheim T, Haugen F, Staff AC, Braekke K, Harsem NK, Drevon CA. Adiponectin is reduced in gestational diabetes mellitus in normal weight women. Acta Obstet Gynecol Scand. 2004;83:341-7.

Thyfault JP, Hedberg EM, Anchan RM, Thorne OP, Isler CM, Newton ER, Dohm GL, deVente JE. Gestational diabetes is associated with depressed adiponectin levels. J Soc Gynecol Investig. 2005;12:41-5.

Ategbo JM, Grissa O, Yessoufou A, Hichami A, Dramane KL, Moutairou K, Miled A, Grissa A, Jerbi M, Tabka Z, Khan NA. Modulation of adipokines and cytokines in gestational diabetes and macrosomia. J Clin Endocrinol Metab. 2006;91:4137-43.

Bennett WL, Odelola OA, Wilson LM, Bolen S, Selvaraj S, Robinson KA et al. Evaluation of guideline recommendations on oral medications for type 2 diabetes mellitus: a systematic review. Ann Intern Med. 2012;156:27-36.

Sterne J. Pharmacology and mode of action of hypoglycaemic guanidine derivatives. In: Campbell GD. (ed.). Oral hypoglycaemic agents. London: Academic; 1969:193-245.

Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev. 1997;18:774-800.

Unlühizarci K, Keleştimur F, Bayram F, Sahin Y, Tutuş A. The effects of metformin on insulin resistance and ovarian steroidogenesis in women with polycystic ovary syndrome. Clin Endocrinol. 1999;51:231-6.

Lee A, Morley JE. Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes. Obes Res. 1998;6:47-53.

Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333:550-4.

Lustig RH. Hypothalamic obesity: the sixth cranial endocrinopathy. The Endocrinologist. 2002;12:210-7.

Sigal RJ, El-Hashimy M, Martin BC, Soeldner JS, Krolewski AS, Warram JH. Acute post-challenge hyperinsulinemia predicts weight gain. Diabetes. 1997;46:1025-9.

Odeleye OE, de Courten M, Pettitt DJ, Ravussin E. Fasting hyperinsulinemia is a predictor of increased body weight gain and obesity in Pima Indian children. Diabetes. 1997;46:1341-5.

Bailey DJ, Turner RC. Metformin. N Engl J Med 1996;334:574-9.

Hermann LS, Melander A. Biguanides: basic aspects and clinical uses. In: Alberti KGMM, DeFronzo RA, Keen H, Zimmet P. (eds.). International textbook of diabetes mellitus. Vol. 1. Chichester, England: John Wiley; 1992:773-95.

Wang M, Tong JH, Zhu G, Liang GM, Yan HF, Wang XZ. Metformin for treatment of antipsychotic-induced weight gain: A randomized, placebo-controlled study. Schizophr Res. 2012;138:54-7.

Bushe CJ, Bradley AJ, Doshi S, Karagianis J. Changes in weight and metabolic parameters during treatment with antipsychotics and metformin: do the data inform as to potential guideline development? A systematic review of clinical studies. Int J Clin Pract. 2009;63:1743-61.

Seifarth C1, Schehler B, Schneider HJ. Effectiveness of metformin on weight loss in non-diabetic individuals with obesity. Exp Clin Endocrinol Diabetes. 2013;121(01):27-31.

Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp.

Derosa G, Maffioli P. Anti-obesity drugs: a review about their effects and their safety. Expert Opin Drug Saf. 2012;11:459-71.

Ara R, Blake L, Gray L, Hernández M, Crowther M, Dunkley A et al. What is the clinical effectiveness and cost-effectiveness of using drugs in treating obese patients in primary care? A systematic review. Health Technol Assess. 2012;16(5):iii-xiv, 1-195.

Levri KM, Slaymaker E, Last A, Yeh J, Ference J, D'Amico F et al. Metformin as treatment for overweight and obese adults: a systematic review. Ann Fam Med. 2005;3:457-61.

Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

Diabetes Prevention Program Research Group. Long-term safety, tolerability, and weight loss associated with metformin in the diabetes prevention program outcomes study. Diabetes Care. 2012;35:731-72.

Fontbonne A, Diouf I, Baccara-Dinet M, Eschwege E, Charles MA. Effects of 1-year treatment with metformin on metabolic and cardiovascular risk factors in non-diabetic upper-body obese subjects with mild glucose anomalies: a post-hoc analysis of the BIGPRO1 trial. Diabetes Metab. 2009;35:385-91.

Gambineri A, Patton L, Vaccina A, Cacciari M, Morselli-Labate AM, Cavazza C et al. Treatment with flutamide, metformin, and their combination added to a hypocaloric diet in overweight-obese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91:3970-80.

Goodpaster BH, Kelley DE, Wing RR et al. Effects of weight loss on regional fat distribution and insulin sensitivity in obesity. Diabetes. 1999;48:839-84.

Glueck CJ, Fontaine RN, Wang P, Subbiah MT, Weber K, Illig E et al. Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30. Metabolism. 2001;50:856-61.

Lee A, Morley JE. Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes. Obes Res. 1998;6(1):47-53.

Mogul HR, Peterson SJ, Weinstein BI, Southren AL. Long-term (2-4 year) weight reduction with metformin plus carbohydrate-modified diet in euglycemic, hyperinsulinemic, midlife women (Syndrome W). Heart Dis. 2003;5:384-92.

Dohm GL, Tapscott E, Pories W, Dabbs DJ, Flickinger EG, Meelheim D et al. An in vitro human muscle preparation suitable for metabolic studies. Decreased insulin stimulation of glucose transport in muscle from morbidly obese and diabetic subjects. J Clin Invest. 1988;82:486-94.

Butte NF. Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus. American J Clin Nutrit. 2000;71(5):1256S-1S.

Catalano PM, Tyzbir ED, Roman NM, Amini SB, Sims EA. Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. American J Obstetr Gynecol. 1991;165:1667-72.

Catalano PM, Tyzbir ED, Wolfe RR, Roman NM, Amini SB, Sims EA. Longitudinal changes in basal hepatic glucose production and suppression during insulin infusion in normal pregnant women. American J Obstetr Gynecol. 1992;167:913-9.

Catalano PM, Tyzbir ED, Wolfe RR, Calles J, Roman NM, Amini SB, Sims EA. Carbohydrate metabolism during pregnancy in control subjects and women with gestational diabetes. American J Physiol. 1993;264:E60-7.

Kuhl C. Aetiology of gestational diabetes. Baillieres Clin Obstetr Gynaecol. 1991;5(2):279-92.

Ryan EA, O'Sullivan MJ, Skyler JS. Insulin action during pregnancy. Studies with the euglycemic clamp technique. Diabetes. 1985;34(4):380-9.

Buchanan TA, Metzger BE, Freinkel N, Bergman RN. Insulin sensitivity and B-cell responsiveness to glucose during late pregnancy in lean and moderately obese women with normal glucose tolerance or mild gestational diabetes. American J Obstetr Gynecol. 1990;162(4):1008-4.

Lesser KB, Carpenter MW. Metabolic changes associated with normal pregnancy and pregnancy complicated by diabetes mellitus. Seminars in Perinatology. 1994;18(5):399-406.

Catalano PM, Nizielski SE, Shao J, Preston L, Qiao L, Friedman JE. Down regulated IRS-1 and PPAR gamma in obese women with gestational diabetes: relationship to FFA during pregnancy. American J Physiol Endocrinol Metabol. 2002;282(3):E522-33.

Schultes B, Oltmanns KM, Kern W, Fehm HL, Born J, Peters A. Modulation of hunger by plasma glucose and metformin. J Clin Endocrinol Metab. 2003;88:1133-41.

Paolisso G, Amato L, Eccellente R, Gambardella A, Tagliamonte MR, Varricchio G et al. Effect of metformin on food intake in obese subjects. Eur J Clin Invest. 1998;28:441-6.

Mick GJ, Wang X, Ling Fu C, McCormick KL. Inhibition of leptin secretion by insulin and metformin in cultured rat adipose tissue. Biochim Biophys Acta. 2000;1502:426-32.

Morin-Papunen LC, Koivunen RM, Tomas C, Ruokonen A, Martikainen HK. Decreased serum leptin concentrations during metformin therapy in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1998;83:2566-8.