|Year : 2014 | Volume
| Issue : 1 | Page : 24-28
The effect of short-term metformin therapy on insulin resistance among obese males in Al-Ramadi, Iraq
Mushtaq Talib Abed1, Marwan S. M. Al-Nimer2, Khalid A Al-Rawi3
1 Department of Clinical Pharmacy, The Al-Ramadi General Hospital, Baghdad, Iraq
2 Department of Pharmacology, College of Medicine, Al-Mustansiriya University, Baghdad, Iraq
3 Department of Medicine, College of Medicine, University Anbar, Ramadi, Baghdad, Iraq
|Date of Web Publication||25-Jul-2014|
Marwan S. M. Al-Nimer
Department of Pharmacology, College of Medicine, Al Mustansiriya University, Baghdad
Source of Support: College of Medicine , Anbar University,, Conflict of Interest: None
Background: Insulin resistance (IR) is one feature of obese patients with type 2 diabetes and associated with a clustering of metabolic abnormalities. Obesity per se is one component of a cluster of metabolic abnormalities that included the hyperinsulinemia. Objectives: This study aims to assess the status of IR in obese nondiabetic subjects using HOME-IR index and demonstrate the therapeutic effect of metformin as an insulin sensitizer. Materials and Methods: A total number of 76 out of 97 obese male completed the study. The subjects assigned to receive a single-dose of metformin (850 mg/daily) for 3 months. Anthropometric measurements and the following biochemical tests were carried on before and after treatment: Fasting serum glucose, glycosylated hemoglobin, and fasting serum insulin. The basal metabolic rate (BMR), HOMA-IR, and insulin sensitivity (IS) were calculated using a specific formula. Results: Metformin therapy resulted in a significant decrease in body mass index of obese subjects. This effect is associated with significant decrease BMR. Significant decrease HOMA-IR observed in Classes I and II obesity (62.95% and 65.13%, respectively) and to a lesser extent in Class III (72.48%). Significant improvement in glycosylated hemoglobin was observed in Classes I and II obesity. HOMA-IR index is significantly correlated with glycosylated hemoglobin before and after treatment. Conclusions: Metformin improves IS in nondiabetic obese men besides its favorable effect in reducing the body weight.
Keywords: Insulin resistance, metformin, obesity
|How to cite this article:|
Abed MT, Al-Nimer MS, Al-Rawi KA. The effect of short-term metformin therapy on insulin resistance among obese males in Al-Ramadi, Iraq. Saudi J Obesity 2014;2:24-8
|How to cite this URL:|
Abed MT, Al-Nimer MS, Al-Rawi KA. The effect of short-term metformin therapy on insulin resistance among obese males in Al-Ramadi, Iraq. Saudi J Obesity [serial online] 2014 [cited 2020 Jun 4];2:24-8. Available from: http://www.saudijobesity.com/text.asp?2014/2/1/24/137594
| Introduction|| |
The degree of insulin resistance (IR), using the homeostasis model assessment (HOMA) method, found to be correlated with the number of metabolic derangements, and when these abnormalities clustered together, IR is always present.  IR is believed to be a central feature of the metabolic syndrome, and it preceded the development of other aspects of the syndrome.  This cluster of metabolic abnormalities found in type 2 diabetes (Type-2 DM) patients and in nondiabetic individuals with the IR syndrome. 
The term IR-dyslipidemic syndrome of visceral obesity used to describe "an excess visceral adipose tissue accumulation", which is proposed to be a component of the IR syndrome.  Metformin is a biguanide oral hypoglycemic agent introduced into clinical practice in the 1950s. Metformin broadly considered as first-line drug treatment for type 2 DM provided if there are no contraindications.  It increasingly used to treat other conditions associated with IR, especially polycystic ovarian syndrome.  The blood glucose-lowering actions of metformin result primarily from a betterment of IR, mainly in liver and muscle, with a lesser effect in adipose tissue.  In normoglycemic states, metformin has little effect upon blood glucose. Therefore, it is termed antihyperglycemic rather than hypoglycemic.  Metformin reduced the body weight in obese patients with and without diabetes and this weight loss have an additional cardiovascular benefits in insulin-resistant persons as the excessive fat localized to the para-intestinal region is a major contribute to the pathogenesis of the cardiovascular metabolic syndrome. ,,
The aim of this study is to assess the beneficial effect of short-term-therapy of metformin as an insulin sensitizer in obese nondiabetic men using the HOMA-IR index.
| Materials and methods|| |
This open-label, nonrandomized clinical trial  conducted in Department of Pharmacology, College of Medicine, Anbar University from January to September 2013. This study approved by the Institutional Scientific Committee. The participants were recruited from patients attended Ramadi General Teaching Hospital seeking medical advice for obesity. Consent form obtained from each subject, and allowed freely to withdraw from the study at any time. The eligible subjects of this study were male gender ageing 30-45 years. The criteria of inclusion were obese subjects with a body mass index (BMI) ≥30 kg/m 2 according to the WHO classification. Criteria of exclusion were diabetes mellitus, familial hyperlipidemia, and hypothyroidism, renal, and hepatic diseases. The following laboratory tests were done to all patients enrolled in this study: Serum creatinine, blood urea, serum hepatic aminotransferases and alkaline phosphatases enzymes, and thyroid stimulating hormone, thyroxine, and triiodothyronine. Any patient with an abnormal level of each test is excluded from the study.
Each patient physically examined by a consultant internal medicine at the time of admission into the study. The anthropometric determinants included weight (kg), and height (m) measured and the BMI calculated using Quetlet's equation:
BMI (kg/m 2 ) = Weight (kg)/height 2 (m)
From the anthropometric measurements, the basal metabolic rate (BMR) is calculated.
BMR = 13.75 × weight (kg) + 5.003 × height (cm) − 6.775 × age + 66.5
The subjects assigned to receive single dose metformin of 850 mg tablet (Merck, Sorono-France) for 3 months and they asked to report any adverse reaction during the study. The authors generously supplied the metformin tablets (each pack contained 30 tablets) to each patient in order to be assured that the patient received medication. The follow-up of patients also documented that all patients who completed the study were regularly take the medicine.
A total number of 97 patients admitted into the study and received the medication (850 mg oral dose daily for 3 months). Seventy-six of patients completed the study that is, the compliance rate was 78.4%. Twenty-one patients failed to adhere to the study because they did not tolerate the gastric upset side-effect of metformin (6 patients), or they missed for unknown cause (15 patients). The patients were sub-grouped according to the classification of obesity as recommended by WHO into Class I (BMI: 30-34.99 kg/m 2 ), Class II (BMI: 35-39.99 kg/m 2 ), and Class III (BMI: ≥40 kg/m 2 ). Fasting venous blood samples obtained from subjects and collected in two test tubes; one with ethylenediaminetetraacetic acid anticoagulant (for determination hemoglobin and glycosylated hemoglobin [HbA 1C %]) and other without anticoagulant. The sera separated by centrifugation (3000 rpm/min) for fasting serum insulin, and fasting glucose.
The cut-off point of HOMA-IR index and the serum fasting insulin level were ≥2.6 and ≥12 mU/L, respectively. 
The (SPSS) System ( SPSS statistics, version 17, McGraw Hill publication, U.K.) and Excel programs (Microsoft cooperation, Redmond, USA) used to analyze the data. The results expressed as number, percent, and mean ± standard deviation. The data analyzed using Student's t-test (two-tailed, paired, and unpaired) and simple (rho) correlation taking the P ≤ 0.05 as the lowest limits of significance.
| Results|| |
[Table 1] shows the characteristics of subjects enrolled in the study. The mean age of participants was 34.9 years. There was a nonsignificant difference in mean age in the different classes of obesity. As the body weight increased, the body fat percent increased and to reach the mean value of the total number of subjects 33.78% that approximated to the mean value of BMI of 34.96 kg/m 2 . The BMR is increased with increase BMI. The status of IR was studied in different aspects. At the time of the entry, the fasting blood sugar was nonsignificantly higher in Class III compared with Classes I and II [Table 2]. Glycosylated hemoglobin (HbA1 c %) level is also nonsignificantly higher in Class III compared with Classes I. The mean value of HOMA-IR index of subjects of Class III was nonsignificantly higher than corresponding mean values of Classes I and II [Table 2]. The IS index, calculated by reciprocal value of IR) achieved lower mean value in Class III compared with Classes I and II. Single daily dose of 850 mg metformin for 3 months significantly reduced the BMI, and the BMR in all classes of obesity [Table 3]. Metformin induced more beneficial effect on these parameters in Class III compared with Classes I and II. The BMI decreased by 3.84% in Class III compared with 2.66% and 3.18% in Class II and I, respectively. The reduction percent of the BMR was 0.89%, 1.83% and 2.78% for Classes I-III, respectively [Table 3]. Fasting serum insulin significantly reduced after 3 months treatment with metformin [Table 3]. Metformin is less effective in lowering fasting serum insulin in Class III compared with Classes I and II subjects. Metformin therapy significantly reduced the fasting blood glucose in Classes I and II, whereas its effect in the Class III did not reach a significant level [Table 3]. The index of HOMA-IR significantly decreased after 3 months therapy with metformin in all obese subjects. Its effect in Class III subjects was inferior to the subjects of Classes I and II. In Class I, the HOMA-IR index reduced to 62.95% of the pretreatment value in Class I that is, the HOMA-IR index decreased by 37.05% [Table 3]. Higher percent (161.1%) of IS observed in Class I obese subjects compared with Class II (123.46) and Class III (141.44). Glycosylated hemoglobin significantly reduced in Classes I and II obese subjects after using metformin therapy, while the changes in glycosylated hemoglobin in subjects of Class III did not reach a significant level [Table 3]. [Table 4] showed that 58 out of 76 patients have a cut-off point of HOMA-IR index ≥2.6, while 29 subjects have a cut-off point of fasting insulin ≥12 mU/L before metformin therapy. Metformin significantly reduced the high values of HOMA-index score and fasting insulin below the cut-off points in 44.8% and 43.1% of obese subjects, respectively.
|Table 3: Effect of single daily (850 mg) dose of metformin for 3 months on the status of obesity related indices|
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|Table 4: Response rates of single daily (850 mg) oral dose of metformin for 3 months in respect to the cut-off points of HOMA-IR index and fasting insulin level|
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| Discussion|| |
The results of this study show that single oral daily dose of 850 mg metformin for 3 months is sufficient to attenuate the status of insulin-resistant in nondiabetic obese men aged 30-40 years old. In this study, men allowed to enroll in this study because IR is a pathological condition that related to base-gender. Men have more visceral and hepatic adipose tissue, whereas women had more peripheral or subcutaneous adipose tissue as well as differences in sex hormones and adipokines, may contribute to a more insulin-sensitive environment in women than in men. , The cause of IR in this study is obesity because the subjects that admitted in this study were men aged 30-40 years and nondiabetic obese. As a class of obesity increased, the fasting serum insulin and glucose increase indicated the peripheral glucose utilization is impaired in obesity and IR existed in term of high HOMA index. The pretreatment value of HOMA-IR (%) in obese subjects is high indicated that the beta-pancreatic cells are still functioning. One study showed that high HOMA-IR was independently associated with an increased odds ratio of incident type-2 DM.  Higher glycosylated hemoglobin percent found in Class III obese subjects compared with Classes I and II. This finding is in agreement with others who found HOMA-IR positively correlated with glycosylated hemoglobin percent in nondiabetic overweight-obese subjects.  Promising results obtained in this study about the effect of short-term therapy of metformin in asymptomatic nondiabetic obese men presented with laboratory evidence of IR. In obese children aged ≤18 years without a diagnosis of diabetes mellitus, metformin therapy provided a statistically significant reduction in BMI after short-term of 6 months therapy.  Although metformin is a promising remedy for IR, it is not enough in improving IS and its molecular mechanism is still not clear.  This study confirmed previous studies that showed metformin significantly reduced the body weight. In one meta-analysis study carried on overweight-obese subjects, metformin reduced waist circumference by −2.11 cm (95% confidence interval: −1.00, −3.22 cm) at 6 months of therapy.  The results of this study show greater decrease HOMA-IR in Class III obesity compared with Class I or Class II, and this is due to the effect of metformin on the fasting insulin rather than on the fasting glucose level. The results of this study are in agreement with previous study carried on patients with type-2 DM that showed the beneficial effect of using metformin in combination with glimepiride on the fasting glucose level, glycosylated hemoglobin, HOMA-IR and HOMA-β (%).  Limitations of the study included small sample size and the hormonal assay that related to obesity, e.g. acylated ghrelin, leptin, and adiponectin are missed, which may help in understanding the mechanism of action of metformin. We concluded that short-term (12 weeks), single small dose (850 mg/daily) of metformin is enough to improve IS in nondiabetic obese giving a response rate less than 50%.
| References|| |
|1.||Nesto RW. The relation of insulin resistance syndromes to risk of cardiovascular disease. Rev Cardiovasc Med 2003;4 Suppl 6:S11-8. |
|2.||Kassi E, Pervanidou P, Kaltsas G, Chrousos G. Metabolic syndrome: Definitions and controversies. BMC Med 2011;9:48. |
|3.||Tadayyon M, Smith SA. Insulin sensitisation in the treatment of type 2 diabetes. Expert Opin Investig Drugs 2003;12:307-24. |
|4.||Turchiano M, Sweat V, Fierman A, Convit A. Obesity, metabolic syndrome, and insulin resistance in urban high school students of minority race/ethnicity. Arch Pediatr Adolesc Med 2012;166:1030-6. |
|5.||Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, et al. Management of hyperglycaemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2006;49:1711-21. |
|6.||Scarpello JH, Howlett HC. Metformin therapy and clinical uses. Diab Vasc Dis Res 2008;5:157-67. |
|7.||Giannarelli R, Aragona M, Coppelli A, Del Prato S. Reducing insulin resistance with metformin: The evidence today. Diabetes Metab 2003;29:6S28-35. |
|8.||Jensterle Sever M, Kocjan T, Pfeifer M, Kravos NA, Janez A. Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin. Eur J Endocrinol 2014;170:451-9. |
|9.||Bray GA, Ryan DH. Update on obesity pharmacotherapy. Ann N Y Acad Sci 2014;1311:1-13. |
|10.||McFarlane SI, Banerji M, Sowers JR. Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab 2001;86:713-8. |
|11.||Rothman KJ. A potential bias in safety evaluation during open-label extensions of randomized clinical trials. Pharmacoepidemiol Drug Saf 2004;13:295-8. |
|12.||Ascaso JF, Pardo S, Real JT, Lorente RI, Priego A, Carmena R. Diagnosing insulin resistance by simple quantitative methods in subjects with normal glucose metabolism. Diabetes Care 2003;26:3320-5. |
|13.||Geer EB, Shen W. Gender differences in insulin resistance, body composition, and energy balance. Gend Med 2009;6 Suppl 1:60-75. |
|14.||Lopes AL, T Fayh AP, de Souza Campos LG, Teixeira BC, Kreismann Carteri RB, Ribeiro JL, et al. The effects of diet- and diet plus exercise-induced weight loss on basal metabolic rate and acylated ghrelin in grade 1 obese subjects. Diabetes Metab Syndr Obes 2013;6:469-75. |
|15.||Kim CH, Kim HK, Kim EH, Bae SJ, Park JY. Relative contributions of insulin resistance and β-cell dysfunction to the development of type 2 diabetes in Koreans. Diabet Med 2013;30:1075-9. |
|16.||Gray B, Muhlhausler BS, Davies PS, Vitetta L. Liver enzymes but not free fatty acid levels predict markers of insulin sensitivity in overweight and obese, nondiabetic adults. Nutr Res 2013;33:781-8. |
|17.||McDonagh MS, Selph S, Ozpinar A, Foley C. Systematic review of the benefits and risks of metformin in treating obesity in children aged 18 years and younger. JAMA Pediatr 2014;168:178-84. |
|18.||Yuan H, Weng C, Yang Y, Huang L, Xing X. Resistin, an adipokine, may affect the improvement of insulin sensitivity in the metabolic syndrome patient treated with metformin. Med Hypotheses 2013;81:969-71. |
|19.||Chilton M, Dunkley A, Carter P, Davies MJ, Khunti K, Gray LJ. The effect of antiobesity drugs on waist circumference: A mixed treatment comparison. Diabetes Obes Metab 2014;16:237-47. |
|20.||Bermúdez-Pirela VJ, Cano C, Medina MT, Souki A, Lemus MA, Leal EM, et al. Metformin plus low-dose glimeperide significantly improves homeostasis model assessment for insulin resistance (HOMA (IR)) and beta-cell function (HOMA (beta-cell)) without hyperinsulinemia in patients with type 2 diabetes mellitus. Am J Ther 2007;14:194-202. |
[Table 1], [Table 2], [Table 3], [Table 4]