Effect of Metformin on Thyroid Function Tests in Type 2 Diabetic Patients

Iraq J Pharm Vol. 14, No.1, 2014

Effect of metformin on thyroid function tests in type 2 diabetic patients

Mohammed N. Abed Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul, Iraq correspondence: [email protected] Received Accepted 14.1.2014 4.3.2014 ABSTRACT Background: Diabetes mellitus (DM) and thyroid disorder appears to be closely related.It has long been recognised that thyroid hormones have marked effects on glucose homeostasis, and although autoimmune thyroid disease is more prevalent in type 1 diabetes as a result of their common origin, in patients with type 2 diabetes the prevalence of hypothyroidism and hyperthyroidism is similar to that of the general population. The present study was conducted to assess the interplay between metformin treatment and thyroid function in type 2 diabetic patients. Methods: A total of 73 diabetic patients were enrolled in this study, they were divided into two groups, the first group included 37 type 2 diabetic patients on metformin therapy, whereas the second group involved 36 type 1 diabetic patients on insulin therapy. Another group involved 35 apparently healthy volunteers were also included in the study as a control group. Blood samples were taken from the patients and controls, then the serum was analyzed for measurement of fasting serum glucose (FSG), total T3, free T3 (FT3), total T4, freeT4 FT4) and TSH using ELFA (Enzyme Linked Fluorescent Assay) technique (minividas). Results: the results showed that there were no significant differences between T3, FT3, FT4 and TSH of the metformin group when compared to the same parameters in the control group. On the other hand FT3 and FT4 of insulin group were significantly lower than that of the control and metformin groups. Also total T4 inmetformin and insulin groups was significantly lower than that of control group, whereas the TSH of insulin group was significantly higher than that of control and metformin groups. Conclusion:Chronic use of metformin in type 2 diabetic patients has no effects on thyroid function tests, and there was no significant correlation between glycemic control and thyroid hormones or TSH. However, TSH, T4, FT3 and FT4 in insulin group were significantly differe from control group and this may indicate the presence of subclinical hypothyroidism. Key words:diabetes mellitus, metformin, insulin, thyroid hormons.

اﻟﺨﻼﺻﺔ ﺧﻠﻔﯿﺔ اﻟﺒﺤﺚ: ﺗﻘﯿﯿﻢ اﻟﻌﻼﻗﺔ ﺑﯿﻦ اﻟﻌﻼج ﺑﺎﻟﻤﯿﺘﻔﻮرﻣﯿﻦ و وظﯿﻔﺔ اﻟﻐﺪة اﻟﺪرﻗﯿﺔ ﻓﻲ ﻣﺮﺿﻰ اﻟﺴﻜﺮي ﻣﻦ اﻟﻨﻮع اﻟﺜﺎﻧﻲ.. اﻟﻤﻮاد واﻟﻄﺮق: ﺗﻢ ﺟﻤﻊ 73 ﻣﺮﯾﻀﺎ ﺑﺎﻟﺴﻜﺮي ﻓﻲ ھﺬه اﻟﺪراﺳﺔ، و ﺟﺮى ﺗﻘﺴﯿﻤﮭﻢ إﻟﻰ ﻣﺠﻤﻮﻋﺘﯿﻦ، ﺷﻤﻠﺖ اﻟﻤﺠﻤﻮﻋﺔ اﻷوﻟﻰ 37 ﻣﺮﯾﺾ ﺳﻜﺮي ﻣﻦ اﻟﻨﻮع اﻟﺜﺎﻧﻲ ﯾﺴﺘﺨﺪم ﻋﻼج اﻟﻤﯿﺘﻔﻮرﻣﯿﻦ، ﻓﻲ ﺣﯿﻦ أن اﻟﻤﺠﻤﻮﻋﺔ اﻟﺜﺎﻧﯿﺔ ﺷﻤﻠﺖ 36 ﻣﺮﯾﺾ ﺳﻜﺮي ﻣﻦ اﻟﻨﻮع اﻻول ﯾﻌﺎﻟﺞ ﺑﻌﻘﺎر اﻻﻧﺴﻮﻟﯿﻦ. وأدرﺟﺖ ﻣﺠﻤﻮﻋﺔ أﺧﺮى ﻓﻲ اﻟﺪراﺳﺔ ﺷﺎرك ﻓﯿﮭﺎ 35ﻣﺘﻄﻮﻋﺎ اﺻﺤﺎء ﻛﻤﺠﻤﻮﻋﺔ ﺿﺒﻂ. اﺧﺬت ﻋﯿﻨﺎت اﻟﺪم ﻣﻦ اﻟﻤﺮﺿﻰ وﻣﻦ ﻣﺠﻤﻮﻋﺔ اﻟﻀﺒﻂ وﺗﻢ ﺗﺤﻠﯿﻞ ﻣﺼﻞ اﻟﺪم ﻟﻘﯿﺎس ﺳﻜﺮ اﻟﻤﺼﻞ وﻓﺤﻮﺻﺎت وظﺎﺋﻒ اﻟﻐﺪة اﻟﺪرﻗﯿﺔ وﻓﺤﺺ اﻟﮭﺮﻣﻮن اﻟﻤﺤﻔﺰ ﻟﻠﻐﺪة اﻟﺪرﻗﯿﺔ ﺑﺎﺳﺘﺨﺪام ﺟﮭﺎز ﻣﯿﻨﻲ ﻓﺎﯾﺪس اﻟﻨﺘﺎﺋﺞ: أظﮭﺮت اﻟﻨﺘﺎﺋﺞ ﻋﺪم وﺟﻮد ﻓﺮوق ذات دﻻﻟﺔ إﺣﺼﺎﺋﯿﺔ ﻣﻌﻨﻮﯾﺔ ﻓﻲ ھﻮرﻣﻮﻧﺎت اﻟﻐﺪة اﻟﺪرﻗﯿﺔ وواﻟﮭﻮرﻣﻮن اﻟﻤﺤﻔﺰ ﻟﮭﺎ ﻓﻲ ﻣﺠﻤﻮﻋﺔ اﻟﻤﯿﺘﻔﻮرﻣﯿﻦ ﻋﻨﺪﻣﻘﺎرﻧﺘﮭﺎ ﻣﻊ ﻣﺠﻤﻮﻋﺔاﻟﻀﺒﻂ. ﺑﯿﻨﻤﺎ ﻟﻮﺣﻆ اﻧﮭﻮرﻣﻮﻧﺎت اﻟﻐﺪة اﻟﺪرﻗﯿﺔ اﻟﺤﺮة ﻓﻲ ﻣﺠﻤﻮﻋﺔ اﻷﻧﺴﻮﻟﯿﻦ ﻛﺎﻧﺖ أﻗﻞ ﺑﻜﺜﯿﺮ ﻣﻦ ﻣﺠﻤﻮﻋﺘﻲ اﻟﻀﺒﻂ واﻟﻤﯿﺘﻔﻮرﻣﯿﻦ. ﻛﺬﻟﻚ ﻟﻮﺣﻆ ﻓﺮق ﻣﻌﻨﻮي ﺑﯿﻦ ھﻮرﻣﻮن اﻟﻐﺪة اﻟﺪرﻗﯿﺔ رﺑﺎﻋﻲ اﻻﯾﻮدﯾﻦ ﻓﻲ ﻣﺠﻤﻮﻋﺘﻲ اﻟﻤﯿﺘﻔﻮرﻣﯿﻦ و اﻻﻧﺴﻮﻟﯿﻦ ﺣﯿﺚ ﻛﺎن أﻗﻞ ﺑﻜﺜﯿﺮ ﻣﻦ اﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ، ﻓﻲ ﺣﯿﻦ ﻛﺎﻧﺎﻟﮭﻮرﻣﻮن اﻟﻤﺤﻔﺰ ﻟﻠﻐﺪة اﻟﺪرﻗﯿﺔ ﻓﻲ ﻣﺠﻤﻮﻋﺔ اﻷﻧﺴﻮﻟﯿﻦ أﻋﻠﻰ ﺑﻜﺜﯿﺮ ﻣﻦ ﻣﺠﻤﻮﻋﺘﻲ اﻟﻀﺒﻂ و اﻟﻤﯿﺘﻔﻮرﻣﯿﻦ.

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اﻻﺳﺘﻨﺘﺎج: اﻻﺳﺘﺨﺪام اﻟﻤﺰﻣﻦ ﻟﻠﻤﯿﺘﻔﻮرﻣﯿﻦ ﻓﻲ ﻣﺮﺿﻰ اﻟﺴﻜﺮي ﻣﻦ اﻟﻨﻮع اﻟﺜﺎﻧﻲ ﻟﯿﺲ ﻟﮫ أي آﺛﺎر ﻓﻲ اﺧﺘﺒﺎرات وظﯿﻔﺔ اﻟﻐﺪة اﻟﺪرﻗﯿﺔ، وﻟﯿﺲ ھﻨﺎك ارﺗﺒﺎط ﻛﺒﯿﺮ ﺑﯿﻦ ﻧﺴﺒﺔ اﻟﺴﻜﺮ ﻓﻲ اﻟﺪم واﻟﺘﺤﻜﻢ ﻓﻲ ھﺮﻣﻮﻧﺎت اﻟﻐﺪة اﻟﺪرﻗﯿﺔ، ﺑﯿﻨﻤﺎﻛﺎﻧﺖ ھﻮرﻣﻮﻧﺎت اﻟﻐﺪة اﻟﺪرﻗﯿﺔ واﻟﮭﻮرﻣﻮن اﻟﻤﺤﻔﺰ ﻟﮭﺎ ﻓﻲ ﻣﺠﻤﻮﻋﺔ اﻻﻧﺴﻮﻟﯿﻦ ﻣﺨﺘﻠﻔﺔ ﺑﺸﻜﻞ ﻣﻠﺤﻮظ ﻋﻦ ﻣﺠﻤﻮﻋﺔ اﻟﻀﺒﻂ وھﺬا ﻗﺪ ﯾﺸﯿﺮ اﻟﻰ وﺟﻮد ﻗﺼﻮر ﻓﻲ وظﺎﺋﻒ اﻟﻐﺪة اﻟﺪرﻗﯿﺔ.

iabetes mellitus (DM) and thyroid therapy for patients with type 2 D disorder appears to be closely diabetes8. Thus far, metformin is the related1.It has long been recognised only antidiabetic agent which has that thyroid hormones have marked shown reduced mortality among effects on glucose homeostasis, and overweight patients with DM in although autoimmune thyroid disease addition to reduction in macrovascular is more prevalent in type 1 diabetes as outcomes which are likely explained a result of their common origin, in by its effects beyond glycemic patients with type 2 diabetes the control9,10. Its primary action is to prevalence of hypothyroidism and inhibit hepatic glucose production and hyperthyroidism is similar to that of glucose uptake and disposal in muscle, the general population 2. but it also increases the sensitivity of A recent study of all available data in peripheral tissues to insulin 11. patients with DM revealed a mean Recently it has been reported that frequency of thyroid disease of 11%3. metformin is able to interfere with The global effects of thyroid function thyroid hormone profile in hypothyroid on insulin secretion, action and glucose patients in stable levothyroxine 12,13,14 uptake can be explained by the action treatment . However, no data are of thyroid hormon on peripheral available for untreated hypothyroid tissue(4).Insulin secretion is under patients or for euthyroid diabetic direct control of thyroid hormon, and patients. Given that both metformin in hypothyroidism, glucose-induced treatment and hypothyroidism are insulin secretion by the β-cells is frequent occurrences in diabetic 15 reduced. Although data are more patients . heterogeneous in hyperthyroidism, β- To further characterise the effect of cell response to glucose or metformin treatment on circulating thyroid function parameters, this study catecholamine stimulation appears to aimed to investigate the effect be increased in hyperthyroidism. This metformin treatment on the serum is accompanied by an increased β-cell levels of thyroid hormones and TSH in mass. In parallel, insulin clearance is patients with type 2 diabetes mellitus. increased in thyrotoxicosis. There are little surveys analysing the Experimental hypothyroidism and relationship between metformin and hyperthyroidism in healthy subjects, thyroid function in diabetic patients. Therefore, the aim of the present study and endogenous thyrotoxicosis or has been to evaluate serum TSH and hypothyroidism, affect glucose thyroid hormons levels in patients with 4,5 uptake . type 2 diabetes, and their relationship For long period of time metformin with metformin. (abiguanide oral antidiabetic compound), was used for the treatment Materials and methods of type 2 diabetes6,7.In recent years, This study was conducted in Mosul- metformin has become the first line Iraq during the period from 15th of

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January 2012 to the 15th of September in plane tube and analyzed. Fasting 2012. A total of 73 diabetic patients serum glucose was estimated by were enrolled in this study, they were glucose-oxidase-peroxidase divided into two groups, the first group spectrophotometric method, by using a included 37 type 2 diabetic patients (17 kit supplied by Biocon company male and 20 female) on metformin (Germany). Thyroid hormones; total therapy; their mean age was triiodothyronine (total T3), free 54.41±8.15 years whereas the second triiodothyronine (FT3), total thyroxine group involved 36 type 1 diabetic (total T4) and free thyroxine (FT4) and patients (15male and 21 female) on TSH were measured using ELFA insulin therapy; their mean age was (Enzyme Linked Fluorescent Assay) 54.60±7.77 years. Another group technique (minividas (biomerieux) involved thirty five apparently healthy France), by using kit supplied by volunteers (16 male and 19 female), Biomerieux company (France). were also included in the study as a control group; their mean age was Statistical analysis 53.65±6.27 years. All values expressed as Mean±SD The study design was case-control and P value of ≤0.05 was considered to study and the patients were excluded if be statistically significant. Two they had a history of hypertension, sample t-test and Pearson’s correlation angina pectoris, myocardial infarction, were used to compare the results of heart failure, renal or hepatic failure or various parameters among the studied those taking hypoglycemic agents groups. Statistical analysis was done other than metformin and insulin. using Minitab for Windows statistical Pregnant women and lactating mother software, version 14. were also excluded from the study. Seven milliliters of venous blood, Results for laboratory evaluation of Age of the participants, body mass biochemical parameters, were obtained index (BMI), and duration of treatment from all participants after an overnight by metformin or insulin and gender are fasting (12-hours) by antecubital vein shown in (table 1). There were no puncture. The blood was allowed to significant differences between the clot at room temperature and after studied groups regarding age and BMI. centrifugation the serum was collected

Table 1. Demographic characteristics of the studied groups Parameters Control Metformin Insulin group group group (No.=35) (No.=37) (No.=36) Age (years) 53.65±6.27 54.41±8.15 NS 54.60±7.77 NS BMI (kg/m2) 27.52±1.62 28.25±2.11 NS 28.77±3.29 NS Duration of treatment (years) …….. 6.5±2.07 7.13±2.11 Gender (male/Female) 16/19 17/20 15/21

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Table 2. the FSG, total T3, FT3, total T4, FT4 and TSH for the studied groups Parameters Control Metformin group Insulin group (No.=37) group (No.=35) (No.=36) FSG (mmol/l) 4.89±0.62 9.03±2.40a 8.87±2.41a FT3(pmol/l) 6.64±2.35 6.92±2.55 4.80±0.36ab FT4(pmol/l) 15.70±2.2 14.22±2.33 12.25±1.45ab Total T3(nmol/l) 1.69±0.26 1.79±0.31 1.68±0.45 Total T4(nmol/l) 112.2±10.1 101.72±9.67a 101.5±13.0a TSH(mIU/l) 1.28±0.62 1.64±1.62 2.56±1.31a a= significant differences (P ≤ 0.05) as compared to the same parameters in the control group. b= significant differences (P ≤ 0.05) as compared to the same parameters in the metformin group.

Table 3. the Pearson’s correlation between FSG and thyroid hormones and TSH

Mean± SD(No. 63 patients) R P value Thyroid function tests FSG (mmol/l) FT3(pmol/l) 5.62±2.2 8.95±2.37 - 0.209 0.258 FT4(pmol/l) 12.76±2.34 8.95±2.37 - 0.280 0.127 Total T3(nmol/l) 1.76±0.42 8.95±2.37 0.151 0.418 Total T4(nmol/l) 100.61±12.36 8.95±2.37 - 0.142 0.445 TSH(mIU/l) 2.37±2.44 8.95±2.37 - 0.036 0.846

There were non significant correlations This matching has a beneficial effect in between the FSG and all thyroid that it excludes any effects of hormone parameters and TSH in differences in age and BMI on the diabetic patients, as shown in (table 3). outcome of the study. This study found that there were no Discussion effect for metformin therapy on TSH, It is important to diagnose FT3 and FT4 values and the oral thyroid dysfunction in diabetic antidiabetic metformin;this finding patients, andthis practice should be suggest that TSH, thyroid hormons inculcated in clinical settings and metformin are not independently withimmediate effect to nourish further related16.Findings of this study are in understanding of thyroiddysfunction line with those of Oleandri et al.study, and diabetes mellitus. which assessed the effects of 3-month To exclude the effect of diabetes on treatment with metformin on thyroid gland, the present study anthropometric, metabolic and compared thyroid function test of hormonal variables, including TSH and metformin with that of type 1 diabetic thyroid hormones. Their results patients on insulin therapy, also, in this showed that metformin did not modify study the patient and the control groups the effect of diet on serum TSH were matched regarding age and BMI. concentrations in patients with

Iraq J Pharm Vol. 14, No.1, 2014 obesity17. The effects of metformin 1 diabetes mellitus. There are a number treatment on the thyroid hormone of reports on the TSH levels in type 1 profile have been evaluated in a recent diabetes mellitus and their results are prospective study including 24 in agreement with the present study euthyroid women with polycystic because many of them have recorded ovary syndrome18. Serum levels of elevated TSH levels22-25. TSH before starting metformin therapy The present study also showed non did not significantly change after a 4- significant correlation between fasting month course of metformin therapy. serum glucose levels and parameters of Similarly, there were no significant thyroid function test. This may changes in serum-free T4 in this group suggests that absence or minimal role of women with euthyroidism18. of blood sugar concentration in thyroid Furthermore, no TSH-lowering effect dysfunction and further studies with could be demonstrated in the group of glycated hemoglobin may be necessary patients with type 2 diabetes and to find out the role of glycemic status integrity of the pituitary–thyroid axis. in causing thyroid dysfunction29, 30. A studies done by Vigersky et al., In conclusion, this studydid not found Cappelli et al.,and Chen et al.19–21 any effect of metformin therapy on evaluated the thyroid hormone profile TSH, thyroid hormonslevels in type 2 by studying the interaction between diabetic patients.However, TSH, FT3 metformin and circulating thyroid and FT4 were significantly different function parameters in patients who from control group in insulin group were started on metformin, their results and this may indicate the presence of regarding thyroid hormons are subclinical hypothyroidism. In such consistent with the present study patients, annual screening of thyroid findings, however these studiesshowed function may be required in particular significant fall of TSH level in in endemic area with goiter because euthyroid patients on levothyroxin their FSG levels do not predict the risk. substitution and subclinical Further prospective studies in large hypothyroid patientswho did not samples of euthyroidpatients with receive levothyroxin treatment.These diabetes are needed to clarify the effect studies concluded that TSH lowering of differentdoses and duration of effect of metformin only seen in treatment with metformin onthyroid untreated hypothyroid patient and with economy. levothyroxin replacement therapy irrespective of thyroid function test and References this may explain their inconsistency 1. Perros P, McCrimmon RJ, Shaw G. with the present study finding Frequency of thyroid dysfunction in regarding TSH level, so it is interesting diabetic patients value of annual that the TSH-reducing effect of screening. Diabetic Med 1995;12: metformin has been reported only in 622–627. diabetic subjects with hypothyroidism, 2. Brenta G. Diabetes and thyroid but not in patients with euthyroidism. disorders. British J Dia Vascul Dis TSH levels in the present studywere 2010;10:172-177. significantly elevated in insulin group 3. Kadiyala R, Peter R, Okosieme OE. when compared to the control and Thyroid dysfunction in patients with metformin group. High TSH level is diabetes: clinical implications and clearly suggestive of the hypothyroid screening strategies. Int J Clin Pract state with lower levels of FT3 and FT4 2010;64:1130–1139. that is commonly associated with type

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