Relationship Between Glycemic Control and Thyroid Function Among Patients with Type 2 Diabetes Mellitus

Khalid Aljabri, S.^1*, Samia Bokhari, A.¹ & Nasser Aljuhani²

¹Department of Endocrinology, King Fahad Armed Forces Hospital, Jeddah, Kingdom of Saudi Arabia
²Division of Endocrinology, East Jeddah Hospital, Jeddah, Kingdom of Saudi Arabia

*Correspondence to: Dr. Khalid Aljabri, S., Department of Endocrinology, King Fahad Armed Forces Hospital, Jeddah, Kingdom of Saudi Arabia.

Copyright © 2019 Dr. Khalid Aljabri, S., et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction
Diabetes mellitus (DM) is a chronic metabolic disorder [1]. The prevalence of DM has been increasing at alarming rates all over the world and is estimated to rise to 552 million adults by 2030 [2]. Saudi Arabia is the seventh of the top ten countries in terms of the prevalence of diabetes among the adult population [3].

Thyroid disorders are also very common in the general population and it is second only to DM as the most common condition to affect the endocrine system [4,5]. Type 2 diabetes mellitus (T2DM) and thyroid diseases tend to co-exist together and thyroid diseases are more common in DM than in general population [6,7]. The association between T2DM and thyroid dysfunction were first published in 1979 [8]. Various studies have estimated the prevalence of thyroid disorder in diabetic patients, in few studies higher prevalence in T2DM has been estimated [9,10].

Altered thyroid hormones have been described in patients with DM especially those with poor glycemic control. T2DM may affect thyroid function either at the level of hypothalamic control of thyroid stimulating hormone (TSH) release or at the conversion of thyroxine (T4) to triiodothyronine (T3) in the peripheral tissue. It has been well documented that hyperglycemia leads to reversible reduction of the activity and hepatic concentration of T4-5-deiodinase, which leads to low serum concentration of T3 and low, normal, or high levels of T4 [11].

Although related to glycemic control, the pathophysiology of thyroid hormone alterations in patients with T2DM has never been fully investigated. In some conditions, T2DM is related to abnormal thyroid function, involving very low glucose level in the blood and also renal disorders [12,13]. The presence of T2DM is also related to the insufficiency of the replacement of thyroid hormone in elderly patients with hypothyroidism [14]. Several studies have been conducted to find out the prevalence of thyroid dysfunction in diabetic patients but only few studies have compared the levels of thyroid hormone with glycemic status in diabetic patients. The present study is carried out to find out the inter relation between the glycemic status and levels of thyroid hormones in T2DM.

Methods
A cross-sectional study was conducted in the Diabetes centre at King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia between January 2018 to December 2018 for a period of 12 months which included 1168 patients who were diagnosed as T2DM on the basis of ADA criteria [15]. Patients who are pregnant were excluded. TSH was measured with a chemiluminescent immunoassay method (CMIA) (Architect i2000 system, Abbott, USA). Serum free thyroxine (FT4) was estimated by radioimmunoassay. The assays have intra- assay precision of 4.3%. TSH levels between 0.22-4.2mIU/L and Free T4 12.0-22.0pmol/L were regarded normal [16]. High performance liquid chromatography was used. HbA1c was expressed as percentage.

Statistical Analysis
Data are presented as means ± standard deviation (SD) or numbers (%). Quantitative variables were compared between two groups by using the Student’s test. Differences in categorical variables were analyzed using the chi-square test. The relationship between continuous variables was assessed using coefficients of correlation. Multivariate linear regression model was constructed using TSH and FT4 as the dependent variables and factors with either a P-value less than 0.15 in the univariate analysis or a previously reported association with either TSH or FT4 as independent variables. Null hypotheses were rejected where p values were less than 0.05. Logistic regression analysis was carried out to estimate odds ratio (OR) and 95% CI. P value <0.05 indicates significance. The statistical analysis was conducted with SPSS version 23.0 for Windows.

Results
A total of 1168 participants with T2DM were included in this study. Average age of the study population was 55.1 ±16.2 years (table 1). 31.7% were male and 68.3% were female. Mean HbA1c (%), TSH and FT4 were 7.4 ±2, 3.3 ±4.8mIU/l and 13.7 ±3.2pmol/L respectively. TSH was statistically significant higher in patients with HbA1c≥7 compared to patients with HbA1c<7 (p=0.02) (figure 1) with statistically non-significant difference between males and females (figure 2). FT4 was statistically significant lower in patients with HbA1c≥7 compared to patients with HbA1c<7 (p=0.009) (figure 3) with statistically significant higher FT4 in females compared to males in patients with HbA1c<7 (p=0.01)(figure 4).

The second linear regression model using serum FT4 level as the dependent variable was performed with age and HbA1c as independent variables (Table 3). In the constructed model, HbA1c level was found to be an independent predictor of serum FT4 level (P=0.03).

A statistically significant positive correlation was observed between TSH and HbA1c (r = 0.060, P = 0.04) (Figures 5). Also, a significant negative correlation was observed between FT4 and HbA1c (r = -0.068, P = 0.03) (figure 6).

Discussion
Since the measurement of HbA1c levels is important not only for monitoring of T2DM, the results of our study showed an obvious association between elevation of HbA1c levels and high TSH and low FT4 in patients with T2DM in corroboration with others [17,18]. Previous studies reported that T2DM do not affect FT4, therefore observed normal level of FT4 in diabetic patients when compared with reference range, hypothesize that medication of T2DM may influence the thyroid hormone profile thus observed normal results of FT4 [19]. However, our observation on the variation in TSH level is in harmony with the results of Cappelli et al. and in contrast to other [19,20]. These differences appear to be also due to DM medications Furthermore, the result of correlation test showed a positive correlation between HbA1C and TSH in T2DM, these observations are consistent with previous studies Udiong et al. who reported significant association between HbA1C and TSH [21]. In contrast the results of HbA1c and FT4 showed significantly negative correlation, this finding was disagreed with studies performed by Saha et al. which showed no correlation between HbA1c and FT4 among diabetic patient with T2DM [18,20].

In our study, there was a raised mean TSH levels in diabetics with HbA1c ≥7 as compared to <7. These findings were supported by the study of Uppal et al who reported raised mean TSH levels in diabetics as compared to controls with a non-significant p value [22]. Other studies like Moura-Neto et al and Islam et al have found the same results with a non-significant p value [23,24]. Some other studies like Farasat et al, Saha et al and Bharat et al showed a significantly raised TSH lev-els in diabetics as compared to healthy controls [25-27]. These findings were contrary to the study done in Calabar, Nigeria by Udiong et al in 2007 on diabetics and healthy controls [28]. They have found a low mean TSH level in diabetics as compared to healthy controls.

In the present study, there was a significant lower serum FT4 levels in diabetics with HbA1c ≥7 as compared to <7. This finding is in discordance with others [25,29,30]. Farasat et al reported that patients with T2DM had significantly raised serum T4 levels as compared to controls with a p value of 0.02.25 But our findings are in accordance to the findings of Uppal et al who conducted a study on 120 diabetics and 117 healthy controls [22] They found a low serum T4 levels in diabetics as compared to controls but with a non-significant p value. Moura-Neto et al conducted a study on 52 diabetics and 52 healthy controls [23]. They found a low serum total thyroxine (TT4) level in diabetics as compared to healthy controls (p=0.006). Other studies also observed a low TT4 levels in diabetics as compared to healthy controls [12,31,32].

It has been suggested that altered thyroid status in T2DM is linked toleration of hypothalamo-pituitarythyroid axis causing decreased formation of TT4. Also there is less activation of AMPK (5’-Adenosine Mono Phosphate activated Protein Kinase) in T2DM that also causes decreased formation of thyroid hormones [33]. Decrease levels of thyroid hormones cause increased TSH release from anterior pituitary gland by feedback mechanism [13,27,34] Most of the T2DM patients were obese who might have increased level of leptin. This increased level of leptin develops leptin resistance centrally that causes decreased formation of thyroid hormones and increase TSH secretion [33]. Moreover the binding affinity of TT4 is increased in T2DM that causes decrease formation of FT4 in blood. [13,27]. T2DM are also associated with obesity, stress, infection that caused changes in hypothalamo-pituitary thyroid axis lead to decrease level of FT4 and increased TSH level in T2DM [33] The hyperglycaemia seen in patients with T2DM is known to have negative effect on thyroid function precisely blunting the pituitary TSH response to stimulation by hypothalamic TRH. This may be due to possible alteration of post translational glycosylation of TRH hence affecting its biological activity [35]. T2DM is associated with increased insulin level and C-peptide level. Insulin is an anabolic hormone known to enhance TSH turnover, which is protein in nature. Recently, C-peptide has been shown to enhance Na+/K+- ATPase activity, an action that may also increase protein synthesis. Such an action would induce increased turnover of TSH, a protein hormone [36,37].

Our results showed a non-statistically significant different levels between thyroid hormones in diabetics with HbA1c ≥7 as compared to <7 in both males and females. Still, detailed molecular mechanisms remain unclear, because sex hormones (such as estrogen, and testosterone) can regulate the thyroid function [38]. The difference in sex hormones may partly explain the sex-difference in the relationship between thyroid hormone levels. However, because levels of sex hormones such as testosterone and estrogen were not measured in this study, further research is needed to explore this issue. In addition, because the sample size was smaller for males (31.7%) than in females (68.3%), the precision and statistical power of the analysis may be lower for males. Further large-scale population studies are required to confirm the above findings.

We aimed to identify the relation between HbA1c and TSH and FT4 levels in patients with T2DM in hospital-based health care setting. Furthermore, due to the cross sectional nature of this study, the observed population reflects a selected yet comprehensive group of patients rather than the general population. In addition, the current study population may appear limited in size and therefore may underestimate the true relation between HbA1c and TSH and FT4 levels in patients with T2DM.

Conclusions
We conclude that despite the limitations of this hospital-based cross sectional study, poor glycemic control is associated with abnormal thyroid hormones in cohort of Saudis with T2DM. In the absence of registry data, larger cooperative studies involving diverse population samples from multiple centers could help to provide further information on the true relation nationally.

Bibliography

1. Marshall, W. J. (2000). Lipids and lipoproteins Clinical chemistry, 4th Ed. London: Mosby book, (pp. 231-235).
2. Whiting, D. R., Guariguata, L., Weil, C. & Shaw, J. (2011). IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract., 94(3), 311-321.
3. IDF Diabetes Atlas 5th edition 2012 update. International Diabetes Federation.
4. Singh, G., Gupta, V., Sharma, A. K. & Gupta, N. (2011). Evaluation of Thyroid Dysfunction Among type 2 diabetic Punjabi population. Advances in Bioresearch, 2(2), 3-9.
5. Sathish, R. & Mohan, V. (2003). Diabetes and thyroid Disease. Int J Diab Dev Countries., 23, 120-123.
6. Perros, P., McCrimmon, R. J., Shaw, G. & Frier, B. M. (1995). Frequency of thyroid dysfunction in diabetic patients: value of annual screening. Diabet Med., 12(7), 622-627.
7. Jung, E. S., Han, D. K., Yang, E. M., Kim, M. S., Lee, D. Y. & Kim, C. J. (2014). Thyroid autoimmunity in children and adolescents with newly diagnosed type 1 diabetes mellitus. Ann Pediatr Endocrinol Metab., 19(2), 76-79.
8. Feely, J. & Isles, T. E. (1979). Screening for thyroid dysfunction in diabetics. Br Med J., 1(6179), 1678.
9. Pasupathi, P., Bakthavathsalam, G., Saravanan, G. & Sundaramoorthi, R. (2008). Screening for thyroid dysfunction in the diabetic / non-diabetic population. Thyroid Science, 3(8), CLSI-6.
10. Pimenta, W. P., Mazeto, G. M., Callegaro, C. F., Shibata, S. A., Marins, L. V., Yamashita, S., et al. (2005). Thyroid disorders in diabetic patients. Arq Bras Endocrinol Metabol., 49, 234-240.
11. Gursoy, N., Tuncel, E., Erturk, E., Imamoglu, S. & Arinik, A. (1999). The relationship between the glycemic control and the hypothalamus-pituitary-thyroid Axis in Diabetic Patients. Turk J Endocrinol Meta., 4, 163-168.
12. Celani, M. F., Bonati, M. E. & Stucci, N. (1994). Prevalence of abnormal thyrotropin concentrations measured by a sensitive assay in patients with type 2 diabetes mellitus. Diabetes Res., 27(1), 15-25.
13. Rai, S., Kumar, J. A., Prajna K, Shetty, S. K., Rai, T., Shrinidhi, K., et al. (2013). Thyroid function in type 2 diabetes mellitus and in diabetic nephropathy. J Clin Diagn Res., 7(8), 1583-1585.
14. Somwaru, L. L., Arnold, A. M., Joshi, N., Fried, L. P. & Cappola, A. R. (2009). High frequency of and factors associated with thyroid hormone overreplacement and under-replacement in men and women aged 65 and over. J Clin Endocrinol Metab., 94(4), 1342-1345.
15. American Diabetes Association (2019). Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2019. Diabetes Care, 42(Supplement 1), S13-S28.
16. dos Remedios, L. V., Weber, P. M., Feldman, R., Schurr, D. A. & Tsoi, T. G. (1980). Detecting unsuspected thyroid dysfunction by the free thyroxine index. Arch Intern Med., 140(8), 1045-1049.
17. Vikhe, V. B., Kanitkar, S. A., Tamakuwala, K. K., Gaikwad, A. N., Kalyan, M. & Agarwal, R. R. (2013). Thyroid dysfunction in patient with type 2 diabetes mellitus at tertiary care centre. Natl J Med Res., 3(4), 377-380.
18. Saha, H. R., Sarkar, B. C., Khan, S. A., Sana, N. K. & Choudhury, S. (2012). A comparative study of thyroid hormone and lipid status in diabetic and non diabetic adults. Open Access Sci Rep., 1(9), 1-5.
19. Cappelli, C., Rotondi, M., Pirola, I., Agosti, B., Gandossi, E., Valentini, U., et al. (2009). TSH-lowering effect of metformin in type 2 diabetic patients: Differences between euthyroid, untreated hypothyroid, and euthyroid on L-T4 therapy patients. Diabetes Care, 32(9), 1589-1590.
20. Karar, T., Alhammad, R. S., Fattah, M. A., Alanazi, A. & Qureshi, S. (2015). Relation between glycosylated hemoglobin and lipid and thyroid hormone among patients with type 2 diabetes mellitus at King Abdulaziz Medical City, Riyadh. J Nat Sc Biol Med., 6(Suppl 1), S75-9.
21. Udiong, C. E., Etukudoh, M. H. & Essien, O. E. (2007). Thyroid hormones and glycemic indices in types 1 and 2 diabetes mellitus. J Med Lab Sci., 16(2), 1192-1195.
22. Uppal, V., Vij, C., Bedi, G. K., Vij, A. & Banerjee, B. D. (2013). Thyroid Disorders in Patients of Type 2 Diabetes Mellitus. Ind J Clin Biochem., 28(4), 336-341.
23. Moura Neto, A., Parisi, M. C., Tambascia, M. A., Alegre, S. M., Pavin, E. J. & Zantut-Wittmann, D. E. (2013). The influence of body mass index and low-grade systemic inflammation on thyroid hormone abnormalities in patients with type 2 diabetes. Endocr J., 60(7), 877-884.
24. Islam, S., Yesmine, S., Khan, S. A., Alam, N. H. & Islam, S. (2008). A Com-parative study of thyroid hormone levels in diabetic and non-diabetic patients. Southeast Asian J Trop Med Public Health., 39(5), 913-916.
25. Farasat, T., Majeed, A., Cheema, et al. (2011). Relationship of Thyroid Hormones with Serum Fasting Insulin and Insulin Resistance in Euthyroid Glycemic Anomalies. Pak J Zool., 43(2), 379-386.
26. Saha, H. R., Khan, H., Sarkar, B. C., Khan, S. A., Sana, N. K., Sugawara, A., et al. (2013). A Comparative Study of Thyroid Hormone and Lipid Status of Patient with and without Diabetes in Adults. Open J Endo Meta Dis., 3(2), 113-119.
27. Bharat, Hijam, D., Gangte, D., Lalnunpui, Premchand, Devi, I., et al. (2013). Thyroid Status in Diabetes Mellitus. J Glycom Lipido., 3, 1-4.
28. Udiong, C. E., Udoh, A. E. & Etukudoh, M. E. (2007). Evaluation of thyroid function in Dtes mellitus. in Calabar Nigeria. Ind J Clin Biochem., 22(2), 74-78.
29. Wadud, S., Ahmad, M. & Khan, F. (2017). Relationship of glycemic control with thyroid hormone levels in patients with type 2 diabetes mellitus. J Postgrad Med Inst., 31(4), 353-356.
30. Narayana, K. S., Koora, S., Basha, S. & Shaker, I. V. (2012). The evaluation of selenium and thyroid hormones among the population with diabetes mellitus. Ind J Bas App Med Res., 1, 251-258.
31. Donckier, J. E. (2003). Endocrine diseases and diabetes In: Pickup JC, Williams G. Editors. Text book of diabetes mellitus Chichester: Blackwell, 21-27.
32. Schlienger, J. L., Anceau, A., Chabrier, G., North, M. L. & Stephan, F. (1982). Effect of diabetic control on the level of circulating thyroid hormones. Diabetologia, 22(6), 486-488.
33. Swami, R. M., Kumar, N., Srinivasa, K., Manjunath, G. N., Byrav, P. D. S. & Venkatesh, G. (2012). Evaluation of hypothyroidism as a complication in Type II Diabetes Mellitus. J Biomed Res., 23(2), 170-172.
34. Hage, M., Mira, S., Zantout, M. S. & Azar, S. T. (2011). Thyroid disorders and diabetes mellitus. J Thy Res., 10, 2-7.
35. Suresh, D. R., Silvia, C. R. & Murthy, U. K. (2014). Inter- relationship of glycemic control and thyroid status in type-2 diabetes mellitus. International Journal of Clinical and Diagnostic Research, 2(4).
36. Bassyouni, A., Ebrashy, I. E., Ismiel, A., Amara, I., Mahfouz, M. & Halmy, N. (2010). Profile of the thyroid function and ultrasound among patients with type-2 diabetes mellitus. Sci Med J., 22(2), 15-28.
37. Shaikh, A. W., Memon, A. S. & Sirichand (2009). Frequency of hypothyroidism in type 2 diabetic patients. Pakistan J Med Health Sci., 2(4).
38. Boucai, L., Hollowell, J. G. & Surks, M. I. (2011). An approach for development of age-, gender-, and ethnicity-specific thyrotropin reference limits. Thyroid, 21(1), 5-11.