Thyroid dysfunction and risk factors in patients with newly diagnosed type 2 diabetes: A cross-sectional study

Background : Diabetes mellitus (DM) and thyroid dysfunction (TD) are two closely associated disorders. The coexistence of TD could adversely influence metabolic control and even increase the long-term mortality in patients with DM. The objective of the present study was to investigate the prevalence and risk factors of TD in patients with type 2 DM (T2DM). Methods : This is an observational cross-sectional study. A total of 340 patients with newly diagnosed T2DM who were admitted to ward of endocrinology department were included for analysis. Thyroid function was examined and its relationship with demographic, metabolic and diabetes-related parameters were evaluated Results : The prevalence of TD was 21.2% in the total population. The low T3 syndrome was the most frequent TD, in 14.7% of patients. Low FT3 level was associated with diabetic complications including presence of diabetic ketosis (DK) or diabetic ketoacidosis (DKA) (r = -0.388, P ≤ 0.001) and microalbuminuria (r = -0.302, P ≤ 0.001). Metabolic and demographic factors, including age, glycemic control and insulin resistance also correlated with levels of thyroid hormones. DK or DKA (OR = 6.161, P ≤ 0.001) and microalbuminuria (OR = 3.950, P = 0.002) were risk factors of low T3 syndrome. Conclusion : TD is not rarely seen in patients with newly diagnosed T2DM. Diabetic complications and diabetes-related metabolic and demographic factors are related to the presence of TD.


Background
Diabetes mellitus (DM) and thyroid dysfunction (TD) are two closely associated disorders. TD is more common in patients with type 2 DM (T2DM) than in those without diabetes and can adversely influence the metabolic control [1,2]. In the long-term, the onset of thyroid dysfunction can further increase the morbidity and mortality associated with diabetes [2]. The relationship between T2DM and TD is complex and the underlying mechanisms have not been fully elucidated. Several studies have investigated the prevalence and risk factors of TD in patients with T2DM. But researches in newly diagnosed patients were relatively rare. The objective of this study was to investigate the prevalence of TD and determine the risk factors in patients with newly diagnosed T2DM.

Study population and design
We studied patients with newly diagnosed T2DM who were admitted to ward of the Department of 3 Endocrinology, The Second Affiliated Hospital of Guangzhou Medical University, from January 2014 to June 2019. The inclusion criteria were adults with newly diagnosed and treated T2DM based on the diagnostic criteria recommended by the Chinese Diabetes Society [3]. The exclusion criteria included: A. with history of thyroid disease or thyroid surgery; B. severe primary liver and kidney dysfunctions; C. using drugs potentially altering thyroid hormone concentrations such as amiodarone, beta-blockers and corticosteroids. A total of 340 patients with newly diagnosed T2DM were finally enrolled.

Measurement and data collection
Demographic information including family history and habit of smoking was collected through the review of medical records. Body mass index (BMI) was calculated as weight (kg) divided by squared height (m). Blood pressure (BP) was detected twice in a sitting position after a 10-minute rest period and recorded as a mean of the two successive measurements.  3.

Statistical analysis
For continuous variables like thyroid hormones, student's t-test or one-way analysis of variance

Baseline characteristics
Detailed baseline demographic and clinical characteristics of included patients were presented in

Analyses of associated factors of thyroid function
Among the categories of thyroid disorders, low T3 syndrome (n = 50, 14.7%) was the most common form, followed by subclinical hyperthyroidism (n = 14, 4.1%), hypothyroidism (n = 6, 1.8%) and subclinical hypothyroidism (n = 2, 0.6%). Higher prevalence of thyroid dysfunction was found in ratio. No factor was found to be strongly correlated with TSH level (Table 2). 6 3.

Analyses of associated factors of low T3 syndrome
Comparisons between patients with low T3 syndrome and patients with normal thyroid function was shown in Table 1. There was a significant association between the presence of low T3 syndrome and DK or DKA, microalbuminuria, HbA1c, fasting C-Peptide, 2-h C-Peptide, 2-h insulin, HOMA-IR and DBP.

Discussion
The prevalence of TD varied in patients with DM in different regions, ranging from 4% to over 20% [2]. The differences can be explained by the large population diversity, the varied degree of iodine intake, different diagnostic criteria of TD and different sensitivities of laboratory assays [6].
Subclinical hypothyroidism or hypothyroidism was reported to be the most common form of thyroid dysfunction in several studies [6][7][8][9]. In this study, a relatively high prevalence of thyroid dysfunction was found, among which low T3 syndrome constituted the majority.
The low T3 syndrome, also known as euthyroid sick syndrome (ESS) or nonthyroidal illness syndrome (NTIS), was initially described in the 1970s. It represents a state of alterations in thyroid hormone economy, which usually present in critically ill patients [10]. The low T3 syndrome is characterized by decreased serum T3 and T4 concentrations, increased serum reverse T3 (rT3) concentrations and unaltered or inappropriately low serum TSH [11]. Complicated mechanisms were involved in its pathogenesis, including downregulation of TRH and TSH production, changes in thyroid hormone metabolism and inhibitory effect of cytokines on the thyroid gland [12]. The presence of low T3 syndrome is a predictor of poor prognosis of acute or chronic illnesses.
DK or DKA was found to be a risk factor of low T3 syndrome in this study. Previous studies mainly focused on type 1 diabetes mellitus (T1DM), but showed similar results. TD including low T3 syndrome and hypothyroidism was more common in patients with DKA [13][14][15][16]. The presence of low T3 syndrome was associated with poor glycemic control [13,14] and free thyroid hormones were correlated with the severity of DKA [14], which was in accordance with our findings. The decreased thyroid hormones could increase to normal soon after correction of DKA [13,15].
The relationship between thyroid hormones and diabetic nephropathy (DN) is becoming a concern these years. A study in euthyroid subjects with T2DM showed that low levels of thyroid hormones (FT3 and FT4) were associated with DN [17]. DN was a risk factor of thyroid dysfunction in patients with T2DM [8.9]. High levels of TSH and low levels of FT3 were observed in T2DM patients with DN [18].
Moreover, high levels of TSH and/or low levels of FT3 were associated with more severe proteinuria, renal insufficiency and glomerular lesions in patients with DN [19]. We also observed lower FT3 level and FT3/FT4 ratio in patients with microalbuminuria. The presence of low T3 syndrome was significantly associated with microalbuminuria. Recently, a study in adult euthyroid patients with T1DM showed that higher FT3 level was related to lower prevalence of microangiopathy and better metabolic control [20], which further supported our findings.
Levels of thyroid hormones were also suggested to be associated with some metabolic and demographic parameters. A study in non-diabetic individuals demonstrated that low T3 levels were significantly associated with decreased HOMA-IR, which indicated an association of thyroid function with insulin resistance [21]. FT3 and FT4 positively and negatively correlated with HOMA-IR and atherogenic lipid profiles, respectively, in a euthyroid population with obesity [22]. In euthyroid subjects, serum FT4 was negatively associated with and TSH was positively associated with insulin resistance. Also, FT4 was associated with risk of metabolic syndrome [23]. TSH and thyroid hormones were found to correlated with multiple cardiometabolic risk factors, with age-and sex-independent effects on cholesterol and glucose metabolism [24]. We also find some relationships between thyroid hormones and metabolic parameters including HOMA-IR, HbA1c, serum insulin and C-peptide levels.
In some studies, obesity was also a risk factor of TD [8. 9]. Both FT3 and FT4 levels were positively correlated with BMI in euthyroid subjects with obesity [23]. Higher FT3 concentration correlated positively with markers of obesity such as BMI in euthyroid T1DM patients [20]. However, we did not find significant difference in levels of thyroid hormones between patients with obesity (BMI ≥ 28 kg/m 2 ) and patients with relatively normal BMI values. A recent large population-based study 8 demonstrated that elevated TSH level within the normal range was a risk marker associated with a series of cardiometabolic changes including central obesity, insulin resistance, elevated BP, dyslipidemia, hyperuricemia, inflammation and hypercoagulability [25]. But in this study, we did not find significant relationship between TSH and other metabolic parameters.
Advanced age, long duration of diabetes and poor glycemic control were commonly indicated to be risk factors of low levels of FT3 and TD in patients with T2DM [8. 9]. And the abnormalities seemed to be reversed upon restoration of metabolic control [26]. We also discovered higher prevalence of TD or low T3 syndrome in patients over 60 years old and patients with higher glycemic levels. TD was reported to be more common in female as compared to male patients with T2DM in many studies [9, 27. 28]. However, no gender difference was indicated in our study. This may be partly attributed to the different inclusion criteria. Most studies did not include low T3 syndrome as a form of TD. This may also explain the relatively higher prevalence of thyroid dysfunction (21.2%) in our study since low T3 syndrome contributed over 50% of the disorders. Furthermore, subjects in the present study were admitted in ward for treatment of diabetes. The conditions of patients, particularly glycemic control, were generally worse than the ones in outpatient clinics. Actually, most subjects in our study had a HbA1c level over 10%. This may also contribute to the high prevalence of TD. There

Availability of data and material
The data used for analysis are available from the corresponding author on reasonable request.

Competing interests
All authors have no competing interests.

Funding
The present study was supported by grants from the National Natural Science Foundation of China

Authors' contributions
XZ designed the study. XZ, YL, YM, DY, and SM collected the data. XZ, YL, and YM analyzed the data.
XZ and WL wrote the manuscript. All authors have read and approved the final manuscript.

Supplementary Files
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