Impaired Sensitivity to Thyroid Hormones Is Associated With Elevated Blood Glucose in Coronary Heart Disease

Context Thyroid hormones influence glucose homeostasis through central and peripheral regulation. To date, the association between thyroid hormone sensitivity and elevated blood glucose (EBG) in patients with coronary heart disease (CHD) remains unknown. The purpose of this study was to investigate the association between thyroid hormone sensitivity and risk of EBG in patients with CHD, and to further explore their association in different sexes and ages. Methods This large multicenter retrospective study included 30,244 patients with CHD (aged 30–80 years) between 1 January 2014 and 30 September 2020. Parameters representing central and peripheral sensitivity to thyroid hormones were calculated. Central sensitivity to thyroid hormones was assessed by calculating the Thyroid Feedback Quantile-based Index (TFQI), Thyroid-stimulating Hormone Index (TSHI), and Thyrotropin Thyroxine Resistance Index (TT4RI), and Parametric Thyroid Feedback Quantile-based Index (PTFQI); peripheral sensitivity to thyroid hormones was evaluated using the ratio of free triiodothyronine (FT3) /free thyroxine (FT4). Taking normal glucose tolerance (NGT) as a reference, logistic regression was used to analyse the relationship between central and peripheral thyroid hormone sensitivity and EBG in patients with CHD. Results Among the 30,244 participants, 15,493 (51.23%) had EBG. The risk of EBG was negatively correlated with TSHI (OR: 0.91; 95%CI: 0.91 to 0.92; P < 0.001), TT4RI (OR: 0.99; 95% CI: 0.99 to 0.99; P<0.001), TFQI (OR: 0.82; 95%CI: 0.80 to 0.84; P <0.001) and PTFQI (OR: 0.76; 95%CI: 0.74 to 0.78; P<0.001). Compared to males and patients aged 60 and below, the OR value for EBG was lower in females and in patients aged over 60 years old. Conversely, EBG risk was positively associated with FT3/FT4 (OR: 1.08; 95% CI: 1.07 to 1.09; P <0.001) and in the sex-categorized subgroups, males had higher OR values than females. Conclusions This study showed that thyroid hormone sensitivity is significantly associated with EBG in patients with CHD. This association is higher in females than in males, and the association in those aged over 60 years old is higher than that in patients aged 60 years and below.


INTRODUCTION
Cardiovascular diseases are the leading cause of death worldwide (1), seriously affecting the patient's quality of life and longevity (2,3). The vast majority of cardiac deaths are caused by coronary heart disease (CHD) secondary to coronary atherosclerosis (4). The relationship between CHD and thyroid hormones is very close, and abnormal thyroid hormones often accompany patients with CHD (5)(6)(7)(8)(9). In addition, patients with CHD and EBG are at a higher risk of nephropathy and other cardiovascular diseases. CHD complicated with diabetes is associated with decreased insulin sensitivity, impaired blood pressure regulation, damaged vascular endothelial cells and dysfunction of the fibrinolytic system (10,11). Lowering blood sugar is extremely important to improve prognosis and prevent the onset of cardiovascular diseases (12)(13)(14). Diabetes has been clinically defined as fasting or postprandial hyperglycaemia or abnormally increased glucose excursion in response to an established glucose load. However, this clinical definition defines a relatively late stage in the disease process. Indeed, a defect in glucose homeostasis can be detected long before diabetes occurs.
For early prevention and treatment of secondary elevated blood glucose (EBG) in patients with CHD, identifying the risk factors of prediabetes and diabetes is a critical step. Recent theories show that hypothyroidism and subclinical hypothyroidism are risk factors for diabetes (15). However, some researchers believe that elevated thyroid stimulating hormone (TSH) is a risk factor for diabetes, and an increase in free triiodothyronine (FT3) and free thyroxine (FT4) has a protective effect on the occurrence of diabetes (16). TI de Vries et al. reported that there was no significant relationship between plasma TSH levels in the normal range and the incidence of diabetes in patients at high cardiovascular risk (17). These contradictory results are common. Moreover, almost all previous analyses focused on the influence of TSH and FT4 levels on the risk of prediabetes or diabetes. No research has investigated the association between thyroid hormone sensitivity and EBG in patients with CHD. Furthermore, results of previous studies investigating EBG prevalence in different sexes and ages Abbreviations: CHD, coronary heart disease; CI, confidence interval; DBP, diastolic blood pressure; EBG, elevated blood glucose; FBG, fasting blood glucose; FT3, free triiodothyronine; FT4, free thyroxine; HbA1c, glycated haemoglobin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NGT, normal glucose tolerance; OR, odds ratio; SBP, Systolic blood pressure; SD, standard deviation; TC, total cholesterol; TG, triglyceride; TH, thyroid hormone; TSH, thyroid stimulating hormone. have been inconsistent (18,19). Due to inconsistent results, the relationship among EBG, sex, and age remains controversial.
The thyroid hormones regulate glucose homeostasis by interacting with the entire central nervous system and surrounding target organs (20). Therefore, this large-scale, multicenter retrospective study aimed to investigate the association of central and peripheral sensitivity to thyroid hormones in patients with CHD and EBG. Further, we aimed to explore the differences of these associations in different sexes and ages to provide a basis for clinical adjustments of medication according to the situation of individual patients with CHD, and to improve patient conditions.

Patients
Participants in this study were 107,301 CHD inpatients of cardiology departments from 1 January 2014 to 30 September 2020 from six hospitals in Tianjin. Patients who were younger than 30 years or older than 80 years, had malignancy, infectious or severe liver or kidney disease, incorrect data, and lack of data on TSH, FT3, FT4, fasting blood glucose (FBG), or glycated haemoglobin (HbA1c) were excluded based on the study design. Ultimately, 30,244 participants were included in the study. A flowchart of the patient recruitment process is shown in Figure 1. This study was approved by the ethics committee of Tianjin University of Traditional Chinese Medicine (approval number TJUTCM-EC20190008) and registered with the Chinese Clinical Trial Registry on 14 July 2019 (registration number ChiCTR-1900024535) and ClinicalTrials.gov on 18 July 2019 (registration number NCT04026724).

Data Collection
Trained medical staff collected personal medical history records. These records included information such as age, sex, history of smoking and drinking, which were investigated using standard structured questionnaires (21). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by experienced technicians using automatic blood pressure monitors. Fasting venous blood samples were collected from all participants in the morning. FBG, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and HbA1c were measured directly using an automatic haematology analyser. Quality control was conducted in the laboratory according to standard procedures.

Baseline Characteristics
The baseline characteristics of the 30,244 participants are shown in Table 1. The average age of the subjects was 64 years old, and the proportion of females (48.3%) was slightly lower than that of males (51.7%). Among the participants, 15,493 patients demonstrated EBG (51.2%). The subjects were divided into two groups according to glucose metabolism level. Compared with NGT participants, EBG participants were more likely to be older females with hypertension, dyslipidaemia, and a tendency to smoke and drink. Hypertension, dyslipidaemia, age, smoking, and alcohol consumption were positively associated with EBG, and participants with EBG tended to have higher levels of FT3/ FT4 and lower levels of TSHI, TT4RI, and PTFQI.

Relationship Between Thyroid Hormone Sensitivity and EBG
The association between thyroid hormone sensitivity and EBG was estimated by using different logistic regression models ( Table 2) After adjusted for sex and age, as a continuous variable, TSHI, TT4RI, PTFQI, and TFQI levels were negatively associated, and FT3/FT4 levels was positively associated with EBG risk. These associations remained significant after multivariate adjustment. In the adjusted model, the OR values of TSHI, TT4RI, and PTFQI were the lowest at T3 when T1 was used as a reference. In addition, when used as a continuous variable, FT3/FT4 level was positively correlated with EBG. Considering the differences between prediabetes and diabetes in the presence of abnormal glucose metabolism, different stratified analyses were performed (Supplementary Tables S1-S3).

Relationship Between Thyroid Hormone Sensitivity and EBG in Different Sexes
The relationship between thyroid hormone sensitivity and EBG in the different sexes is shown in Table 3. Subgroup analyses stratified by sex showed that thyroid hormone sensitivity was significantly associated with EBG in both sexes. After adjusted for age, as a continuous variable, the OR values of males for TSHI, PTFQI, TFQI, and EBG were slightly higher than those of females. These differences remained significant after adjusting for the model (P <0.001). Of all the indicators representing central thyroid hormone sensitivity, the PTFQI had the lowest OR value, with females (OR: 0.76; 95%CI: 0.73 to 0.79; P <0.001) having a lower PTFQI than males (OR: 0.77; 95%CI: 0.74 to 0.80; P <0.001).

Relationship Between Thyroid Hormone Sensitivity and EBG In Different Age Stratifications
The relationship between thyroid hormone sensitivity and EBG in different age stratifications is shown in Table 4. After adjusted for sex, as a continuous variable, the OR values of TSHI, PTFQI, and TFQI in patients aged 60 years were slightly higher than

Relationship Between Thyroid Hormone Sensitivity and EBG in Different Sexes and Different Ages
Based on the individual sex and age stratification results, the relationship between thyroid hormone sensitivity and EBG in different sexes and ages was analysed. As shown in Table 5, in the unadjusted and adjusted models, all the central thyroid hormone sensitivity indices had lower OR values with EBG in females aged over 60 years old, and the peripheral thyroid sensitivity index had a higher OR with EBG in females aged 60 and below.

DISCUSSION
To our knowledge, this is the first study to evaluate and confirm the relationship between central and peripheral sensitivity to thyroid hormone indicators and EBG risk in a large sample of patients in China with CHD. Our study found that the central thyroid hormone sensitivity indices TSHI, TT4RI, TFQI, and PTFQI were negatively associated with EBG risk in patients with CHD. With a gradual increase in TSHI, TT4RI, and PTFQI, the OR value of EBG also gradually decreased. Peripheral thyroid hormone sensitivity index FT3/FT4 was positively associated with EBG. Finally, most associations were observed in different sexes and age groups when considered separately.
Previous studies have shown that almost two-thirds of patients with cardiovascular disease suffer from abnormal glucose metabolism (30). Due to the various changes of thyroid hormones in patients with CHD (31), the various effects of thyroid hormones in patients with CHD and EBG deserve attention. However, previous studies showed that higher TSH and lower FT4 (16,32,33), lower TSH (34), higher FT4 (35), and lower FT3 (16,34) levels were all associated with the risk of EBG. Therefore, TSH or thyroid hormone levels alone may not be sufficient to explain the relationship between the thyroid system and glycaemic disorders. Given these inconsistencies in previously proposed central thyroid hormone sensitivity indices (TSHI, TT4RI) and peripheral thyroid hormone sensitivity indices FT3/FT4 (28,(36)(37)(38), in 2019, Laclaustra et al. proposed a new resistance index of central thyroid hormones: TFQI and PTFQI, which approximates TFQI (29). These new indices may have smaller deviations and will not produce extreme values in cases of thyroid dysfunction, which will help to better explain the different associations between the changes in thyroid hormones and diabetes (29).
Based on the new indices, recent studies have found that the increase in TSHI, TT4RI, and PTFQI was associated with reduced prediabetes risk, and the increased FT3/FT4 ratio was associated with an increased risk of prediabetes (23). Unlike our study, the latter had no significant correlation after adjusting for multiple confounding factors. Moreover, our results also suggest that elevated TFQI is associated with a reduced risk of EBG. Laclaustra et al. reported that the cross-section of the TSHI level was not associated with diabetes (29), which is contrary to our results and conclusion. The reasons for these differences are not clear, but may be attributable to confounding factors, differences in study partitions, and sample sizes. Therefore, further studies are needed to validate and confirm these results. Several pathways may explain the observed association between the thyroid hormone central resistance index and EBG. Previous studies have shown that thyroid dysfunction can increase insulin resistance in muscle and adipose tissue and reduce glucose transport in muscle cells (39,40). FT3 may also affect the expression of glucose-secreted insulin and an important protein of lipid metabolism (41); lower FT3 and FT4 levels can promote higher insulin resistance in tissues (42). The change in serum TSH may directly affect metabolic parameters and stimulate leptin secretion (43,44). It is well known that hepatic glucose output is critical for maintaining fasting glucose homeostasis. Leptin has been shown to stimulate hepatic glucose production in vivo and in vitro (45). Moreover, the loss of leptin can lead to problems such as overeating, decreased energy expenditure, and severe obesity, which are important risk factors affecting glucose homeostasis (46). Therefore, the sensitivity of central thyroid hormones may change leptin secretion, affect insulin resistance, and lead to a change in glucose metabolism level. However, the exact regulatory mechanism underlying the relationship between central thyroid hormone sensitivity and leptin remains unclear.
Interestingly, our study also found that when used as a reference in the T1 group, the level of peripheral thyroid hormone sensitivity FT3/FT4 was negatively associated with EBG in the T2 group, but significantly positively associated with EBG when used as a continuous variable. Previously, many studies confirmed the positive effects of elevated FT3/FT4 on diabetes, gestational diabetes, obesity-related inflammatory markers, cardiovascular risk, and arterial stiffness markers (38,(47)(48)(49). Regarding the result of the negative correlation of FT3/FT4 with EBG in the T2 group, the promotion of peripheral deiodinase activity may increase the level of FT3/FT4 (38), and the inhibition of peripheral deiodinase activity may reduce the basal metabolic rate, which is closely related to the pathogenesis of diabetes (50,51). To address sex-and age-specific differences noted in previous studies (35,52,53), we analysed the relationship between thyroid hormone sensitivity and diabetes by sex and age, respectively. The results showed that TSHI, PTFQI, and TFQI of females aged > 60 years had lower OR values for EBG risk, while FT3/FT4 had higher OR values. Sex hormones (such as oestrogen and testosterone) can regulate thyroid function, and oestrogen levels affect the development of diabetes, especially after 60 years of age (54)(55)(56). The differences in sex hormones may partly explain the sex differences in the relationship between thyroid hormone sensitivity and EBG found in this study. However, since this study did not measure the levels of sex hormones, further research is needed to explore this concept.

LIMITATIONS
There are several limitations to the present study. First, although large scale, this was a cross-sectional study, and causality cannot be inferred. However, the study supports the important hypothesis that adding the examination of thyroid hormone sensitivity levels to the examination of pure thyroid hormone levels may be helpful in assessing the risk of EBG. Second, although we have adjusted for many potential confounding factors, we cannot rule out the possibility that EBG is affected by other lifestyle variables, including iodine supplementation, which is intrinsically related to thyroid hormone levels. Third, this study was conducted among individuals who were Chinese, and racial differences may exist. Fourth, this study did not have a track record of whether participants were undergoing diabetes or thyroid disease-specific treatment. Therefore, well-designed randomized controlled trials are needed to validate these results.

CONCLUSION
The decrease in central thyroid hormone indices represents an increase in central thyroid hormone sensitivity. This study showed that thyroid hormone sensitivity is significantly associated with EBG in patients with CHD. This association is higher in females than in males, and the association in those aged over 60 years is higher than that in patients aged 60 years and below. This study provides reliable evidence which will improve the prevention strategies and clinical treatment of EBG in patients with CHD.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

ACKNOWLEDGMENTS
We thank all the participants in the study and the members of the survey teams, as well as the financial support.