Impaired sensitivity to thyroid hormones is associated with elevated blood glucose in coronary heart disease — a RCSCD-TCM study in China

doi:10.21203/rs.3.rs-1429317/v1

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Impaired sensitivity to thyroid hormones is associated with elevated blood glucose in coronary heart disease — a RCSCD-TCM study in China

https://doi.org/10.21203/rs.3.rs-1429317/v1

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Background

Thyroid hormone influences glucose homeostasis through central and peripheral regulations. So far, 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 is 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 CHD patients (aged from 30 to 80) between January 1, 2014 and September 30, 2020. The study calculated the parameters representing central and peripheral sensitivity to thyroid hormones. 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 peripheral sensitivity to thyroid hormones was evaluated by the ratio of FT3/FT4. Taking normal glucose tolerance (NGT) as a reference, participants with diabetes or prediabetes were assigned to the EBG group. The study used logistic regression to analyze the relationship between central and peripheral thyroid hormone sensitivity and EBG in CHD patients.

Results

Among the 30,244 participants, 15,493 (51.23%) had EBG. The risk of EBG was negatively associated with TSHI (OR: 0.86; 95%CI: 0.85 to 0.87; P < 0.001), TT4RI (OR: 0.99; 95% CI: 0.99 to 0.99; P<0.001), TFQI (OR: 0.72; 95%CI: 0.70 to 0.73; P <0.001) and PTFQI (OR: 0.60; 95%CI: 0.58 to 0.61; P<0.001). Compared to males and people aged 60 and below, the OR value for EBG was lower in females and those aged over 60 years old. Conversely, EBG risk was positively associated with FT3/FT4 (OR: 1.25; 95% CI: 1.24 to 1.26; P <0.001) and in the sex-categorized subgroups, males had higher OR values than females.

Conclusions

This study shows that the increase in central thyroid hormone sensitivity is associated with the reduced risk of EBG in CHD patients, among which females and people aged over 60 years old are at higher risk.

elevated blood glucose

coronary heart disease

thyroid hormone sensitivity

diabetes

resistance to thyroid hormones

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 CHD secondary to coronary atherosclerosis [4]. The relationship between CHD and thyroid hormones is very close, patients with CHD are often accompanied by abnormal thyroid hormones [5, 6, 7, 8, 9]. In addition, CHD patients with EBG are at 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 fibrinolytic system [10, 11]. Lowering blood sugar is extremely important to improve prognosis and prevent the onset of cardiovascular diseases [12, 13, 14]. Although diabetes has been clinically defined, that was fasting or postprandial hyperglycemia 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, the defect of glucose homeostasis can be detected long before obvious diabetes occurs.

For early prevention and treatment of secondary EBG in CHD patients, finding risk factors of prediabetes and diabetes is a critical step. Recent theories show that hypothyroidism and subclinical hypothyroidism are risk factors of diabetes [15]. However, some studies believed that the elevated thyroid stimulating hormone (TSH) is a risk factor for diabetes, the increase of free triiodothyronine(FT3) and free thyroxine(FT4) had a protective effect on the occurrence of diabetes [16]. T I de Vries et al. reported that there was no significant relationship between plasma TSH levels in the normal range and incidence of diabetes in patients at high cardiovascular risk [17]. These contradictory results seem to be a common problem. Moreover, almost all previous analyses focused on the influence of TSH and free thyroxine levels on the risk of prediabetes or diabetes. There is no research to investigate the association between thyroid hormone sensitivity and EBG that CHD patients may have. Furthermore, despite previous studies investigating EBG prevalence in different sexes and ages [18, 19], the results are not consistent. Because of such inconsistent results, the relationship between EBG and sex and age remains controversial.

The thyroid hormone regulates glucose homeostasis through its interaction with the whole central nervous system and surrounding target organs [20]. Therefore, this study aimed to investigate the association of central and peripheral sensitivity to thyroid hormones with EBG in CHD patients in a large-scale and multi-center retrospective study and to further explore the differences of these correlations in different sexes and ages, to provide a basis for clinical CHD patients' medication according to the situation, and to better control the patient's condition.

Patients

Participants in this study were 107,301 CHD inpatients in cardiology departments from January 1, 2014 to September 30, 2020, in 6 hospitals in Tianjin. Patients who were younger than 30 years or older than 80 years, malignancy, infectious or severe liver, and kidney disease, incorrect data, and lack of data on TSH, FT3, FT4, and fasting blood glucose (FBG) or glycated haemoglobin (HbA1c) were excluded based on study design. Ultimately, a total of 30,244 participants were included in this study. The flow chart of patient recruitment is shown in Fig. 1. This study was approved by the ethics committee of the Tianjin University of Traditional Chinese Medicine (approval number TJUTCM-EC20190008) and registered with the Chinese Clinical Trial Registry on July 14, 2019 (registration number ChiCTR-1900024535) and in ClinicalTrials.gov on July 18, 2019 (registration number NCT04026724).

Data collection

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

Hypertension is defined as elevated blood pressure (SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg) [22]. Dyslipidemia is defined as TG ≥ 1.7 mmol/L or TC ≥ 5.2 mmol/L or LDL ≥ 3.4 mmol/L or HDL ≤ 1.0 mmol/L [23]. Different levels of glucose metabolism, namely NGT, prediabetes and diabetes, are defined as FPG < 5.6 mmol/L or HbA1c < 5.7%, FPG 5.6 to 6.9 mmol/L or HbA1c 5.7 to 6.4%, FPG ≥ 7.0 mmol/L or HbA1c ≥ 6.5% [24]. Participants with prediabetes or diabetes were assigned to the EBG group and the rest of the NGT group [25, 26].

Indices of thyroid hormone sensitivity

Central indices of thyroid hormone sensitivity included TSH index (TSHI), TSH T4 resistance index (TT4RI), Thyroid Feedback Quantile-based Index (TFQI), and Parametric Thyroid Feedback Quantile-based Index (PTFQI). TSH index, TSHI = ln TSH (mIU/L) + 0.1345 * FT4 (pmol/L) [27]. TSH T4 resistance index, TT4RI = FT4 (pmol/L) * TSH (mIU/L) [28]. TFQI and PTFQI were calculated using the algorithm developed by Laclaustra et al [29]. FT3/FT4 ratio was calculated to evaluate the peripheral thyroid hormone sensitivity.

Statistical analyses

The characteristics of the participants in the different groups were compared using χ2 tests and Mann-Whitney tests. Age, sex, smoking, drinking, hypertension, and hyperlipidemia were considered as potential confounding factors of the association. The TSHI index was divided into tertiles, T1: TSHI index ≤ 1.5, T2: 1.50 < TSHI index < 2.49, T3: TSHI index ≥ 2.49. The TT4RI index was divided into tertiles, T1: TT4RI index ≤ 9.01, T2: 9.01 < TT4RI index < 25.58, T3: TT4RI index ≥ 25.58. The TFQI index was divided into tertiles, T1: TFQI index ≤ -0.23, T2: -0.23 < TFQI index < 0.12, T3: TFQI index ≥ 0.12. The PTFQI index was divided into tertiles, T1: PTFQI index ≤ -0.13, T2: -0.13 < PTFQI index < 0.24, T3: PTFQI index ≥ 0.24. The FT3/FT4 index was divided into tertiles, T1: FT3/FT4 index ≤ 0.29, T2: 0.29 < FT3/FT4 index < 0.41, T3: FT3/FT4 index ≥ 0.41. Logistic regression analysis was used to compare the relationship between thyroid hormone sensitivity and EBG in different tertiles. Missing values are calculated by multiple complement calculation method. All statistical analyses were performed using SPSS 24.0 (IBM Corp, New York, NY, USA).

Baseline characteristics

Baseline characteristics of the 30,244 participants were shown in Table 1. The average age of subjects was 64 years old, and the proportion of females (48.3%) was slightly lower than that of males (51.7%). Among them, 15,493 patients had EBG (51.2%). All subjects were divided into two groups according to the level of glucose metabolism. Compared with NGT participants, EBG participants were more likely to be older females with hypertension and dyslipidemia, who tended to be more likely to smoke and drink. Our results showed that hypertension, dyslipidemia, 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.

Table 1

Baseline characteristics
Characteristic	Total(n = 30244)	NGT(n = 14751)	EBG(n = 15493)	P-value
Sex,n(%)				0.192
Males	15640(51.71)	7605(51.56)	8035(51.86)
Females	14604(48.29)	7146(48.44)	7458(48.14)
Age(y),median(IQR)	64(58,69)	64(57,68)	64(58,69)	<0.001
Dyslipidemia,%	19427,64.23	8617,58.42	10810,0.70	<0.001
Hypertension,%	11674,38.60	4878,33.07	6796,0.44	<0.001
Smoking,%	9328,40.37	4413,39.17	4915,0.32	<0.001
Drinking,%	6844,29.71	3222,28.71	3622,0.23	<0.001
FPG(mmol/L),median(IQR)	5.53(4.90,6.96)	4.90(4.56,5.20)	6.98(6.1,8.89)	<0.001
HbA_1c(%),median(IQR)	6.30(5.70,7.40)	5.70(5.40,6.10)	6.7(5.9,7.8)	<0.001
FT3(pmol/L),median(IQR)	3.83(2.87,4.43)	3.99(3.31,4.52)	3.61(2.64,4.32)	<0.001
FT4(pmol/L),median(IQR)	12.05(4.01,14.32)	12.16(8.34,14.04)	11.88(1.13,14.64)	<0.001
TSH(mIU/L),median(IQR)	1.80(1.18,2.75)	1.83(1.21,2.78)	1.78(1.14,2.72)	<0.001
FT3/FT4,median(IQR)	0.33(0.27,2.10)	0.33(0.28,0.44)	0.34(0.27,2.30)	<0.001
TSHI,median(IQR)	2.06(1.15,2.71)	2.16(1.40,2.73)	1.93(0.95,2.69)	<0.001
TT4RI,median(IQR)	17.17(4.55,30.91)	19.22(8.50,32.44)	14.47(2.76,29.44)	<0.001
TFQI,median(IQR)	−0.05(−0.33,0.22)	−0.02(−0.29,0.22)	−0.08(−0.37,0.21)	<0.001
PTFQI,median(IQR)	0.06(−0.24,0.32)	0.10(−0.17,0.33)	0.01(−0.31,0.31)	<0.001
Data are presented as median (interquartile) or number (proportion, %).

Relationship between thyroid hormone sensitivity and EBG

The association between thyroid hormone sensitivity and EBG was estimated using different logistic regression models. Table 2 In the unadjusted model, as a continuous variable, TSHI, TT4RI, PTFQI, and TFQI levels were negatively associated with EBG risk, FT3/FT4 level is positively associated with EBG risk. These associations remained significant after multivariate adjustment. In both unadjusted and adjusted models, the TSHI, TT4RI ,and PTFQI levels for T2 and T3 were associated with an increased OR for EBG when T1 was used as a reference; however, the relationship between TFQI level and EBG showed an opposite trend (P for trend < 0.001). In addition, compared with the T1 group, FT3/FT4 level was negatively associated with EBG in the T2 group (OR: 0.56;95%CI: 0.54 to 0.57), however, it was positively correlated with EBG in the T3 group (OR: 1.22;95%CI: 1.19 to 1.25). Considering the differences between prediabetes and diabetes in the presence of abnormal glucose metabolism, this study carried out different stratified analyses.(Table S1-S3)

Table 2

Relationship between thyroid hormone sensitivity and EBG
Variables	EBG
Variables	OR(95% CI)¹	P-value	OR(95% CI)²	P-value
TSHI	0.86(0.85–0.87)	<0.001	0.85(0.84–0.85)	<0.001
T1	Reference		Reference
T2	0.56(0.55,0.57)	<0.001	0.56(0.55–0.57)	<0.001
T3	0.65(0.63,0.66)	<0.001	0.63(0.61–0.64)	<0.001
P for Trend		<0.001		<0.001
TT4RI	0.99(0.99–0.99)	<0.001	0.99(0.99–0.99)	<0.001
T1	Reference		Reference
T2	0.49(0.48–0.50)	<0.001	0.49(0.48–0.50)	<0.001
T3	0.55(0.54–0.56)	<0.001	0.54(0.52–0.55)	<0.001
P for Trend		<0.001		<0.001
TFQI	0.72(0.70–0.73)	<0.001	0.68(0.67–0.70)	<0.001
T1	Reference		Reference
T2	0.77(0.75–0.79)	<0.001	0.76(0.74–0.78)	<0.001
T3	0.76(0.75–0.79)	<0.001	0.73(0.71–0.75)	<0.001
P for Trend		<0.001		<0.001
PTFQI	0.60(0.58–0.61)	<0.001	0.57(0.56–0.59)	<0.001
T1	Reference		Reference
T2	0.61(0.59–0.62)	<0.001	0.61(0.59–0.62)	<0.001
T3	0.65(0.64–0.67)	<0.001	0.63(0.62–0.65)	<0.001
P for Trend		<0.001		<0.001
FT3/FT4	1.25(1.24–1.26)	<0.001	1.26(1.25–1.27)	<0.001
T1	Reference		Reference
T2	0.56(0.54–0.57)	<0.001	0.57(0.56–0.58)	<0.001
T3	1.22(1.19–1.25)	<0.001	1.25(1.22–1.28)	<0.001
P for Trend		<0.001		<0.001
¹Model 1: adjusted for age, sex;
²Model 2: adjusted for age, sex, hypertension, hyperlipidemia, smoking, drinking.

Relationship between thyroid hormone sensitivity and EBG in different sexs

The relationship between thyroid hormone sensitivity and EBG in different sexes

were shown in Table 3. Subgroup analyses stratified by sex showed that thyroid hormone sensitivity was significantly associated with EBG in both sexes. In the unadjusted model, as a continuous variable, the OR value of males for TSHI, PTFQI, TFQI, and EBG were slightly higher than those of females, and the OR value of FT3/FT4 was also slightly lower than that of females. These differences remain significant after adjusting the model (P < 0.001). And taking T1 as a reference, with the increase of TSHI, TT4RI, PTFQI, and FT3/FT4 levels, the OR value of EBG also increased gradually in both males and females. Of all the indicators representing central thyroid hormone sensitivity, the PTFQI had the lowest OR value, with females (OR: 0.54;95%CI: 0.52 to 0.56) having a lower PTFQI than males (OR: 0.67;95%CI: 0.64 to 0.69).

Table 3

Relationship between thyroid hormone sensitivity and EBG in different sexes
Sex	Variables	EBG
Sex	Variables	OR (95% CI)¹	P-value	OR (95% CI)²	P-value
Males	TSHI	0.89(0.88–0.90)	< 0.001	0.88(0.87–0.89)	< 0.001
	T1	Reference		Reference
	T2	0.60(0.58–0.62)	< 0.001	0.60(0.58–0.62)	< 0.001
	T3	0.73(0.71–0.76)	< 0.001	0.71(0.68–0.73)	< 0.001
	TT4RI	0.99(0.99–0.99)	< 0.001	0.99(0.99–0.99)	< 0.001
	T1	Reference		Reference
	T2	0.55(0.53–0.56)	< 0.001	0.54(0.53–0.56)	< 0.001
	T3	0.63(0.61–0.65)	< 0.001	0.61(0.59–0.63)	< 0.001
	PTFQI	0.67(0.64–0.69)	< 0.001	0.64(0.62–0.67)	< 0.001
	T1	Reference		Reference
	T2	0.63(0.61–0.65)	< 0.001	0.63(0.61–0.65)	< 0.001
	T3	0.73(0.71–0.76)	< 0.001	0.71(0.68–0.73)	< 0.001
	TFQI	0.80(0.77–0.82)	< 0.001	0.76(0.73–0.79)	< 0.001
	T1	Reference		Reference
	T2	0.79(0.76–0.81)	< 0.001	0.78(0.76–0.81)	< 0.001
	T3	0.86(0.83–0.88)	< 0.001	0.82(0.80–0.85)	< 0.001
	FT3/FT4	1.21(1.20–1.23)	< 0.001	1.22(1.20–1.24)	< 0.001
	T1	Reference		Reference
	T2	0.56(0.54–0.58)	< 0.001	0.57(0.55–0.59)	< 0.001
	T3	1.09(1.05–1.12)	< 0.001	1.12(1.08–1.16)	< 0.001
Females	TSHI	0.83(0.82–0.84)	< 0.001	0.82(0.81–0.83)	< 0.001
	T1	Reference		Reference
	T2	0.52(0.51–0.54)	< 0.001	0.52(0.50–0.54)	< 0.001
	T3	0.57(0.56,0.59)	< 0.001	0.55(0.54–0.57)	< 0.001
	TT4RI	0.99(0.99–0.99)	< 0.001	0.99(0.99–0.99)	< 0.001
	T1	Reference		Reference
	T2	0.44(0.42–0.45)	< 0.001	0.44(0.42–0.45)	< 0.001
	T3	0.49(0.47–0.50)	< 0.001	0.47(0.46–0.49)	< 0.001
	PTFQI	0.54(0.52–0.56)	< 0.001	0.52(0.50–0.53)	< 0.001
	T1	Reference		Reference
	T2	0.59(0.57–0.61)	< 0.001	0.59(0.57–0.61)	< 0.001
	T3	0.58(0.57–0.61)	< 0.001	0.57(0.55–0.59)	< 0.001
	TFQI	0.64(0.62–0.67)	< 0.001	0.61(0.59–0.63)	< 0.001
	T1	Reference		Reference
	T2	0.75(0.72–0.77)	< 0.001	0.74(0.71–0.76)	< 0.001
	T3	0.68(0.65–0.70)	< 0.001	0.65(0.62–0.67)	< 0.001
	FT3/FT4	1.29(1.27–1.30)	< 0.001	1.29(1.28–1.31)	< 0.001
	T1	Reference		Reference
	T2	0.54(0.53–0.56)	< 0.001	0.56(0.54–0.58)	< 0.001
	T3	1.35(1.30–1.39)	< 0.001	1.37(1.33–1.42)	< 0.001
¹Model 1: adjusted for age;
²Model 2: adjusted for age, hypertension, hyperlipidemia, smoking, drinking.

Relationship between thyroid hormone sensitivity and EBG in different age stratifications

The relationship between thyroid hormone sensitivity and EBG in different age stratifications were shown in Table 4. In the unadjusted model, as a continuous variable, the OR values of TSHI, PTFQI, TFQI in people aged 60 and below were slightly higher than that in people aged over 60 years old. These differences remain significant after adjusting the model (P < 0.001). And taking T1 as a reference, with the increase of TSHI, TT4RI, PTFQI, and FT3/FT4 levels, the OR value of EBG also increased gradually in T2 and T3. The same as the sex rating in the age rating was that PTFQI also had the lowest OR among all measures representing central thyroid hormone sensitivity, the PTFQI of patients aged over 60 years old (OR: 0.58;95%CI: 0.56 to 0.60) was lower than that of patients aged 60 and below (OR: 0.63;95%CI: 0.61 to 0.66).

Table 4

Relationship between thyroid hormone sensitivity and EBG in different age stratification
Age	Variables	EBG
Age	Variables	OR (95% CI)¹	P-value	OR (95% CI)²	P-value
≤ 60	TSHI	0.88(0.87–0.89)	< 0.001	0.87(0.86–0.89)	< 0.001
	T1	Reference		Reference
	T2	0.58(0.56–0.60)	< 0.001	0.58(0.56–0.60)	< 0.001
	T3	0.69(0.66–0.72)	< 0.001	0.67(0.65–0.70)	< 0.001
	TT4RI	0.99(0.99–0.99)	< 0.001	0.99(0.99–0.99)	< 0.001
	T1	Reference		Reference
	T2	0.50(0.48–0.52)	< 0.001	0.51(0.49–0.53)	< 0.001
	T3	0.59(0.57–0.61)	< 0.001	0.58(0.55–0.60)	< 0.001
	PTFQI	0.63(0.61–0.66)	< 0.001	0.62(0.59–0.64)	< 0.001
	T1	Reference		Reference
	T2	0.61(0.58–0.63)	< 0.001	0.61(0.58–0.63)	< 0.001
	T3	0.68(0.66–0.71)	< 0.001	0.67(0.64–0.69)	< 0.001
	TFQI	0.77(0.74–0.80)	< 0.001	0.74(0.71–0.78)	< 0.001
	T1	Reference		Reference
	T2	0.78(0.75–0.81)	< 0.001	0.77(0.74–0.80)	< 0.001
	T3	0.80(0.77–0.83)	< 0.001	0.77(0.74–0.81)	< 0.001
	FT3/FT4	1.25(1.24–1.27)	< 0.001	1.25(1.24–1.27)	< 0.001
	T1	Reference		Reference
	T2	0.55(0.53–0.57)	< 0.001	0.57(0.54–0.59)	< 0.001
	T3	1.10(1.05–1.14)	< 0.001	1.12(1.08–1.17)	< 0.001
>60	TSHI	0.85(0.84–0.86)	< 0.001	0.83(0.83–0.84)	< 0.001
	T1	Reference		Reference
	T2	0.55(0.53–0.56)	< 0.001	0.55(0.53–0.56)	< 0.001
	T3	0.63(0.61–0.64)	< 0.001	0.60(0.58–0.62)	< 0.001
	TT4RI	0.99(0.99–0.99)	< 0.001	0.99(0.99–0.99)	< 0.001
	T1	Reference		Reference
	T2	0.48(0.46–0.49)	< 0.001	0.47(0.46–0.49)	< 0.001
	T3	0.53(0.52–0.55)	< 0.001	0.51(0.50–0.53)	< 0.001
	PTFQI	0.58(0.56–0.60)	< 0.001	0.55(0.54–0.57)	< 0.001
	T1	Reference		Reference
	T2	0.60(0.59–0.62)	< 0.001	0.60(0.58–0.62)	< 0.001
	T3	0.64(0.62–0.66)	< 0.001	0.61(0.60–0.63)	< 0.001
	TFQI	0.69(0.67–0.71)	< 0.001	0.66(0.64–0.68)	< 0.001
	T1	Reference		Reference
	T2	0.76(0.74–0.79)	< 0.001	0.75(0.73–0.78)	< 0.001
	T3	0.74(0.72–0.77)	< 0.001	0.71(0.69–0.73)	< 0.001
	FT3/FT4	1.25(1.24–1.27)	< 0.001	1.26(1.25–1.27)	< 0.001
	T1	Reference		Reference
	T2	0.54(0.53–0.56)	< 0.001	0.56(0.54–0.57)	< 0.001
	T3	1.28(1.24–1.31)	< 0.001	1.31(1.27–1.35)	< 0.001

¹Model 1: adjusted for sex;

²Model 2: adjusted for sex, hypertension, hyperlipidemia, smoking, drinking.

Relationship between thyroid hormone sensitivity and EBG in different sexes and different ages

According to the separate results of sex and age stratification, the study analyzed the relationship between thyroid hormone sensitivity and EBG in different sexes and ages. As shown in Table 5, in the unadjusted and adjusted models, all the central thyroid hormone sensitivity indices had lower OR value with EBG in females aged over 60 years old, the peripheral thyroid sensitivity index had higher OR with EBG in females aged 60 and below.

Table 5

Relationship between thyroid hormone sensitivity and EBG in different sexes and different ages
Sex	Age	Variables	EBG
Sex	Age	Variables	OR(95% CI)¹	P-value	OR (95% CI)²	P-value
Males	≤ 60	TSHI	0.90(0.89–0.92)	< 0.001	0.90(0.88–0.92)	< 0.001
		TT4RI	0.99(0.99–0.99)	< 0.001	0.99(0.99–0.99)	< 0.001
		TFQI	0.84(0.80–0.89)	< 0.001	0.84(0.79–0.89)	< 0.001
		PTFQI	0.69(0.65–0.73)	< 0.001	0.69(0.65–0.73)	< 0.001
		FT3/FT4	1.22(1.19–1.24)	< 0.001	1.21(1.18–1.23)	< 0.001
	>60	TSHI	0.88(0.87–0.89)	< 0.001	0.86(0.85–0.88)	< 0.001
		TT4RI	0.99(0.99–0.99)	< 0.001	0.99(0.99–0.99)	< 0.001
		TFQI	0.77(0.73–0.80)	< 0.001	0.72(0.68–0.75)	< 0.001
		PTFQI	0.65(0.63–0.68)	< 0.001	0.61(0.59–0.64)	< 0.001
		FT3/FT4	1.22(1.20–1.24)	< 0.001	1.23(1.21–1.25)	< 0.001
Females	≤ 60	TSHI	0.86(0.84–0.87)	< 0.001	0.84(0.82–0.85)	< 0.001
		TT4RI	0.99(0.99–0.99)	< 0.001	0.99(0.99–0.99)	< 0.001
		TFQI	0.68(0.63–0.72)	< 0.001	0.62(0.58–0.66)	< 0.001
		PTFQI	0.56(0.53–0.60)	< 0.001	0.52(0.49–0.56)	< 0.001
		FT3/FT4	1.30(1.27–1.33)	< 0.001	1.32(1.29–1.35)	< 0.001
	>60	TSHI	0.82(0.81–0.83)	< 0.001	0.81(0.80–0.82)	< 0.001
		TT4RI	0.99(0.99–0.99)	< 0.001	0.99(0.99–0.99)	< 0.001
		TFQI	0.63(0.60–0.65)	< 0.001	0.61(0.58–0.63)	< 0.001
		PTFQI	0.52(0.50–0.55)	< 0.001	0.51(0.49–0.53)	< 0.001
		FT3/FT4	1.28(1.27–1.30)	< 0.001	1.28(1.26–1.30)	< 0.001
¹Model 1: unadjusted;
²Model 2: adjusted for hypertension, hyperlipidemia, smoking, drinking.

To our knowledge, this is the first study to evaluate and prove the relationship between central and peripheral sensitivity to thyroid hormones indicators and EBG risk in large Chinese CHD patients. Our study found that central thyroid hormone sensitivity indices TSHI, TT4RI, TFQI, PTFQI were negatively associated with EBG risk in CHD patients, with the gradual increase of TSHI, TT4RI, and PTFQI, the OR value of EBG also gradually increased. The peripheral thyroid hormone sensitivity index FT3/FT4 was positively associated with EBG. However, in the tertile model, with T1 as a reference, the FT3/FT4 ratio was negatively associated with EBG at T2, but significantly positively correlated at T3. Finally, when considered separately, most associations were observed in different sexes and different age grades.

Previous studies have shown that almost two-thirds of patients with cardiovascular disease suffer from abnormal glucose metabolism [30]. Due to the different changes of thyroid hormones in CHD patients [31], the various effects of thyroid hormones on CHD patients with EBG deserve attention. The relationship between TSH, FT3, FT4, and insulin resistance or glucose level. However, higher TSH and lower FT4 [16, 32, 33], lower TSH [34], higher FT4 [35], and lower FT3 [16, 34] were all considered to be associated with the risk of EBG in previous studies. Therefore, TSH or thyroid hormones levels alone may not be sufficient to explain the relationship between the thyroid system and glycemic disorders. In view of these inconsistent reports, 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 the case of thyroid dysfunction, which will help to better explain the different associations between the changes of thyroid hormones and diabetes [29].

Based on these new indices, recent studies have found that the increase of TSHI, TT4RI, and PTFQI were associated with reduced risk of prediabetes, and the increased FT3/FT4 ratio was associated with increased risk of prediabetes [23]. Different from our study, the latter had no significant correlation after adjusting for multiple confounding factors. Moreover, our results also suggested that elevated TFQI was associated with a reduced risk of EBG level, although the OR value of EBG tended to decrease with the increasing TFQI level. Laclaustra et al. considered that the cross-section of TSHI level was not associated with diabetes [29], this also seems to be contrary to our conclusion. The reasons for these differences are not clear, but that may be attributed to confounding factors, differences in study partitions, and sample sizes, and further studies are needed to confirm these conclusions.

Several pathways might explain the observed association between 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 important protein of lipid metabolism [41], lower FT3 and FT4 levels can promote higher insulin resistance in tissues [42]. The change of serum TSH may directly affect metabolic parameters and stimulate the secretion of leptin [43, 44]. It is well known that the hepatic glucose output is critical for maintaining fasting glucose homeostasis, leptin has been shown to stimulate hepatic glucose production in vivo and vitro [45]. Moreover, the loss of leptin will also 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 the secretion of leptin, affect insulin resistance and lead to the change of glucose metabolism level. However, the exact regulatory mechanism between central thyroid hormone sensitivity and leptin remains unclear.

In addition, 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 in the T3 group. Before this, many studies have 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]. As for the result that FT3/FT4 was negatively correlated with EBG in the T2 group, it may be that the promotion of peripheral deiodinase activity will increase the level of FT3/FT4 [38], so the inhibition of peripheral deiodinase activity will reduce the basal metabolic rate, which is closely related to the pathogenesis of diabetes [50, 51].

For sex and age-specific differences in previous studies [35, 52, 53], we analyzed the relationship between thyroid hormone sensitivity and diabetes by sex and age, respectively. The results showed that TSHI, PTFQI, and TFQI of females aged over 60 years old had lower OR value of EBG risk, while FT3/FT4 had higher OR value. Sex hormones (such as estrogen and testosterone) can regulate thyroid function, and the level of estrogen will 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 in this study. However, since this study did not measure the levels of sex hormones such as testosterone and estrogen, further research is needed to explore this question.

There are several limitations to the current research. First of all, this is a cross-sectional study, and it cannot infer causality. However, the current large-scale cross-sectional study supports such an important hypothesis that the thyroid hormone sensitivity levels may be helpful to supplement the pure thyroid hormone levels to assess the risk of EBG. Secondly, although we have adjusted quite a number of 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. Thirdly, this study was conducted among Chinese people, and there may be racial differences. Therefore, well-designed randomized controlled trials are needed to validate these results.

The decrease of central thyroid hormone indices represents the increase of central thyroid hormone sensitivity. Therefore, this study shows that reduced central thyroid hormone sensitivity is associated with a reduced risk of CHD with EBG, among them, females and patients aged over 60 years old are at higher risk. However, the increase of peripheral thyroid hormone sensitivity index is related to the increased risk of EBG in patients with CHD.

CHD

coronary heart disease

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 cholestero

NGT

normal glucose tolerance

odds ratio

SBP

Systolic blood pressure

standard deviation

total cholesterol

triglyceride

thyroid hormone

TSH

thyroid stimulating hormone

Authors’ contributions

CY, LL and QX were responsible for the study protocol and statistical analysis; LY and ZL analysed the data together and drafted the article; RY, GP, QC, YH, YL, FL, MM, TY, YW, JS conducted data collection; YZ and SG revised the article critically. All authors revised the article for important intellectual content and approved the article. The authors read and approved the final manuscript.

Acknowledgments

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

This study was supported by the National Basic Research Program of China

(973 project, grant numbers: 2014CB542902).

Declaration of conflict of interest

The authors declare no competing interests.

Funding

This study was supported by the National Basic Research Program of China (973 project, grant number: 2014CB542902).

Availability of data and materials

The datasets used and/or analyzed in the current study are available from the corresponding author upon reasonable request.

Ethics approval and consent to participate

This study was approved by the ethics committee of Tianjin University of Traditional Chinese Medicine (TJUTCM-EC20190008) and registered in the Chinese Clinical Trial Registry (ChiCTR-1900024535) and in Clinical Trials.gov ( NCT04026724).

Consent for publication

Not applicable.

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No competing interests reported.

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Impaired sensitivity to thyroid hormones is associated with elevated blood glucose in coronary heart disease — a RCSCD-TCM study in China

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Abstract

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Background

Methods

Patients

Data collection

Indices of thyroid hormone sensitivity

Statistical analyses

Results

Baseline characteristics

Relationship between thyroid hormone sensitivity and EBG

Relationship between thyroid hormone sensitivity and EBG in different sexs

Relationship between thyroid hormone sensitivity and EBG in different age stratifications

Relationship between thyroid hormone sensitivity and EBG in different sexes and different ages

Discussion

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Conclusion

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