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 . Due to the different changes of thyroid hormones in CHD patients , 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 , higher FT4 , 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 . 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 .
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 . 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 , 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 , lower FT3 and FT4 levels can promote higher insulin resistance in tissues . 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 . 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 . 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 , 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.