Recent studies have suggested alternations in thyroid hormone levels within the normal range are valuable predictors for adverse cardiac events; So far, almost no any related literature reported the association between FT3 and carotid atherosclerosis. Furthermore, to our knowledge, no studies have investigated the relationship on FT3 and DPN in individuals with normal thyroid function as of now.
In order to fill this gap in the literature, we undertook an analysis to explore whether there existed relationships on FT3, DPN and carotid atherosclerotic lesions in Chinese type 2 diabetic patients with normal thyroid function, and verified that low-normal FT3 concentration was negatively correlated to the incidence of DPN but not to carotid atherosclerotic lesions in type 2 diabetic patients.
DPN as the most common complication of diabetes, has impacted on around half of the patients which inevitably result in lower living quality and heavier socioeconomic burden [23, 24]. Therefore, it is really necessary to prevent and treat DPN. Although great progress has been made in the study of the pathophysiological mechanisms of DPN, the underlying pathophysiological mechanisms have not been completely elucidated by far. It is generally accepted that not only the hyperglycemia's toxic effects, but also some other elements like dyslipidemia, smoking, DN, and DR, act an important part in the genesis of DPN [25–28]. In line with the above research, we found that in the first FT3 quartile group the prevalence of DPN was higher in males than in females after controlling for age and DD; whereas further adjusted for smoking, no significant sex-related discrepancy were found. Likewise, further controlling for smoking, there were no statistical age-related difference in each FT3 quartile group.
More importantly, we first confirmed that subjects from the first to the third FT3 quartile group had remarkably increased risks of DPN in relation to those in the last quartile group. The literatures on the relationship between thyroid hormone and DPN are quite limited. Recently, Zhao et al. [29] demonstrated that the SCH subjects had higher prevalence and signs of DPN compared with the euthyroid subjects; the multivariate analysis showed that TSH had an independent correlation with DPN and a high TSH level implied to an enhanced risk of DPN in type 2 diabetics. Zhu et al. [30] also showed that serum FT3 levels in normal nerve conduction group were statistically higher than those in abnormal nerve conduction group (4.55 ± 0.65 vs 4.37 ± 0.63, p < 0.05). Consistent with this finding, we also found that the FT3 levels were significantly lower in the diabetic patients with DPN than those without DPN.
DPN is often occurred with DR and DN, but so far only three observations revealed the correlation between FT3 levels and the incidence of DR and DN in type 2 diabetes with normal thyroid function. Resembled with our findings, Wu et al. [13] first discovered that the euthyroid patients with DN got lower FT3 levels compared with those without DN. Zou et al. [31] further found that the prevalence of diabetic kidney disease exhibited a significant downward trend on the FT3 quartiles (41.1%, 30.6%, 23.8%, and 18.9%, p < 0.001). Compared with the first FT3 quartile group, the adjusted odds ratio for diabetic kidney disease in the second to fourth FT3 quartile group were 0.655 [95% confidence interval (CI): 0.406–1.057], 0.493 (95%CI: 0.299–0.813), 0.406 (95%CI: 0.237–0.697). Likewise, Zou and his team also found the similar results in DR, that is, there was inverse correlation between FT3 within normal range and DR in T2DM patients [32].
So far, the underlying mechanisms on the association between FT3 and DPN remain elusive, but the following enzymes and pathways may be involved in the development of DPN. Firstly, T3 acted directly or indirectly on the endothelial function in vitro by relaxing vascular smooth muscle [33]. The latest study showed that even small fibro neuropathy was related to damaged vascular endothelial function in type 2 diabetic patients [34]; therefore, low FT3 level and DPN may involve to the endothelial dysfunction. Secondly, T3 can facilitate progressive kidney impairment in db/db mice through significantly decreasing phosphatidylinositol 3-kinase activity as well as increasing the expression of transforming growth factor-β1 [35], which were also reported to accelerate the progression of DPN [36, 37]. Finally, in vivo and in vitro experimental models further showed that 3, 5-Diiodothyronine, a natural metabolite of T3, could ameliorate DN by regulating Sirtuin 1 [38], which also played a vital role in prevention and reversal of DPN [39].
On the contrary, we found that FT3 didn't have remarkable association with atherosclerotic lesions in type 2 diabetic patients. Currently no paper regarding the relationship of FT3 and carotid atherosclerosis are obtainable, several studies have reported there exists a powerful connection on FT3 and the presence and severity of CAD which had been well-studied in euthyroid individuals [40, 41]. For example, Ertaş et al. [40] found that FT3 levels within the normal range were negatively related to the presence and severity of CAD for patients undergoing coronary angiography. Daswani et al. [41] also found that the genesis of CAD was in connection with lower serum FT3 levels; the concentrations of serum FT3 were associated with the Gensini score as well which could make an independent prediction on the severity of CAD in euthyroid stable angina patients.
Lately, some scholars further explored the associations of FT3 Levels and macrovascular complications in type 2 diabetic patients with normal thyroid function [42, 43]. Different from us, Wang et al. [42] showed that diabetic patients with low-normal FT3 level were more likely to suffer from macrovascular complications than those with mid-and-high normal FT3 level. Hu et al. [43] also revealed that there was a remarkable relationship between diabetic macrovascular complications and normal FT3 (OR = 0.534, 95% CI 0.358–0.796). This discrepancy between above studies and our studies can be explained by the fact that the definition of macrovascular complications atherosclerosis included atherosclerosis of the aorta, coronary, basilar, carotid in above studies, while our current study mainly focused on carotid atherosclerosis. Thus, our study confirmed for the first time that FT3 within the normal range didn’t have an independent association with carotid atherosclerosis, which was considered as an early biomarker of cardiovascular disease, in type 2 diabetic patients with euthyroid function.
Additionally, we found that the incidence of carotid atherosclerotic plaque and stenosis in type 2 diabetic patients with DPN was significantly higher than those without DPN; whereas no significant difference in CIMT was observed between them, which suggested that DPN may be related to late rather than early carotid atherosclerotic lesions in type 2 diabetes. This finding further provided strong evidence that diabetes-induced endothelial dysfunction was an important and initial factor in the development of diabetic vascular complications [44, 45].
Some limitations in our study need to be mentioned. Firstly, further studies need to verify whether our results can be applied to ethnicity or other types of diabetes as the participants in our report were Chinese Han type 2 diabetic patients. Secondly, the causal connection on the reduced FT3 and DPN need further verification due to the nature of cross-sectional study. Thus, prospective research should be made to explore the connection on low-grade FT3 and the occurrence of DPN in various population and other type of diabetes. Thirdly, other medications for the patients were not considered in our study expect the thyroid-related drugs.