Association between thyroid dysfunction and type 2 diabetes: a meta-analysis of prospective observational studies

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease that results from pancreatic beta-cell dysfunction and peripheral insulin resistance. The worldwide prevalence is 9.1%, equating to 415 million adults suffering from the disease [1]. T2DM is a complex disease arising from a combination of genetic and lifestyle factors. Recently, evidence has suggested that low circulating levels of thyroid hormone, even within the normal reference concentrations, may be related to an elevated risk of developing T2DM, especially within the prediabetes population [2].

Like diabetes, thyroid dysfunction results from dysregulated hormone secretion. Recent data from the Colorado Thyroid Disease Prevalence study showed that 9.5% of 25,862 participants had an elevated thyroid-stimulating hormone (TSH); conversely, 2.2% had low TSH [3]. The thyroid hormone axis includes TSH, thyroxine (T4), and triiodothyronine (T3), all of which are required to maintain the normal functioning of the thyroid. The imbalance of these hormones may lead to metabolic overactivity (hyperthyroidism; excess thyroid hormone) or underactivity (hypothyroidism; inadequate thyroid hormone). Based on the severity of the imbalance, hyperthyroidism and hypothyroidism can be diagnosed as either clinical or subclinical, of which the latter is the more prevalent [4]. Subclinical thyroid dysfunction is commonly defined as having an abnormal TSH but normal T4 concentration. The presence or absence of symptoms may be independent of T4 levels [5, 6]. Despite being mild, subclinical thyroid dysfunction has been linked to several complications, including cardiovascular disease (CVD) [7], chronic kidney disease [8], and type 1 diabetes in children [9].

Thyroid dysfunction has been reported to be associated with T2DM in a number of studies [10‐12]. Some studies have suggested a bidirectional influence of diabetes and thyroid disorders upon each other [10, 13]. The Third National Health and Nutrition Examination Survey (NHANES III), a large cross-sectional survey study which included 17,353 participants in the USA, revealed that hypothyroidism was present in 4.6% of the study population and hyperthyroidism in 1.3% of subjects [14]. In addition, NHANES III found an increased frequency of thyroid dysfunction in subjects with diabetes compared to those without diabetes.

Thyroid hormone has been demonstrated to regulate carbohydrate metabolism and pancreatic function [15]. Conversely, diabetes can variably influence thyroid function. For example, the response of TSH to thyrotropin-releasing hormone has been shown to be impaired in diabetes, leading to hypothyroidism and concomitant lower T3 levels [16]. It has been suggested that lower T3 levels may also be explained by a lower level of conversion of T3 from T4 in diabetes based on studies of hyperglycemia-induced reversible reduction to deiodinase activity and hepatic concentration of thyroxine [17]. Other studies have suggested that short-term T3 excess may induce insulin resistance; hence leading to T2DM [18, 19].

However, the relationship between thyroid hormone levels and T2DM risk remains highly contested and human studies have demonstrated conflicting findings. Several reports have suggested a positive effect of high TSH and low free thyroxine levels on hyperglycemia and insulin resistance [20‐23], but some claimed no relationship found in their researches [24]. Therefore, it has become apparent that a comprehensive evaluation of the association between TSH, free thyroxine, and T2DM is needed. Moreover, virtually all previous analyses have focused on examining the influence of baseline levels of TSH and free thyroxine on the risk of developing T2DM [25‐27], but few studies have investigated the dose-response influence of thyroid hormone levels on T2DM risk, so this analysis was conducted here.

Using both electronic and manual searches, a total of 7184 articles were identified after the removal of 945 duplicates. After title/abstract screening, 151 articles were included for further full-text review. Of those, a total of 14 articles were identified for inclusion, among them, 10 articles (12 studies) for analyzing the association between thyroid status and T2DM risk, and an additional 4 articles (4 studies) for evaluating the association between thyroid status and CVD prognosis among T2DM patients (Fig. 1).

The goal of our meta-analysis was to evaluate the relationship between thyroid function and T2DM. We found that high TSH and low FT3/FT4 are associated with a higher risk of developing T2DM and that the risk of T2DM rises in a dose-dependent manner as TSH rises and thyroid hormones decrease. Investigations determined that for each 1 mIU/L elevation in TSH, 1 pmol/L reduction in FT3 or FT4 was associated with either an 11%, 23%, and 16.8% higher risk for T2DM among the normal population, respectively. Thyroid function tests were not associated with CVD or all-cause mortality among T2DM patients; this may be due to the limited number of studies, and additional studies in this area are warranted.

Our results confirmed that hypothyroidism seems to be associated with an elevated risk T2DM. A previous review examined the association between subclinical hypothyroidism and diabetic complications [43] in T2DM. This meta-analysis on 36 case-control and cross-sectional studies found that T2DM patients were more likely to have subclinical hypothyroidism when compared to the general population, and T2DM patients with subclinical hypothyroidism were more likely to have complications (such as diabetic nephropathy, retinopathy, and peripheral neuropathy). Numerous studies have suggested that the diabetes-thyroid relationship might be bidirectional [44]. High insulin levels found in prediabetes and early type 2 diabetes can stimulate thyroid tissue hyperplasia, leading to thyroid enlargement and nodule formation [45, 46]. Thyroid dysfunction may in turn affect the glucose metabolism in diabetes. Changes in serum TSH were found to be correlated with changes in glycated hemoglobin (HbA1c) [47]. It is reported that improvement of glycemic control was significantly related with a reduction of major cardiovascular events [48]. Since hyperthyroidism may worsen the glucose control in diabetic patients, while hypothyroidism can increase the risk of hypoglycaemia, and therefore, both may increase the risk of cardiovascular disease [49‐51]. Nevertheless, we did not observe significant associations of low TSH, high FT3, or high FT4 with risk of T2DM. This could be partially explained by their “J-shaped” or “inverted J-shaped” relationship, indicating a weaker association with low TSH, high FT3, and high FT4, compared with high TSH, low FT3, and low FT4, respectively. Hyper- and hypothyroidism have different underlying mechanism to impact the glucose homeostasis. Hyperthyroidism could promote hyperglycaemia [52] and reduce the half-life of insulin, leading to an increased rate of degradation and an enhanced release of biologically inactive insulin precursors [18, 53]. As for hypothyroidism, glucose metabolism is affected via a reduced rate of liver glucose production [54] and the decrease in insulin requirement. The cross-sectional study observed a much higher prevalence of hypothyroidism (~30%) than hyperthyroidism (12%) in diabetes [55]. However, limited directly prospective evidence on which one, hypothyroidism vs. hyperthyroidism, is more likely to develop diabetes, which warrants further evidence from a well-designed prospective study.

A significant body of evidence among T2DM patients suggests that increased age, gender (female), obesity, and thyroid peroxidase antibody positivity are associated with an increased risk of developing hypothyroidism [49, 56‐58]. The prevalence of subclinical hypothyroidism is known to increase with age [10‐12, 16‐19]. Males and females have different propensities for thyroid dysfunction [59], and obesity has been found to be significantly related to hypothyroidism [60]. A meta-analysis of 36 studies confirmed a higher prevalence of subclinical hypothyroidism in females and T2DM patients over age 60 [43]. Furthermore, a cross-sectional observational study among 1508 adult T2DM patients in India found a significant increased risk of hypothyroidism in elderly patients with T2DM (> 65 years) with an OR of 4.2, and an overt difference between males and females (OR 4.82 vs. 2.60), and patients with obesity and without obesity (OR 2.56 vs. 3.11) [61]. However, our subgroup analyses found a consistent and positive association between hypothyroidism and risk T2DM regardless of sex (women ≥ 50% vs. women < 50%), age (< 60 years vs. ≥ 60 years) of participants in the studies, and outcomes (T2DM vs. T2DM & T1DM). The hypothyroidism causes a decrease in basal metabolic rate and thermogenesis and leading a weight increase [62]. As we have known, overweight/obesity is an overt risk of T2DM [63]. It is reasonable to deduce that the association between TSH and T2DM would be stronger among those with overweight or obesity. However, our study showed a conflict result that the association between high TSH and T2DM risk was non-significant among those with overweight/obesity. This might be caused by our BMI subgroups which were only according to the mean BMI levels of all participants since no identified study reported the results for the BMI subgroup and do not represent the exact overweight/obesity population. Similarly, a significant subgroup of medication use was found; however, the difference between those non-users and mixed users was non-significant. Few studies have explored the sex and age difference in association between thyroid function and T2DM, and those that have did not find any statistical significance [39]. Sex hormones, influenced by age, sex, and BMI status, may further play a complicated role in the T2DM and thyroid function [64]. The mixture of participants with different proportions of age, gender, and BMI groups and a limited number of relevant studies precluded us from evaluating the interaction of these factors.

Both hypothyroidism and hyperthyroidism are able to influence the metabolism of insulin and thus induce insulin resistance [39], suggesting a non-linear, possible U-shaped, relationship between thyroid function and diabetes. An L-shaped relationship between FT4 levels and metabolic syndrome incidence was observed in the prospective population-based Tehran Thyroid Study [65]. Our dose-response analysis of 9 studies depicted a J-shaped relationship with TSH and inverted-J shaped relationship with both FT3 and FT4 levels with T2DM, showing a relatively high risk of T2DM among those with elevated TSH levels and reduced FT3 and FT4 levels. The range of the thyroid function levels in most of the included studies was a semi-closed interval, with values only on one side of the reference range. We hypothesize that this might be a reason why we did not detect a U-shaped relationship. There appears to be a positive linear relationship between TSH and risk of T2DM even within the normal reference range according to a 7-year longitudinal study on 6235 euthyroid subjects without pre-existing T2DM [25]. These results suggest that lower levels of thyroid hormone might contribute to a higher risk of insulin resistance and diabetes [66, 67]. We assessed the influence of thyroid function on CVD among T2DM patients and did not find an association, though this was based on only 4 studies.

In this study, we conducted a comprehensive meta-analysis of prospective studies in order to evaluate the association between thyroid function and T2DM and CVD prognosis of T2DM patients. All studies included were sufficiently high-quality with an NOS score of ≥ 6 points and had large sample sizes (range: 556–91,120). In addition, a subgroup analysis stratified by prespecified factors and a sensitivity analysis was conducted to explore and evaluate the potential heterogeneity. Several limitations merit consideration. First, most of the studies included for evaluating the progress of T2DM were from China and more well-designed, large-scale, and long follow-up studies should be included in any future analyses. Second, only a few studies reported the glucose levels and evaluated the relations between thyroid function and glucose levels. Third, most studies did not distinguish between type 1 and type 2 diabetes. Additionally, only one study [35] evaluated thyroid peroxidase antibody titers. Finally, publication bias and residual confounders inherent in observational studies also merit further consideration.

In summary, our meta-analysis demonstrated that thyroid dysfunction is associated with an increased risk of T2DM. There was no evidence that thyroid dysfunction was associated with CVD events and all-cause mortality in T2DM, though limited studies were available. Therefore, measuring TSH in patients with risk factors for diabetes may help further assess the risk for the development of T2DM.