The present study indicated no synergistic impact of GDM with thyroid disorders on the incidence of T2DM. Despite the higher risk of incident T2DM among women with a history of GDM, women with thyroid dysfunction had similar risk for development of T2DM, compared to their counterparts with normal thyroid function. Therefore, women with a history of GDM should be followed up regarding a high risk of T2DM beyond their experience of thyroid disorders.
To the best of our knowledge, no previous studies have investigated the synergistic impact of GDM with thyroid disorders on the development of T2DM. However, several have investigated the associations of GDM and thyroid disorders per se with the risk of incident T2DM [21-24]. The findings of our study showed a higher risk of developing T2DM in patients with a history of GDM, compared to those without a history of GDM, an observation consistent with the findings of previous studies [21-24]. In a very recent meta-analysis, the subsequent risk of T2DM in women with GDM compared to those without GDM was 9.51 (95% CI: 7.14 to 12.67) Another meta-analysis of cohort studies conducted by Bellamy et al. revealed that the risk of incident T2DM in women with a history of GDM was 7.43 (95%CI:4.79-11.51) times higher than those without any history . The adverse association of GDM with developing T2DM may be attributable to epigenetic changes induced by maternal hyperglycemia in target tissues, such as skeletal muscle and subcutaneous adipose tissue . Moreover, increase in circulating levels of leptin, inflammatory biomarkers e.g., TNF-α and C-reactive protein (CRP) and the fat content in liver and muscle, as well as the decreased adiponectin concentration reported in women with prior GDM, may partly explain woman's predisposition to T2DM following GDM .
It should be noted that we observed a significant association between GDM and higher subsequent T2DM risk after adjusting for age, but this association became attenuated and non-significant after further adjustment for BMI, educational status, smoking and family history of DM, TG, TC, HDL-C, SBP, DBP, and FBS. The major reduction in the effect size was observed after controlling for BMI, educational status, smoking, and family history of DM. It can be explained by the positive association of BMI with the development of T2DM among women with a history of GDM. Accumulation of fat in body and excess weight are well-defined risk factors for T2DM in a population [27,28]. On the other side, women experiencing GDM are more prone to weight gain at the onset of elevated FBS and developed GDM as well as a higher probability for the development of T2DM in later life . The presence of GDM is a hallmark to make a recommendation to monitor their weight after delivery . Therefore, the association between GDM and incidence of T2DM could partly be attributed to the BMI. The same cofounding effect could exist for other adjusted covariates, especially for smoking and family history of DM.
There is no consensus about the adverse influence of thyroid dysfunction on the further development of T2DM. The present study showed no statistically significant increase in the development of T2DM following thyroid disorders. In agreement with the results of our research, Sadatamini et al. showed that the incidence of thyroid dysfunction in T2DM patients was not higher than non-diabetic participants during 12 years of follow up . However, a longitudinal cohort study conducted among 25,575 adults aged >18 years by Chen et al. in Taiwan with follow up of >10 years reported that the incidence of T2DM was higher among individuals with either hypo- or hyperthyroidism, with most incident cases of T2DM occurring the first five years of thyroid disorders . In another prospective cohort of 8,452 participants with a 7.9 year follow up, hypothyroidism was identified as a risk factor for increased risk of incident T2DM, more so in pre-diabetic patients , findings contrary to those of our investigation; their findings however also indicated that the risk for developing T2DM drops from 35% to 15% when FT4 reached to normal levels . Thyroid hormones have a regulatory function on carbohydrates metabolism . Thus, impairment in thyroid regulation had an undesirable impact on carbohydrate metabolism and glucose homeostasis s through their direct effect on the control of insulin secretion and the preservation of beta-cell proliferation and viability [34,35]. Increased higher FT3 levels are associated with impaired glucose tolerance through elevated liver gluconeogenesis and the development of insulin resistance . However, evidence indicated that the incidence of T2DM in patients with hyperthyroidism was only 2% to 3.3% . Interestingly, thyroxine intervention in patients with diagnosed hypothyroidism decreased HbA1c, independent of changes in plasma glucose . Besides, the value of HbA1c patients with hypothyroid was higher in comparison to those in the control group . This observation was also beyond the level of FPG. It seems that there is a very high false-positive rate for HbA1c among patients with hypothyroidism.
No significant associations of serum FT4, TSH, and TPOAb levels with incidence of T2DM were observed in our data, using either simple or pooled logistic regression analyses. In contrast of our findings, Yeqing et al. in a cross-sectional study (n=15,296), performed in China, demonstrated that decreased FT3, FT3/FT4 ratios, and increased FT4 levels are independently related to a higher prevalence of T2DM in both males and females, and TSH is inversely associated with T2DM in males only ; however the results of the Mohammed et al. study of 2797 type 2 diabetic patients, revealed no significant differences in serum thyroid levels between T2DM patients and their healthy counterparts (P < 0.05); their results also indicated that the frequency of thyroid autoimmunity was not significantly higher in type 2 diabetic patients than in the non-diabetic control group .
According to the results of the current study, the incidence of T2DM increased significantly with time and age, a finding in agreement with the results of previous studies [41-43]. Evidence suggests that senescent cells, implicated in the generation of insulin resistance, accumulate in various tissues with aging .
Regarding study strengths, this is the first study with a longitudinal design, long term follow-up, and large sample size investigating the possible interaction between the history of GDM and thyroid disorders in the incidence of T2DM. Also, using pooled logistic approaches helped us to further adjust our results for assumed confounders that were precisely measured in this study including age, familial history of diabetes, smoking, anthropometric indices, and lipid profiles. However, the present analyses do have some limitations, which should be addressed. First, GDM was determined based on a self-reporting questionnaire and medical records, although the universal screening strategy of GDM in Iran and subsequent monitoring and treatment of GDM may restrict this bias. Our study is limited by lack of data on some parameters such as insulin use that may affect the progression to T2DM. Furthermore, Of 1894 participants of the present study, 146 (7.7%) of whom had hypothyroidism. Unfortunately, there was not enough power to check the interaction term between hypothyroidism and age, which was the limitation of this study. Last but not least, serum FT3 levels, as biologically active hormones involved in glucose metabolism were not assessed in the current study.