Clinical Characteristics and Related Risk Factors of Thyroid Dysfuncti

Introduction

Diabetes mellitus is primarily classified into type 1 diabetes (T1D) and type 2 diabetes (T2D). However, some patients exhibit clinical features intermediate between T1D and T2D, a condition termed latent autoimmune diabetes in adults (LADA), also known as type 1.5 diabetes. LADA is a slowly progressive autoimmune diabetes characterized by the presence of autoantibodies, with glutamic acid decarboxylase 65 antibodies (GAD65-Ab) being the most significant immunological marker. GAD65-Ab may coexist with other pancreatic autoantibodies, such as insulin autoantibodies (IAA), which serve as early indicators of pancreatic β-cell dysfunction and play a crucial role in the pathogenesis of LADA.¹

Patients with one autoimmune disorder are at an increased risk of developing another. LADA has been associated with other autoimmune diseases, including Hashimoto’s thyroiditis, Sjögren’s syndrome, and dermatomyositis, which share common autoimmune components and genetic susceptibility loci, such as human leukocyte antigen DR (HLA-DR), cytotoxic T-lymphocyte-associated protein 4(CTLA-4), CD25, protein tyrosine phosphatase non-receptor 22(PTPN22), and forkhead box P3 (FOXP3) genes.^2–6 Recent studies suggest that specific variants in these genes, such as those in PTPN22, may determine the onset of distinct diseases with different phenotypic and clinical characteristics.^7–9 These findings, both clinically and mechanistically, support the association between autoimmune thyroid diseases and LADA. However, the clinical characteristics of thyroid dysfunction in LADA patients from the Xuzhou region of Jiangsu, China, remain unclear. Therefore, the objective of this study is to investigate the clinical features and risk factors associated with thyroid dysfunction in LADA patients in Xuzhou, Jiangsu, to facilitate early intervention and treatment.

Materials and Methods

We conducted a single-center, cross-sectional study involving 95 hospitalized LADA patients from the Affiliated Hospital of Xuzhou Medical University between January 2024 and April 2025. The patients were divided into two groups based on the presence or absence of thyroid dysfunction: 39 LADA patients without thyroid dysfunction and 56 LADA patients with thyroid dysfunction.

Inclusion Criteria

1. Diagnosis of LADA (based on WHO criteria and the latest guidelines).
2. No recent use of medications affecting thyroid function.

Exclusion Criteria

1. Known history of thyroid disease.
2. Pregnancy or severe hepatic/renal dysfunction.
3. Other types of diabetes.

Data collection included clinical parameters and thyroid function assessment. The following variables were recorded: age, disease duration (Duration), systolic blood pressure (SBP), diastolic blood pressure (DBP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (Scr), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), uric acid (UA), fasting blood glucose (FBG), glycated hemoglobin (HbA1c), GAD65-Ab (GADA), urinary albumin-to-creatinine ratio (UACR), triglyceride-glucose index (TyG), TyG-body mass index (TyG-BMI), estimated glomerular filtration rate (eGFR), fasting C-peptide (FCP), postprandial 2-hour C-peptide (P2hCP), free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TGAb), thyrotropin receptor antibodies (TRAb), IAA, 25-hydroxyvitamin D [25(OH)D], proinsulin (PI), and calcitonin (CT). Blood samples were stored at −80°C. Thyroid function was evaluated by measuring FT3, FT4, TSH, TPOAb, TGAb, and TRAb levels using chemiluminescence assays.

Statistical analysis was performed using SPSS 24.0. Normally distributed data were expressed as mean ± standard deviation and compared using independent samples t-tests. Non-normally distributed data were expressed as median (interquartile range) and analyzed using the Mann–Whitney U-test. To explore correlations between variables, Pearson’s correlation analysis was performed for features with P < 0.05, and a heatmap of correlation coefficients was generated. Univariate logistic regression analysis was also conducted. A P-value < 0.05 was considered statistically significant.

All participants provided written informed consent, and the study was approved by the Ethics Committee of the Affiliated Hospital of Xuzhou Medical University. The study complies with the Declaration of Helsinki.

Results

Baseline characteristics (Table 1) revealed significant differences between the two groups in UACR, FCP, P2hCP, FT3, FT4, TPOAb, TGAb, TRAb, and IAA (all P < 0.05). Compared to LADA patients without thyroid dysfunction, those with thyroid dysfunction exhibited higher UACR, lower FCP and P2hCP levels, reduced FT3 and FT4, significantly elevated TPOAb and TGAb, and increased TRAb and IAA levels.

Subsequently, to explore inter-feature correlations, we performed Pearson correlation tests on variables with P < 0.05, calculating correlation coefficients between variables and generating Pearson correlation heatmaps. We investigated associations among UACR, FCP, P2hCP, FT3, FT4, TPOAb, TGAb, TRAb, and IAA in LADA patients. The correlation analysis revealed that FCP showed positive correlations with P2hCP and FT3, while demonstrating a negative correlation with IAA. FT3 was positively correlated with P2hCP and FT4. Additionally, TPOAb exhibited positive correlations with both TGAb and TRAb (see Table 2 and Figure 1).

Table 2 Correlations Among UACR, FCP, P2hCP, FT3, FT4, TPOAb, TGAb, TRAb, and IAA in LADA Patients

Figure 1 Heatmap of Pearson Correlation Coefficients Among UACR, FCP, P2hCP, FT3, FT4, TPOAb, TGAb, TRAb, and IAA in LADA Patients.

Finally, univariate binary logistic regression analysis (Table 3) revealed that lower FCP, P2hCP, and FT3 levels, as well as higher TPOAb and TGAb levels, were associated with the occurrence of thyroid dysfunction in LADA patients.

Table 3 Univariate Binary Logistic Regression Analysis of Thyroid Dysfunction in LADA Patients

Discussion

Our findings demonstrate that LADA patients with thyroid dysfunction exhibit significantly higher UACR, lower FCP and P2hCP levels, decreased FT3 and FT4, along with markedly elevated TPOAb and TGAb, and increased TRAb and IAA levels. These results suggest that compared to LADA patients without thyroid dysfunction, those with concomitant thyroid abnormalities are more prone to diabetic nephropathy, exhibit more severe islet dysfunction, and have higher susceptibility to autoimmune thyroid diseases—particularly Hashimoto’s thyroiditis—while also indicating greater disease severity and progression risk in LADA.

The observed association between thyroid dysfunction and LADA corroborates previous cross-sectional observations.^10–14 A 2025 Diabetologia study further elucidated this relationship mechanistically, revealing that MHC-driven immune responses—encompassing both innate and adaptive pathways—represent the primary shared biological pathway connecting LADA with Crohn’s disease, ulcerative colitis, hypothyroidism, hyperthyroidism, and vitiligo. These pathways involve diverse immune cells (B cells, T cells, and natural killer cells) and molecules (cytokines, immunoglobulins, and interferons).¹⁵

Diabetes mellitus (DM) substantially increases chronic complication risks. Diabetic kidney disease (DKD), one of the most prevalent microvascular complications affecting up to 25% of DM patients, constitutes a leading cause of chronic kidney disease and end-stage renal disease,^16,17 imposing significant economic burdens and severely compromising quality of life. Thyroid hormones critically influence glucose metabolism, where both overt and subclinical thyroid dysfunction adversely affect disease control in DM patients, particularly in LADA. DKD diagnosis primarily relies on elevated urinary albumin-to-creatinine ratio (UACR) and reduced estimated glomerular filtration rate (eGFR). The 2025 Diabetologia study reported higher retinopathy incidence in LADA versus T2DM, corroborating prior findings.^15,18 Clinically, elevated UACR shows positive association with subclinical hypothyroidism (OR 3.51, 95% CI: 1.10–10.0),^19,20 aligning with our results. Mechanistically, thyroid hormones and DKD interact bidirectionally: hyperglycemia-induced inflammation suppresses 5’-deiodinase activity, impairing peripheral T4-to-T3 conversion²¹ and reducing FT3, thereby disrupting the hypothalamic-pituitary-thyroid axis.²² Concurrently, glomerular structural damage in DKD promotes protein loss, further depressing FT3 and exacerbating hypothyroidism.^23,24 Thus, worsening DKD severity progressively lowers FT3, intensifying thyroid dysfunction, which in turn accelerates DKD progression—creating a vicious cycle.

Correlation analyses revealed positive associations between FT3 and FCP/P2hCP/FT4. Clinically, severe LADA often manifests low T3 syndrome which is a thyroid hormone metabolism disorder caused by systemic non-thyroidal illnesses, where pronounced glucotoxicity exacerbates islet dysfunction—consistent with the proposed mechanism of hyperglycemia-induced 5’-deiodinase suppression impairing T3 conversion.^21,22 We also observed positive correlations among TPOAb, TGAb, and TRAb, explaining the frequent coexistence of autoimmune disorders (eg, Hashimoto’s thyroiditis and Graves’ disease) through shared immunopathogenic mechanisms.¹⁵ Notably, the inverse FCP-IAA correlation aligns with 2024 Endocrine findings: elevated plasmablasts and Breg (B10) phenotypes in LADA positively correlate with islet cell antibodies and IAA but negatively with FCP, suggesting PB-mediated β-cell destruction²⁵—mechanistically supporting our observations.

Univariate binary logistic regression confirmed that low FCP, P2hCP, and FT3, alongside high TPOAb and TGAb, predict thyroid dysfunction in LADA. Prior studies validate thyroid antibodies as key predictors.²⁶ Thus, we recommend: (1) annual/biennial thyroid antibody and FT3 screening from LADA onset to minimize undiagnosed thyroid dysfunction;²⁷ and (2) triannual/semiannual islet function assessments to optimize insulin initiation timing and tailor thyroid therapy, enabling early intervention to mitigate progression risks.

Limitations: First, single-center design and limited sample size may introduce bias, necessitating multicenter cohorts with refined subgroup analyses. Second, GADA assay specificity (98%) permits potential misclassification of T2DM as LADA, potentially attenuating observed thyroid dysfunction associations. Finally, the study selected a hospitalized population, which may introduce some selection bias and lacks a healthy control group. Therefore, further improvements are needed in future research.

Conclusion

In conclusion, our study identifies low FCP/P2hCP/FT3 and high TPOAb/TGAb as predictors of thyroid dysfunction in LADA, warranting regular thyroid and islet function monitoring for timely intervention.

Ethical Statement

Ethics approval and consent to participate Written informed consent for all data was obtained from patients during their hospitalization, and the Ethics Committee of the Affiliated Hospital of Xuzhou Medical University approved the study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no conflicts of interest in this work.

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