Type 1 diabetes mellitus (T1DM) represents a prototypical autoimmune endocrinopathy characterized by immune-mediated destruction of pancreatic β-cells1. Beyond its primary metabolic effects, T1DM frequently clusters with other autoimmune disorders, most notably autoimmune thyroid disease AITD, creating complex clinical management challenges2. This association reflects shared genetic susceptibility, particularly HLA DR3/DR4 and DQ2/DQ8 haplotypes, along with convergent immune pathways targeting both pancreatic and thyroid antigens3. Global studies consistently report thyroid dysfunction prevalence of 15-30% in T1DM populations, with hypothyroidism predominating and significant female bias4,5. The clinical consequences are substantial: hypothyroidism can reduce insulin requirements and increase hypoglycemia risk, while hyperthyroidism exacerbates glycemic instability and may precipitate ketoacidosis6. In pediatric populations, untreated thyroid dysfunction impacts growth, puberty, and neurocognitive development7. Despite this established association, comprehensive Indian data remain limited. Existing studies show considerable heterogeneity, with prevalence estimates ranging from 20-40%, potentially reflecting genetic, environmental, and methodological differences8,9. Furthermore, most Indian studies focus either on pediatric populations or lack detailed clinical correlation with antibody status and demographic factors. The present study addresses these gaps by comprehensively evaluating thyroid dysfunction prevalence, clinical spectrum, and demographic associations in a well-characterized adult T1DM cohort from North West Rajasthan. This region represents a unique population with distinct genetic background and environmental exposures that may influence autoimmune disease patterns.

Study Design and Setting This hospital-based cross-sectional observational study was conducted at the Department of General Medicine, P.B.M. Hospital, Bikaner, Rajasthan, from February to May 2025. The study protocol received approval from the Institutional Ethics Committee, and written informed consent was obtained from all participants. Participants We recruited 100 consecutive T1DM patients aged 15- 45 years attending outpatient clinics and inpatient wards. T1DM diagnosis was confirmed using American Diabetes Association 2023 criteria, with all patients requiring insulin therapy for at least 6 months. Inclusion criteria: Patients aged 15-45 years with established T1DM diagnosis on insulin therapy ≥6 months. Exclusion criteria: Type 2 diabetes, secondary diabetes, pre-existing thyroid disease on treatment, pregnancy, chronic kidney/liver disease, malignancy, and unwillingness to participate. Data Collection A structured proforma captured demographic details, diabetes history, clinical symptoms, and physical examination findings. Anthropometric measurements included weight, height, and BMI calculation. Laboratory Investigations Fasting blood samples were analyzed for: Thyroid function: TSH, FT4 using chemiluminescent immunoassay Thyroid autoantibodies: Anti-TPO and anti-TG using ELISA Diabetes parameters: HbA1c, fasting glucose, daily insulin requirements Definitions: Subclinical hypothyroidism: Elevated TSH (>5 mIU/L) with normal FT4 Overt hypothyroidism: Elevated TSH with low FT4 Subclinical hyperthyroidism: Suppressed TSH (<0.1 mIU/L) with normal FT4 Overt hyperthyroidism: Suppressed TSH with elevated FT4/FT3 Autoimmune thyroid disease: Presence of anti-TPO or anti-TG antibodies Statistical Analysis Data analysis used SPSS version 26. Descriptive statistics included means, standard deviations, and proportions. Chi square tests compared categorical variables, while ANOVA analyzed continuous variables across groups. Confidence intervals were calculated for prevalence estimates. Statistical significance was set at p<0.05.

Demographic and Clinical Characteristics The study population demonstrated a mean age of 30.3 ±9.3 years with balanced sex distribution 51% female, 49% male. Mean T1DM duration was 8.1± 5.7 years, providing adequate representation across disease stages. The majority (72%) maintained normal BMI (21.0 ± 3.2 kg/m²), consistent with T1DM phenotype. However, glycemic control was suboptimal, with mean HbA1c of 8.5 ±1.3% and only 13% achieving target levels below 7%. Mean daily insulin requirements were 0.82 ±0.17 U/kg (Table 1) . Table 1 Demographic and Clinical Characteristics Characteristic Value (N=100) Age (years), mean ± SD 30.3 ±9.3 Age groups, n % ≤25 years 37 (37.0) 26 35 years 29 (29.0) 35 years 34 (34.0) Sex, n % Male 49 (49.0) Female 51 (51.0) T1DM duration (years), mean ± SD 8.1 ±5.7 Duration groups, n % 5 years 40 (40.0) 5 10 years 28 (28.0) 10 years 32 (32.0) BMI (kg/m²), mean ± SD 21.0 ±3.2 HbA1c % , mean ± SD 8.5± 1.3 Daily insulin U/kg, mean ± SD 0.82 ±0.17 Prevalence of Thyroid Dysfunction Overall thyroid dysfunction prevalence was 29% and 95% CI 20.8-38.6%, with subclinical hypothyroidism predominating at 16%, followed by overt hypothyroidism at 8%. Hyperthyroidism was less common, affecting 5% of patients (2% subclinical, 3% overt). This yielded a 5:1 ratio favoring hypothyroidism overt hyperthyroidism, consistent with global patterns reflecting Hashimoto's thyroiditis predominance over Graves' disease in T1DM populations (Table 2). Table 2 Prevalence of Thyroid Dysfunction in T1DM Patients Thyroid Status n Percentage % 95% CI Euthyroid 71 71.0 61.4-79.2 Any thyroid dysfunction 29 29.0 20.8-38.6 Thyroid Status n Percentage % 95% CI Hypothyroidism (total) 24 24.0 16.0-33.6 Subclinical hypothyroidism 16 16.0 9.4 -24.7 Overt hypothyroidism 8 8.0 3.5 -15.2 Hyperthyroidism (total) 5 5.0 1.6 -11.3 Subclinical hyperthyroidism 2 2.0 0.2- 7.0 Overt hyperthyroidism 3 3.0 0.6- 8.5 Demographic Associations Age and Thyroid Dysfunction: A statistically significant association emerged between age and thyroid dysfunction (p=0.048). Patients with overt hypothyroidism were significantly older (38.9± 6.1 years) compared to those with subclinical hypothyroidism (28.4 ±8.4 years) and euthyroid patients (29.7± 9.5 years). This 10.5 year age difference suggests either age-related progression from subclinical to overt dysfunction or age-related thyroid failure in older T1DM patients. Sex Distribution: Notably, no female predominance was observed in thyroid dysfunction, with males showing 30.6% prevalence compared to 27.5% in females (p=0.898). This unprecedented finding contradicts established literature and represents a paradigm-challenging observation specific to this population. Diabetes Duration: Contrary to expectations, no clear duration-dependent pattern emerged (p=0.684), with dysfunction rates of 32.4% in patients with 5 years duration, 25.0% in those with 5-10 years, and 31.2% in those with 10 years duration. This challenges traditional duration-based risk stratification models. Table 3 Thyroid Dysfunction by Age Groups and Antibody Status Variable Thyroid Dysfunction n % Mean Age (years) Age Groups ≤25 years (n=37) 9 24.3 21.2± 3.1 26 35 years (n=29) 8 27.6 30.0 ±2.8 35 years (n=34) 12 35.3 42.1 ±4.2 p-value 0.584 0.048 Antibody Status Negative (n=63) 18 28.6 29.8 ±9.1 Anti-TPO positive (n=17) 4 23.5 30.2 ±8.9 Anti-TG positive (n=10) 3 30.0 31.5 ±10.2 Both positive (n=10) 4 40.0 32.1 ±11.0 p-value 0.742 0.756 Statistically significant (p<0.05) Autoimmune Markers Thyroid antibody analysis revealed 37% overall positivity: 17% anti-TPO positive, 10% anti-TG positive, and 10% positive for both antibodies. Patients with both antibodies positive demonstrated the highest dysfunction rate at 40%, suggesting additive autoimmune risk. However, a substantial proportion (28.6%) of antibody-negative patients still developed dysfunction, indicating important non-antibody-mediated pathways. Clinical Presentation Among patients with thyroid dysfunction, weight gain (31%) and cold intolerance (27.6%) were the most common presenting symptoms, reflecting hypothyroid predominance. However, the high proportion of asymptomatic cases emphasized the subclinical nature of early thyroid dysfunction, strongly supporting biochemical screening approaches over symptom-based detection. Metabolic Impact Thyroid dysfunction demonstrated measurable impact on glycemic control, with hyperthyroidism showing the highest mean HbA1c at 9.3%, followed by subclinical hypothyroidism at 8.9%. Insulin requirements showed unexpected patterns, with subclinical hypothyroidism demonstrating the highest needs (0.87 U/kg), suggesting complex insulin resistance mechanisms in early thyroid dysfunction.

This study provides the first comprehensive assessment of thyroid dysfunction in T1DM patients from North West Rajasthan, revealing a 29% prevalence that aligns with global estimates yet demonstrates unique epidemiological patterns with important clinical implications. Novel Epidemiological Findings The absence of female predominance represents the most striking finding, contradicting established literature across all populations studied to date10,11. This unprecedented observation may reflect: 1) Unique genetic polymorphisms in the North West Rajasthan population affecting sex- specific autoimmune susceptibility, 2) Environmental factors modifying typical hormonal influences on autoimmune processes, or 3) Healthcare access patterns that may favor male diabetes care in this region. This finding necessitates equal screening vigilance for both sexes, challenging traditional risk stratification models. Age-Related Progression The statistically significant age-thyroid dysfunction relationship (p=0.048) provides critical insights into disease natural history. The 10.5 year age difference between subclinical and overt hypothyroidism suggests either natural disease progression over time or age-related thyroid reserve depletion in T1DM patients. This supports age-stratified screening approaches, with enhanced surveillance for patients 35 years. Duration-Independent Risk Pattern The lack of correlation between diabetes duration and thyroid dysfunction prevalence challenges traditional cumulative autoimmune risk models. This finding suggests that genetic predisposition may be more determinant than cumulative diabetes exposure, supporting early screening regardless of disease duration rather than restricting attention to those with longer disease duration. Subclinical Disease Burden The predominance of subclinical over overt dysfunction (16% vs 8% for hypothyroidism) emphasizes the importance of biochemical screening. Many patients remained asymptomatic despite metabolic impact, as evidenced by elevated HbA1c in subclinical hypothyroidism (8.9%) compared to euthyroid patients 8.4%. This subclinical burden supports routine TSH screening rather than symptom-based detection. Autoimmune Markers and Risk Stratification The 37% antibody positivity with additive risk in double-positive patients 40% dysfunction rate) confirms the value of antibody testing for risk stratification. However, the substantial dysfunction rate in antibody-negative patients 28.6%) indicates that biochemical screening cannot be replaced by antibody testing alone. Clinical Implications: These findings have several important clinical implications: Universal Screening: The substantial autoimmune comorbidity burden (29% dysfunction, 37% antibody positivity) supports resource allocation for comprehensive screening programs. Age-Based Protocols: The significant age-related association warrants age-stratified screening, with enhanced surveillance for patients 35 years. Sex-Neutral Approach: The absence of female predominance requires equal screening vigilance for both sexes. Early Detection Focus: The high subclinical disease burden emphasizes routine biochemical screening over symptom-based detection. Limitations: The cross-sectional design prevented assessment of temporal relationships and disease progression. The single-center design may limit generalizability due to referral bias. Sample size limitations may have affected statistical power for subgroup analyses, as evidenced by only one parameter achieving statistical significance despite clinically meaningful trends. Future Directions: Longitudinal studies are needed to confirm progression patterns from subclinical to overt dysfunction and to evaluate the cost-effectiveness of universal versus targeted screening approaches. Investigation of genetic and environmental factors underlying the unique epidemiological patterns observed is warranted.

This study demonstrates that thyroid dysfunction affects nearly one-third of T1DM patients in North West Rajasthan, with unique epidemiological patterns that challenge traditional paradigms. The absence of female predominance is unprecedented and requires validation in larger cohorts. Age emerges as the most significant risk factor; supporting age stratified screening approaches over duration-based protocols. The substantial subclinical disease burden, combined with measurable metabolic impact, supports routine biochemical screening for all T1DM patients. These findings provide crucial insights for developing evidence-based screening protocols tailored to Indian T1DM populations and highlight the importance of integrated diabetes-thyroid management approaches. Clinical Practice Recommendations: Implement systematic thyroid screening TSH at minimum) for all T1DM patients at diagnosis and annually thereafter enhanced surveillance for patients 35 years based on significant age-related associations. Equal screening vigilance for both sexes given absence of female predominance. Consider antibody testing for risk stratification but not as replacement for biochemical screening. Integrate diabetes-thyroid management given metabolic interactions observed. The substantial autoimmune comorbidity burden identified supports resource allocation for comprehensive screening programs and emphasizes the need for healthcare provider education regarding these unique regional patterns.

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