Telomere Length as Both Cause and Consequence in Type 1 Diabetes: Evidence from Bidirectional Mendelian Randomization
<b>Background/Objectives:</b> Diabetes is the most prevalent metabolic disease globally, characterized by dysregulated glucose control and accompanied by multiple refractory complications. As a critical marker of cellular homeostasis, telomere length (TL) may be associated with the progr...
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MDPI AG
2025-03-01
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| author | Guanping Wei Ruiping Chen Shupeng Liu Shenhua Cai Zhijun Feng |
| author_facet | Guanping Wei Ruiping Chen Shupeng Liu Shenhua Cai Zhijun Feng |
| author_sort | Guanping Wei |
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| description | <b>Background/Objectives:</b> Diabetes is the most prevalent metabolic disease globally, characterized by dysregulated glucose control and accompanied by multiple refractory complications. As a critical marker of cellular homeostasis, telomere length (TL) may be associated with the progression of diabetes. However, the causal relationship between diabetes and TL remains unclear, particularly whether cellular homeostasis imbalance acts as a consequence of diabetic complications or a precipitating factor in disease development. <b>Methods:</b> We performed a bidirectional Mendelian randomization (MR) analysis using genome-wide association study (GWAS) data. Following the three core assumptions of MR analysis, we conducted quality control on all instrumental variables to ensure methodological rigor. The inverse variance weighted (IVW) method served as the primary analytical method, supplemented by additional MR methods to evaluate the significance of the results. Furthermore, we performed sensitivity analyses to ensure the reliability and robustness of the findings. <b>Results:</b> Forward analysis revealed that shortened TL significantly increases the risk of broadly defined Type 1 diabetes (T1D) and unspecified types of diabetes (<i>p</i> < 0.05). Additionally, we identified a positive causal relationship between TL and several diabetes-related complications, including co-morbidities, diabetic nephropathy, and diabetic ketoacidosis (<i>p</i> < 0.05). Interestingly, the reverse analysis demonstrated a positive causal effect of T1D and its complications on TL (<i>p</i> < 0.05); however, this effect disappeared after adjusting for insulin use (<i>p</i> > 0.05). <b>Conclusions:</b> Bidirectional MR analyses revealed a complex relationship between TL and T1D, where shortened telomeres increase T1D risk while T1D itself may trigger compensatory mechanisms affecting telomere maintenance, with insulin playing a crucial regulatory role in this relationship. These findings suggest telomere biology may be fundamentally involved in T1D pathogenesis and could inform future therapeutic approaches. |
| format | Article |
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| language | English |
| publishDate | 2025-03-01 |
| publisher | MDPI AG |
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| series | Biomedicines |
| spelling | doaj-art-0b6a10f76e3e4c9bb0114169d057f6f42025-08-20T03:14:17ZengMDPI AGBiomedicines2227-90592025-03-0113477410.3390/biomedicines13040774Telomere Length as Both Cause and Consequence in Type 1 Diabetes: Evidence from Bidirectional Mendelian RandomizationGuanping Wei0Ruiping Chen1Shupeng Liu2Shenhua Cai3Zhijun Feng4Department of Emergency, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Thoracic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, ChinaGuangdong Provincial Key Laboratory of Tropical Disease Research, Department of Radiation Medicine, School of Public Health, Southern Medical University, Guangzhou 510515, ChinaDepartment of Breast Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, ChinaGuangdong Provincial Key Laboratory of Tropical Disease Research, Department of Radiation Medicine, School of Public Health, Southern Medical University, Guangzhou 510515, China<b>Background/Objectives:</b> Diabetes is the most prevalent metabolic disease globally, characterized by dysregulated glucose control and accompanied by multiple refractory complications. As a critical marker of cellular homeostasis, telomere length (TL) may be associated with the progression of diabetes. However, the causal relationship between diabetes and TL remains unclear, particularly whether cellular homeostasis imbalance acts as a consequence of diabetic complications or a precipitating factor in disease development. <b>Methods:</b> We performed a bidirectional Mendelian randomization (MR) analysis using genome-wide association study (GWAS) data. Following the three core assumptions of MR analysis, we conducted quality control on all instrumental variables to ensure methodological rigor. The inverse variance weighted (IVW) method served as the primary analytical method, supplemented by additional MR methods to evaluate the significance of the results. Furthermore, we performed sensitivity analyses to ensure the reliability and robustness of the findings. <b>Results:</b> Forward analysis revealed that shortened TL significantly increases the risk of broadly defined Type 1 diabetes (T1D) and unspecified types of diabetes (<i>p</i> < 0.05). Additionally, we identified a positive causal relationship between TL and several diabetes-related complications, including co-morbidities, diabetic nephropathy, and diabetic ketoacidosis (<i>p</i> < 0.05). Interestingly, the reverse analysis demonstrated a positive causal effect of T1D and its complications on TL (<i>p</i> < 0.05); however, this effect disappeared after adjusting for insulin use (<i>p</i> > 0.05). <b>Conclusions:</b> Bidirectional MR analyses revealed a complex relationship between TL and T1D, where shortened telomeres increase T1D risk while T1D itself may trigger compensatory mechanisms affecting telomere maintenance, with insulin playing a crucial regulatory role in this relationship. These findings suggest telomere biology may be fundamentally involved in T1D pathogenesis and could inform future therapeutic approaches.https://www.mdpi.com/2227-9059/13/4/774telomere lengthdiabetesdiabetic complicationMendelian randomization |
| spellingShingle | Guanping Wei Ruiping Chen Shupeng Liu Shenhua Cai Zhijun Feng Telomere Length as Both Cause and Consequence in Type 1 Diabetes: Evidence from Bidirectional Mendelian Randomization Biomedicines telomere length diabetes diabetic complication Mendelian randomization |
| title | Telomere Length as Both Cause and Consequence in Type 1 Diabetes: Evidence from Bidirectional Mendelian Randomization |
| title_full | Telomere Length as Both Cause and Consequence in Type 1 Diabetes: Evidence from Bidirectional Mendelian Randomization |
| title_fullStr | Telomere Length as Both Cause and Consequence in Type 1 Diabetes: Evidence from Bidirectional Mendelian Randomization |
| title_full_unstemmed | Telomere Length as Both Cause and Consequence in Type 1 Diabetes: Evidence from Bidirectional Mendelian Randomization |
| title_short | Telomere Length as Both Cause and Consequence in Type 1 Diabetes: Evidence from Bidirectional Mendelian Randomization |
| title_sort | telomere length as both cause and consequence in type 1 diabetes evidence from bidirectional mendelian randomization |
| topic | telomere length diabetes diabetic complication Mendelian randomization |
| url | https://www.mdpi.com/2227-9059/13/4/774 |
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