Association of Leukocyte Telomere Length with Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes
Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of liver disease globally and has seen a sharp rise in prevalence in many parts of the world. NAFLD and type 2 diabetes mellitus (T2DM) frequently coexist due to their shared pathogenic characteristics of insulin resistance and excess adiposity. Studies suggest that the prevalence of NAFLD in T2DM patients ranges from 29.6% to 87.1%. T2DM increases the risk of cirrhosis, hepatocellular carcinoma, and liver-related death, while NAFLD may increase the risk of major adverse cardiac events and overall mortality in T2DM patients. Therefore, screening for NAFLD in T2DM patients is crucial, and identifying biomarkers for NAFLD diagnosis is of significant importance.
Telomeres are regions of repetitive G-rich DNA at the ends of eukaryotic chromosomes that protect chromosome tips from end-to-end fusion and degradation. Leukocyte telomere length (LTL) is considered a marker of chronic inflammation and systemic oxidative stress, resulting in higher leukocyte turnover. Previous studies have indicated that telomere length could be a useful indicator of risk for metabolic diseases, with shorter telomere length related to components of metabolic dysfunction such as insulin resistance, abdominal obesity, and hypertension. Shorter telomere length also predicts the development of insulin resistance, T2DM, and progression of metabolic syndrome. However, the relationship between telomere length and NAFLD remains ambiguous, with conflicting findings in different studies.
This cross-sectional study aimed to investigate the association of LTL with NAFLD in T2DM patients. The study included 120 T2DM patients without NAFLD and 120 age-matched T2DM patients with NAFLD. Clinical features were collected, and LTL was measured using Southern blot-based terminal restriction fragment length analysis. NAFLD was clinically defined by manifestations of ultrasonography. The correlation between LTL and clinical and biochemical parameters was analyzed using Pearson or Spearman correlation analysis. Factors for NAFLD in T2DM patients were identified using multiple logistic regressions.
The results showed that LTL in T2DM patients with NAFLD was significantly longer than in those without NAFLD (6400.2 ± 71.8 base pairs [bp] vs. 6023.7 ± 49.5 bp, P < 0.001). This difference was especially evident when the diabetes duration was less than 2 years. Additionally, a trend of shorter LTL was associated with increased diabetes duration in T2DM patients with NAFLD but not in those without NAFLD. Multiple logistic regression analysis revealed that LTL (odds ratio [OR]: 1.001, 95% confidence interval [CI]: 1.000–1.002, P = 0.001), body mass index (BMI) (OR: 1.314, 95% CI: 1.169–1.477, P < 0.001), and triglycerides (TG) (OR: 1.984, 95% CI: 1.432–2.747, P < 0.001) were significantly associated with NAFLD status in T2DM patients.
The study concluded that T2DM patients with NAFLD had significantly longer LTL than those without NAFLD, particularly in the early stages of T2DM. This suggests that longer LTL may serve as a biomarker for NAFLD in T2DM patients. The findings highlight the potential role of LTL in the early detection and intervention of NAFLD in T2DM patients, which could be more critical than shorter LTL as an indicator in the later stages of NAFLD.
The study also found that LTL was negatively associated with age and diabetes duration, consistent with previous research. However, the association between LTL and diabetes duration lost statistical significance after adjusting for age. Notably, LTL was not correlated with insulin secretion and sensitivity in this study, possibly due to the severe insulin resistance in the study subjects. This aligns with previous research suggesting that LTL is more likely to predict insulin resistance later in life rather than in cross-sectional studies.
The study further explored the effect of diabetes duration on LTL by stratifying T2DM patients with and without NAFLD into four subgroups based on diabetes duration (8 years). T2DM patients with NAFLD had significantly longer LTL than those without NAFLD when the diabetes duration was less than two years (P < 0.005). The trend of shorter LTL with increased diabetes duration was observed in T2DM patients with NAFLD but not in those without NAFLD.
In terms of NAFLD, the mechanism linking LTL with NAFLD remains unclear. While shorter LTL is associated with systemic oxidative stress and chronic inflammation, which are pathogenic characteristics of NAFLD, longer LTL has also been observed in other oxidative stress and inflammation-related diseases such as chronic pancreatitis, hepatitis B virus-related hepatocellular carcinoma, and visceral adipose tissue in T2DM patients. Longer LTL seems to be often associated with metabolic diseases, and our findings that longer LTL was negatively associated with age and diabetes duration align with previous studies.
The study also identified that LTL, along with BMI and TG, were independent factors for NAFLD in T2DM patients. BMI and TG are well-known risk factors for NAFLD, and their inclusion in the logistic regression analysis further supports the significance of LTL as a biomarker for NAFLD. The area under the receiver operating characteristic (ROC) curve (AUC) for the telomere model (LTL + BMI + TG) was 0.860 (95% CI: 0.804–0.917), which was larger than that of LTL alone (AUC = 0.654, 95% CI: 0.573–0.734). This indicates that the combination of LTL, BMI, and TG provides a more accurate diagnosis of NAFLD in T2DM patients.
The study has several strengths, including the use of Southern blot-based terminal restriction fragment length analysis, which is considered the gold standard for measuring LTL. This method provides an exact value of LTL and is more accurate and repeatable compared to quantitative polymerase chain reaction used in other studies. Additionally, ultrasonography was used to diagnose NAFLD, which is more accurate than relying on high serum ALT levels, as done in some previous studies.
However, the study also has limitations. It lacked a population-based healthy control group and patients with only NAFLD. The diagnosis of NAFLD was based on ultrasonography, which, while widely available and cost-effective, is less accurate than methods such as computed tomography scan, magnetic resonance imaging (MRI), or biopsy-proven steatosis. Liver biopsy, the gold standard for NAFLD, is invasive and not feasible for all patients. MRI, although highly precise, is time-consuming and expensive. Therefore, ultrasonography remains the most practical method for NAFLD diagnosis in clinical settings.
In conclusion, this study provides valuable insights into the association between LTL and NAFLD in T2DM patients. The findings suggest that longer LTL may serve as an early biomarker for NAFLD in T2DM patients, particularly in the early stages of diabetes. Further research is needed to explore the mechanisms linking longer LTL and NAFLD and to validate the role of LTL as a potential predictor for NAFLD in T2DM patients. The study underscores the importance of early detection and intervention in managing NAFLD in T2DM patients, which could significantly impact patient outcomes.
doi.org/10.1097/CM9.0000000000000559
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