Introduction

Objectives and Methods

• Inclusion Criteria: Participants with baseline prediabetes, defined by hemoglobin A1c (HbA1c) levels between 5.7% and 6.4% (39–47.9 mmol/mol) per the 2023 American Diabetes Association (ADA) guidelines.
• Exclusion Criteria: Individuals with baseline diabetes or missing handgrip strength data.
• Sarcopenia Definition: Based on the 2019 European Working Group on Sarcopenia in Older People (EWGSOP2) criteria:
  • Probable Sarcopenia: Low handgrip strength alone.
  • Confirmed Sarcopenia: Low handgrip strength plus low muscle mass.
  • Severe Sarcopenia: Confirmed sarcopenia plus poor physical performance (assessed via self-reported slow walking pace due to lack of gait speed data).
• Outcome: Incident T2DM during follow-up, identified via hospital inpatient records and registries using ICD-10 codes E11.
• Analysis: Multivariable Cox proportional hazards models adjusted for sociodemographic factors, lifestyle, comorbidities, laboratory measures, and used subgroup and sensitivity analyses to test robustness.

Key Findings

Population Characteristics:

• A total of 60,325 participants with prediabetes were included (mean age 59.6 years; 54.5% female).
• Sarcopenia prevalence was 11.8% (7,139 participants).
• Participants with sarcopenia were generally older, had higher BMI and HbA1c, lower muscle mass and strength, and a greater burden of comorbidities such as hypertension and cancer.

Incident T2DM:

• Over a mean follow-up of 11.4 years, 9,305 (15.4%) developed T2DM.
• Cumulative incidence of T2DM was significantly higher in those with sarcopenia than those without (19.3% vs. 14.9%, P < 0.001).

Association between Sarcopenia and T2DM Risk:

• Sarcopenia was associated with a 22% increased risk of incident T2DM after full adjustment (Hazard Ratio [HR] = 1.22; 95% Confidence Interval [CI]: 1.15–1.30).
• When categorized by severity:
  • Probable sarcopenia: HR = 1.18 (95% CI: 1.09–1.26)
  • Confirmed/severe sarcopenia: HR = 1.33 (95% CI: 1.18–1.50)
• Sensitivity analyses using alternate prediabetes definitions, competing risk models, propensity score matching, and adjustment for physical activity confirmed robustness.

Subgroup Analyses:

• The association was stronger in participants with waist-to-hip ratio (WHR) < 0.9 (HR = 1.43) compared to those with WHR ≥ 0.9 (HR = 1.17), with significant interaction (P for interaction < 0.001).
• A non-significant trend suggested a stronger association in younger participants (<65 years) than older ones.
• Other subgroups (sex, BMI, smoking, comorbidities) showed no significant effect modification after correction for multiple testing.

Mediation Analysis:

• Approximately 15.4% of the effect of sarcopenia on T2DM risk was mediated through baseline HbA1c, indicating sarcopenia influences T2DM development via both glycemic and non-glycemic pathways.

Interpretation and Mechanisms

• Impaired Glucose Uptake: Reduced muscle mass decreases insulin-stimulated glucose disposal, promoting insulin resistance.
• Inflammation and Mitochondrial Dysfunction: Muscle atrophy may release pro-inflammatory cytokines disrupting insulin signaling, while mitochondrial dysfunction impairs oxidative capacity and glucose metabolism.
• Bidirectional Relationship: Although prediabetes can contribute to sarcopenia, this study’s mediation analysis supports sarcopenia as a distinct predictor of T2DM beyond glycemic control.

Clinical Implications

• Sarcopenia assessment, incorporating handgrip strength and muscle mass, may help identify prediabetic individuals at higher risk of T2DM.
• Interventions aimed at preserving and improving muscle health—such as resistance training and optimized protein intake—could represent novel strategies to delay or prevent T2DM onset in prediabetic populations.
• Given the increasing global burden of T2DM, incorporating muscle health into prevention paradigms may enhance current strategies focused primarily on glycemic control.

Strengths and Limitations

Strengths:

• Large, nationally representative prospective cohort with over 60,000 prediabetic adults.
• Long follow-up duration (mean 11.4 years).
• Comprehensive adjustment for confounders.
• Use of validated sarcopenia criteria (EWGSOP2) with combined muscle strength and mass measurements.
• Robust sensitivity and subgroup analyses.

Limitations:

• Observational design limits causal inference.
• Potential under-ascertainment of T2DM due to reliance on hospital and registry data.
• Predominantly White population (90.6%), limiting generalizability.
• Lack of longitudinal sarcopenia assessments and direct gait speed measurements.
• Possible residual confounding despite adjustments.

Conclusion

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