HbA1c and skeletal muscle health in type 2 diabetes: phenotype-specific associations across different analytical directions and mechanistic insights

Sarcopenia is increasingly recognized as a clinically relevant complication of type 2 diabetes mellitus (T2DM), but its association with glycated hemoglobin (HbA1c) remains unclear. This review synthesizes evidence from 30 clinical reports examining the relationship between HbA1c-derived glycemic exposure measures and skeletal muscle outcomes in adults with T2DM, with studies categorized by muscle phenotype and analytical direction. Risk of bias was assessed using design-specific JBI checklists (lower/moderate/higher concern:11/16/3), and conclusions emphasized adjusted estimates from lower or moderate-concern studies. Available evidence indicates that the association between HbA1c-derived glycemic exposure measures and skeletal muscle health differs substantially across phenotypes. Longitudinal studies provide more consistent temporal evidence linking HbA1c trajectories to changes in muscle mass, whereas some prospective studies suggest that baseline muscle characteristics may provide prognostic information regarding subsequent glycemic outcomes. Evidence for physical performance remains inconsistent, and associations with composite sarcopenia vary according to diagnostic frameworks and phenotype composition. Potential biological mechanisms involving impaired insulin signaling, advanced glycation end product accumulation, mitochondrial dysfunction, inflammation, neuropathy, and microvascular impairment may represent biologically plausible and overlapping pathways contributing to these associations. However, direct human evidence supporting pathway-specific effects on individual muscle phenotypes remains limited. Current evidence supports a phenotype-specific interpretation of the HbA1c–skeletal muscle relationship but does not establish bidirectional causality. HbA1c should be interpreted as a marker of glycemic exposure rather than an indicator of overall skeletal muscle health, and satisfactory glycemic control does not exclude sarcopenia or impairment in individual muscle domains. Prospective studies with repeated glycemic assessments and multidimensional muscle evaluations are needed to clarify temporal relationships and clinical implications.