HbA1c Tracks Blood Sugar, Not Muscle Health, in Type 2 Diabetes

High HbA1c has long been treated as a warning sign for the slow erosion of muscle that shadows type 2 diabetes, but a new structured narrative review argues that this single blood-sugar number cannot stand in for the health of the muscle itself. The analysis, published in Frontiers in Endocrinology, pulled together 30 clinical reports examining how HbA1c-derived glycemic exposure measures relate to skeletal muscle outcomes in adults with type 2 diabetes, and its central conclusion is deliberately narrow: the relationship is phenotype-specific, not uniform, and it does not establish bidirectional causality. HbA1c, the authors contend, should be read 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.

The review was not a meta-analysis. Because the included studies differed so sharply in participants, HbA1c definitions, muscle measurement techniques, and sarcopenia diagnostic criteria, the authors instead built a structured narrative synthesis, categorizing studies by muscle phenotype and by analytical direction. Database and citation searches identified 2,167 records; after duplicates and screening, 36 full-text reports were assessed and 30 unique reports met the eligibility criteria. Risk of bias was appraised with design-specific JBI checklists, yielding 11 studies of lower concern, 16 of moderate concern, and 3 of higher concern, and the conclusions leaned on adjusted estimates from the lower or moderate-concern studies. Higher-concern studies were retained for completeness but were not used alone to support the main conclusions.

That methodological discipline matters because the evidence streams point in different directions. Some studies treated HbA1c-derived glycemic exposure as the exposure and skeletal muscle as the outcome; others reversed the arrow, asking whether muscle mass or strength predicts later glycemic control. The review insists these are distinct questions that cannot be merged into a claim of biological bidirectionality. What emerged most consistently, among lower or moderate-concern studies, was longitudinal: changes in HbA1c exposure were associated with concurrent changes in muscle mass, particularly when analyses examined within-person change rather than a single HbA1c measurement. In one multicenter longitudinal study of 588 people with type 2 diabetes, a decrease in HbA1c of at least 1% was independently associated with improvement in skeletal muscle mass index and in usual gait speed, but not in handgrip strength. A separate longitudinal cohort of 380 patients found delta HbA1c negatively associated with change in muscle mass, standardized beta -0.18.

Cross-sectional findings, by contrast, were far messier. Adjusted associations between a single HbA1c measurement and muscle mass were heterogeneous: some studies reported inverse associations, while others found weak or non-significant relationships after adjustment for body composition and clinical factors. In a cross-sectional analysis of 1,009 patients, higher HbA1c was associated with lower DXA-derived muscle mass index in men but not in women. In another cross-sectional study of 838 patients, HbA1c was not retained as an independent determinant of muscle mass, handgrip strength, or gait speed in the final multivariable models. One retrospective single-arm study even found that higher baseline HbA1c predicted greater gain in CT-derived skeletal muscle index after a remote resistance-training program, a positive direction the authors attribute cautiously to regression to the mean, selection for training, and greater initial muscle impairment, with the absence of an untreated comparator precluding causal interpretation.

Muscle strength told a different story, and an intriguingly reversed one. In the opposite analytical direction, the strongest evidence came from prospective studies showing that lower baseline handgrip strength predicted subsequent poorer glycemic control or a lower likelihood of achieving glycemic targets. In a prospective cohort of 100 patients, low handgrip strength carried a hazard ratio of 2.23 for glycemic deterioration, and in women each higher handgrip-strength quartile was associated with lower risk. Another prospective study of 233 patients found that middle and high handgrip-strength tertiles were associated with markedly higher likelihood of achieving an HbA1c below 7% compared with the lowest tertile. These studies provide direction-specific evidence that muscle strength may precede later changes in glycemic status, but the review is explicit that they do not demonstrate biological bidirectionality.

When the arrow ran from glycemia to strength, the picture grew inconsistent. Some studies identified weaker strength or poorer muscle quality at higher HbA1c levels, including one in which HbA1c of at least 8.5% was associated with decreased muscle quality, and another in which HbA1c of at least 8% was associated with weak handgrip strength. Yet several adjusted analyses found weak or non-significant associations. A complementary cross-sectional study added a curious wrinkle: HbA1c was independently associated with lower maximal inspiratory pressure, a respiratory muscle measure, but not with maximum voluntary ventilation. Because that outcome reflects respiratory rather than limb muscle strength, the reviewers interpreted it separately rather than folding it into handgrip-strength estimates.

Physical performance fared worst of all. Only a limited number of lower or moderate-concern studies examined it, and their findings were inconsistent. The longitudinal finding that an HbA1c reduction of at least 1% was associated with gait-speed improvement stood against several cross-sectional analyses that identified no independent association after adjustment. Higher-concern studies reporting positive chair-stand or flexibility results were considered insufficient to establish consistency because the estimates were unadjusted and based on a very small sample of 30 patients. The reviewers note that performance is a multidimensional outcome influenced by neurological function, cardiovascular reserve, pain, balance, cognition, and behavior as well as skeletal muscle, and they conclude that current data do not support a consistent HbA1c-physical-performance association.

Composite sarcopenia, meanwhile, proved hostage to its definition. Prevalence estimates swung wildly across diagnostic frameworks: AWGS-based estimates ranged from 6.3% to 35.8%, FNIH-based reports found 12.9% and 16.2%, and in one cohort the same data produced an EWGSOP1 prevalence of 16.9% but an EWGSOP2 prevalence of 7.0%, while another older cohort reported 45.5% by EWGSOP2. Longitudinal data showed sarcopenia is dynamic, with 12.6% of initially non-sarcopenic patients developing it and 23.8% of initially sarcopenic patients no longer meeting criteria over a median of 36 months. Among adjusted models, positive associations appeared in some studies using AWGS or EWGSOP2 criteria, whereas other adjusted analyses found no independent association. When component-specific results were available, positive composite associations were often driven by low muscle mass rather than by impaired strength or physical performance.

To make biological sense of this patchwork, the review lays out overlapping mechanistic hypotheses, while stressing that direct human evidence linking specific molecular pathways to specific muscle outcomes remains limited. Impaired insulin signaling may disrupt the PI3K/AKT-driven balance between protein synthesis and degradation, reducing muscle mass and impairing glucose uptake. Persistent hyperglycemia promotes accumulation of advanced glycation end products, which may stiffen collagen in the muscle-tendon unit and impair force transmission, while receptor activation promotes oxidative and inflammatory signaling. Mitochondrial dysfunction and oxidative stress may limit ATP production and contribute to fatigability, and chronic low-grade inflammation involving TNF-alpha, IL-1 beta, and IL-6 may interfere with anabolic signaling. Diabetic peripheral neuropathy and microvascular dysfunction may erode strength and performance partly independently of muscle quantity, through axonal loss, impaired neuromuscular activation, and diminished oxygen and nutrient delivery during activity.

The clinical upshot is a caution against a common shortcut. The authors argue that HbA1c should not be used as a diagnostic or surrogate marker for sarcopenia, and that a satisfactory HbA1c should not be read as excluding sarcopenia or impairment in an individual muscle domain. Poor glycemic control may flag patients who warrant closer attention to muscle health, but HbA1c alone cannot determine the presence, type, or severity of muscle impairment; muscle mass, strength, and physical performance should be assessed directly using validated measures when clinically indicated. The observational evidence, with its residual confounding from antidiabetic therapy, physical activity, nutritional status, body composition, and diabetes duration, does not establish that modifying HbA1c alone will improve muscle outcomes. The reviewers call for prospective studies with repeated glycemic assessments, multidimensional muscle evaluations, standardized exposure and outcome definitions, and integration of continuous glucose monitoring metrics, since HbA1c reflects average exposure over roughly two to three months and misses short-term glycemic fluctuations entirely.

Subject of Research: The phenotype-specific relationship between HbA1c-derived glycemic exposure and skeletal muscle outcomes in adults with type 2 diabetes

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

Article References: Lian, Z., Liu, Y., Liu, G., Li, M., Zhong, Z., Wang, W., Wu, S., Wang, H., & Yao, L. (2026). HbA1c and skeletal muscle health in type 2 diabetes: phenotype-specific associations across different analytical directions and mechanistic insights. Frontiers in Endocrinology, 17, Article 1993144. https://doi.org/10.3389/fendo.2026.1993144

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1993144

Keywords: HbA1c, type 2 diabetes, sarcopenia, muscle mass, muscle strength, physical performance, glycemic exposure, insulin resistance, advanced glycation end products, mitochondrial dysfunction, diabetic neuropathy, structured narrative review