Journal of the Endocrine Society · Jun 24, 2026

Alpha-klotho, insulin resistance, and adiposity among older adults

By Ahmad A, Shardell M, Kalyani RR et al.

CONTEXT: Alpha-klotho is a circulating protein linked to better metabolic and aging-related outcomes. However, alpha-klotho's relationship with insulin resistance, and the role of adiposity, remain unclear, especially among older adults. OBJECTIVE: To evaluate the association of circulating alpha-klotho with measures of insulin resistance and incident diabetes among older adults and examine whether these relationships differ by body mass index (BMI). MAIN OUTCOME MEASURES: The primary outcome was Homeostatic Model Assessment for Insulin Diabetes (HOMA-IR). Secondary outcomes were serum fasting glucose and insulin, and incident diabetes. DESIGN SETTING AND PARTICIPANTS: This secondary analysis examined associations of alpha-klotho with outcomes among 825 community-dwelling adults aged ≥55 years enrolled in the Invecchiare in Chianti Study, a prospective population-based cohort. Alpha-klotho and outcomes were assessed 3 years after enrollment. We performed BMI-stratified regression analysis, with adjustment for covariates, including measures of glucose and insulin taken at enrollment. RESULTS: Among 370 overweight participants (BMI 25.0-29.9 kg/m²), each logarithm unit of alpha-klotho (pg/mL) was associated with 0.51 higher HOMA-IR (95% confidence interval [CI], 0.07-0.94), after covariate adjustment. Alpha-klotho was significantly associated with serum glucose (Beta = 0.56, 95% CI: 0.04-1.09), but not serum insulin after covariate adjustment. No significant associations were found among participants with BMI < 25.0 (n = 279) or ≥30 kg/m² (n = 124) (P for interaction = 0.18). Alpha-klotho was not significantly associated with incident diabetes, overall or in any BMI subgroup. CONCLUSION: Alpha-klotho was positively associated with insulin resistance, but not incident diabetes, among overweight adults. Findings suggest that alpha-klotho may have a context-dependent relationship with insulin resistance, but not incident diabetes.

doi.org/10.1210/jendso/bvag140Open accessPubMed 42440939Populations