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

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.

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).

The primary outcome was Homeostatic Model Assessment for Insulin Diabetes (HOMA-IR). Secondary outcomes were serum fasting glucose and insulin, and incident diabetes.

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.

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.

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.