Positive association of the anti-aging protein α-Klotho with insulin resistance and its inverse L-shaped relationship with glycaemic control in the middle-aged and elderly population.

α-Klotho has been linked to insulin resistance (IR) in basic research. However, experimental evidence is inconsistent, and there is a lack of data from human research. This study seeks to elucidate the association of α-Klotho with IR in a nationwide, multiracial population. A total of 5289 participants aged 40-79 years were included in the National Health and Nutrition Examination Survey (NHANES) spanning 2007-2016. Serum α-Klotho was measured using enzyme-linked immunosorbent assays (ELISA), and IR was evaluated by the homeostatic model assessment of insulin resistance (HOMA-IR). Weighted multivariate logistic and linear regression analysis, subgroup analysis stratified by demographic characteristics, medical condition or obesity status, and sensitivity analysis using propensity score matching (PSM) were performed. Restricted cubic splines (RCS) were performed to explore the nonlinear relationship. In the fully adjusted logistic regression model, a significant positive association was observed between log-transformed α-Klotho and IR (OR = 3.63, 95% CI: 1.56, 8.45), particularly in males or nonobese individuals (Pinteraction < 0.05). In the linear regression model, log10(α-Klotho) was associated with fasting blood glucose (FBG, β = 1.25, 95% CI: 0.74, 1.76) and glycosylated hemoglobin (HbA1c, β = 0.49, 95% CI: 0.20, 0.77). RCS revealed an inverse L-shaped dose-response relationship of α-Klotho with FBG and HbA1c (Pnonlinear <0.05). Beyond the inflection point of log10(α-Klotho) at 2.79, β coefficients sharply rose for these glycaemic control indicators. The study provides clinical evidence supporting a positive association between α-Klotho and IR. Moreover, the inverse L-shaped relationship suggests that α-Klotho should reach a certain level to predict glycaemic changes effectively.

Wang K ，Liu J 《-》

Gender differences in the relationship between the triglyceride-glucose index and serum Klotho concentrations among the middle-aged and elderly: a cross-sectional analysis.

The triglyceride-glucose (TyG) index is recognized as a robust indicator for evaluating insulin resistance (IR). Despite the well-documented anti-aging biological functions of Klotho protein, its correlation with the TyG index remains unexplored. A cross-sectional analysis was conducted involving participants from the National Health and Nutrition Examination Surveys (NHANES) 2007-2016. The TyG index was computed using laboratory data, while serum Klotho concentrations was determined using ELISA kit. After adjusting potential confounding variables, multivariate regression models were employed to evaluate the association between the TyG index and Klotho protein levels among middle-aged and elderly females and males separately. Additionally, smooth curve fitting and segmented regression model were applied to investigate potential threshold effects and identify the inflection point. A total of 6,573 adults qualified for inclusion, comprising 3,147 (47.88%) males and 3,426 (52.12%) females. Multivariate regression analysis revealed that females with a higher TyG index exhibited significantly lower serum Klotho concentrations (β=-83.41, 95% CI: -124.23 to -42.60, P < 0.0001). This association was not statistically significant in males (β = 15.40, 95% CI: -19.16 to 49.95, P = 0.3827). Subgroup analyses revealed a significant interaction effect by diabetes status in females (P-interaction = 0.0121), where non-diabetic females showed a stronger negative association between TyG index and serum Klotho levels compared to diabetic females. In the female group, when TyG index was divided into quartiles, individuals in the highest quartile of TyG index exhibited reduced levels of Klotho protein (Q4: -88.77 pg/ml) compared to those in the lowest quartile (Q1) after full adjustment (P = 0.0041). Segmented regression analysis indicated a turning point value of 9.4 in females. Notably, a 1-unit increase in TyG index was significantly associated with a decrease in Klotho levels by -111.43 pg/ml (95% CI: -157.34 to -65.52, P < 0.0001) when TyG index was below 9.4, while above this threshold, the association was not significant (Log likelihood ratio test: 0.009). The findings highlight a non-linear correlation between the TyG index and serum Klotho concentrations among females, indicative of a saturation effect. This relationship was particularly pronounced in non-diabetic women. In contrast, no statistically significant association was observed in male participants.

Wang C ，Liu D ，Lu J ，Huang B ，Feng B ，Yin J ，Qiu J ，Zhang Z ... -  《BMC Endocrine Disorders》

Associations between the TyG index and the ɑ-Klotho protein in middle-aged and older population relevant to diabetes mellitus in NHANES 2007-2016.

The anti-aging protein Klotho has diverse functions in antioxidative stress and energy metabolism through several pathways. While it has been reported that α-Klotho is downregulated in patients with insulin resistance (IR), the association between Klotho and IR is complex and controversial. The triglyceride-glucose (TyG) index has provided a practical method for assessing IR. With this in mind, our study aimed to investigate the relationship between the TyG index and soluble α-Klotho protein levels in US populations, both with and without diabetes mellitus. This cross-sectional study analyzed data from middle-aged and older participants in the National Health and Nutrition Examination Survey (NHANES) conducted between 2007 and 2016. The participants were divided into two groups based on their diabetes mellitus status: those with diabetes and those without diabetes. To evaluate the relationship between the TyG index and the concentration of the α-Klotho protein in each group, a series of survey-weighted multivariable linear regression models were employed. Furthermore, to examine the association between these two variables, multivariable-adjusted restricted cubic spline curves and subgroup analysis were generated. The study involved 6,439 adults aged 40 years or older, with a mean age of 57.8 ± 10.9 years. Among them, 1577 (24.5%) had diabetes mellitus. A subgroup analysis indicated that the presence of diabetes significantly affected the relationship between the TyG index and the α-Klotho level. After considering all covariables, regression analysis of the participants without diabetes revealed that the α-Klotho concentration decreased by 32.35 pg/ml (95% CI: -50.07, -14.64) with each one unit increase in TyG (p < 0.001). The decline in α-Klotho levels with elevated TyG was more pronounced in the female population. In patients with diabetes mellitus, a non-linear association between the TyG index and α-Klotho was observed. There was no significant correlation observed between the two when TyG index were below 9.7. However, there was an increase in klotho levels of 106.44 pg/ml for each unit increase in TyG index above 9.7 (95% CI: 28.13, 184.74) (p = 0.008). Our findings suggested that the presence of diabetes may influence the relationship between the TyG index and soluble α-Klotho. Furthermore, there seem to be sex differences in individuals without diabetes. Further studies are necessary to validate these findings.

Qiu S ，Li C ，Zhu J ，Guo Z ... -  《Lipids in Health and Disease》

Association Between the Serum α-Klotho Level and Insulin Resistance in Adults: NHANES 2007-2016.

Xiao Y ，Hou Y ，Zeng J ，Gong Y ，Ma L ... -  《-》

Serum Klotho and insulin resistance: Insights from a cross-sectional analysis.

The prevalence of diabetes has surged globally, posing significant health and economic burdens. Insulin resistance underlies the initiation and development of type 2 diabetes. Klotho is a crucial endogenous antiaging factor, associated with atherosclerotic cardiovascular diseases, cancer, neurological disorders, and renal diseases. It additionally has a function in controlling glucose metabolism and holds promise as a new therapeutic target for diabetes. However, its relationship with insulin resistance remains unclear. This study utilizes the National Health and Nutrition Examination Survey (NHANES) 2007 to 2016 data to investigate the relationship between serum Klotho concentrations and insulin resistance. In this observational study, information from the NHANES spanning 2007 to 2016 was employed. The sample consisted of 6371 participants. Weighted linear regression model and chi-square tests were utilized to assess differences in continuous and categorical variables, respectively, among groups categorized by Klotho quartiles. The relationship between Klotho and HOMA-IR (homeostatic model assessment of insulin resistance) was studied using multiple linear regression. Smooth curve fitting was used to analyze nonlinear relationships and the inflection point was determined through a 2-stage linear regression method. After adjusting for multiple confounding factors, serum Klotho levels were found to be positively correlated with insulin resistance [0.90 (0.68, 1.13)]. This correlation is nonlinear and exhibits a saturation effect, with the inflection point identified at 1.24 pg/µL. When Klotho levels are below 1.24 pg/µL, for every unit increase in Klotho, HOMA-IR increases by 1.30 units. Conversely, when Klotho levels exceed 1.24 pg/µL, there is no correlation between HOMA-IR and Klotho. Subgroup analysis reveals that the relationship between HOMA-IR and Klotho varies depending on diabetes and body mass index (BMI). This positive correlation was most prominent in the obese nondiabetic population. There is a positive correlation between serum Klotho and insulin resistance.

Yan L ，Hu X ，Wu S ，Zhao S ... -  《-》