Effect Modification of Body Mass Index and Kidney Function on Insulin Sensitivity Among Patients With Moderate CKD and Healthy Controls

Abstract

Introduction: Insulin resistance and obesity are prevalent in chronic kidney disease (CKD) patients. The interaction of body mass index (BMI) and kidney function across the continuum of estimated glomerular filtration rate (eGFR) is unknown.

Methods: In a cross-sectional study of 139 patients, 52 with CKD stages 3 and 4 and 87 patients with normal eGFR, we measured the insulin sensitivity index (ISI) using the hyperinsulinemic euglycemic clamp and homeostasis model assessment of insulin resistance (HOMA-IR). We investigated the interaction between eGFR and BMI in their association with ISI and HOMA-IR using linear models with robust standard errors.

Results: Median age was 56 (42, 66) years, 50.4% were female, and 36% were African American. Patients with low eGFR (∼30 ml/min per 1.73 m²) had low ISI (2.3 mg/min per μU/ml) regardless of BMI. Among patients with preserved eGFR (>90 ml/min per 1.73m²), BMI had a greater effect on ISI (6.3 mg/min per μU/ml at a BMI of 20 kg/m² vs. 4.6 mg/min per μU/ml at a BMI of 30 kg/m²) (P for interaction = 0.046). In models adjusted for demographics, and log transformed interleukin-6, high-sensitivity C-reactive protein, leptin, and adiponectin, a 1-SD (28 ml/min per 1.73 m²) lower eGFR was associated with a statistically significant 1.14-unit decrease in ISI (95% confidence interval = -1.80, -0.48) among nonobese patients. Among obese patients, the effect estimate was -0.25 (95% confidence interval = -0.88, 0.39). The association between BMI and HOMA-IR was stronger in patients with lower eGFR (P for interaction = 0.005).

Conclusion: Both eGFR and BMI are independently associated with insulin sensitivity, but the strength of the association between BMI and insulin sensitivity varies significantly across eGFR.

Keywords: chronic kidney disease; insulin resistance; interaction; kidney function; obesity.

Graphical abstract

Figure 1

(a) Interaction between estimated glomerular filtration rate (eGFR) and body mass index (BMI) for the association with clamp-derived insulin sensitivity index (ISI). Patients with low eGFR (in particular, the lower margin of the chronic kidney disease [CKD] stage 3 range, 30 ml/min per 1.73 m²) had lower ISI even with BMI within the normal range. At higher eGFR, there was a greater change in ISI per unit change in BMI. P for interaction = 0.046, indicating differences in the association between BMI and ISI at lower versus higher eGFR. (b) Linear relationship between clamp-derived ISI and eGFR across BMI categories. A 1-SD lower eGFR was associated with a greater decrease in ISI among nonobese compared to obese participants. (c) Linear relationship between clamp-derived ISI and BMI across eGFR categories. A 1-SD higher BMI was associated with a greater decrease in ISI among participants with eGFR ≥60 compared to those with eGFR <60.

Figure 2

(a) Interaction between estimated glomerular filtration rate (eGFR) and body mass index (BMI) for the association with the homeostasis assessment model of insulin resistance (HOMA-IR). The HOMA-IR score was lower for persons with higher eGFR compared to lower eGFR regardless of BMI. Also, persons with high eGFR (e.g., 120 ml/min per 1.73 m²) had low HOMA-IR even with BMI in the obese range. The change in HOMA-IR per unit change in BMI was greater at lower eGFR. P for interaction = 0.005, indicating significant differences in the association between BMI and HOMA-IR at lower versus higher eGFR. (b) Linear relationship between HOMA-IR and glomerular filtration rate (GFR) across BMI categories. Each 1-SD lower eGFR was associated with a greater increase in HOMA-IR among obese compared to nonobese participants. (c) Linear relationship between HOMA-IR and BMI across eGFR categories. A 1-SD higher BMI was associated with a greater increase in HOMA-IR among participants with eGFR <60 compared to those with eGFR ≥60.