Insulin Sensitivity and Diabetic Kidney Disease in Children and Adolescents With Type 2 Diabetes: An Observational Analysis of Data From the TODAY Clinical Trial

Abstract

Lower estimated insulin sensitivity was associated with risk for hyperfiltration over time, whereas increased albumin excretion was associated with hyperglycemia in youth-onset T2DM.

Renal Hyperfiltration in Adolescents with Type 2 Diabetes: Physiology, Sex Differences, and Implications for Diabetic Kidney Disease

“…This paradigm is supported by the observation that IR and hyperfiltration are strongly correlated in youth with T2D who participated in the RESISTANT and TODAY studies (4, 5). In the RESISTANT cohort, adolescents with T2D exhibited significantly lower peripheral insulin sensitivity measured by hyperinsulinemic-euglycemic clamp, and higher eGFR compared to obese or lean controls (5).…”

“…We previously reported a prevalence of 24% for hyperfiltration and 35% for elevated albumin excretion in a small cohort of youth with T2D (mean age of 15±2 years) (2). In a separate analysis of longitudinal data from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, the prevalence of increased albumin excretion rose from 6.3% of participants at baseline to 16.6% at 3.9 years follow-up (3) and 18.0% at 5 years follow-up (4). In the SEARCH study, the age-adjusted prevalence of DKD in youth with T2D was 20%, which was significantly greater than DKD in youth with T1D (6%, p<0.001) (24).…”

“…Furthermore, IR, but not HbA1c, LDL-C or BP, was also inversely associated with eGFR after adjusting for sex and pubertal stage (5). In the TODAY study, there was an annual increase in eGFR, and decrease in eIS over 5 years, and IR independently conferred a 2.1-fold increased risk of hyperfiltration, even after adjusting for other established risk factors (HR: 2.15, p=0.01) (4). Importantly, IR, rather than traditional risk factors, was the strongest determinant of renal health (4, 5).…”

“…In TODAY, girls with T2D had higher estimated GFR levels at baseline compared to boys (123±19 vs. 108±17 ml/min/1.73m 2 , p<0.0001 [n=532]), and a 3-fold greater risk of developing hyperfiltration over 5 years, even after adjustment for age, ethnicity, treatment group, BMI, HbA1c, hypertension, loss of glycemic control and estimated insulin sensitivity (Figure 2) (4). These sex-related findings do not appear to be unique to T2D.…”

“…Since elevated albumin excretion, the traditional measure of renal injury in T2D, does not reliably reflect progressive DKD and commonly regresses to normal albumin excretion (6), it is important to directly examine early changes in renal function that are associated with future DKD risk, such as hyperfiltration. Hyperfiltration impacts between 24–50% of youth with T2D as assessed by estimated GFR (eGFR) using creatinine and cystatin-C equations (4, 5), which is likely an underestimation of GFR, especially with increasing GFR values in the hyperfiltration range (7). …”