Higher Prevalence of Elevated Albumin Excretion in Youth With Type 2 Than Type 1 Diabetes: The SEARCH for Diabetes in Youth Study

Maahs DM, Snively BM, Bell RA, et al. Diabetes Care. 2007 Jul 13; [Epub ahead of print]

Increased concentration of albumin in the urine is one of the earliest clinical signs of diabetic nephropathy. The presence of microalbuminuria not only indicates progression of diabetic nephropathy, but also reveals an increased risk of cardiovascular disease (CVD). Screening for both diabetic nephropathy and albuminuria can be conducted by assessing the albumin-to-creatinine ratio. Although both microalbuminuria and elevated albumin-to-creatinine ratio in children and adolescents with type 1 diabetes mellitus (T1DM), along with diabetic nephropathy in adults with type 2 diabetes mellitus (T2DM), have received much attention, few studies have been designed to measure them in youth with T2DM.

The SEARCH for Diabetes in Youth Study is an ongoing, multi-center, population-based trial, and this interim analysis was designed to identify factors associated with elevated albumin-to-creatinine ratio and their relationship to either T1DM or T2DM. Assessments of A1C, fasting glucose, C-peptide, lipids, fibrinogen, high-sensitivity C-reactive protein (CRP), and diabetes autoantibodies were conducted at each visit, along with measurements of systolic blood pressure (BP), diastolic BP, height, weight, waist circumference, and body mass index (BMI). High BP was defined by the presence of any of the following: use of antihypertensive medication; systolic BP or diastolic BP > 95th percentile for age, sex, and height among patients ≤ 17 years old; or systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg if they were ≥ 18 years old. Participants who had BMI ≥ 95th percentile for their age and sex according to the 2000 Centers for Disease Control and Prevention (CDC) growth charts were classified as overweight. Spot urine samples were obtained in the morning following an overnight rest, and American Diabetes Association (ADA) guidelines were used to categorize albumin-to-creatinine ratio < 30 mcg/mg as normal, 30 to 299 mcg/mg as microalbuminuria, and ≥ 300 mcg/mg as macroalbuminuria. Elevated albumin-to-creatinine ratio was defined as ≥ 30 mcg/mg, and prevalence was stratified according to type of diabetes, duration of diabetes, age, sex, race/ethnicity, and BMI category. Five sequential models were used to identify any associations between metabolic risk factors, type of diabetes, and elevated albumin-to-creatinine ratio. The covariates included in the models were: 1) type of diabetes, demographic factors, and disease duration (model 1); 2) model 1 covariates plus hyperglycemia (model 2); 3) model 1 covariates plus factors related to insulin resistance with different distributions according to type of diabetes (model 3); 4) all covariates from models 1 through 3 and their associations with albumin-to-creatinine ratio (model 4); and 5) a subset of participants (n = 2561) with measurements of fibrinogen and CRP added to model 4 covariates (model 5).

A total of 8768 patients participated in the SEARCH Study from 2001 to 2003, and 3259 were included in this analysis, 2885 of whom had T1DM and 374 of whom had T2DM. Patients with T1DM had an average age of 11.9 years and duration of diabetes of 3.7 years, and T2DM patients had an average age of 16.2 years and diabetes duration of 1.9 years. Patients with T2DM had a 2.3-times greater prevalence of elevated albumin-to-creatinine ratio than patients with T1DM (22.2% vs 9.2%, respectively). Among participants with T1DM, a higher albumin-to-creatinine ratio was more common in adolescents than younger children (P < .0001) and in females than males (P = .0005); however, there were no such significant differences among patients with T2DM. The prevalence of increased albumin-to-creatinine ratio became greater as duration of diabetes increased, especially if > 60 months, among those with T1DM (overall P = .004) or T2DM (overall P = .0004). Although the percentage of youth with T1DM that had elevated albumin-to-creatinine ratio did not vary substantially between race/ethnicity subgroups, a significantly (P = .032) greater percentage of minorities than non-Hispanic white youths with T2DM had elevated levels. The leanest youth with T1DM had the greatest prevalence of elevated albumin-to-creatinine ratio (P = .007), but among youth with T2DM, there were no significant differences between patients who met BMI categories of < 85%, ≥ 85 to ≤ 95%, and ≥ 95%.

Factors assessed in model 1 failed to explain the elevated albumin-to-creatinine ratio among patients with T2DM (OR = 2.08 [95% CI, 1.47-2.95]). In model 2, the addition of A1C to the covariates actually resulted in an increase rather than a decrease in the OR for the association between type of diabetes and elevated albumin-to-creatinine ratio (OR = 2.42 [1.68-3.49]). In model 3, the addition of features related to insulin resistance (eg, hypertension, BMI, waist circumference, LDL-C, HDL-C, and triglyceride concentrations) to measurements obtained in model 1 resulted in the OR decreasing to 1.68 (1.05-2.67) and explained 19% of the increased prevalence of elevated albumin-to-creatinine ratio in patients with T2DM versus T1DM. However, the results from model 3 revealed that even after accounting for all of these covariates, youth with T2DM were 68% more likely to have an elevated albumin-to-creatinine ratio than their T1DM peers. The adjustments made in model 4 did not weaken the association between type of diabetes and elevated albumin-to-creatinine ratio (OR = 1.79 [1.11-2.88]). When inflammatory markers were added as potential covariates (model 5), the OR was slightly reduced (OR = 1.68 [1.00-2.81]), providing further evidence that factors contributing to insulin resistance may also contribute to the increased prevalence of elevated albumin-to-creatinine ratio among youth with T2DM.

This study demonstrated that young patients with T2DM were more than twice as likely to have an elevated albumin-to-creatinine ratio compared with T1DM patients. Youth with T2DM may have been afflicted by an elevated albumin-to-creatinine ratio for a shorter period of time, since their average duration of diabetes was approximately 1/10 of the group with T1DM. Such accelerated progression of the disease has been associated with earlier onset of diabetes-related vascular complications, including diabetic nephropathy and CVD; therefore, efforts to prevent or delay the onset of T2DM in children and young adults are essential. Elevated albumin-to-creatinine ratio among youth with T2DM may be an indicator of underlying obesity-associated insulin resistance, as revealed by differences in elevated levels between patients with T1DM and T2DM becoming greater as BMI increased.

Although insulin resistance may partially explain the increased prevalence of elevated albumin-to-creatinine ratio among young patients with T2DM, a bulk of the variance in the relationship between diabetes type and elevated albumin-to-creatinine ratio remains largely unexplained. Factors that contribute to insulin resistance and inflammation can explain some of the increased prevalence of elevated albumin-to-creatinine ratio in youth with T2DM, and hyperglycemia, high BP, and hypertriglyceridemia are significant determinants of elevated albumin excretion among patients with either type of diabetes.[lap1]  Future studies should be designed to obtain longitudinal data on the natural evolution, screening, and treatment of microalbuminuria among youth with either T1DM or T2DM, since the prevalence of both types of diabetes is increasing and nephropathy and other types of vascular complications can produce overwhelming consequences.