Alterations in Insulin-like Growth Factor Binding Protein-1 and Sex Hormone Binding Globulin Levels in Type 1 Diabetic Adolescents With Microalbuminuria

Puberty is considered a critical period for the development of microvascular complications of diabetes. Recently, we documented that more pronounced progression of albuminuria occurs during puberty than before or after puberty (1). This supports the concept that endocrine changes of puberty can lead to early initiation or acceleration of diabetic kidney damage. Therefore, we attempted to investigate the relationship between incipient nephropathy and pubertal hormones in adolescents with diabetes.

A total of 26 type 1 diabetic patients were selected for this study. Subjects were classified into two groups according to the presence of incipient nephropathy: patients with persistent microalbuminuria (5 boys and 5 girls, albumin excretion rate [AER] 20 μg/min three times within 3 months, age 14.4 ± 3.0 years, diabetes duration 6.2 ± 2.5 year, and mean HbA_1c 8.4 ± 8.4%) and patients with normoalbuminuria (8 boys and 8 girls, AER <20 μg/min, age 14.1 ± 3.3 years, diabetes duration 6.0 ± 2.2 years, and mean HbA_1c 8.2 ± 2.7%). A group of healthy subjects were recruited as control subjects (5 boys and 5 girls, age 14.2 ± 3.1 years). All subjects were in puberty (Tanner stage ≥2), and had normal blood pressure. The three groups were matched for age and pubertal stage, and the diabetic group was matched for diabetes duration and mean HbA_1c since the onset of diabetes. BMI and height standard deviation scores did not differ among the study groups. Fasting serum levels for IGF binding proteins (IGFBPs)-1, -2, and -3, IGF-I, human growth hormone (hGH), sex hormone binding globulin (SHBG), estradiol, and testosterone were measured by radioimmunoassay (IGFBP-1, SHBG, hGH, and estradiol and testosterone: Diagnostic Systems Laboratories, Webster, Texas; IGF-I, IGFBP-2, and IGFBP-3: Mediagnost, Tübingen, Germany). AER was measured by immunonephelometric method (Orion Diagnostica, Espoo, Finland) from a timed overnight urine collection. For comparisons among groups, one-way analysis of variance was performed. Where overall significance was attained, differences between any two groups were tested by Wilcoxon’s test. Multiple regression analysis was applied to assess relationships between AER and endocrine variables. IGFBP-1 was higher in microalbuminuric patients than in normoalbuminuric patients and in control subjects (median 85.3 [95% CI 72.1–98.5], P < 0.003 vs. 61.4 [49.1–73.3] and 55.0 [50.6–70.7] ng/ml, respectively). Patients with microalbuminuria had a lower IGF-I level than those with normoalbuminuria and control subjects (209.2 [151.0–243.1], P < 0.01, vs. 368.7 [280.1–403.0] and 412.0 [310.4–501.5] ng/ml, respectively). In the microalbuminuric group, basal hGH was higher than in the normoalbuminuric and control groups (12.8 [6.7–23.6], P < 0.001, vs. 7.2 [4.2–11.3] and 5.6 [3.3–9.1] μU/ml, respectively). SHBG was lower in microalbuminuric patients than in normoalbuminuric patients and control subjects (26.1 [22.0–33.9], P < 0.01, vs. 42.2 [33.0–58.6] and 55.2 [40.1–59.9] nmol/l, respectively. IGFBP-2, IGFBP-3, estradiol, and testosterone levels did not differ in the study groups, and no difference was found in the daily dose of insulin in the diabetic groups. Multiple regression analysis showed that IGFBP-1 (r² = 0.23, P = 0.012), SHBG (r² = 0.20, P = 0.021), hGH (r² = 0.13, P = 0.030), and HbA_1c (r² = 0.12, P = 0.041) were independently predictive for log AER as dependent variables. Together, these variables explained 68% of the variation of the AER (r² = 0.68, P = 0.002).

Alterations in the growth hormone/IGF axis are well documented in adult diabetic patients with renal involvment (2), but very few data are available in pediatric patients. Recently, one study described high IGFBP-1 levels (3) and another study demonstrated low SHBG levels in relation to microalbuminuria in adolescent patients (4). This is the first observation in microalbuminuric pubertal patients to show simultaneous alterations in both binding protein systems, suggesting the role of high IGFBP-1 (resulting in decreased bioactivity of IGF-I and increased hGH secretion via feed back mechanism) and/or low SHBG levels (reflecting enhanced tissue effect of androgens) in the initiation of diabetic renal damage in this period of life.