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Evaluation of the components of insulin-like growth factor (IGF)-IGF binding protein (IGFBP) system in adolescents with type 1 diabetes and persistent microalbuminuria: relationship with increased urinary excretion of IGFBP-3 18 kD N-terminal fragment

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IGFs and their binding proteins (IGFBPs) have an important role in controlling glucose homeostasis and there is evidence to support their involvement in complications related to type I diabetes. The aim of this study was to evaluate the components of the IGF-IGFBP system in adolescents with type 1 diabetes that had developed persistent microalbuminuria (MA). DESIGN AND PATIENTS

A cohort of 49 adolescents with type 1 diabetes were enrolled in the study. Patients were evaluated at baseline and 1 year later (follow-up). Twenty-six patients with persistent urinary albumin excretion (UAE) of more than 20 μg/min/1.73 m2 (21.6–109.4 μg/min/1.73 m2) in three different nocturnal urinary collections within 6 months were considered to have MA (baseline mean: 41.9 ± 22.3 μg/min/1.73 m2; follow-up: 55.9 ± 24.8 μg/min/1.73 m2). Twenty-three patients with UAE of less than 20 μg/min/1.73 m2 were assigned to the group without MA (baseline mean: 8.6 ± 3.7 μg/min/1.73 m2; follow-up: 11.8 ± 4.2 μg/min/1.73 m2). Fasting serum levels of IGFBP-1, IGFBP-2, IGFBP-3, IGF-I and free-IGF-I were determined using appropriate immunoenzymatic, radioimmuno- or immunoradiometric assays. Overnight 12-h urinary collections were obtained and assessed for IGFBP-3 levels, determined by immunoradiometric assay. Urinary and circulating immunoreactive IGFBP-3 forms were determined by Western-immunoblotting (WIB) analysis using a specific polyclonal antibody and monoclonal antibodies directed against N-terminal and C-terminal epitopes of IGFBP-3. IGFBP-3 protease activity was determined using protease assay and by analysis of the intact over the fragmented immunoreactive forms of IGFBP-3 determined by WIB analysis. RESULTS

Patients with MA showed higher levels of urinary IGFBP-3 (649 ± 440 ng/h/m2) than patients without MA (398 ± 229 ng/h/m2; P < 0.05). Urinary levels of IGFBP-3 were directly correlated to UAE (P < 0.001). WIB analysis, using monoclonal antibodies directed against characterized N-terminal and C-terminal IGFBP-3 epitopes, determined that the immunoreactive form of IGFBP-3 found in urine from patients with diabetes was an N-terminal 18 kD fragment. Serum IGFBP-3 levels were lower in patients with MA (baseline: 3613 ± 598 μg/l; one year follow-up: 3347 ± 624 μg/l) compared with patients without MA (baseline: 4701 ± 1484 μg/l; follow-up: 4177 ± 703 μg/l; P < 0.001). In serum from patients with MA, intact IGFBP-3 was decreased, as indicated by WIB analysis. Conversely, IGFBP-3 proteolysis was increased in patients with MA (baseline: 131 ± 21% of control; follow-up: 130 ± 23% of control), compared to patients with normal UAE (baseline: 96 ± 23% of control; follow-up: 96 ± 14% of control; P < 0.001). Serum IGFBP-3 protease activity was directly correlated to urinary IGFBP-3 levels (P < 0.001). Serum IGFBP-1 levels were increased in patients with MA (baseline: 36 ± 20 μg/l; follow-up: 36 ± 17 μg/l) compared with patients without MA (baseline: 17 ± 11 μg/l; follow-up: 18 ± μg/l; P < 0.05). Serum IGFBP-2 levels were also persistently increased in patients with MA (baseline: 503 ± 134 μg/l; follow-up: 484 ± 166 μg/l) compared with patients without MA (baseline: 375 ± 83 μg/l; follow-up: 390 ± 85 μg/l; P < 0.05). On the other hand, free IGF-I levels were decreased in patients with MA (baseline: 2.3 ± 1.5 μg/l; follow-up: 2.5 ± 1.4 μg/l) compared with those patients without MA (baseline: 4.1 ± 2.1 μg/l; follow-up: 4.0 ± 2.2 μg/l; P < 0.05). CONCLUSIONS

It has been demonstrated that in adolescents with type 1 diabetes and persistent microalbuminuria, the IGF-IGFBP system is deranged. A urinary 18 kD N-terminal IGFBP-3 fragment has been characterized that, in patients with microalbuminuria, correlates with urinary albumin excretion and with serum IGFBP-3 protease activity. The mechanisms behind these changes remain unclear, but alterations in circulating levels of IGFBPs may alter IGF-I bioactivity. Determination of urinary levels of IGFBP-3 might be supportive to the measurement of urinary albumin as an early sign of diabetic nephropathy.
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Document Type: Research Article

Affiliations: 1: Department of Paediatrics, Oregon Health Sciences University,USA, 2: Department of Paediatrics, University of Chieti, Italy, 3: Department of Paediatrics, Tor Vergata University, Rome, Italy

Publication date: November 1, 1999

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