Patients with type 1 diabetes develop microangiopathic complications such as retinopathy, peripheral neuropathy, and nephropathy (1), which are responsible for morbidity in adulthood. These complications usually have a prolonged asymptomatic phase, sometimes starting in adolescence, characterized by early subclinical functional and structural abnormalities (2).

Since matrix metalloproteinases (MMPs) represent a serum marker of vascular disease (4), the aim of our study was to detect MMP-2 and -9 levels and activity in type 1 diabetic children and adolescents.

Twenty-five children and adolescents (13 boys and 12 girls), median age 10.6 years (7.9−11.7), were longitudinally evaluated at clinical diagnosis and during a 5-year follow-up period.

Peripheral neuropathy, assessed by peroneal motor nerve conduction velocity, developed in 12 patients (6 boys and 6 girls) 5.7 years (3.7−6.5) from disease diagnosis. Background diabetic retinopathy (microaneurisms), assessed by fundus photography, developed in three patients (two boys and one girl) 6.6, 5.8, and 6.0 years from disease diagnosis, respectively.

For control subjects, we randomly chose 19 nondiabetic subjects (9 boys and 10 girls), median age 12.0 years (11.0−13.0), from among those reporting for their first hepatitis B virus vaccination and for the 5-year follow-up visit.

Informed consent was obtained from all parents. The study was approved by the local ethics committee. MMP-2 and -9 levels and activity were detected by ELISA (Amersham, Pharmacia Biotech); GAD antibody, IA-2 antigen, and insulin autoantibody levels were detected by radioimmunoassay (CIS Bio International). HbA1c levels were evaluated by high-performance liquid chromatography (BioRad). All samples were stored at −80°C until analysis was performed.

No significant correlation was observed among MMP results (both levels and activity) and chronologic age, autoantibody, and HbA1c levels.

At baseline, MMP-2 levels were significantly higher in type 1 diabetic patients and type 1 diabetic patients with complications than in nondiabetic subjects (1,100 [915–1,326], 1,742 [1,426–1,908], and 907 ng/ml [735–970], respectively), as was MMP-2 activity (31 [30–37], 152 [127–176], and 97% [88–101], respectively) (P < 0.0001). No significant differences were observed for MMP-9 level and activity.

Patients who developed microangiopathic complications during the follow-up period had significantly higher MMP-2 activity (P < 0.001) and levels (P = 0.009) than patients without complications.

At 5-year follow-up, MMP-2 levels were significantly higher in patients with microangiopathic complications compared with control subjects (1,782 [1,741–2,089] and 1,022 ng/ml [897–1,125], respectively; P < 0.0001), as was MMP-2 activity (116 [104–151] and 46% [37–68], respectively; P < 0.0005) and compared with patients without complications (1,371 ng/ml [1,197–1,479] and 31% [30–34] for levels and activity, respectively; P < 0.0001).

MMP-9 levels were significantly lower in patients with microangiopathic complications (44 ng/ml [30–63]) compared with control subjects (95 ng/ml [58–126]; P = 0.024) and patients without complications (82 ng/ml [46–99]; P = 0.0013), but no difference was found between control subjects and patients without complications. No difference was observed for MMP-9 activity among the three groups.

The three groups did not differ in terms of percentage change of MMP-2 levels and MMP-9 activity, but did differ in terms of percentage change of MMP-2 activity (P = 0.0036) and MMP-9 levels (P = 0.009).

Our results allow us to postulate that MMP-2 may be a good index of severity and stability of microangiopathy, and the literature reports MMP-9 as a marker of macroangiopathy (4).

The relationship between MMPs and the presence of diabetic complications needs to be elucidated; further studies are necessary to clarify their possible involvement in the onset or progression of diabetic complications.

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