Early onset of proteinuria and focal segmental glomerulosclerosis in obese, hyperinsulinemic adolescents developing metabolic syndrome

Background: The metabolic syndrome (MTS) is comprised of insulin resistance, glucose intolerance, obesity, hypertension, and dyslipidemia. Secondary renal dysfunction can develop after prolonged duration of each component except for dyslipidemia. Here we present 7 obese individuals in whom MTS and proteinuria developed concomitantly during adolescence. Subject and methods: Seven (f:m = 4:3) individuals (Caucasian or African American, ages 11-17 at disease onset) developed macroproteinuria of whom 6 were directly evaluated and had typical MTS characteristics. Body mass index range was 30.8-73.2 kg/m², being highest in African Americans. All had positive family history of MTS. Six patients underwent complete general, hormonal and metabolic work-up, including fasting and stimulated insulin and C-peptide levels. Genomic DNA of 4 patients and their relatives was studied by linkage analysis for MODY 1-4 genes, and for a locus associated with focal segmental glomerulosclerosis (FSGS) and microalbuminuria. Results: Fasting and stimulated insulin and C-peptide levels were elevated. All patients were normoalbuminemic, and five of six patients had mildly elevated liver enzymes. The 24-h urinary protein excretion range was 2.5-9 g, and decreased markedly in 2 patients who lost weight. Renal biopsy of 3 patients showed FSGS. In 2 pedigrees FSGS was familial. Genomic DNA analysis excluded any linkage with common MODY genes or with familial FSGS. Conclusions: The early concomitant development of MTS, proteinuria and FSGS appears to be associated with hyperinsulinemia, presenting as early as adolescence, and may be reversed by weight loss. We propose that in genetically predisposed individuals, excessive insulin plays a crucial pathogenic role in development of the metabolic syndrome and FSGS.