We evaluated the
glucose and lipid metabolism in 65 patients (aged 1.1-55 years) with mulibrey (
muscle-liver-brain-eye) nanism (MUL), which is a monogenic disorder with prenatal-onset growth failure and typical clinical characteristics. MUL is caused by mutations in the TRIM37 gene, encoding a peroxisomal
protein (TRIM37) with
E3 ubiquitin-ligase activity. The subjects underwent clinical evaluation, abdominal ultrasonography, and laboratory measurements, including a 3-h oral
glucose tolerance test. The results showed a dramatic change in
glucose and lipid metabolism with age in MUL subjects. While the children had low fasting
glucose and
insulin levels, 90% of the adults had high fasting and postload
insulin values (up to 1,450 mU/l). A 10-fold decrease in the fasting
glucose-to-
insulin ratio and a 4-fold decrease in whole-body
insulin sensitivity index were observed.
Insulin resistance,
fatty liver, high serum
leptin,
hypertension, and acantosis nigricans were already evident in many slim prepubertal children. Half of the adults had
type 2 diabetes, and an additional 42% showed
impaired glucose tolerance. Seventy percent fulfilled the National
Cholesterol Education Program criteria for
metabolic syndrome. The peroxisomal targeting and the functional link of TRIM37 to the
ubiquitin-proteosome pathway may provide novel clues to the development of
metabolic syndrome.