Two well-characterized patients with
congenital, generalized lipodystrophy have been studied by the euglycaemic hyperinsulinaemic clamp technique in combination with indirect calorimetry. Furthermore,
glycogen synthase in muscle biopsies was studied in one patient with regard to
enzyme activity, immunoreactive
protein and
mRNA levels. The patients had fasting hyperinsulinaemia, and the rate of total
glucose disposal was severely impaired, primarily due to a decreased non-oxidative
glucose metabolism. In the patient studied with muscle biopsy, the expected activation of
glycogen synthase by
insulin did not occur. In both patients there was severely increased hepatic
glucose output in the basal state, suggesting a failure of
insulin to suppress hepatic gluconeogenesis. During
insulin infusion a substantially elevated rate of
lipid oxidation remained in the patients, in contrast to the almost completely suppressed
lipid oxidation in the controls. It is concluded that patients with
congenital generalized lipodystrophy may present severe
insulin resistance with regard to hepatic
glucose production as well as muscle
glycogen synthesis and
lipid oxidation. The results suggest a postreceptor defect in the action of
insulin in
congenital generalized lipodystrophy. The further localization of such a defect is hampered by the still incomplete understanding of the pathways that link
insulin-stimulated
tyrosine phosphorylation to the ultimate action of
insulin upon target cells.