Insulin resistance is a common metabolic disorder. It plays an important role in the
metabolic syndrome (or syndrome X),
type 2 diabetes,
obesity and in the lipodystrophic syndromes recently described, associated with treatments of HIV disease and represent a worrying cardiovascular risk. However, its pathophysiology remains poorly understood in these situations. Syndromes of major
insulin resistance, although rare, allow investigations of the mechanisms leading to alterations in the
insulin transduction pathways. Mutations of the
insulin receptor gene have been discovered in rare patients. Therefore alterations at the post-receptor level are probably causative in other cases. Furthermore, the role of body fat repartition seems determinant in the apparition of
insulin resistance, as attested by the clinical characteristics of
lipodystrophies, either congenital or acquired. The two lipodystrophic syndromes which molecular defect is identified are the
familial partial lipodystrophy of the Dunnigan type, due to mutations of the
lamin A/C gene, and the
congenital generalized lipodystrophy, linked to alterations in the
protein seipin. However, their physiopathology remains mysterious.
Lamin A/C is indeed an ubiquitous
nuclear protein, which is also mutated in a genetic squelettic and/or cardiac
myopathy, and seipin is a
protein of unknown function mainly expressed in brain. Progresses in the understanding of these syndromes, in particular
lipodystrophies which can be considered as caricatural models of the
metabolic syndrome, will probably allow to clarify the physiopathology of the more common forms of
insulin resistance.