What the Genetics of Lipodystrophy Can Teach Us About Insulin Resistance and Diabetes

Genetic lipodystrophic syndromes are rare diseases characterized by generalized or partial fat atrophy (lipoatrophy) associated with severe metabolic complications such as insulin resistance (IR), diabetes, dyslipidemia, nonalcoholic fatty liver disease, and ovarian hyperandrogenism. During the last 15 years, mutations in several genes have been shown to be responsible for monogenic forms of lipodystrophic syndromes, of autosomal dominant or recessive transmission. Although the molecular basis of lipodystrophies is heterogeneous, most mutated genes lead to impaired adipogenesis, adipocyte lipid storage, and/or formation or maintenance of the adipocyte lipid droplet (LD), showing that primary alterations of adipose tissue (AT) can result in severe systemic metabolic and endocrine consequences. The reduced expandability of AT alters its ability to buffer excess caloric intake, leading to ectopic lipid storage that impairs insulin signaling and other cellular functions (lipotoxicity). Genetic studies have also pointed out the close relationships between ageing, inflammatory processes, lipodystrophy, and IR.