GENETIC SYNDROMES OF EXTREME INSULIN RESISTANCE AND DIABETES MELLITUS DUE TO DEFECTS IN INSULIN RECEPTOR GENE TRANSCRIPTION

Insulin resistance is a metabolic abnormality characterized by a reduced sensitivity in the tissues of the body to the action of insulin. It represents a prominent feature of type 2 (non insulin-dependent) diabetes mellitus (DM) and plays an important role also in type 1 (insulin-dependent) DM. Epidemiological and clinical evidences indicate that insulin resistance is genetically determined as confirmed by studies with cultured cells of patients with genetic syndromes of insulin resistance (Type A syndrome of insulin resistance and acanthosis nigricans, Leprechaunism, and the Rabson-Mendenhall syndrome). Although rare, these syndromes show extremely severe insulin resistance and a simple mendelian pattern of inheritance. Thus, they represent models for investigating the molecular mechanisms that cause diabetes. The interaction of insulin with the insulin receptor (IR) represents a crucial step in insulin action and mutations at the level of the IR gene have been described in these and other individuals, followed by defects in the biological action of the hormone. HMGA1 is an architectural nuclear factor that specifically interacts with the IR gene, and activates IR gene expression by facilitating the recruitment and assembly, in a unique multiprotein-DNA complex, of known transcription factors (Sp1, C/EBPb, etc.) to the IR DNA. Recently, in preliminary studies, we found that functional integrity of this complex was impaired in cells from several patients with genetic syndromes of insulin resistance and DM. In these cells, HMGA1 abundance was markedly reduced and this defect paralleled the decrease in IR content. We hypothesize that abnormalities of HMGA1 and/or other molecular partners, in affected individuals, may cause insulin resistance and DM.