Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice.

Type 2 diabetes mellitus is a widespread disease, affecting millions of people globally. Although genetics and environmental
factors seem to have a role, the cause of this metabolic disorder is largely unknown. Here we report a genetic flaw that markedly
reduced the intracellular expression of the high mobility group A1 (HMGA1) protein, and adversely affected insulin receptor
expression in cells and tissues from four subjects with insulin resistance and type 2 diabetes. Restoration of HMGA1 protein
expression in subjects' cells enhanced INSR gene transcription, and restored cell-surface insulin receptor protein expression and
insulin-binding capacity. Loss of Hmga1 expression, induced in mice by disrupting the Hmga1 gene, considerably decreased
insulin receptor expression in the major targets of insulin action, largely impaired insulin signaling and severely reduced insulin
secretion, causing a phenotype characteristic of human type 2 diabetes.