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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.

Pubmed ID: 15924147


  • Foti D
  • Chiefari E
  • Fedele M
  • Iuliano R
  • Brunetti L
  • Paonessa F
  • Manfioletti G
  • Barbetti F
  • Brunetti A
  • Croce CM
  • Fusco A
  • Brunetti A


Nature medicine

Publication Data

July 14, 2005

Associated Grants

  • Agency: Telethon, Id: GGP04245
  • Agency: Telethon, Id: GTF04002

Mesh Terms

  • 3' Untranslated Regions
  • Adolescent
  • Adult
  • Animals
  • Antigens, CD
  • Cells, Cultured
  • Child
  • Diabetes Mellitus, Type 2
  • Female
  • Gene Expression Regulation
  • Glucose
  • Glucose Transporter Type 4
  • HMGA1a Protein
  • Homeostasis
  • Humans
  • Insulin
  • Insulin Resistance
  • Insulin-Like Growth Factor Binding Protein 1
  • Insulin-Like Growth Factor Binding Proteins
  • Male
  • Mice
  • Mice, Mutant Strains
  • Monosaccharide Transport Proteins
  • Muscle Proteins
  • Mutation
  • Pancreas
  • Pedigree
  • Positron-Emission Tomography
  • Pregnancy Proteins
  • RNA Stability
  • Receptor, Insulin
  • Signal Transduction