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.
Foti
Daniela
D
Dipartimento di Medicina Sperimentale e Clinica G. Salvatore, Università di Catanzaro Magna Graecia, via T. Campanella 115, 88100 Catanzaro, Italy.
Chiefari
Eusebio
E
Fedele
Monica
M
Iuliano
Rodolfo
R
Brunetti
Leonardo
L
Paonessa
Francesco
F
Manfioletti
Guidalberto
G
Barbetti
Fabrizio
F
Brunetti
Arturo
A
Croce
Carlo M
CM
Fusco
Alfredo
A
Brunetti
Antonio
A
D020413:3' Untranslated Regions; D000293:Adolescent; D000328:Adult; D000818:Animals; D015703:Antigens, CD; D002478:Cells, Cultured; D002648:Child; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4; D025741:HMGA1a Protein / Q000235:genetics* / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D018970:Insulin-Like Growth Factor Binding Protein 1; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D049268:Positron-Emission Tomography; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism; D020871:RNA Stability; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D020413:3' Untranslated Regions; D015703:Antigens, CD; D051275:Glucose Transporter Type 4; C032231:IGFBP1 protein, human; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D018969:Insulin-Like Growth Factor Binding Proteins; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D011257:Pregnancy Proteins; C495692:SLC2A4 protein, human; C495693:Slc2a4 protein, mouse; D025741:HMGA1a Protein; C435941:INSR protein, human; D011972:Receptor, Insulin; D005947:Glucose