Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions
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Adolescent
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Adult
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Animals
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Antigens, CD
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Cells, Cultured
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Child
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Diabetes Mellitus, Type 2 / genetics*
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Female
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Gene Expression Regulation
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Glucose / metabolism
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Glucose Transporter Type 4
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HMGA1a Protein / genetics*
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HMGA1a Protein / metabolism
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Homeostasis / genetics
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Humans
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Insulin / metabolism
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Insulin Resistance / genetics*
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Insulin Secretion
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Insulin-Like Growth Factor Binding Protein 1
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Insulin-Like Growth Factor Binding Proteins / genetics
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Insulin-Like Growth Factor Binding Proteins / metabolism
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Male
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Mice
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Mice, Mutant Strains
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Monosaccharide Transport Proteins / genetics
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Monosaccharide Transport Proteins / metabolism
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Muscle Proteins / genetics
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Muscle Proteins / metabolism
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Mutation
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Pancreas / metabolism
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Pancreas / pathology
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Pedigree
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Positron-Emission Tomography
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Pregnancy Proteins / genetics
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Pregnancy Proteins / metabolism
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RNA Stability
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Receptor, Insulin / genetics
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Receptor, Insulin / metabolism
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Signal Transduction
Substances
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3' Untranslated Regions
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Antigens, CD
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Glucose Transporter Type 4
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IGFBP1 protein, human
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Insulin
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Insulin-Like Growth Factor Binding Protein 1
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Insulin-Like Growth Factor Binding Proteins
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Monosaccharide Transport Proteins
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Muscle Proteins
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Pregnancy Proteins
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SLC2A4 protein, human
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Slc2a4 protein, mouse
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HMGA1a Protein
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INSR protein, human
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Receptor, Insulin
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Glucose