Abstract
We have examined glucose homeostasis in mice hypomorphic for the homeotic transcription factor gene Prep1. Prep1-hypomorphic (Prep1(i/i)) mice exhibit an absolute reduction in circulating insulin levels but normal glucose tolerance. In addition, these mice exhibit protection from streptozotocin-induced diabetes and enhanced insulin sensitivity with improved glucose uptake and insulin-dependent glucose disposal by skeletal muscle. This muscle phenotype does not depend on reduced expression of the known Prep1 transcription partner, Pbx1. Instead, in Prep1(i/i) muscle, we find normal Pbx1 but reduced levels of the recently identified novel Prep1 interactor p160. Consistent with this reduction, we find a muscle-selective increase in mRNA and protein levels of PGC-1alpha, accompanied by enhanced expression of the GLUT4 transporter, responsible for insulin-stimulated glucose uptake in muscle. Indeed, using L6 skeletal muscle cells, we induced the opposite effects by overexpressing Prep1 or p160, but not Pbx1. In vivo skeletal muscle delivery of p160 cDNA in Prep1(i/i) mice also reverses the molecular phenotype. Finally, we show that Prep1 controls the stability of the p160 protein. We conclude that Prep1 controls insulin sensitivity through the p160-GLUT4 pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blood Glucose / metabolism*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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DNA-Binding Proteins
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Diabetes Mellitus, Experimental* / metabolism
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Diabetes Mellitus, Experimental* / prevention & control
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Female
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Glucagon / metabolism
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Glucose Tolerance Test
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Glucose Transporter Type 4 / genetics
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Glucose Transporter Type 4 / metabolism
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Homeostasis
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Humans
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Insulin / metabolism*
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Islets of Langerhans / cytology
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Islets of Langerhans / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Muscle, Skeletal / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Phenotype
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Pre-B-Cell Leukemia Transcription Factor 1
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RNA-Binding Proteins
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Signal Transduction / physiology
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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Blood Glucose
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Carrier Proteins
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DNA-Binding Proteins
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Glucose Transporter Type 4
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Homeodomain Proteins
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Insulin
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Mybbp1a protein, mouse
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Nuclear Proteins
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Pbx1 protein, mouse
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Pknox1 protein, mouse
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Ppargc1a protein, mouse
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Pre-B-Cell Leukemia Transcription Factor 1
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RNA-Binding Proteins
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Slc2a4 protein, mouse
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Trans-Activators
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Transcription Factors
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Glucagon