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1 Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University School of Medicine, Nashville, TN, USA
2 Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashvlle, TN, USA
3 Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA
4 Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, USA
5 Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashvlle, TN, USA; VA Tennessee Valley Healthcare System, Nashville, TN, USA
* To whom correspondence should be addressed. E-mail: Al.Powers{at}Vanderbilt.edu.
In type 2 diabetes mellitus, insulin resistance and an inadequate pancreatic 
cell response to
the demands of insulin resistance lead to impaired insulin secretion and hyperglycemia. PDX-1,
a homeodomain transcription factor required for normal pancreatic development, also plays a
key role in normal insulin secretion by islets. To investigate the role of PDX-1 in islet
compensation for insulin resistance, we examined glucose disposal, insulin secretion, and islet
cell mass in mice of four different genotypes: wild type mice (WT), mice with one PDX-1 allele
inactivated (PDX-1+/-, resulting in impaired insulin secretion), mice with one GLUT4 allele
inactivated (GLUT4+/-, resulting in insulin resistance), and mice heterozygous for both PDX-1
and GLUT4 (GLUT4+/-;PDX-1+/-). The combination of PDX-1 and GLUT4 heterozygosity
markedly prolonged glucose clearance. GLUT4+/-;PDX-1+/- mice developed -cell hyperplasia,
but failed to increase their -cell insulin content. These results indicate that PDX-1
heterozygosity (~60% of normal protein levels) abrogates the cell's compensatory response to
insulin resistance, impairs glucose homeostasis, and may contribute to the pathogenesis of type
2 diabetes.
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