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Reduced PDX-1 expression impairs islet response to insulin resistance and worsens glucose homeostasis

¹Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, ²Department of Molecular Physiology and Biophysics, and ³Department of Cell Biology, Vanderbilt University School of Medicine; ⁴Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee; and ⁵Department of Biochemistry, Albert Einstein College of Medicine, New York, New York

Submitted 14 June 2004 ; accepted in final form 10 November 2004

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. Pancreatic duodenal homeodomain-1 (PDX-1), a 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, 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.

pancreatic duodenal homeodomain-1; diabetes; pancreatic islets; transcription factors

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