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

Marcela Brissova, Michael Blaha, Cathi Spear, Wendell Nicholson, Aramandla Radhika, Masakazu Shiota, Maureen J. Charron, Christopher V.E. Wright, Alvin C. Powers

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

In type 2 diabetes mellitus, insulin resistance and an inadequate pancreatic β-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 β-cell hyperplasia but failed to increase their β-cell insulin content. These results indicate that PDX-1 heterozygosity (∼60% of normal protein levels) abrogates the β-cell's compensatory response to insulin resistance, impairs glucose homeostasis, and may contribute to the pathogenesis of type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)E707-E714
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume288
Issue number4 51-4
DOIs
StatePublished - Apr 1 2005

Keywords

  • Diabetes
  • Pancreatic duodenal homeodomain-1
  • Pancreatic islets
  • Transcription factors

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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