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

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)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume288
Issue number4 51-4
DOIs
StatePublished - Apr 2005
Externally publishedYes

Fingerprint

Insulin Resistance
Homeostasis
Insulin
Glucose
Type 2 Diabetes Mellitus
Alleles
Medical problems
Islets of Langerhans
Hyperglycemia
Hyperplasia
Transcription Factors
Genotype
Proteins

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Endocrinology
  • Biochemistry

Cite this

Reduced PDX-1 expression impairs islet response to insulin resistance and worsens glucose homeostasis. / Brissova, Marcela; Blaha, Michael; Spear, Cathi; Nicholson, Wendell; Radhika, Aramandla; Shiota, Masakazu; Charron, Maureen J.; Wright, Christopher V E; Powers, Alvin C.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 288, No. 4 51-4, 04.2005.

Research output: Contribution to journalArticle

Brissova, Marcela ; Blaha, Michael ; Spear, Cathi ; Nicholson, Wendell ; Radhika, Aramandla ; Shiota, Masakazu ; Charron, Maureen J. ; Wright, Christopher V E ; Powers, Alvin C. / Reduced PDX-1 expression impairs islet response to insulin resistance and worsens glucose homeostasis. In: American Journal of Physiology - Endocrinology and Metabolism. 2005 ; Vol. 288, No. 4 51-4.
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