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Reduction in pancreatic transcription factor PDX-1 impairs glucose-stimulated insulin secretion

Marcela Brissova1, Masakazu Shiota, Wendell E Nicholson

  • 1Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee 37212, USA.

The Journal of Biological Chemistry
|January 10, 2002
PubMed

Insights

Reduced pancreatic and duodenal homeobox protein 1 (PDX-1) impairs glucose-stimulated insulin secretion and islet function. This study in PDX-1(+/-) mice reveals critical roles for PDX-1 in maintaining normal pancreatic islet physiology.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Diabetes Research

Background:

  • Transcription factor PDX-1 is essential for pancreatic development; its deficiency causes pancreatic agenesis.
  • PDX-1 mutations are linked to maturity-onset diabetes of the young (MODY) and type 2 diabetes.
  • The precise impact of reduced PDX-1 on adult islet function remains to be fully elucidated.

Purpose of the Study:

  • To investigate the effects of heterozygous PDX-1 deficiency on insulin secretion and islet physiology.
  • To determine the functional consequences of altered PDX-1 levels in pancreatic islets.

Main Methods:

  • Analysis of glucose tolerance, insulin secretion, and islet gene expression in PDX-1(+/-) mice.
  • Assessment of NAD(P)H generation and insulin release from perfused pancreata.
  • Evaluation of insulin secretory responses to various stimuli including glucose, arginine, GLP-1, 2-ketoisocaproate, and KCl.

Main Results:

  • PDX-1(+/-) mice exhibited impaired glucose tolerance and reduced insulin secretion during glucose challenge.
  • Islet expression of PDX-1 and glucose transporter 2 was decreased, while glucokinase remained unchanged.
  • NAD(P)H generation was reduced by 30%, and insulin secretion stimulated by glucose, 2-ketoisocaproate, and KCl was significantly impaired.

Conclusions:

  • A modest reduction in PDX-1 significantly impairs glucose-stimulated insulin secretion in adult pancreatic islets.
  • PDX-1 plays a crucial role in regulating key steps of insulin secretion, including NAD(P)H generation and mitochondrial function.
  • These findings highlight the importance of PDX-1 in maintaining normal islet function and suggest its potential role in diabetes pathogenesis.

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