Glucose-induced Translational Control of Proinsulin Biosynthesis is Proportional to Preproinsulin mRNA Levels in Islet β-Cells but Not Regulated via a Positive Feedback of Secreted Insulin

Barton Wicksteed, Cristina Alarcon, Isabelle Briaud, Melissa K. Lingohr, Christopher J. Rhodes*

*Corresponding author for this work

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

Proinsulin biosynthesis is regulated in response to nutrients, most notably glucose. In the short term (≤2 h) this is due to increases in the translation of pre-existing mRNA. However, prolonging glucose stimulation (24 h) also increases preproinsulin mRNA levels. It has been proposed that secreted insulin from the pancreatic β-cell regulates its own synthesis through a positive autocrine feedback mechanism. Here the comparative contributions of translation and mRNA levels on the levels of proinsulin biosynthesis were examined in isolated pancreatic islets. Also, the autocrine role of insulin upon four β-cell functions (insulin secretion, proinsulin translation, preproinsulin mRNA levels, and total protein synthesis) was investigated in parallel. The results showed that proinsulin biosynthesis is regulated, in the short term (1 h), solely at the level of translation, through an ∼6-fold increase in response to glucose (2.8 mM versus 16.7 mM glucose). In the longer term, when preproinsulin mRNA levels have increased ∼2-fold, a corresponding increase was observed in the fold response of proinsulin translation to a stimulatory glucose concentration (≥10-fold). Importantly, neither exogenously added nor secreted insulin were found to play any role in regulating insulin secretion, proinsulin translation, preproinsulin mRNA levels, or total protein synthesis. The results presented here indicate that long term nutritional state sets the preproinsulin mRNA level in the β-cell at which translation control regulates short term changes in rates of proinsulin biosynthesis in response to glucose, but this is not mediated by any autocrine effect of insulin.

Original languageEnglish (US)
Pages (from-to)42080-42090
Number of pages11
JournalJournal of Biological Chemistry
Volume278
Issue number43
DOIs
StatePublished - Oct 24 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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