Distinct roles for insulin and insulin-like growth factor-1 receptors in pancreatic beta-cell glucose sensing revealed by RNA silencing

Gabriela Da Silva Xavier, Qingwen Qian, Peter J Cullen, Guy A Rutter

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69 Citations (Scopus)


The importance of the insulin receptor (IR) and the insulin-like growth factor-1 receptor (IGF-1R) for glucose-regulated insulin secretion and gene expression in pancreatic islet beta-cells is at present unresolved. Here, we have used small interfering RNAs (siRNAs) to silence the expression of each receptor selectively in clonal MIN6 beta-cells. Reduction of IR levels by >90% completely inhibited glucose (30 mM compared with 3 mM)-induced insulin secretion, but had no effect on depolarization-stimulated secretion. IR depletion also blocked the accumulation of preproinsulin (PPI), pancreatic duodenum homoeobox-1 (PDX-1) and glucokinase (GK) mRNAs at elevated glucose concentrations, as assessed by quantitative real-time PCR analysis (TaqMan). Similarly, depletion of IGF-1R inhibited glucose-induced insulin secretion but, in contrast with the effects of IR silencing, had little impact on the regulation of gene expression by glucose. Moreover, loss of IGF-1R, but not IR, markedly inhibited glucose-stimulated increases in cytosolic and mitochondrial ATP, suggesting a role for IGF-1R in the maintenance of oxidative metabolism and in the generation of mitochondrial coupling factors. RNA silencing thus represents a useful tool for the efficient and selective inactivation of receptor tyrosine kinases in isolated beta-cells. By inhibiting glucose-stimulated insulin secretion through the inactivation of IGF-1R, this approach also demonstrates the existence of insulin-independent mechanisms whereby elevated glucose concentrations regulate PPI, PDX-1 and GK gene expression in beta-cells.

Original languageEnglish
Pages (from-to)149-158
Number of pages10
JournalBiochemical Journal
Issue number1
Publication statusPublished - 1 Jan 2004


  • Adenosine Triphosphate/metabolism
  • Animals
  • Cell Line
  • Diazoxide/pharmacology
  • Gene Expression Regulation
  • Glucokinase/genetics
  • Glucose/pharmacology
  • Homeodomain Proteins
  • Insulin/pharmacology
  • Mice
  • Pancreas/drug effects
  • Proinsulin/genetics
  • Protein Precursors/genetics
  • RNA Interference
  • RNA, Messenger/metabolism
  • Receptor, IGF Type 1/genetics
  • Receptor, Insulin/genetics
  • Trans-Activators/genetics


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