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

doi:10.1042/BJ20031260

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

Journal article

Open access

Peer reviewed

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 and Guy A Rutter

Biochemical journal, Vol.377(Pt 1), pp.149-158

01/01/2004

DOI: 10.1042/BJ20031260

PMCID: PMC1223855

PMID: 14563207

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Abstract

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.

Adenosine Triphosphate - metabolism

Animals

Cell Line

Diazoxide - pharmacology

Gene Expression Regulation

Glucokinase - genetics

Glucokinase - metabolism

Glucose - pharmacology

Homeodomain Proteins

Insulin - metabolism

Insulin - pharmacology

Insulin Secretion

Mice

Pancreas - drug effects

Pancreas - metabolism

Proinsulin - genetics

Proinsulin - metabolism

Protein Precursors - genetics

Protein Precursors - metabolism

Receptor, IGF Type 1 - genetics

Receptor, IGF Type 1 - physiology

Receptor, Insulin - genetics

Receptor, Insulin - physiology

RNA Interference

RNA, Messenger - metabolism

Trans-Activators - genetics

Trans-Activators - metabolism

Details

Title: Subtitle: Distinct roles for insulin and insulin-like growth factor-1 receptors in pancreatic beta-cell glucose sensing revealed by RNA silencing
Creators: Gabriela Da Silva Xavier - University of Bristol
Qingwen Qian - University of Bristol
Peter J Cullen - University of Bristol
Guy A Rutter - University of Bristol
Resource Type: Journal article
Publication Details: Biochemical journal, Vol.377(Pt 1), pp.149-158
DOI: 10.1042/BJ20031260
PMID: 14563207
PMCID: PMC1223855
NLM abbreviation: Biochem J
ISSN: 0264-6021
eISSN: 1470-8728
Grant note: 13/0004672 / Diabetes UK
Language: English
Date published: 01/01/2004
Academic Unit: Anatomy and Cell Biology
Record Identifier: 9984420945002771

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