Identification of Insulin Signaling Elements in Human β-Cells
Autocrine Regulation of Insulin Gene Expression
- 1Beta Cell Development and Function Group, Division of Reproduction and Endocrinology, School of Biomedical and Health Sciences, King’s College London, London, U.K
- 2Division of Gene and Cell Based Therapy, King’s College London, London, U.K
- Address correspondence and reprint requests to Dr. D. Muller, Beta Cell Development & Function Group, Division of Reproduction and Endocrinology, School of Biomedical and Health Sciences, King’s College London, London SE1 1UL, U.K. E-mail: dany.muller{at}kcl.ac.uk
Abstract
Although many studies using rodent islets and insulinoma cell lines have been performed to determine the role of insulin in the regulation of islet function, the autocrine effect of insulin on insulin gene expression is still controversial, and no consensus has yet been achieved. Because very little is known about the insulin signaling pathway in human islets, we used single-cell RT-PCR to profile the expression of genes potentially involved in the insulin signaling cascade in human β-cells. The detection of mRNAs for insulin receptor (IR)A and IRB; insulin receptor substrate (IRS)-1 and IRS-2; phosphoinositide 3-kinase (PI3K) catalytic subunits p110α, p110β, PI3KC2α, and PI3KC2γ; phosphoinositide-dependent protein kinase-1; protein kinase B (PKB)α, PKBβ, and PKBγ in the β-cell population suggests the presence of a functional insulin signaling cascade in human β-cells. Small interfering RNA–induced reductions in IR expression in human islets completely suppressed glucose-stimulated insulin gene expression, suggesting that insulin regulates its own gene expression in human β-cells. Defects in this regulation may accentuate the metabolic dysfunction associated with type 2 diabetes.
- IGF-1R, IGF-1 receptor
- IR, insulin receptor
- IRS, IR substrate
- PDK, phosphoinositide-dependent kinase
- PI3K, phosphoinositide-3 kinase
- PI(3,4,5)P3, phosphatidylinositol 3,4,5-triphosphate
- PKB, protein kinase B
- PPG, preproglucagon
- PPI, proproinsulin
- PPS, preprosomatostatin
- qPCR, quantitative PCR
- siRNA, small interfering RNA
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted June 16, 2006.
- Received April 19, 2006.
- DIABETES
