title: Identification of insulin signaling elements in human beta-cells: autocrine regulation of insulin gene expression.
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 beta-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 p110alpha, p110beta, PI3KC2alpha, and PI3KC2gamma; phosphoinositide-dependent protein kinase-1; protein kinase B (PKB)alpha, PKBbeta, and PKBgamma in the beta-cell population suggests the presence of a functional insulin signaling cascade in human beta-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 beta-cells. Defects in this regulation may accentuate the metabolic dysfunction associated with type 2 diabetes.
authors.affiliation: Beta Cell Development & Function Group, Division of Reproduction and Endocrinology, School of Biomedical and Health Sciences, King's College London, London SE1 1UL, UK. dany.muller@kcl.ac.uk
authors.forename: Dany
authors.initials: D
authors.lastname: Muller
authors.forename: Guo Cai
authors.initials: GC
authors.lastname: Huang
authors.forename: Stephanie
authors.initials: S
authors.lastname: Amiel
authors.forename: Peter M
authors.initials: PM
authors.lastname: Jones
authors.forename: Shanta J
authors.initials: SJ
authors.lastname: Persaud
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D020869:Gene Expression Profiling; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D050417:Insulin-Secreting Cells / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis; D010750:Phosphoproteins / Q000096:biosynthesis; D011384:Proinsulin / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D011972:Receptor, Insulin / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011384:Proinsulin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D011972:Receptor, Insulin; C526292:IRS1 protein, human; C526297:IRS2 protein, human