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Regulation of Gene Expression by Glucose in Pancreatic β-Cells (MIN6) via Insulin Secretion and Activation of Phosphatidylinositol 3′-Kinase*

  • Gabriela da Silva Xavier
    Affiliations
    Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, United Kingdom
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  • Aniko Varadi
    Affiliations
    Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, United Kingdom
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  • Edward K. Ainscow
    Affiliations
    Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, United Kingdom
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  • Guy A. Rutter
    Correspondence
    To whom correspondence should be addressed. Tel.: 44-117-928-9724; Fax: 44-117-928-8274
    Affiliations
    Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, United Kingdom
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  • Author Footnotes
    * This work was supported by project grants from the Wellcome Trust, Diabetes UK (formerly the British Diabetes Association), the Medical Research Council (United Kingdom), and the Biotechnology and Biological Sciences Research Council.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Open AccessPublished:November 17, 2000DOI:https://doi.org/10.1074/jbc.M006597200
      Increases in glucose concentration control the transcription of the preproinsulin (PPI) gene and several other genes in the pancreatic islet β-cell. Although recent data have demonstrated that secreted insulin may regulate the PPI gene (Leibiger, I. B., Leibiger, B., Moede, T., and Berggren, P. O. (1998)Mol. Cell 1, 933–938), the role of insulin in the control of other β-cell genes is unexplored. To study the importance of insulin secretion in the regulation of the PPI and liver-type pyruvate kinase (L-PK) genes by glucose, we have used intranuclear microinjection of promoter-luciferase constructs into MIN6 β-cells and photon-counting imaging. The activity of each promoter was increased either by 30 (versus 3) mm glucose or by 1–20 nm insulin. These effects of insulin were not due to enhanced glucose metabolism since culture with the hormone had no impact on the stimulation of increases in intracellular ATP concentration caused by 30 mm glucose. Furthermore, the islet-specific glucokinase promoter and cellular glucokinase immunoreactivity were unaffected by 30 mm glucose or 20 nm insulin. Inhibition of insulin secretion with the Ca2+ channel blocker verapamil, the ATP-sensitive K+ channel opener diazoxide, or the α2-adrenergic agonist clonidine blocked the effects of glucose on L-PK gene transcription. Similarly, 30 mmglucose failed to induce the promoter after inhibition of phosphatidylinositol 3′-kinase activity with LY294002 and the expression of dominant negative-acting phosphatidylinositol 3′-kinase (Δp85) or the phosphoinositide 3′-phosphatase PTEN (phosphatase and tensin homologue). LY294002 also diminished the activation of the L-PK gene caused by inhibition of 5′-AMP-activated protein kinase with anti-5′-AMP-activated protein kinase α2 antibodies. Conversely, stimulation of insulin secretion with 13 mm KCl or 10 μm tolbutamide strongly activated the PPI and L-PK promoters. These data indicate that, in MIN6 β-cells, stimulation of insulin secretion is important for the activation by glucose of L-PK as well as the PPI promoter, but does not cause increases in glucokinase gene expression or glucose metabolism.
      PPI
      preproinsulin
      L-PK
      liver-type pyruvate kinase
      [Ca2+]i
      intracellular free Ca2+ concentration
      USF
      upstream stimulatory factor
      SREBP-1c
      sterol response element-binding protein-1c
      GK
      glucokinase (hexokinase type IV)
      PI3K
      phosphatidylinositol 3′-kinase
      AMPK
      5′-AMP-activated protein kinase
      KRB
      Krebs-Ringer bicarbonate
      CMV
      cytomegalovirus
      PIP3
      phosphatidylinositol 3,4,5-trisphosphate
      Elevated glucose concentrations stimulate the transcription of the preproinsulin (PPI)1 gene (
      • Welsh M.
      • Nielsen D.A.
      • MacKrell A.J.
      • Steiner D.F.
      ,
      • Docherty K.
      • Clark A.R.
      ) and several other genes in islet β-cells, including the liver-type pyruvate kinase (L-PK) gene (
      • Marie S.
      • Diaz-Guerra M.-J.
      • Miquerol L.
      • Kahn A.
      • Iynedjian P.B.
      ), acetyl-CoA carboxylase I (
      • Brun T.
      • Roche E.
      • Kim K.H.
      • Prentki M.
      ), GLUT2 (
      • Yasuda K.
      • Yamada Y.
      • Inagaki N.
      • Yano H.
      • Okamoto Y.
      • Tsuji K.
      • Fukumoto H.
      • Imura H.
      • Seino S.
      • Seino Y.
      ), and a raft of other genes involved in insulin synthesis and release (
      • Webb G.C.
      • Akbar M.S.
      • Zhao C.J.
      • Steiner D.F.
      ). However, the molecular mechanisms involved in the regulation of transcription by glucose are only partly understood (
      • Vaulont S.
      • Kahn A.
      ,
      • Rutter G.A.
      • Tavare J.M.
      • Palmer D.G.
      ). Recent observations have suggested that the release of insulin may play an important part in the regulation of the preproinsulin gene by glucose, at least under certain conditions (
      • Leibiger I.B.
      • Leibiger B.
      • Moede T.
      • Berggren P.O.
      ,
      • Rutter G.A.
      ). Consistent with this, increases in intracellular free Ca2+ concentration ([Ca2+]i), which are important in the activation of insulin release, have been reported to be essential for regulation of PPI gene expression by glucose in some systems (
      • Efrat S.
      • Surana M.
      • Fleischer N.
      ,
      • German M.S.
      • Moss L.G.
      • Rutter W.J.
      ). On the other hand, several studies have indicated that glucose can also regulate the PPI gene independently of insulin secretion (
      • de Vargas L.M.
      • Sobolewski J.
      • Siegel R.
      • Moss L.G.
      ,
      • Kennedy H.J.
      • Rafiq I.
      • Pouli A.E.
      • Rutter G.A.
      ,
      • Goodison S.
      • Kenna S.
      • Ashcroft S.J.H.
      ). Furthermore, PPI gene expression appears to be largely unaltered after targeted disruption of the insulin receptor gene in the islet β-cell, at least in younger animals (
      • Kulkarni R.N.
      • Bruning J.C.
      • Winnay J.N.
      • Postic C.
      • Magnuson M.A.
      • Kahn C.R.
      ).
      By contrast, the role of insulin secretion in the regulation of other glucose-sensitive islet β-cell genes is largely uninvestigated (
      • Rutter G.A.
      • Tavare J.M.
      • Palmer D.G.
      ,
      • Prentki M.
      • Tornheim K.
      • Corkey B.E.
      ). Elevations of glucose concentration enhance the expression of the L-PK gene in hepatocytes through activated transcription (
      • Vaulont S.
      • Munnich A.
      • Decaux J.F.
      • Kahn A.
      ). This effect of glucose is dependent upon a cis-acting upstream region of the gene from nucleotides −183 to +10 with respect to the cap site (
      • Cuif M.H.
      • Porteu A.
      • Kahn A.
      • Vaulont S.
      ), and a glucose response element has been mapped to a palindromic repeat of two E-boxes (CACGGG) located in the region at base pairs −170 to −150 with respect to the transcriptional start site (
      • Towle H.C.
      ). A similar region is also present in other glucose-responsive genes (
      • Rutter G.A.
      • Tavare J.M.
      • Palmer D.G.
      ), including those encoding Spot14 (
      • Shih H.
      • Towle H.C.
      ), acetyl-CoA carboxylase I (
      • Luo X.C.
      • Kim K.H.
      ,
      • Lopez J.M.
      • Bennett M.K.
      • Sanchez H.B.
      • Rosenfeld J.M.
      • Osborne T.E.
      ), and fatty-acid synthase (
      • Su H.S.
      • Latasa M.J.
      • Moon Y.
      • Kim K.H.
      ).
      Phosphorylation of glucose appears to be essential for the transcriptional effects of the sugar on L-PK gene transcription in liver (
      • Vaulont S.
      • Kahn A.
      ). Thus, glucose 6-phosphate and the pentose phosphate intermediate xylulose 5-phosphate (
      • Doiron B.
      • Cuif M.-H.
      • Chen R.
      • Kahn A.
      ) may be key signaling intermediates. The identity of the transcription factors mediating the transcriptional response is still debated, with evidence both for (
      • Kennedy H.J.
      • Viollet B.
      • Rafiq I.
      • Kahn A.
      • Rutter G.A.
      ,
      • Lefrancois-Martinez A.M.
      • Martinez A.
      • Antoine B.
      • Raymondjean M.
      • Kahn A.
      ) and against (
      • Qian J.
      • Kaytor E.N.
      • Towle H.C.
      • Olson L.K.
      ,
      • Kaytor E.N.
      • Shih H.
      • Towle H.C.
      ) a role for the ubiquitous upstream stimulatory factor (USF1 and USF2). Recent data have also implicated sterol response element-binding protein-1c (SREBP-1c) (
      • Foretz M.
      • Carling D.
      • Guichard C.
      • Ferre P.
      • Foufelle F.
      ) and other less well defined factors (
      • Yamada K.
      • Noguchi T.
      ).
      L-PK gene transcription is also strongly stimulated by insulin in cultured liver cells. Under most experimental conditions, this effect requires elevated glucose concentrations and has been considered to be due mainly to up-regulation of the glucokinase (GK) gene (
      • Iynedjian P.B.
      • Pilot P.-R.
      • Nouspikel T.
      • Milburn J.L.
      • Quaade C.
      • Hughes S.
      • Ucla C.
      • Newgard C.B.
      ) and thus increased intracellular concentrations of Glu-6-P or xylulose 5-phosphate (
      • Doiron B.
      • Cuif M.H.
      • Kahn A.
      • Diaz-Guerra M.J.M.
      ,
      • Kahn A.
      ). However, insulin also activates the L-PK promoter after culture of hepatocytes from starved rats after constitutive expression of GK (
      • Cuif M.H.
      • Doiron B.
      • Kahn A.
      ), indicating that an additional, glucose-independent mechanism of action of the hormone must exist.
      Since high glucose concentrations stimulate islet GK gene expression relatively weakly (
      • Tiedge M.
      • Steffeck H.
      • Elsner M.
      • Lenzen S.
      ,
      • Liang Y.
      • Najafi H.
      • Matschinsky F.M.
      ), if at all (
      • Marie S.
      • Diaz-Guerra M.-J.
      • Miquerol L.
      • Kahn A.
      • Iynedjian P.B.
      ,
      • Iynedjian P.B.
      • Pilot P.-R.
      • Nouspikel T.
      • Milburn J.L.
      • Quaade C.
      • Hughes S.
      • Ucla C.
      • Newgard C.B.
      ), the inductive effect of glucose on L-PK gene transcription in islets and β-cell-derived INS-1 (
      • Marie S.
      • Diaz-Guerra M.-J.
      • Miquerol L.
      • Kahn A.
      • Iynedjian P.B.
      ) and MIN6 (
      • Kennedy H.J.
      • Viollet B.
      • Rafiq I.
      • Kahn A.
      • Rutter G.A.
      ,
      • Rafiq I.
      • da Silva Xavier G.
      • Hooper S.
      • Rutter G.A.
      ) cells has previously been attributed solely to an increase in the intracellular concentration of a glucose metabolite (e.g. Glu-6-P or xylulose 5-phosphate; see above). However, glucose also stimulates the release of stored insulin from the β-cell, so the potential exists for a para- or autocrine effect of the hormone on gene expression. We have therefore investigated the effects of added insulin on the PPI, L-PK, and GK gene promoters in the highly glucose-responsive model MIN6 β-cell line (
      • Miyazaki J.
      • Araki K.
      • Yamato E.
      • Ikegami H.
      • Asano T.
      • Shibasaki Y.
      • Oka Y.
      • Yamamura K.
      ). This system has enabled us to determine the relative importance of activated insulin secretion, glucose metabolism, and changes in [Ca2+]i in the transcriptional regulation of the L-PK gene by glucose. Our results suggest that, under appropriate conditions, secretion of insulin and the activation of a signaling pathway dependent upon phosphatidylinositol 3′-kinase (PI3K) largely explain the transcriptional effects of glucose on PPI and L-PK gene expression in this β-cell model.

      Acknowledgments

      We thank Alan Leard and Dr. Mark Jepson (Bristol Medical Research Council Imaging Facility) for assistance with imaging experiments. We thank Dr. C. Zhao for measurements of insulin secretion, Drs. L. Agius and C. B. Newgard for providing GK adenovirus, and Drs. Isabelle Leclerc and Axel Kahn for useful discussions.

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