N Sekine

University Hospital Medical Information Network, Edo, Tōkyō, Japan

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Publications (18)99.53 Total impact

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    ABSTRACT: Direct effects of adrenomedullin on insulin secretion from pancreatic beta-cells were investigated using a differentiated insulin-secreting cell line INS-1. Adrenomedullin (1-100 pM) inhibited insulin secretion at both basal (3 mM) and high (15 mM) glucose concentrations, although this inhibitory effect was not observed at higher concentrations of adrenomedullin. The inhibition of glucose-induced insulin secretion by adrenomedullin was restored with 12-h pretreatment with 1 microg/ml pertussis toxin (PTX), suggesting that this effect could be mediated by PTX-sensitive G proteins. Cellular glucose metabolism evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide colorimetric assay was not affected by adrenomedullin at concentrations that inhibited insulin secretion. Moreover, electrophysiological studies revealed that 10 pM adrenomedullin had no effect on membrane potential, voltage-gated calcium currents, or cytosolic calcium concentration induced by 15 mM glucose. Finally, insulin release induced by cAMP-raising agents, such as forskolin plus 3-isobutyl-1-methylxanthine or the calcium ionophore ionomycin, was significantly inhibited by 10 and 100 pM adrenomedullin. In conclusion, adrenomedullin at picomolar concentrations directly inhibited insulin secretion from beta-cells. This effect is likely due to the inhibition of insulin exocytosis through the activation of PTX-sensitive G proteins.
    AJP Endocrinology and Metabolism 08/2006; 291(1):E9-E14. · 4.51 Impact Factor
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    ABSTRACT: Pancreatic AR42J cells have the feature of pluripotency of the precursor cells of the gut endoderm. Betacellulin (BTC) and activin A (Act) convert them into insulin-secreting cells. Using mRNA differential display techniques, we have identified a novel mitochondrial transporter, which is highly expressed during the course of differentiation, and have designated it citrate transporter protein-like protein (CTPL). Recently sideroflexin 1 (Sfxn1) was shown to be a susceptible gene of flexed-tail (f/f) mice, and CTPL has turned out to be a rat orthologous protein of Sfxn3, a member of sideroflexin family. CTPL/Sfxn3 was targeted to mitochondrial membrane like Sfxn1. The expression levels of CTPL/Sfxn3, Sfxn2, and Sfxn5 were upregulated in the early phase of differentiation into insulin-secreting cells but the expression levels of Sfxn1 and Sfxn3 did not change. All Sfxn family members were expressed in rat pancreatic islet. The expression levels of CTPL/Sfxn3, Sfxn2, and Sfxn5 were also upregulated in islets of streptozotocin-induced diabetic rats compared to normal rats. The downregulation of CTPL/Sfxn3 in a rat insulinoma cell line, INS-1, with the antisense oligonucleotide did not affect the insulin secretion. Taken together, CTPL/Sfxn3 and some other family members might be important in the differentiation of pancreatic beta-cells as a channel or a carrier molecule and be related to the regeneration of pancreatic endocrine cells.
    Journal of Cellular Biochemistry 09/2005; 95(6):1157-68. · 3.06 Impact Factor
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    ABSTRACT: Triglyceride (TG) accumulation in pancreatic beta-cells is thought to be associated with impaired insulin secretory response to glucose (lipotoxicity). To better understand the mechanism of the impaired insulin secretory response to glucose in beta-cell lipotoxicity, we overexpressed a constitutively active form of the sterol regulatory element-binding protein- 1c (SREBP-1c), a master transcriptional factor of lipogenesis, in INS-1 cells with an adenoviral vector. This treatment was associated with strong activation of transcription of the genes involved in fatty acid biosynthesis, increased cellular TG content, severely blunted glucose-stimulated insulin secretion, and enhanced expression of the uncoupling protein-2 (UCP-2), which supposedly dissipates the mitochondrial electrochemical potential. To decrease the up-regulated UCP-2 expression, small interfering RNA for UCP-2 was used. Introduction of the small interfering RNA increased the ATP/ADP ratio and partially rescued the glucose-stimulated insulin secretion in the cells overexpressing SREBP-1c, but did not affect the cellular TG content. Next, the effect of the AMP-activated protein kinase (AMPK) agonist, 5-amino-4-imidazolecarboxamide riboside, was examined in the lipotoxicity model. Exposure of the cells with lipotoxicity to 5-amino-4-imidazolecarboxamide riboside increased free fatty acid oxidation, partially reversed the TG accumulation, phosphorylated AMPK and acetyl-coenzyme A carboxylase, and improved the impaired glucose-stimulated insulin secretion. These results suggest that UCP-2 down-regulation and AMPK activation could be candidate targets for releasing beta-cells from lipotoxicity.
    Endocrinology 09/2004; 145(8):3566-77. · 4.72 Impact Factor
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    ABSTRACT: Interferon-gamma and TNFalpha synergistically induce the inducible isoform of nitric oxide synthase and elicit severe cytotoxicity in pancreatic beta-cells. We demonstrate here that GH, the well known beta-cell mitogen, inhibits nitric oxide production by reducing inducible nitric oxide synthase gene induction by the two cytokines and counteracts their cytotoxic effect in insulin-secreting INS-1 cells. To elucidate the underlying mechanism, we examined activation of the transcription factors implicated in the induction of inducible nitric oxide synthase, signal transducer and activator of transcription-1, and nuclear factor-kappa B. GH inhibited tyrosine phosphorylation and DNA binding of signal transducer and activator of transcription-1 promoted by interferon-gamma, whereas nuclear factor-kappa B activation by TNFalpha was not affected by GH. GH was found to induce suppressor of cytokine signaling-1 and -3, both of which are able to inhibit interferon-gamma activation of signal transducer and activator of transcription-1, suggesting that they are likely to mediate the inhibitory action of GH. Finally, exposure of INS-1 cells to interferon-gamma resulted in the impairment of insulin secretion in response to glucose, which was restored by the addition of GH. These results indicate that GH counteracts the effect of interferon-gamma through the inhibition of signal transducer and activator of transcription-1. This action of GH may be sufficient to suppress the synergistic induction of inducible nitric oxide synthase by interferon-gamma and TNFalpha, thereby preventing the cytotoxicity to beta-cells.
    Endocrinology 10/2001; 142(9):3909-16. · 4.72 Impact Factor
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    ABSTRACT: Interferon- and TNF synergistically induce the inducible isoform of nitric oxide synthase and elicit severe cytotoxicity in pancreatic -cells. We demonstrate here that GH, the well known -cell mitogen, inhibits nitric oxide production by re- ducing inducible nitric oxide synthase gene induction by the two cytokines and counteracts their cytotoxic effect in insu- lin-secreting INS-1 cells. To elucidate the underlying mecha- nism, we examined activation of the transcription factors im- plicated in the induction of inducible nitric oxide synthase, signal transducer and activator of transcription-1, and nu- clear factor-B. GH inhibited tyrosine phosphorylation and DNA binding of signal transducer and activator of transcrip- tion-1 promoted by interferon-, whereas nuclear factor-B activation by TNF was not affected by GH. GH was found to induce suppressor of cytokine signaling-1 and -3, both of which are able to inhibit interferon- activation of signal transducer and activator of transcription-1, suggesting that they are likely to mediate the inhibitory action of GH. Finally, exposure of INS-1 cells to interferon- resulted in the impair- ment of insulin secretion in response to glucose, which was restored by the addition of GH. These results indicate that GH counteracts the effect of interferon- through the inhibition of signal transducer and activator of transcription-1. This action of GH may be sufficient to suppress the synergistic induction of inducible nitric oxide synthase by interferon- and TNF, thereby preventing the cytotoxicity to -cells. (Endocrinology 142: 3909 -3916, 2001)
    Endocrinology 01/2001; 142(9):3909-3916. · 4.72 Impact Factor
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    ABSTRACT: Interferon-gamma (IFN-gamma) is known to exert deleterious effects on pancreatic beta-cells and is implicated in the development of type 1 (autoimmune) diabetes mellitus. In this study, we investigated signaling mechanisms mediating the effects of IFN-gamma in pancreatic beta-cells using a differentiated rat insulin-secreting cell line, INS-1, with special reference to the activation of transcription factors STAT (signal transducers and activators of transcription)1 and NF-kappaB. Exposure of INS-1 cells to 100 IU/ml IFN-gamma for 24 h resulted in significant inhibition of nutrient-induced insulin secretion associated with impaired metabolism. In combination with tumor necrosis factor-alpha (TNF-alpha) (50 ng/ml), IFN-gamma elicited severe cytotoxicity and induced the expression of the inducible isoform of nitric oxide synthase (iNOS) mRNA. IFN-gamma promoted tyrosine phosphorylation and DNA-binding of STAT1 through Janus kinase (JAK)1 activation without apparent phosphorylation of JAK2. TNF-alpha did not affect STAT1 activation, but stimulated DNA-binding and transcriptional activity of NF-kappaB, both of which were further increased by IFN-gamma. These effects of IFN-gamma and TNF-alpha seem physiologically relevant, because either inhibition of STAT1 by the tyrosine kinase inhibitor herbimycin A or that of NF-kappaB by sulfasalazine resulted in the reduction of iNOS mRNA expression. In conclusion, IFN-gamma activates STAT1 and potentiates TNF-alpha-induced NF-kappaB activation in INS-1 cells, thereby inducing iNOS and cell destruction.
    Journal of Cellular Physiology 08/2000; 184(1):46-57. · 4.22 Impact Factor
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    ABSTRACT: Prostaglandin A1 (PGA1) increases heat shock element (HSE)-mediated transcription, thereby enhancing expression of HSE-bearing genes, including heat shock proteins. Because we recently found functional HSEs in the human and rodent c-fos promoters, we hypothesized that PGA1 might increase c-fos expression through the HSE. In this study, we revealed that PGA1 induces c-fos expression at least partly by increasing the binding between heat shock factor-1 and the HSE, and that PGA1 enhances activity of activating protein-1 (AP-1). Interestingly, so far as PGA, is present in the medium, AP-1-mediated transcription enhanced by PGA1 cannot be detected by the standard luciferase reporter gene assay. Instead, it can be detected by either checking luciferase mRNA levels in the presence of PGA1 or measuring luciferase activities just after removal of PGA1. These results showed that protein products of some stress-responsive genes can increase, not during the stressful condition, but immediately after recovery from stress.
    Molecular and Cellular Endocrinology 07/2000; 164(1-2):77-85. · 4.04 Impact Factor
  • Journal of Cellular Physiology - J CELL PHYSIOL. 01/2000; 184(1):46-57.
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    ABSTRACT: Generation of free radicals is thought to mediate the cytotoxic action of alloxan on the pancreatic β-cell. In this investigation, the early effects of alloxan on cell function were studied. When INS-1D insulinoma cells were exposed to alloxan (1 mM) for 45 min followed by a 3-hr recovery period, the drug increased basal insulin release while abolishing the effect of glucose in static incubations. This was associated with impaired stimulation of cellular metabolism by glucose and reduced viability, both monitored colorimetrically with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). These alterations were largely counteracted by the antioxidant butylated hydroxyanisol (BHA). Similar changes occurred when glucose was added directly after 5 min of alloxan treatment, whereas KCl-induced secretion was only partially inhibited. In perifusion, alloxan caused transient insulin secretion to 50% of the rates obtained with glucose 30 min later. Under these conditions, epinephrine abolished the stimulation due to both agents. Membrane potential and cytosolic calcium concentrations ([Ca2+]i) were recorded to clarify the action of alloxan. Alloxan-induced insulin release correlated with depolarization of INS-1D cells and a rise in [Ca2+]i. Alloxan did not augment [Ca2+]i in the presence of BHA or the absence of extracellular calcium. Nickel chloride blocked the effect of alloxan on [Ca2+]i, whereas verapamil was ineffective. This suggests that alloxan promotes Ca2+ influx through channels distinct from L-type channels, perhaps through non-selective cation channels. Thus, alloxan causes changes in INS-1D cells prevented by antioxidant treatment, suggesting that free radicals may modulate the ionic permeability leading to functional activation.
    Biochemical Pharmacology 04/1999; · 4.58 Impact Factor
  • N Sekine, C B Wollheim, T Fujita
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    ABSTRACT: GH and its related peptide PRL are known to stimulate proliferation and insulin biosynthesis in pancreatic beta-cells, and assumed to be involved in their functional maturation. We investigated signal transduction of GH and PRL in insulin-secreting cells using the differentiated rat insulinoma cell line, INS-1. In these cells, both hormones stimulated proliferation and DNA synthesis, increased viability, cellular metabolism and insulin content. GH induced cytosolic Ca2+ ([Ca2+]i) rises, which appear to be due to Ca2+-influx through voltage-gated Ca2+-channels. GH also promoted tyrosine phosphorylation of several proteins in INS-1 cells, one of which was identified as JAK2 tyrosine kinase. Moreover, GH caused changes in DNA binding of nuclear proteins to some interferon-gamma-activated sites. Verapamil inhibited neither DNA synthesis nor JAK2 phosphorylation stimulated by GH, whereas a tyrosine kinase inhibitor, lavendustin A, blocked the mitogenic effect. Involvement of cAMP is also suggested because Rp-cAMPS, a competitive inhibitor of protein kinase A, abolished both [Ca2+]i rises and DNA synthesis stimulated by GH. The effects of GH and PRL on [Ca2+]i, JAK2 phosphorylation and DNA binding of the STATs were virtually identical in INS-1 cells. Since both hormones failed to activate MAP kinase in these cells, it is strongly suggested that activation of the JAK-STAT pathway is the major signalling event for the mitogenic effects of GH and PRL in beta-cells. It remains to be clarified whether the [Ca2+]i rise mediates other effects of these hormones.
    Endocrine Journal 05/1998; 45 Suppl:S33-40. · 2.23 Impact Factor
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    ABSTRACT: GH binding to its receptor, which belongs to the cytokine receptor superfamily, activates Janus kinase (JAK) 2 tyrosine kinase, thereby activating a number of intracellular key proteins such as STAT (signal transducers and activators of transcription) proteins and mitogen-activated protein (MAP) kinases, which finally lead to GH's biological actions including gene expression. In contrast to receptor tyrosine kinases, the signalling pathways leading to MAP kinase activation by GH are poorly understood but appear to involve Grb2 and Shc. We now show that GH stimulated tyrosine phosphorylation of epidermal growth factor receptor (EGFR) and its association with Grb2, and concomitantly stimulated MAP kinase activity in liver, a major target tissue. Expression of EGFR and its mutants into CHO-GH receptor (GHR) cells revealed that GH-induced full activation of MAP kinase and c-fos expression required tyrosine phosphorylation sites of EGFR but not its intrinsic tyrosine kinase activity. Moreover, by also using dominant negative JAK2 and in vitro kinase assay, we demonstrated that tyrosine 1068 of EGFR was evidently one of the major phosphorylation and Grb2 binding sites stimulated by GH via JAK2. These data suggest that the role of EGFR in GH signalling is to be phosphorylated by JAK2, thereby providing docking sites for Grb2 and activating MAP kinases and gene expression. This novel cross talk pathway may provide the first example of the hormone and cytokine receptor superfamily transducing signals via associated nonreceptor tyrosine kinase by phosphorylating growth factor receptor and utilizing it as a docking protein independent of its receptor tyrosine kinase activity.
    Endocrine Journal 05/1998; 45 Suppl:S27-31. · 2.23 Impact Factor
  • Endocrine Journal - ENDOCR J. 01/1998; 45.
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    ABSTRACT: When growth hormone binds to its receptor, which belongs to the cytokine receptor superfamily, it activates the Janus kinase Jak2 which has tyrosine-kinase activity and initiates an activation of several key intracellular proteins (for example, mitogen-activated protein (MAP) kinases) that eventually execute the biological actions induced by growth hormone, including the expression of particular genes. In contrast to receptors that themselves have tyrosine kinase activity, the signalling pathways leading to MAP kinase activation that are triggered by growth hormone are poorly understood, but appear to be mediated by the proteins Grb2 and Shc. We now show that growth hormone stimulates tyrosine phosphorylation of the receptor for epidermal growth factor (EGFR) and its association with Grb2 and at the same time stimulates MAP kinase activity in liver, an important target tissue of growth hormone. Expression of EGFR and its mutants revealed that growth-hormone-induced activation of MAP kinase and expression of the transcription factor c-fos requires phosphorylation of tyrosines on EGFR, but not its own intrinsic tyrosine-kinase activity. Moreover, tyrosine at residue 1,068 of the EGFR is proposed to be one of the principal phosphorylation sites and Grb2-binding sites stimulated by growth hormone via Jak2. Our results indicate that the role of EGFR in signalling by growth hormone is to be phosphorylated by Jak2, thereby providing docking sites for Grb2 and activating MAP kinases and gene expression, independently of the intrinsic tyrosine kinase activity of EGFR. This may represent a novel cross-talk pathway between the cytokine receptor superfamily and growth factor receptor.
    Nature 12/1997; · 38.60 Impact Factor
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    ABSTRACT: To study the regulation of growth and differentiated function of insulin-secreting cells, the rat insulinoma cell line INS-1 was cultured in a defined serum-free medium containing prolactin, IGF-I, and triiodothyronine, which was originally reported to maintain insulin secretion of islet cells. Growth and viability, as well as cellular insulin content of INS-1 cells in the defined medium, were comparable to the control cells cultured in the complete medium containing 10% fetal calf serum. However, after a 3-day culture in this medium, insulin secretion in response to glucose, pyruvate, and leucine was markedly blunted compared with the control cells (-78, -68, and -56%, respectively), whereas the response to 30 mmol/l K+ was only slightly decreased. In these cells: 1) nutrient metabolism assessed by tetrazolium salt reduction was reduced in response to pyruvate and leucine, which are mainly metabolized in the mitochondria; 2) oxidation of both [3,4-(14)C]glucose and [1-(14)C]pyruvate was decreased (-22 and -32%, respectively); 3) glucose failed to depolarize the membrane potential, whereas tolbutamide was fully active; 4) video imaging analysis of cytosolic Ca2+ showed a decrease in the population of glucose-responsive cells, while the response to 30 mmol/l K+ was preserved; 5) serum replenishment for 3 days restored glucose-induced insulin secretion. Interestingly, conditioned serum-free medium from rat islets maintained the insulin secretory function of INS-1 cells, although glucagon, somatostatin, and some other factors failed to restore the function. In contrast, conditioned media from HepG2, PC12, and human umbilical vein endothelial cells did not substitute for serum. Thus, the impaired insulin secretion of the cells cultured in the defined medium is best explained by defective mitochondrial metabolism. Islet cells, but not INS-1 cells, produce factors required for normal signal generation by nutrient secretagogues.
    Diabetes 10/1997; 46(9):1424-33. · 7.90 Impact Factor
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    ABSTRACT: Signal transduction of two mitogens for pancreatic beta-cells, GH and PRL, was investigated using the differentiated insulin-secreting cell line, INS-1. Addition of human GH (hGH) or ovine PRL in a serum-substitute medium increased growth, insulin content, and nutrient metabolism evaluated by tetrazolium salt reduction. hGH, bovine GH (bGH), and PRL also stimulated [3H]thymidine incorporation in a dose-dependent manner (1 pM - 1 nM). hGH induced cytosolic Ca2+ ([Ca2+]i) rises, which were transient, dependent on the presence of extracellular Ca2+, blocked by verapamil, calciseptine, and the hyperpolarizing agent diazoxide, suggesting that hGH stimulates Ca(2+)-influx through L-type Ca(2+)-channels. Similar effects on [Ca2+]i were observed with bGH or PRL. hGH caused membrane depolarization in a small proportion of the cells ( < 25%) as detected by cell-attached patch-clamp analysis. However, hGH failed to stimulate acute insulin secretion. hGH, bGH, and PRL promoted tyrosine phosphorylation of JAK2 tyrosine kinase. Verapamil inhibited neither [3H]thymidine incorporation nor JAK2 phosphorylation stimulated by hGH, whereas a tyrosine kinase inhibitor, lavendustin A, blocked the mitogenic effect. Involvement of cAMP is suggested because Rp-cyclic adenosine-3', 5'-monophosphorothioate, a competitive inhibitor of protein kinase A, abolished hGH-induced [Ca2+]i rises and DNA synthesis. cAMP appears to play a permissive role, although hGH failed to raise cellular cAMP levels. These results support the idea that activation of JAK2 is a major signaling event, whereas the [CA2+]i rise is not a prerequisite, for the mitogenic effects of GH and PRL in insulin-secreting cells.
    Endocrinology 05/1996; 137(5):1841-50. · 4.72 Impact Factor
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    ABSTRACT: The signaling pathways whereby glucose and hormonal secretagogues regulate insulin-secretory function, gene transcription, and proliferation of pancreatic beta-cells are not well defined. We show that in the glucose-responsive beta-cell line INS-1, major secretagogue-stimulated signaling pathways converge to activate 44-kDa mitogen-activated protein (MAP) kinase. Thus, glucose-induced insulin secretion was found to be associated with a small stimulatory effect on 44-kDa MAP kinase, which was synergistically enhanced by increased levels of intracellular cAMP and by the hormonal secretagogues glucagon-like peptide-1 and pituitary adenylate cyclase-activating polypeptide. Activation of 44-kDa MAP kinase by glucose was dependent on Ca2+ influx and may in part be mediated by MEK-1, a MAP kinase kinase. Stimulation of Ca2+ influx by KCl was in itself sufficient to activate 44-kDa MAP kinase and MEK-1. Phorbol ester, an activator of protein kinase C, stimulated 44-kDa MAP kinase by both Ca(2+)-dependent and -independent pathways. Nerve growth factor, independently of changes in cytosolic Ca2+, efficiently stimulated 44-kDa MAP kinase without causing insulin release, indicating that activation of this kinase is not sufficient for secretion. In the presence of glucose, however, nerve growth factor potentiated insulin secretion. In INS-1 cells, activation of 44-kDa MAP kinase was partially correlated with the induction of early response genes junB, nur77, and zif268 but not with stimulation of DNA synthesis. Our findings suggest a role of 44-kDa MAP kinase in mediating some of the pleiotropic actions of secretagogues on the pancreatic beta-cell.
    Journal of Biological Chemistry 05/1995; 270(14):7882-9. · 4.65 Impact Factor
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    ABSTRACT: Nutrient metabolism was examined with regard to insulin secretion in purified rat islet beta- and non-beta-cells, beta-cell lines, and hepatocytes. Lactate dehydrogenase (LDH) activity (nanomoles.min-1.mg protein-1) was remarkably low in the glucose-sensitive INS-1 cell line (15.7) and in beta-cells (22.3). Thus, beta-cell LDH was respectively 8-, 122-, 17-, and 136-fold lower than in islet non-beta, liver, HIT-T15, and RINm5F cells. Plasma membrane lactate transport activity was 3-10-fold lower in beta- or INS-1 cells than in the other cell types. Conversely, mitochondrial glycerol phosphate dehydrogenase was strongly expressed only in beta- and INS-1 cells. The significance of these findings to nutrient recognition was explored using INS-1 cells as a model of native beta-cells. Glucose-stimulated lactate output and glucose utilization were, respectively, 12- and 5-fold lower in INS-1 than in RINm5F cells. Each process was entirely blocked by respiratory chain inhibitors in INS-1 cells, whereas glucose utilization was barely affected and lactate output stimulated in RINm5F cells. Glucose oxidation represented 73% of total utilization in INS-1 cells, but only 9% in RINm5F cells. Absolute rates of glucose oxidation, and the extent of mitochondrial NAD(P) reduction, were similar in the two cell types, and glucose stimulated insulin secretion 1.9-fold in INS-1 and 1.4-fold in RINm5F cells. The mitochondrial substrates, monomethyl succinate, pyruvate, and leucine, each triggered secretion in INS-1 cells. The balance of LDH, plasma membrane lactate transport, and mitochondrial glycerol phosphate dehydrogenase activities therefore appear to be important in beta- and INS-1 cell glucose recognition to ensure that mitochondrial oxidation is the principle fate of pyruvate and NADH produced by glycolysis. The resultant close coupling of glycolysis with mitochondrial oxidation explains the absence in beta-cells of Crabtree and Pasteur effects.
    Journal of Biological Chemistry 03/1994; 269(7):4895-902. · 4.65 Impact Factor

Publication Stats

634 Citations
99.53 Total Impact Points

Institutions

  • 2000
    • University Hospital Medical Information Network
      Edo, Tōkyō, Japan
  • 1997
    • The University of Tokyo
      • Division of Internal Medicine
      Tokyo, Tokyo-to, Japan
  • 1994–1997
    • University of Geneva
      • Department of Internal Medicine
      Genève, GE, Switzerland