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  • 1.
    Li, Jia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Yu, Qian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ahooghalandari, Parvin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gribble, Fiona M.
    Reimann, Frank
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Submembrane ATP and Ca2+ kinetics in alpha-cells: unexpected signaling for glucagon secretion2015In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, no 8, p. 3379-3388Article in journal (Refereed)
    Abstract [en]

    Cytoplasmic ATP and Ca2+ are implicated in current models of glucose's control of glucagon and insulin secretion from pancreatic alpha- and beta-cells, respectively, but little is known about ATP and its relation to Ca2+ in alpha-cells. We therefore expressed the fluorescent ATP biosensor Perceval in mouse pancreatic islets and loaded them with a Ca2+ indicator. With total internal reflection fluorescence microscopy, we recorded subplasma membrane concentrations of Ca2+ and ATP ([Ca2+](pm); [ATP](pm)) in superficial alpha- and beta-cells of intact islets and related signaling to glucagon and insulin secretion by immunoassay. Consistent with ATP's controlling glucagon and insulin secretion during hypo- and hyperglycemia, respectively, the dose-response relationship for glucoseinduced [ATP](pm) generation was left shifted in alpha-cells compared to beta-cells. Both cell types showed [Ca2+](pm) and [ATP](pm) oscillations in opposite phase, probably reflecting energy-consuming Ca2+ transport. Although pulsatile insulin and glucagon release are in opposite phase, [Ca2+](pm) synchronized in the same phase between alpha- and beta-cells. This paradox can be explained by the overriding of Ca2+ stimulation by paracrine inhibition, because somatostatin receptor blockade potently stimulated glucagon release with little effect on Ca2+. The data indicate that an alpha-cell-intrinsic mechanism controls glucagon in hypoglycemia and that paracrine factors shape pulsatile secretion in hyperglycemia.

  • 2.
    Li, Jia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Yu, Qian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ahooghalandari, Parvin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gribble, Fiona M
    Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge, United Kingdom.
    Reimann, Frank
    Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge, United Kingdom.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Submembrane ATP and Ca2+ kinetics in α‑cells: unexpected signaling for glucagon secretion2015In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, no 8, p. 3379-3388Article in journal (Refereed)
    Abstract [en]

    Cytoplasmic ATP and Ca(2+) are implicated in current models of glucose's control of glucagon and insulin secretion from pancreatic α- and β-cells, respectively, but little is known about ATP and its relation to Ca(2+) in α-cells. We therefore expressed the fluorescent ATP biosensor Perceval in mouse pancreatic islets and loaded them with a Ca(2+) indicator. With total internal reflection fluorescence microscopy, we recorded subplasma membrane concentrations of Ca(2+) and ATP ([Ca(2+)]pm; [ATP]pm) in superficial α- and β-cells of intact islets and related signaling to glucagon and insulin secretion by immunoassay. Consistent with ATP's controlling glucagon and insulin secretion during hypo- and hyperglycemia, respectively, the dose-response relationship for glucose-induced [ATP]pm generation was left shifted in α-cells compared to β-cells. Both cell types showed [Ca(2+)]pm and [ATP]pm oscillations in opposite phase, probably reflecting energy-consuming Ca(2+) transport. Although pulsatile insulin and glucagon release are in opposite phase, [Ca(2+)]pm synchronized in the same phase between α- and β-cells. This paradox can be explained by the overriding of Ca(2+) stimulation by paracrine inhibition, because somatostatin receptor blockade potently stimulated glucagon release with little effect on Ca(2+). The data indicate that an α-cell-intrinsic mechanism controls glucagon in hypoglycemia and that paracrine factors shape pulsatile secretion in hyperglycemia.

  • 3.
    Shuai, Hongyan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Xu, Yunjian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Yu, Qian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Fluorescent protein vectors for pancreatic islet cell identification in live-cell imaging2016In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 468, no 10, p. 1765-1777Article in journal (Refereed)
    Abstract [en]

    The islets of Langerhans contain different types of endocrine cells, which are crucial for glucose homeostasis. beta- and alpha-cells that release insulin and glucagon, respectively, are most abundant, whereas somatostatin-producing delta-cells and particularly pancreatic polypeptide-releasing PP-cells are more scarce. Studies of islet cell function are hampered by difficulties to identify the different cell types, especially in live-cell imaging experiments when immunostaining is unsuitable. The aim of the present study was to create a set of vectors for fluorescent protein expression with cell-type-specific promoters and evaluate their applicability in functional islet imaging. We constructed six adenoviral vectors for expression of red and green fluorescent proteins controlled by the insulin, preproglucagon, somatostatin, or pancreatic polypeptide promoters. After transduction of mouse and human islets or dispersed islet cells, a majority of the fluorescent cells also immunostained for the appropriate hormone. Recordings of the sub-plasma membrane Ca2+ and cAMP concentrations with a fluorescent indicator and a protein biosensor, respectively, showed that labeled cells respond to glucose and other modulators of secretion and revealed a striking variability in Ca2+ signaling among alpha-cells. The measurements allowed comparison of the phase relationship of Ca2+ oscillations between different types of cells within intact islets. We conclude that the fluorescent protein vectors allow easy identification of specific islet cell types and can be used in live-cell imaging together with organic dyes and genetically encoded biosensors. This approach will facilitate studies of normal islet physiology and help to clarify molecular defects and disturbed cell interactions in diabetic islets.

  • 4.
    Tuomi, Tiinamaija
    et al.
    Helsinki Univ Hosp, Abdominal Ctr, Endocrinol, FI-00014 Helsinki, Finland.;Folkhalsan Res Ctr, FI-00250 Helsinki, Finland.;Univ Helsinki, Res Programs Unit, Diabet & Obes Res Program, FI-00014 Helsinki, Finland.;Univ Helsinki, Finnish Inst Mol Med, FI-00014 Helsinki, Finland..
    Nagorny, Cecilia L. F.
    Lund Univ, Ctr Diabet, Unit Mol Metab, SE-20502 Lund, Sweden..
    Singh, Pratibha
    Lund Univ, Ctr Diabet, Unit Mol Metab, SE-20502 Lund, Sweden..
    Bennet, Hedvig
    Lund Univ, Ctr Diabet, Unit Diabet & Celiac Dis, SE-20502 Lund, Sweden..
    Yu, Qian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Alenkvist, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Isomaa, Bo
    Folkhalsan Res Ctr, FI-00250 Helsinki, Finland.;Univ Helsinki, Finnish Inst Mol Med, FI-00014 Helsinki, Finland.;Dept Social Serv & Hlth Care, FI-68601 Pietarsaari, Finland..
    Ostman, Bjarne
    Folkhalsan Res Ctr, FI-00250 Helsinki, Finland..
    Soderstrom, Johan
    Folkhalsan Res Ctr, FI-00250 Helsinki, Finland.;Univ Helsinki, Finnish Inst Mol Med, FI-00014 Helsinki, Finland..
    Pesonen, Anu-Katriina
    Univ Helsinki, Inst Behav Sci, FI-00014 Helsinki, Finland..
    Martikainen, Silja
    Univ Helsinki, Inst Behav Sci, FI-00014 Helsinki, Finland..
    Raikkonen, Katri
    Univ Helsinki, Inst Behav Sci, FI-00014 Helsinki, Finland..
    Forsen, Tom
    Folkhalsan Res Ctr, FI-00250 Helsinki, Finland..
    Hakaste, Liisa
    Helsinki Univ Hosp, Abdominal Ctr, Endocrinol, FI-00014 Helsinki, Finland.;Folkhalsan Res Ctr, FI-00250 Helsinki, Finland.;Univ Helsinki, Res Programs Unit, Diabet & Obes Res Program, FI-00014 Helsinki, Finland..
    Almgren, Peter
    Univ Helsinki, Inst Behav Sci, FI-00014 Helsinki, Finland.;Lund Univ, Ctr Diabet, Unit Diabet & Endocrinol, SE-20502 Lund, Sweden..
    Storm, Petter
    Lund Univ, Ctr Diabet, Unit Diabet & Endocrinol, SE-20502 Lund, Sweden..
    Asplund, Olof
    Lund Univ, Ctr Diabet, Unit Diabet & Endocrinol, SE-20502 Lund, Sweden..
    Shcherbina, Liliya
    Lund Univ, Ctr Diabet, Unit Neuroendocrine Cell Biol, SE-20502 Lund, Sweden..
    Fex, Malin
    Lund Univ, Ctr Diabet, Unit Diabet & Celiac Dis, SE-20502 Lund, Sweden..
    Fadista, Joao
    Lund Univ, Ctr Diabet, Unit Diabet & Endocrinol, SE-20502 Lund, Sweden..
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Wierup, Nils
    Lund Univ, Ctr Diabet, Unit Neuroendocrine Cell Biol, SE-20502 Lund, Sweden..
    Groop, Leif
    Univ Helsinki, Finnish Inst Mol Med, FI-00014 Helsinki, Finland.;Lund Univ, Ctr Diabet, Unit Diabet & Endocrinol, SE-20502 Lund, Sweden..
    Mulder, Hindrik
    Lund Univ, Ctr Diabet, Unit Mol Metab, SE-20502 Lund, Sweden..
    Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes2016In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 23, no 6, p. 1067-1077Article in journal (Refereed)
    Abstract [en]

    Type 2 diabetes (T2D) is a global pandemic. Genome-wide association studies (GWASs) have identified >100 genetic variants associated with the disease, including a common variant in the melatonin receptor 1 b gene (MTNR1B). Here, we demonstrate increased MTNR1B expression in human islets from risk G-allele carriers, which likely leads to a reduction in insulin release, increasing T2D risk. Accordingly, in insulin-secreting cells, melatonin reduced cAMP levels, and MTNR1B overexpression exaggerated the inhibition of insulin release exerted by melatonin. Conversely, mice with a disruption of the receptor secreted more insulin. Melatonin treatment in a human recall-by-genotype study reduced insulin secretion and raised glucose levels more extensively in risk G-allele carriers. Thus, our data support a model where enhanced melatonin signaling in islets reduces insulin secretion, leading to hyperglycemia and greater future risk of T2D. The findings also imply that melatonin physiologically serves to inhibit nocturnal insulin release.

  • 5.
    Wang, Xuan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jiang, L.
    Chinese Acad Agr Sci, Inst Anim Sci, Beijing, Peoples R China..
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Yu, Qian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Klaesson, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Welsh, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    ZBED6 negatively regulates insulin content, glucose-stimulated insulin secretion, neuronal differentiation and cell aggregation in MIN6 cells2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, p. S214-S215Article in journal (Refereed)
  • 6.
    Wang, Xuan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jiang, Lin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Chinese Acad Agr Sci, Inst Anim Sci, Key Lab Farm Anim Genet Resources & Utilizat, Minist Agr China, Beijing, Peoples R China.
    Wallerman, Ola
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.
    Younis, Shady
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Ain Shams Univ, Dept Anim Prod, Cairo, Egypt.
    Yu, Qian
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Klaesson, Axel
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tengholm, Anders
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Welsh, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.
    ZBED6 negatively regulates insulin production, neuronal differentiation, and cell aggregation in MIN6 cells2019In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, no 1, p. 88-100Article in journal (Refereed)
    Abstract [en]

    Zinc finger BED domain containing protein 6 (Zbed6) has evolved from a domesticated DNA transposon and encodes a transcription factor unique to placental mammals. The aim of the present study was to investigate further the role of ZBED6 in insulin-producing cells, using mouse MIN6 cells, and to evaluate the effects of Zbed6 knockdown on basal -cell functions, such as morphology, transcriptional regulation, insulin content, and release. Zbed6-silenced cells and controls were characterized with a range of methods, including RNA sequencing, chromatin immunoprecipitation sequencing, insulin content and release, subplasma membrane Ca2+ measurements, cAMP determination, and morphologic studies. More than 700 genes showed differential expression in response to Zbed6 knockdown, which was paralleled by increased capacity to generate cAMP, as well as by augmented subplasmalemmal calcium concentration and insulin secretion in response to glucose stimulation. We identified >4000 putative ZBED6-binding sites in the MIN6 genome, with an enrichment of ZBED6 sites at upregulated genes, such as the -cell transcription factors v-maf musculoaponeurotic fibrosarcoma oncogene homolog A and Nk6 homeobox 1. We also observed altered morphology/growth patterns, as indicated by increased cell clustering, and in the appearance of axon-like Neurofilament, medium polypeptide and tubulin 3, class III-positive protrusions. We conclude that ZBED6 acts as a transcriptional regulator in MIN6 cells and that its activity suppresses insulin production, cell aggregation, and neuronal-like differentiation.Wang, X., Jiang, L., Wallerman, O., Younis, S., Yu, Q., Klaesson, A., Tengholm, A., Welsh, N., Andersson, L. ZBED6 negatively regulates insulin production, neuronal differentiation, and cell aggregation in MIN6 cells.

  • 7.
    Wuttke, Anne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Yu, Qian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Autocrine Signaling Underlies Fast Repetitive Plasma Membrane Translocation of Conventional and Novel Protein Kinase C Isoforms in beta Cells2016In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 29, p. 14986-14995Article in journal (Refereed)
    Abstract [en]

    PKC signaling has been implicated in the regulation of many cell functions, including metabolism, cell death, proliferation, and secretion. Activation of conventional and novel PKC isoforms is associated with their Ca2+- and/or diacylglycerol (DAG)-dependent translocation to the plasma membrane. In 13 cells, exocytosis of insulin granules evokes brief (<10 s) local DAG elevations ("spiking") at the plasma membrane because of autocrine activation of P2Y(1), purinoceptors by ATP co-released with insulin. Using total internal reflection microscopy, fluorescent protein -tagged PKCs, and signaling biosensors, we investigated whether DAG spiking causes membrane recruitment of PKCs and whether different classes of PKCs show characteristic responses. Glucose stimulation of MINE cells triggered DAG spiking with concomitant repetitive translocation of the novel isoforms PKCI, PKCE, and PKCirp The conventional PKCa, PKCI3I, and PKC beta II isoforms showed a more complex pattern with both rapid and slow translocation. K+ depolarization-induced PKCE translocation entirely mirrored DAG spiking, whereas PKC beta 1 translocation showed a sustained component, reflecting the subplasma membrane Ca2+ concentration ([Ca2+)pm), with additional effect during DAG spikes. Interference with DAG spiking by purinoceptor inhibition prevented intermittent translocation of PKCs and reduced insulin secretion but did not affect [Ca2+]{,1 elevation or sustained PKCAI translocation. The muscarinic agonist carbachol induced pronounced transient PKCi3I translocation and sustained recruitment of PKCE. When rise of [Ca2+](p), was prevented, the carbachol-induced DAG and PKCE responses were somewhat reduced, but PKCI3I translocation was completely abolished. We conclude that exocytosis-induced DAG spikes efficiently recruit both conventional and novel PKCs to the beta cell plasma membrane. PKC signaling is thus implicated in autocrine regulation of beta cell function.

  • 8.
    Yu, Qian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    α-Cell signalling in glucose-regulated glucagon secretion2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Glucagon is a blood glucose-elevating hormone released from α-cells in the islets of Langerhans during hypoglycaemia. Glucagon is critical for glucose homeostasis and inappropriate regulation of its secretion underlies both impaired counter-regulation of hypoglycaemia and chronic hyperglycaemia in diabetes patients. The mechanisms by which glucose controls glucagon secretion are poorly understood, but have been suggested to involve both direct effects of the sugar on α-cells and indirect effects mediated by paracrine factors released within the islet, including insulin and gamma-hydroxybutyrate (GHB) from β-cells, and somatostatin from δ-cells. This thesis addresses the role of the intracellular messengers ATP, Ca2+ and cAMP in glucose-regulated glucagon secretion. Various fluorescence microscopy techniques were used to monitor changes of these messengers in single, dispersed α-cells and those in situ within intact islets, and glucagon secretion from islets was measured with an immunoassay. Glucose induced elevations of α-cell ATP, which were smaller and showed a left-shifted concentration-dependence compared to those in β-cells, consistent with α-cells being less dependent on oxidative metabolism and optimized for sensing hypoglycaemia. α-Cells showed Ca2+ oscillations with little glucose dependence. Surprisingly, these oscillations became synchronized in phase with Ca2+ oscillations in β-cells at high glucose. Since Ca2+ is a main trigger of exocytosis in both cell types, and since insulin and glucagon secretion is pulsatile in opposite phase, the results indicate that factors other than Ca2+ are more important for shaping glucagon secretion. Consistent with a key role of cAMP for the regulation of glucagon release, the concentration of the messenger was relatively high in α-cells at low glucose concentrations, and elevations of glucose suppressed cAMP in parallel with glucagon secretion. This effect was independent of paracrine signalling from insulin and somatostatin. The glucose-induced suppression of glucagon secretion was prevented by cAMP-elevating agents and mimicked by inhibitors of protein kinase A. GHB lacked effects both on Ca2+, cAMP and glucagon secretion from mouse islets, but tended to stimulate glucagon secretion by a somatostatin-receptor-dependent mechanism in human islets. The data indicate that GHB is not an inhibitor of glucagon secretion and that α-cell-intrinsic glucose sensing involves signalling via cAMP and protein kinase A.

    List of papers
    1. Submembrane ATP and Ca2+ kinetics in alpha-cells: unexpected signaling for glucagon secretion
    Open this publication in new window or tab >>Submembrane ATP and Ca2+ kinetics in alpha-cells: unexpected signaling for glucagon secretion
    Show others...
    2015 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, no 8, p. 3379-3388Article in journal (Refereed) Published
    Abstract [en]

    Cytoplasmic ATP and Ca2+ are implicated in current models of glucose's control of glucagon and insulin secretion from pancreatic alpha- and beta-cells, respectively, but little is known about ATP and its relation to Ca2+ in alpha-cells. We therefore expressed the fluorescent ATP biosensor Perceval in mouse pancreatic islets and loaded them with a Ca2+ indicator. With total internal reflection fluorescence microscopy, we recorded subplasma membrane concentrations of Ca2+ and ATP ([Ca2+](pm); [ATP](pm)) in superficial alpha- and beta-cells of intact islets and related signaling to glucagon and insulin secretion by immunoassay. Consistent with ATP's controlling glucagon and insulin secretion during hypo- and hyperglycemia, respectively, the dose-response relationship for glucoseinduced [ATP](pm) generation was left shifted in alpha-cells compared to beta-cells. Both cell types showed [Ca2+](pm) and [ATP](pm) oscillations in opposite phase, probably reflecting energy-consuming Ca2+ transport. Although pulsatile insulin and glucagon release are in opposite phase, [Ca2+](pm) synchronized in the same phase between alpha- and beta-cells. This paradox can be explained by the overriding of Ca2+ stimulation by paracrine inhibition, because somatostatin receptor blockade potently stimulated glucagon release with little effect on Ca2+. The data indicate that an alpha-cell-intrinsic mechanism controls glucagon in hypoglycemia and that paracrine factors shape pulsatile secretion in hyperglycemia.

    Keywords
    oscillations, islet of Langerhans, signal transduction, paracrine
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-261252 (URN)10.1096/fj.14-265918 (DOI)000358796900025 ()25911612 (PubMedID)
    Funder
    Swedish Diabetes AssociationSwedish Research CouncilNovo Nordisk
    Available from: 2015-09-01 Created: 2015-08-31 Last updated: 2018-07-31Bibliographically approved
    2. Glucose controls glucagon secretion by directly modulating cAMP in α‑cells
    Open this publication in new window or tab >>Glucose controls glucagon secretion by directly modulating cAMP in α‑cells
    Show others...
    (English)In: Article in journal (Other (popular science, discussion, etc.)) Submitted
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-356473 (URN)
    Available from: 2018-07-29 Created: 2018-07-29 Last updated: 2018-07-31
    3. Quantitative assessment of glucose-regulated cAMP signalling and protein kinase A-mediated glucagon secretion.
    Open this publication in new window or tab >>Quantitative assessment of glucose-regulated cAMP signalling and protein kinase A-mediated glucagon secretion.
    (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-356474 (URN)
    Available from: 2018-07-29 Created: 2018-07-29 Last updated: 2018-08-03
    4. γ-Hydroxybutyrate does not mediate glucose inhibition of glucagon secretion
    Open this publication in new window or tab >>γ-Hydroxybutyrate does not mediate glucose inhibition of glucagon secretion
    Show others...
    (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-356475 (URN)
    Available from: 2018-07-29 Created: 2018-07-29 Last updated: 2018-07-31
  • 9.
    Yu, Qian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Quantitative assessment of glucose-regulated cAMP signalling and protein kinase A-mediated glucagon secretion.Manuscript (preprint) (Other (popular science, discussion, etc.))
  • 10.
    Yu, Qian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lai, Bao Khanh
    Université Catholique de Louvain, Brussels, Belgium.
    Ahooghalandari, Parvin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Helander, Anders
    Karolinska Institutet.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gilon, Patrick
    Université Catholique de Louvain, Brussels, Belgium.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    γ-Hydroxybutyrate does not mediate glucose inhibition of glucagon secretionManuscript (preprint) (Other (popular science, discussion, etc.))
  • 11.
    Yu, Qian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Li, Jia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ahooghalandari, Parvin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Paradoxical Ca2+ kinetics in islet-located glucagon-releasing alpha cells2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1, p. S268-S269Article in journal (Other academic)
  • 12.
    Yu, Qian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Li, Jia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Paradoxical synchronisation of Ca2+ oscillations between alpha and beta cells within intact pancreatic islets2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no S1, p. S252-S252Article in journal (Other academic)
  • 13.
    Yu, Qian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Shuai, Hongyan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ahooghalandari, Parvin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Glucose controls glucagon secretion by directly modulating cAMP in alpha cells2019In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, no 7, p. 1212-1224Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis

    Glucagon is critical for normal glucose homeostasis and aberrant secretion of the hormone aggravates dysregulated glucose control in diabetes. However, the mechanisms by which glucose controls glucagon secretion from pancreatic alpha cells remain elusive. The aim of this study was to investigate the role of the intracellular messenger cAMP in alpha-cell-intrinsic glucose regulation of glucagon release.

    Methods

    Subplasmalemmal cAMP and Ca2+ concentrations were recorded in isolated and islet-located alpha cells using fluorescent reporters and total internal reflection microscopy. Glucagon secretion from mouse islets was measured using ELISA.

    Results

    Glucose induced Ca2+-independent alterations of the subplasmalemmal cAMP concentration in alpha cells that correlated with changes in glucagon release. Glucose-lowering-induced stimulation of glucagon secretion thus corresponded to an elevation in cAMP that was independent of paracrine signalling from insulin or somatostatin. Imposed cAMP elevations stimulated glucagon secretion and abolished inhibition by glucose elevation, while protein kinase A inhibition mimicked glucose suppression of glucagon release.

    Conclusions/interpretation

    Glucose concentrations in the hypoglycaemic range control glucagon secretion by directly modulating the cAMP concentration in alpha cells independently of paracrine influences. These findings define a novel mechanism for glucose regulation of glucagon release that underlies recovery from hypoglycaemia and may be disturbed in diabetes.

  • 14.
    Yu, Qian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Shuai, Hongyan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ahooghalandari, Parvin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Glucose controls glucagon secretion by directly modulating cAMP in α‑cellsIn: Article in journal (Other (popular science, discussion, etc.))
  • 15.
    Yu, Qian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Shuai, Hongyan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ahooghalandari, Parvin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Glucose lowers cAMP to inhibit glucagon secretion by a direct effect on alpha cells2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, p. S266-S267Article in journal (Refereed)
1 - 15 of 15
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