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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.
    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.

  • 3.
    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)
  • 4.
    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)
  • 5.
    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)
  • 6.
    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 - 6 of 6
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