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  • 1.
    Gustavsson, Natalia
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Abedi, Golbarg
    Larsson-Nyrén, Gerd
    Lindström, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Timing of Ca2+ response in pancreatic ß-cells is related to mitochondrial massManuscript (Other academic)
  • 2.
    Gustavsson, Natalia
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Larsson-Nyrén, Gerd
    Lindström, Per
    Cell specificity of Ca2+ response to tolbutamide is impaired in ß-cells from hyperglycemic mice2006In: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 190, no 2, p. 461-470Article in journal (Refereed)
  • 3.
    Gustavsson, Natalia
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Larsson-Nyrén, Gerd
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Lindström, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Pancreatic beta cells from db/db mice show cell-specific [Ca2+]i and NADH responses to glucose but not to alpha-ketoisocaproic acid.2005In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 31, no 3, p. 242-250Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: We recently showed that timing and magnitude of the glucose-induced cytoplasmic calcium [Ca2+]i response are reproducible and specific for the individual beta cell. We now wanted to identify which step(s) of stimulus-secretion coupling determine the cell specificity of the [Ca2+]i response and whether cell specificity is lost in beta-cells from diabetic animals. Besides glucose, we studied the effects of glyceraldehyde, a glycolytic intermediate, and alpha-ketoisocaproic acid (KIC), a mitochondrial substrate. METHODS: Early [Ca2+]i changes were studied stimulations in fura-2-labeled dispersed beta cells from lean, ob/ob, and db/db mice. Lag time and peak height were compared during 2 consecutive stimulations with the same stimulator. Nicotinamide adenine dinucleotide (NADH) responses to glucose and KIC were studied as a measure of metabolic flux. RESULTS: Both glyceraldehyde and KIC induced cell-specific temporal responses in lean mouse beta cells with a correlation between lag times for [Ca2+]i rise during the first and second stimulation. Beta cells from ob/ob and db/db mice showed cell-specific temporal [Ca2+]i responses to glucose and glyceraldehyde but not to KIC. Glucose induced cell-specific NADH responses in all 3 models, but KIC did so only in lean mouse [beta] cells. CONCLUSIONS: A cell-specific response may be induced at several steps of beta-cell stimulus-secretion coupling. Mitochondrial metabolism generates a cell-specific response in normal beta cells but not in db/db and ob/ob mouse beta cells.

  • 4.
    Larsson-Nyrén, G
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Sehlin, J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Anion-selective amplification of glucose-induced insulin secretion.2002In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 39, no 1, p. 41-7Article in journal (Refereed)
    Abstract [en]

    The functional roles of anions on glucose-induced insulin secretion are poorly understood. We investigated the effects of the monovalent anions thiocyanate, iodide, bromide, nitrate and chloride on the dynamics of insulin secretion in isolated pancreatic islets from non-inbred Umeå ob/ob mice. All anion species (12 mM), except Cl-, significantly amplified glucose-induced (20 mM) first- and second-phase insulin secretion (selectivity sequence: SCN->NO3->I->Br->Cl-). Simultaneously, the anions reduced the lag-time prior to the initiation of the secretion (SCN-=I-=NO3->Br->Cl-). The results indicate that pancreatic beta-cell activation can be initiated and amplified by an anion-selective mechanism showing increasing degrees of activation in the order of the anion series of Hofmeister. On the basis of the strikingly similar anion selectivity of amplified secretion and shortened lag-phase, we suggest that both types of anion effects are caused by action at a single site on the beta-cell.

  • 5.
    Larsson-Nyrén, Gerd
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Grapengiesser, Eva
    Hellman, Bo
    Phospholipase A2 is important for glucose induction of rhythmic Ca2+ signals in pancreatic beta cells.2007In: Pancreas, ISSN 1536-4828, Vol. 35, no 2, p. 173-9Article in journal (Other academic)
    Abstract [en]

    OBJECTIVES: Pancreatic beta cells respond to glucose stimulation with pulses of insulin release generated by oscillatory rises of the cytoplasmic Ca2+ concentration ([Ca2+]i). The observation that exposure to external ATP and other activators of cytoplasmic phospholipase A2 (cPLA2) rapidly induces rises of [Ca2+]i similar to ordinary oscillations made it important to analyze whether suppression of the cPLA2 activity affects glucose-induced [Ca2+]i rhythmicity in pancreatic beta cells. METHODS: Ratiometric fura-2 technique was used for measuring [Ca2+]i in single beta cells and small aggregates prepared from ob/ob mouse islets. RESULTS: Testing the effects of different inhibitors of cPLA2 in the presence of 20 mM glucose, it was found that N-(p-amylcinnamoyl)anthranilic acid (ACA) removed the oscillations at a concentration of 25 microM, arachidonyl trifluoromethyl ketone (AACOCF3) at 10 microM, and bromoenol lactone (BEL) at 10 to 15 microM. Withdrawal of ACA and BEL resulted in reappearance of the oscillations. Suppression of the arachidonic acid production by addition of 5 microM of the diacylglycerol lipase inhibitor 1,6-bis-(cyclohexyloximinocarbonylamino)-hexane (RHC 80267) effectively removed the [Ca2+]i oscillations, an effect reversed by removal of the inhibitor or addition of 100 microM tolbutamide. Suppression of the arachidonic acid production had a restrictive influence also on the transients of [Ca2+]i supposed to synchronize the beta-cell rhythmicity. Although less sensitive than the oscillations, most transients disappeared during exposure to 50 microM ACA or 35 microM RHC 80267. CONCLUSIONS: The results support the idea that cyclic variations of cPLA2 activity are important for the generation and synchronization of the beta-cell [Ca2+]i oscillations responsible for pulsatile release of insulin.

  • 6.
    Larsson-Nyrén, Gerd
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Pakhtusova, Natalia
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Sehlin, Janove
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Isolated mouse pancreatic β-cells show cell-specific temporal response pattern2002In: American Journal of Physiology - Cell Physiology, ISSN 0363-6143, E-ISSN 1522-1563, Vol. 282, no 6, p. C1199-C1204Article in journal (Refereed)
    Abstract [en]

    The length of the silent lag time before elevation of the cytosolic free Ca2+ concentration ([Ca2+]i) differs between individual pancreatic beta-cells. One important question is whether these differences reflect a random phenomenon or whether the length of lag time is inherent in the individual beta-cell. We compared the lag times, initial dips, and initial peak heights for [Ca2+]i from two consecutive glucose stimulations (with either 10 or 20 mM glucose) in individual ob/ob mouse beta-cells with the fura 2 technique in a microfluorimetric system. There was a strong correlation between the lengths of the lag times in each beta-cell (10 mM glucose: r = 0.94, P < 0.001; 20 mM glucose: r = 0.96, P < 0.001) as well as between the initial dips in [Ca2+]i (10 mM glucose: r = 0.93, P < 0.001; 20 mM glucose: r = 0.79, P < 0.001) and between the initial peak heights (10 mM glucose: r = 0.51, P < 0.01; 20 mM glucose: r = 0.77, P < 0.001). These data provide evidence that the response pattern, including both the length of the lag time and the dynamics of the subsequent [Ca2+]i, is specific for the individual beta-cell.

  • 7.
    Larsson-Nyrén, Gerd
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Sehlin, Janove
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Rorsman, Patrik
    Lund University, Department of Molecular and Cellular Physiology, Diabetes Research Unit, Lund, Sweden, .
    Renström, Erik
    Lund University, Department of Physiological Sciences, Lund, Sweden, .
    Perchlorate stimulates insulin secretion by shifting the gating of L-type Ca2+ currents in mouse pancreatic B-cells towards negative potentials2001In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 441, no 5, p. 587-595Article in journal (Refereed)
    Abstract [en]

    The effects of the chaotrophic anion perchlorate (ClO4-) on glucose-induced electrical activity, exocytosis and ion channel activity in mouse pancreatic B-cells were investigated by patch-clamp recordings and capacitance measurements. ClO4- stimulated glucose-induced electrical activity and increased the action potential frequency by 70% whilst not affecting the membrane potential when applied in the presence of a subthreshold concentration of the sugar. ClO4- did not influence ATP-dependent K (KATP) channel activity and voltage-gated delayed K+ current. Similarly, ClO4- had no effect on Ca2+-dependent exocytosis. The stimulation of electrical activity and insulin secretion was instead attributable to an enhancement of the whole-cell Ca2+ current. This effect was particularly pronounced at voltages around the threshold for action potential initiation and a doubling of the current amplitude was observed at -30 mV. This was due to a 7-mV shift in the gating of the Ca2+ current towards negative voltages. The action of ClO4- was more pronounced when added in the presence of 0.1 mM BAY K8644, whereas no stimulation was observed when applied at a maximal concentration of the agonist (1 mM). Single-channel recordings revealed that the effect of ClO4- on whole-cell currents was principally due to a 60% increase in the mean duration of the long openings and the number of active channels. We propose that ClO4- stimulates insulin secretion and electrical activity by exerting a BAY K8644-like action on Ca2+ channel gating.

  • 8.
    Ma, Zuheng
    et al.
    Karolinska Institutet.
    Wirström, Tina
    Karolinska Institutet.
    Borg, L. A. Håkan
    University of Uppsala.
    Larsson-Nyren, Gerd
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Hals, Ingrid
    Norwegian University of Science and Technology.
    Hansen, John Bondo
    5Novo Nordisk Research and Development; Målöv.
    Grill, Valdemar
    Karolinska Institutet, Norwegian University of Science and Technology, St. Olav’s University Hospital; Trondheim.
    Björklund, Anneli
    Karolinska Institutet.
    Diabetes reduces beta-cell mitochondria and induces distinct morphological abnormalities, which are reproducible by high glucose in vitro with attendant dysfunction2012In: Islets, ISSN 1938-2014, Vol. 4, no 3, p. 233-242Article in journal (Refereed)
    Abstract [en]

    We investigated the impact of a diabetic state with hyperglycemia on morphometry of beta-cell mitochondria and modifying influence of a K+-ATP channel opener and we related in vivo findings with glucose effects in vitro. For in vivo experiments, islets from syngeneic rats were transplanted under the kidney capsule to neonatally streptozotocin-diabetic or nondiabetic recipients. Diabetic recipients received vehicle, or tifenazoxide (NN414), intragastrically for 9 weeks. Non-diabetic rats received vehicle. Transplants were excised 7 d after cessation of treatment (wash-out) and prepared for electron microscopy. Morphological parameters were measured from approx. 25,000 mitochondria. Rat islets were cultured in vitro for 2-3 weeks at 27 or 11 (control) mmol/l glucose. Transplants to diabetic rats displayed decreased numbers of mitochondria (-31%, p < 0.05), increased mitochondrial volume and increased mitochondrial outer surface area, p < 0.001. Diabetes increased variability in mitochondrial size with frequent appearance of mega-mitochondria. Tifenazoxide partly normalized diabetes-induced effects, and mega-mitochondria disappeared. Long-term culture of islets at 27 mmol/l glucose reproduced the in vivo morphological abnormalities. High-glucose culture was also associated with reduced ATP and ADP contents, reduced oxygen consumption, reduced signaling by MitoTracker Red and reduction of mitochondrial proteins (complexes I-IV), OPA 1 and glucose-induced insulin release. We conclude that (1) a long-term diabetic state leads to a reduced number of mitochondria and to distinct morphological abnormalities which are replicated by high glucose in vitro; (2) the morphological abnormalities are coupled to dysfunction; (3) K+-ATP channel openers may have potential to partly reverse glucose-induced effects.

  • 9.
    Pakhtusova, Natalia
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Zaostrovskaya, Lidia
    Department of Histology, Cytology and Embryology, Northern State Medical University, Troitsky 51, 163051 Arkhangelsk, Russia.
    Lindström, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Larsson-Nyrén, Gerd
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Cell-specific Ca2+ responses in glucose-stimulated single and aggregated ß-cells2003In: Cell Calcium, ISSN 0143-4160, E-ISSN 1532-1991, Vol. 34, no 2, p. 121-129Article in journal (Refereed)
    Abstract [en]

    A rise in the cytoplasmic calcium concentration ([Ca(2+)](i)) is a key event for insulin exocytosis. We have recently found that the 'early [Ca(2+)](i) response' in single ob/ob mouse beta-cells is reproduced during consecutive glucose stimulations. It, therefore, appears that the response pattern is a characteristic of the individual beta-cell. We have now investigated if a cell-specific [Ca(2+)](i) response is a general phenomenon in rodent beta-cells, and if it can be observed when cells are functionally coupled. With the use of the fura-2 technique, we have studied the 'early [Ca(2+)](i) response' in single dispersed beta-cells, in beta-cell clusters of different size and in intact islets from the ob/ob mouse during repeated glucose stimulation (20mM). beta-Cells from lean mouse and rat, and intact islets from lean mouse were also investigated. Significant correlations between the first and second stimulation were found for the parameters lag-time for Ca(2+) rise (calculated as the time from start of stimulation of the cell until the first value above an extrapolated baseline), nadir of initial lowering (difference between the baseline and lowest [Ca(2+)](i) value), and peak height (difference between baseline and the highest [Ca(2+)](i) value of the first calcium peak) in single dispersed beta-cells, in 'single beta-cell within a small cluster', in clusters of medium and large size, and in single dispersed beta-cells from lean mouse and rat. The lag-times for Ca(2+) rise and peak heights were correlated within the pairs of stimulation also in intact ob/ob islets. In summary, despite a large heterogeneity of the 'early [Ca(2+)](i) response' among individual cells, the lag-time for [Ca(2+)](i) rise, the nadir of initial lowering and the height of the first peak response can be identified as cell-specific markers in beta-cells.

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