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  • 1.
    Bergqvist, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sundström, Sara
    Karolinska Institutet.
    Dimberg, Lina Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Masucci, Maria G.
    Karolinska Institutet.
    The Hepatitis C Virus Core Protein Modulates T Cell Responses by Inducing Spontaneous and Altering T-cell Receptor-triggered Ca2+ Oscillations2003In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 278, no 21, p. 18877-18883Article in journal (Refereed)
    Abstract [en]

    Alterations of cytokine responses are thought to favor the establishment of persistent hepatitis C virus (HCV) infection, enhancing the risk of liver cirrhosis and hepatocellular carcinoma. Expression of the HCV core (C) protein modulates transcription of the IL-2 promoter in T lymphocytes by activating the nuclear factor of activated T lymphocyte (NFAT) pathway. Here we report on the effect of HCV C on Ca2+ signaling, which is essential for activation of NFAT. Expression of HCV C correlated with increased levels of cytosolic Ca2+ and spontaneous Ca2+ oscillations in transfected Jurkat cells. Triggering of the T-cell receptor induced a prolonged Ca2+ response characterized by vigorous high frequent oscillations in a high proportion of the responding cells. This was associated with decreased sizes and accelerated emptying of the intracellular calcium stores. The effect of HCV C on calcium mobilization was not dependent on phospholipase C-1 (PLC-) activity or increased inositol 1,4,5-trisphosphate (IP3) production and did not require functional IP3 receptors, suggesting that insertion of the viral protein in the endoplasmic reticulum membrane may be sufficient to promote Ca2+ leakage with dramatic downstream consequences on the magnitude and duration of the response. Our data suggest that expression of HCV C in infected T lymphocytes may contribute to the establishment of persistent infections by inducing Ca2+ oscillations that regulate both the efficacy and information content of Ca2+ signals and are ultimately responsible for induction of gene expression and functional differentiation.

  • 2.
    Berts, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Dryselius, S
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, E
    Hellman, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Glucose stimulation of somatostatin-producing islet cells involves oscillatory Ca2+ signaling1996In: Endocrinology, Vol. 137, p. 693-Article in journal (Refereed)
  • 3.
    Berts, Alf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ball, Andrew
    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.
    Hellman, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Suppression of Ca2+ oscillations in glucagon-producing alfa2-cells by insulin/glucose and amino acids1996In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1310, no 2, p. 212-216Article in journal (Refereed)
    Abstract [en]

    The cytoplasmic Ca2+ concentration ([Ca2+]i) was continuously monitored in single glucagon-producing α2-cells isolated from the mouse pancreas and later identified by immunostaining. Up to 60% of the α2-cells exhibited spontaneous [Ca2+]i oscillations (frequency 0.1–0.3/min) in a medium containing 3 mM glucose. In originating from a basal level of 60–100 nM, reaching peak values of 300–400 nM and promptly disappearing after blocking voltage-dependent Ca2+ channels with methoxyverapamil, the oscillations resembled those in insulin-releasing β-cells stimulated by glucose. The oscillatory activity was suppressed when combining elevation of glucose to 20 mM with the addition of 2–2000 ng/ml insulin. Whereas 10 mM of l-arginine or l-glycine transformed the oscillations into sustained elevation of [Ca2+];, there was no response to 1 mM tolbutamide or 0.1–1 mM γ-aminobutyric acid. The observations that α2-cells differ from islet cells secreting insulin and somatostatin in responding to adrenaline with mobilisation of intracellular calcium can be used for their rapid identification. It is suggested that the oscillations reflect periodic entry of Ca2+ due to variations of the membrane potential.

  • 4.
    Berts, Alf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Liu, Yi-Jia
    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.
    Hellman, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Oscillatory Ca2+ signaling in somatostatin-producing cells from the human pancreas1997In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 46, no 4, p. 366-369Article in journal (Refereed)
    Abstract [en]

    Oscillatory Ca2+ signaling was studied in human somatostatin-releasing pancreatic δ cells identified by immunostaining. A ratiometric fura-2 technique was used for measuring cytoplasmic concentrations of Ca2+ and Sr2+ in δ cells exposed to the respective cation. Rhythmic activity in terms of slow (frequency, 0.1 to 0.4 per minute) oscillations from close to the basal level was seen in the presence of 3 to 20 mmol/L glucose during superfusion with medium containing 2.6 to 5 mmol/L Ca2+ or 5 mmol/L Sr2. These oscillations could be transformed into a sustained increase by decreasing extracellular Ca2+ or adding 1 mmol/L tolbutamide or 20 nmol/L glucagon. Addition of glucagon to a medium containing 20 mmol/L glucose resulted in the generation of short (< 30 seconds) transients, which disappeared upon exposure to 100 nmol/L of the intracellular Ca2+-adenosine triphosphatase (ATPase) inhibitor thapsigargin. When analyzing small aggregates of islet cells, it became evident that oscillatory activity in δ cells can be synchronous with that in adjacent non—δ cells. It is concluded that secretion of pancreatic somatostatin in man involves Ca2+ signaling similar to that regulating the pulsatile release of insulin.

  • 5. Chow, R H
    et al.
    Lund, P-E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Löser, S
    Panten, U
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Coincidence of early glucose-induced depolarization with lowering of cytoplasmic Ca2+ in mouse pancreatic beta-cells1995In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 485, no 3, p. 607-617Article in journal (Refereed)
    Abstract [en]

    1. The temporal relationship between the early glucose-induced changes of membrane potential and cytoplasmic Ca2+ concentration ([Ca2+]i) was studied in insulin-releasing pancreatic beta-cells. 2. The mean resting membrane potential and [Ca2+]i were about -70 mV and 60 nM, respectively, in 3 mM glucose. 3. Elevating the glucose concentration to 8-23 mM typically elicited a slow depolarization, which was paralleled by a lowering of [Ca2+]i. When the slow depolarization had reached a threshold of -55 to -40 mV, there was rapid further depolarization to a plateau with superimposed action potentials, and [Ca2+]i increased dramatically. 4. Imposing hyperpolarizations and depolarizations of 10 mV from a holding potential of -70 mV had no detectable effect on [Ca2+]i. Furthermore, glucose elevation elicited a decrease in [Ca2+]i even at a holding potential of -70 mV. 5. Step depolarizations induced [Ca2+]i transients, which decayed with time courses well fitted by double exponentials. The slower component became faster by a factor of about 4 upon elevation of glucose, suggesting involvement of ATP-dependent Ca2+ sequestration or extrusion of [Ca2+]i. 6. Glucose stimulation increased the size and accelerated the recovery of carbachol-triggered [Ca2+]i transients, and thapsigargin, an intracellular Ca(2+)-ATPase inhibitor, counteracted the glucose-induced lowering of [Ca2+]i, indicating that calcium transport into intracellular stores is involved in glucose-induced lowering of [Ca2+]i. 7. The results support the notion that in beta-cells, nutrient-induced elevation of ATP leads initially to ATP-dependent removal of Ca2+ from the cytoplasm, paralleled by a slow depolarization due to inhibition of ATP-sensitive K+ channels. Only after depolarization has reached a threshold do action potentials occur, inducing a sharp elevation in [Ca2+]i.

  • 6. Dezaki, Katsuya
    et al.
    Damdindorj, Boldbaatar
    Sone, Hideyuki
    Dyachok, Oleg
    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.
    Kurashina, Tomoyuki
    Yoshida, Masashi
    Kakei, Masafumi
    Yada, Toshihiko
    Ghrelin Attenuates cAMP-PKA Signaling to Evoke Insulinostatic Cascade in Islet beta-Cells2011In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 9, p. 2315-2324Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE-Ghrelin reportedly restricts insulin release in islet beta-cells via the G alpha(i2) subtype of G-proteins and thereby regulates glucose homeostasis. This study explored whether ghrelin regulates cAMP signaling and whether this regulation induces insulinostatic cascade in islet beta-cells. RESEARCH DESIGN AND METHODS-Insulin release was measured in rat perfused pancreas and isolated islets and cAMP production in isolated islets. Cytosolic cAMP concentrations ([cAMP](i)) were monitored in mouse MIN6 cells using evanescent-wave fluorescence imaging. In rat single beta-cells, cytosolic protein kinase-A activity ([PKA](i)) and Ca(2+) concentration ([Ca(2+)](i)) were measured by DR-II and fura-2 microfluorometry, respectively, and whole cell currents by patch-clamp technique. RESULTS-Ghrelin suppressed glucose (8.3 mmol/L)-induced insulin release in rat perfused pancreas and isolated islets, and these effects of ghrelin were blunted in the presence of cAMP analogs or adenylate cyclase inhibitor. Glucose-induced cAMP production in isolated islets was attenuated by ghrelin and enhanced by ghrelin receptor antagonist and anti-ghrelin antiserum, which counteract endogenous islet-derived ghrelin. Ghrelin inhibited the glucose-induced [cAMP](i) elevation and [PKA](i) activation in MIN6 and rat beta-cells, respectively. Furthermore, ghrelin potentiated voltage-dependent K(+) (Kv) channel currents without altering Ca(2+) channel currents and attenuated glucose-induced [Ca(2+)](i) increases in rat beta-cells in a PKA-dependent manner. CONCLUSIONS-Ghrelin directly interacts with islet beta-cells to attenuate glucose-induced cAMP production and PKA activation, which lead In activation of Kv channels and suppression of glucose-induced [Ca(2+)](i) increase and insulin release.

  • 7.
    Dyachok, Oleg
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Ca2+-induced Ca2+ Release via Inositol 1,4,5-trisphosphate Receptors Is Amplified by Protein Kinase A and Triggers Exocytosis in Pancreatic β-Cells2004In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 279, no 44, p. 45455-45461Article in journal (Refereed)
    Abstract [en]

    Hormones, such as glucagon and glucagon-like peptide-1, potently amplify nutrient stimulated insulin secretion by raising cAMP. We have studied how cAMP affects Ca2+-induced Ca2+ release (CICR) in pancreatic β-cells from mice and rats and the role of CICR in secretion. CICR was observed as pronounced Ca2+ spikes on top of glucose- or depolarization-dependent rise of the cytoplasmic Ca2+ concentration ([Ca2+]i). cAMP-elevating agents strongly promoted CICR. This effect involved sensitization of the receptors underlying CICR, because many cells exhibited the characteristic Ca2+ spiking at low or even in the absence of depolarization-dependent elevation of [Ca2+]i. The cAMP effect was mimicked by a specific activator of protein kinase A in cells unresponsive to activators of cAMP-regulated guanine nucleotide exchange factor. Ryanodine pretreatment, which abolishes CICR mediated by ryanodine receptors, did not prevent CICR. Moreover, a high concentration of caffeine, known to activate ryanodine receptors independently of Ca2+, failed to mobilize intracellular Ca2+. On the contrary, a high caffeine concentration abolished CICR by interfering with inositol 1,4,5-trisphosphate receptors (IP3Rs). Therefore, the cell-permeable IP3R antagonist 2-aminoethoxydiphenyl borate blocked the cAMP-promoted CICR. Individual CICR events in pancreatic β-cells were followed by [Ca2+]i spikes in neighboring human erythroleukemia cells, used to report secretory events in the β-cells. The results indicate that protein kinase A-mediated promotion of CICR via IP3Rs is part of the mechanism by which cAMP amplifies insulin release.

  • 8.
    Dyachok, Oleg
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Store-operated influx of Ca2+ in the pancreatic β-cells exhibits graded dependence on the filling of the endoplasmic reticulum2001In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 114, no Pt 11, p. 2179-2186Article in journal (Refereed)
    Abstract [en]

    The store-operated pathway for Ca2+ entry was studied in individual mouse pancreatic β-cells by measuring the cytoplasmic concentrations of Ca2+ ([Ca2+]i) and Mn2+ ([Mn2+]i) with the fluorescent indicator fura-2. Influx through the store-operated pathway was initially shut off by pre-exposure to 20 mM glucose, which maximally stimulates intracellular Ca2+ sequestration. To avoid interference with voltage-dependent Ca2+ entry the cells were hyperpolarized with diazoxide and the channel blocker methoxyverapamil was present. Activation of the store-operated pathway in response to Ca2+ depletion of the endoplasmic reticulum was estimated from the sustained elevation of [Ca2+]i or from the rate of increase in [Mn2+]i due to influx of these extracellular ions. Increasing concentrations of the inositol 1,4,5-trisphosphate-generating agonist carbachol or the sarco(endo)plasmatic reticulum Ca2+-ATPase inhibitor cyclopiazonic acid (CPA) cause gradual activation of the store-operated pathway. In addition, the carbachol- and CPA-induced influx of Mn2+ depended on store filling in a graded manner. The store-operated influx of Ca2+/Mn2+ was inhibited by Gd3+ and 2-aminoethoxydiphenyl borate but neither of these agents discriminated between store-operated and voltage-dependent entry. The finely tuned regulation of the store-operated mechanisms in the β-cell has direct implications for the control of membrane potential and insulin secretion.

  • 9.
    Dyachok, Oleg
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Idevall-Hagren, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sågetorp, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tian, Geng
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Wuttke, Anne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Arrieumerlou, Cecile
    Infection Biology, Biozentrum, University of Basel, Switzerland.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    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-induced cyclic AMP oscillations regulate pulsatile insulin secretion2008In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 8, no 1, p. 26-37Article in journal (Refereed)
    Abstract [en]

    Cyclic AMP (cAMP) and Ca2+ are key regulators of exocytosis in many cells, including insulin-secreting β-cells. Glucose-stimulated insulin secretion from β cells is pulsatile and involves oscillations of the cytoplasmic Ca2+ concentration ([Ca2+]i), but little is known about the detailed kinetics of cAMP signalling. Using evanescent-wave fluorescence imaging we found that glucose induces pronounced oscillations of cAMP in the sub-membrane space of single MIN6-cells and primary mouse β-cells. These oscillations were preceded and enhanced by elevations of [Ca2+]i. However, conditions raising cytoplasmic ATP could trigger cAMP elevations without accompanying [Ca2+]i rise, indicating that adenylyl cyclase activity may be controlled also by the substrate concentration. The cAMP oscillations correlated with pulsatile insulin release. Whereas elevation of cAMP enhanced secretion, inhibition of adenylyl cyclases suppressed both cAMP oscillations and pulsatile insulin release. We conclude that cell metabolism directly controls cAMP, and that glucose-induced cAMP oscillations regulate the magnitude and kinetics of insulin exocytosis.

  • 10.
    Dyachok, Oleg
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Tufveson, Gunnar
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Gylfe, Erik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Ca2+-induced Ca2+ release by activation of inositol 1,4,5-trisphosphate receptors in primary pancreatic β-cells2004In: Cell Calcium, ISSN 0143-4160, E-ISSN 1532-1991, Vol. 36, no 1, p. 1-9Article in journal (Refereed)
    Abstract [en]

    The effect of sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) inhibition on the cytoplasmic Ca2+ concentration ([Ca2+]i) was studied in primary insulin-releasing pancreatic β-cells isolated from mice, rats and human subjects as well as in clonal rat insulinoma INS-1 cells. In Ca2+-deficient medium the individual primary β-cells reacted to the SERCA inhibitor cyclopiazonic acid (CPA) with a slow rise of [Ca2+]i followed by an explosive transient elevation. The [Ca2+]i transients were preferentially observed at low intracellular concentrations of the Ca2+ indicator fura-2 and were unaffected by pre-treatment with 100 μM ryanodine. Whereas 20 mM caffeine had no effect on basal [Ca2+]i or the slow rise in response to CPA, it completely prevented the CPA-induced [Ca2+]i transients as well as inositol 1,4,5-trisphosphate-mediated [Ca2+]i transients in response to carbachol. In striking contrast to the primary β-cells, caffeine readily mobilized intracellular Ca2+ in INS-1 cells under identical conditions, and such mobilization was prevented by ryanodine pre-treatment. The results indicate that leakage of Ca2+ from the endoplasmic reticulum after SERCA inhibition is feedback-accelerated by Ca2+-induced Ca2+ release (CICR). In primary pancreatic β-cells this CICR is due to activation of inositol 1,4,5-trisphosphate receptors. CICR by ryanodine receptor activation may be restricted to clonal β-cells.

  • 11.
    Gylfe, Erik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Ca2+ signalling underlying pulsatile insulin secretion2005In: Diabetes mellitus combat the challenge, 2005, p. 96-115Chapter in book (Other scientific)
  • 12.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Department of Medical Cell Biology: Annual Report 20092010Collection (editor) (Other (popular science, discussion, etc.))
  • 13.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Department of Medical Cell Biology: Annual Report 20102011Collection (editor) (Other (popular science, discussion, etc.))
  • 14.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Department of Medical Cell Biology: Annual Report 20112012Collection (editor) (Other (popular science, discussion, etc.))
  • 15.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Department of Medical Cell Biology: Annual Report 20122013Collection (editor) (Other (popular science, discussion, etc.))
  • 16.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Department of Medical Cell Biology: Annual Report 20132014Collection (editor) (Other (popular science, discussion, etc.))
  • 17.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Glucose Control of Glucagon Secretion: There Is More to It Than K-ATP Channels2013In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, no 5, p. 1391-1393Article in journal (Other academic)
  • 18.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Glucose control of glucagon secretion: 'There's a brand-new gimmick every year'2016In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, no 2, p. 120-132Article, review/survey (Refereed)
    Abstract [en]

    Glucagon from the pancreatic alpha-cells is a major blood glucose-regulating hormone whose most important role is to prevent hypoglycaemia that can be life-threatening due to the brain's strong dependence on glucose as energy source. Lack of blood glucose-lowering insulin after malfunction or autoimmune destruction of the pancreatic beta-cells is the recognized cause of diabetes, but recent evidence indicates that diabetic hyperglycaemia would not develop unless lack of insulin was accompanied by hypersecretion of glucagon. Glucagon release has therefore become an increasingly important target in diabetes management. Despite decades of research, an understanding of how glucagon secretion is regulated remains elusive, and fundamentally different mechanisms continue to be proposed. The autonomous nervous system is an important determinant of glucagon release, but it is clear that secretion is also directly regulated within the pancreatic islets. The present review focuses on pancreatic islet mechanisms involved in glucose regulation of glucagon release. It will be argued that alpha-cell-intrinsic processes are most important for regulation of glucagon release during recovery from hypoglycaemia and that paracrine inhibition by somatostatin from the delta-cells shapes pulsatile glucagon release in hyperglycaemia. The electrically coupled beta-cells ultimately determine islet hormone pulsatility by releasing synchronizing factors that affect the alpha- and delta-cells.

  • 19.
    Gylfe, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gilon, Patrick
    Glucose regulation of glucagon secretion2014In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 103, no 1, p. 1-10Article, review/survey (Refereed)
    Abstract [en]

    Glucagon secreted by pancreatic alpha-cells is the major hyperglycemic hormone correcting acute hypoglycaemia (glucose counterregulation). In diabetes the glucagon response to hypoglycaemia becomes compromised and chronic hyperglucagonemia appears. There is increasing awareness that glucagon excess may underlie important manifestations of diabetes. However opinions differ widely how glucose controls glucagon secretion. The autonomous nervous system plays an important role in the glucagon response to hypoglycaemia. But it is clear that glucose controls glucagon secretion also by mechanisms involving direct effects on alpha-cells or indirect effects via paracrine factors released from non-alpha-cells within the pancreatic islets. The present review discusses these mechanisms and argues that different regulatory processes are involved in a glucose concentration-dependent manner. Direct glucose effects on the a-cell and autocrine mechanisms are probably most significant for the glucagon response to hypoglycaemia. During hyperglycaemia, when secretion from beta-and delta-cells is stimulated, paracrine inhibitory factors generate pulsatile glucagon release in opposite phase to pulsatile release of insulin and somatostatin. High concentrations of glucose have also stimulatory effects on glucagon secretion that tend to balance and even exceed the inhibitory influence. The latter actions might underlie the paradoxical hyperglucagonemia that aggravates hyperglycaemia in persons with diabetes.

  • 20.
    Gylfe, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Grapengiesser, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Dansk, Heléne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hellman, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    The Neurotransmitter ATP Triggers Ca2+ Responses Promoting Coordination of Pancreatic Islet Oscillations2012In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 41, no 2, p. 258-263Article in journal (Refereed)
    Abstract [en]

    Objectives: Pulsatile insulin release into the portal vein is critically dependent on entrainment of the islets in the pancreas into a common oscillatory phase. Because the pulses reflect periodic variations of the cytoplasmic Ca2+ concentration ([Ca2+](i)), we studied whether the neurotransmitters adenosine triphosphate (ATP) and acetylcholine promote synchronization of [Ca2+](i) oscillations between islets lacking contact.

    Methods: Medium-sized and small mouse islets and cell aggregates were used for measuring [Ca2+](i) with the indicator fura-2.

    Results: Exposure to acetylcholine resulted in an initial [Ca2+](i) peak followed by disappearance of the [Ca2+](i) oscillations induced by 11-mmol/L glucose. The effect of ATP was often restricted to an elusive [Ca2+](i) peak. The incidence of distinct [Ca2+](i) responses to ATP increased under conditions (accelerated superfusion, small islets, or cell aggregates) intended to counteract purinoceptor desensitization owing to intercellular accumulation of ATP. Attempts to imitate neural activity by brief (15 seconds) exposure to ATP or acetylcholine resulted in temporary synchronization of the glucose-induced [Ca2+](i) oscillations between islets lacking contact.

    Conclusions: The data support the idea that purinergic signaling has a key role for coordinating the oscillatory activity of the islets in the pancreas, reinforcing previous arguments for the involvement of nonadrenergic, noncholinergic neurons.

  • 21.
    Gylfe, Erik
    et al.
    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.
    Neurotransmitter control of islet hormone pulsatility2014In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 16, no S1, p. 102-110Article, review/survey (Refereed)
    Abstract [en]

    Pulsatile secretion is an inherent property of hormone-releasing pancreatic islet cells. This secretory pattern is physiologically important and compromised in diabetes. Neurotransmitters released from islet cells may shape the pulses in auto/paracrine feedback loops. Within islets, glucose-stimulated -cells couple via gap junctions to generate synchronized insulin pulses. In contrast, - and -cells lack gap junctions, and glucagon release from islets stimulated by lack of glucose is non-pulsatile. Increasing glucose concentrations gradually inhibit glucagon secretion by -cell-intrinsic mechanism/s. Further glucose elevation will stimulate pulsatile insulin release and co-secretion of neurotransmitters. Excitatory ATP may synchronize -cells with -cells to generate coinciding pulses of insulin and somatostatin. Inhibitory neurotransmitters from - and -cells can then generate antiphase pulses of glucagon release. Neurotransmitters released from intrapancreatic ganglia are required to synchronize -cells between islets to coordinate insulin pulsatility from the entire pancreas, whereas paracrine intra-islet effects still suffice to explain coordinated pulsatile release of glucagon and somatostatin. The present review discusses how neurotransmitters contribute to the pulsatility at different levels of integration.

  • 22.
    Hellman, Bo
    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.
    Grapengiesser, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Dansk, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Salehi, Albert
    Insulinoscillationer - en kliniskt betydelsefull rytmik. Diabetesläkemedel bör öka den pulsatila komponenten av insulinfrisättningen: Insulin oscillations -- clinically important rhythm. Antidiabetics should increase the pulsatile component of insulin release2007In: Läkartidningen, ISSN 0023-7205, Vol. 104, no 32, p. 2236-2239Article in journal (Refereed)
    Abstract [en]

    The concentration of circulating insulin oscillates with periods of 3-6 min due to pulsatile release of the hormone from the pancreas. Pulsatile insulin secretion from the individual * cell is driven by slow cycles of Ca2+ elevation due to periodic depolarisation. The Ca2+ oscillations of individual * cells in the islets of Langerhans are entrained into a common rhythm by gap junctional coupling and diffusible factors. Autonomic ganglia coordinate the oscillatory activity of the million islets in the pancreas. ATP binding to purinoceptors causes pronounced Ca2+ spikes that are important for synchronizing the *-cells within and among islets in the pancreas. Inhibition of purinergic P2Y1 receptors selectively abolishes pulsatile insulin release without reducing the average rate of secretion. The insulin oscillations are particularly important for the liver. This organ is also exposed to oscillating levels of glucagon. The latter oscillations are in opposite phase allowing maximal exposure to insulin when the glucagon concentration is at minimum.

  • 23.
    Hellman, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Salehi, Albert
    Grapengiesser, Eva
    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.
    Isolated mouse islets respond to glucose with an initial peak of glucagon release followed by pulses of insulin and somatostatin in antisynchrony with glucagon2012In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 417, no 4, p. 1219-1223Article in journal (Refereed)
    Abstract [en]

    Recent studies of isolated human islets have shown that glucose induces hormone release with repetitive pulses of insulin and somatostatin in antisynchrony with those of glucagon. Since the mouse is the most important animal model we studied the temporal relation between hormones released from mouse islets. Batches of 5-10 islets were perifused and the hormones measured with radioimmunoassay in 30 s fractions. At 3 mM glucose, hormone secretion was stable with no detectable pulses of glucagon, insulin or somatostatin. Increase of glucose to 20 mM resulted in an early secretory phase with a glucagon peak followed by peaks of insulin and somatostatin. Subsequent hormone secretion was pulsatile with a periodicity of 5 min. Cross-correlation analyses showed that the glucagon pulses were antisynchronous to those of insulin and somatostatin. In contrast to the marked stimulation of insulin and somatostatin secretion, the pulsatility resulted in inhibition of overall glucagon release. The cytoarchitecture of mouse islets differs from that of human islets, which may affect the interactions between the hormone-producing cells. Although indicating that paracrine regulation is important for the characteristic patterns of pulsatile hormone secretion, the mouse data mimic those of human islets with more than 20-fold variations of the insulin/glucagon ratio. The data indicate that the mouse serves as an appropriate animal model for studying the temporal relation between the islet hormones controlling glucose production in the liver.

  • 24.
    Idevall Hagren, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Barg, Sebastian
    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.
    cAMP Mediators of Pulsatile Insulin Secretion from Glucose-stimulated Single β-Cells2010In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 30, p. 23005-23016Article in journal (Refereed)
    Abstract [en]

    Pulsatile insulin release from glucose-stimulated beta-cells is driven by oscillations of the Ca2+ and cAMP concentrations in the subplasma membrane space ([Ca2+](pm) and [cAMP](pm)). To clarify mechanisms by which cAMP regulates insulin secretion, we performed parallel evanescent wave fluorescence imaging of [cAMP](pm), [Ca2+](pm), and phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the plasma membrane. This lipid is formed by autocrine insulin receptor activation and was used to monitor insulin release kinetics from single MIN6 beta-cells. Elevation of the glucose concentration from 3 to 11 mM induced, after a 2.7-min delay, coordinated oscillations of [Ca2+](pm), [cAMP](pm), and PIP3. Inhibitors of protein kinase A (PKA) markedly diminished the PIP3 response when applied before glucose stimulation, but did not affect already manifested PIP3 oscillations. The reduced PIP3 response could be attributed to accelerated depolarization causing early rise of [Ca2+](pm) that preceded the elevation of [cAMP](pm). However, the amplitude of the PIP3 response after PKA inhibition was restored by a specific agonist to the cAMP-dependent guanine nucleotide exchange factor Epac. Suppression of cAMP formation with adenylyl cyclase inhibitors reduced already established PIP3 oscillations in glucose-stimulated cells, and this effect was almost completely counteracted by the Epac agonist. In cells treated with small interfering RNA targeting Epac2, the amplitudes of the glucose-induced PIP3 oscillations were reduced, and the Epac agonist was without effect. The data indicate that temporal coordination of the triggering [Ca2+](pm) and amplifying [cAMP](pm) signals is important for glucose-induced pulsatile insulin release. Although both PKA and Epac2 partake in initiating insulin secretion, the cAMP dependence of established pulsatility is mediated by Epac2.

  • 25.
    Li, Jia
    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.
    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.
    Oscillations of sub-membrane ATP in glucose-stimulated beta cells depend on negative feedback from Ca2+2013In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, no 7, p. 1577-1586Article in journal (Refereed)
    Abstract [en]

    ATP links changes in glucose metabolism to electrical activity, Ca2+ signalling and insulin secretion in pancreatic beta cells. There is evidence that beta cell metabolism oscillates, but little is known about ATP dynamics at the plasma membrane, where regulation of ion channels and exocytosis occur. The sub-plasma-membrane ATP concentration ([ATP](pm)) was recorded in beta cells in intact mouse and human islets using total internal reflection microscopy and the fluorescent reporter Perceval. Glucose dose-dependently increased [ATP](pm) with half-maximal and maximal effects at 5.2 and 9 mmol/l, respectively. Additional elevations of glucose to 11 to 20 mmol/l promoted pronounced [ATP](pm) oscillations that were synchronised between neighbouring beta cells. [ATP](pm) increased further and the oscillations disappeared when voltage-dependent Ca2+ influx was prevented. In contrast, K+-depolarisation induced prompt lowering of [ATP](pm). Simultaneous recordings of [ATP](pm) and the sub-plasma-membrane Ca2+ concentration ([Ca2+](pm)) during the early glucose-induced response revealed that the initial [ATP](pm) elevation preceded, and was temporarily interrupted by the rise of [Ca2+](pm). During subsequent glucose-induced oscillations, the increases of [Ca2+](pm) correlated with lowering of [ATP](pm). In beta cells, glucose promotes pronounced oscillations of [ATP](pm), which depend on negative feedback from Ca2+ (.) The bidirectional interplay between these messengers in the sub-membrane space generates the metabolic and ionic oscillations that underlie pulsatile insulin secretion.

  • 26.
    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.

  • 27.
    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.

  • 28.
    Lindholm, Cecilia K
    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.
    Zhang, Weigu
    Samelson, Lawrence E
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Requirement of the Src homology 2 domain protein Shb for T cell receptor-dependent activation of the Interleukin-2 gene nuclear factor for activation of T cells element in Jurkat T cells1999In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 274, no 39, p. 28050-28057Article in journal (Refereed)
    Abstract [en]

    Stimulation of the T cell antigen receptor (TCR) induces tyrosine phosphorylation of numerous intracellular proteins. We have recently investigated the role of the adaptor protein Shb in the early events of T cell signaling and observed that Shb associates with Grb2, linker for activation of T cells (LAT) and the TCR zeta-chain in Jurkat cells. We now report that Shb also associates with phospholipase C-gamma1 (PLC-gamma1) in these cells. Overexpression of Src homology 2 domain defective Shb caused diminished phosphorylation of LAT and consequently the activation of mitogen-activated protein kinases was decreased upon TCR stimulation. In addition, the Shb mutant also blocked phosphorylation of PLC-gamma1 and the increase in cytoplasmic Ca(2+) following TCR stimulation. Nuclear factor for activation of T cells is a major target for Ras and calcium signaling pathways in T cells following TCR stimulation, and the overexpression of the mutant Shb prevented TCR-dependent activation of the nuclear factor for activation of T cells. Consequently, endogenous interleukin-2 production was decreased under these conditions. The results indicate a role for Shb as a link between the TCR and downstream signaling events involving LAT and PLC-gamma1 and resulting in the activation of transcription of the interleukin-2 gene.

  • 29.
    Liu, Yi-Jia
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Vieira, Elaine
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic Alfa-cell2004In: Cell Calcium, ISSN 0143-4160, E-ISSN 1532-1991, no 35, p. 357-365Article in journal (Refereed)
  • 30.
    Liu, Y-J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Grapengiesser, Eva
    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.
    Hellman, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Glucose induces oscillations of cytoplasmic Ca2+, Sr2+ and Ba2+ in pancreatic beta-cells without participation of the thapsigargin-sensitive store1995In: Cell Calcium, Vol. 18, no 2, p. 165-173Article in journal (Refereed)
    Abstract [en]

    Individual pancreatic beta -cells were used to study the glucose effects on the handling of Ca2+, Sr2+ and Ba2+. In extracellular medium containing one of these ions, single beta -cells responded to 11 mM glucose with large amplitude oscillations in cytoplasmic Ca2+, Sr2+ or Ba2+ with indistinguishable average frequencies (0.30-0.33/min). The oscillations disappeared after hyperpolarization with 400 microM diazoxide. Under such hyperpolarization, glucose stimulated the sequestration of Ca2+ and Sr2+ but not of repetitively mobilized by consecutive exposures to 100 microM carbachol. A 2-3 min exposure to 100 nM of the intracellular Ca(2+)-ATPase inhibitor thapsigargin also mobilized Ca2+ and Sr2+ and irreversibly abolished subsequent release by carbachol. However, thapsigargin did not prevent the large amplitude oscillations in Ca2+, Sr2+ or Ba2+ under non-hyperpolarizing conditions although the frequency of the Ca2+ oscillations was almost doubled. The results indicate that the slow oscillatory behavior of glucose-stimulated individual beta -cells does not depend on inositol 1,4,5-trisphosphate mediated release of intracellular Ca2+.

  • 31. Marie, JC
    et al.
    Bailbe, D
    Gylfe, Erik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Portha, B
    Defective glucose-dependent cytosolic Ca2+ handling in islets of GK and nSTZ rat models of type 2 diabetes2001In: J Endocrinol, Vol. 169, p. 169-Article in journal (Refereed)
  • 32.
    Ridefelt, Peter
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Bjorklund, E
    Åkerström, Göran
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Olsson, MJ
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Rastad, Jonas
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Gylfe, Erik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Ca2+-induced Ca2+ oscillations in parathyroid cells1995In: Biochem Biophys Rew Commun, Vol. 215, p. 903-Article in journal (Refereed)
  • 33.
    Ridelfelt, Peter
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Gylfe, Erik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Åkerström, Göran
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Ljunghall, Sverker
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Rastad, Jonas
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Effects of the antihypercalcemic drugs gallium nitrate and pamidronate on hormone release of pathologic human parathyroid cells1995In: Surgery, Vol. 117, p. 56-Article in journal (Refereed)
  • 34.
    Sakwe, Amos M
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rask, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gylfe, Erik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Protein Kinase C Modulates Agonist-sensitive Release of Ca2+ from Internal Stores in HEK293 Cells Overexpressing the Calcium Sensing Receptor.2005In: J Biol Chem, ISSN 0021-9258, Vol. 280, no 6, p. 4436-41Article in journal (Refereed)
  • 35.
    Salehi, Albert
    et al.
    Institutionen för klinisk vetenskap, Malmö universitetssjukhus, Lunds universitet.
    Vieira, Elaine
    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 stimulation of glucagon secretion by high glucose concentrations2006In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 55, no 8, p. 2318-2323Article in journal (Refereed)
    Abstract [en]

    Hypersecretion of glucagon contributes to the dysregulation of glucose homeostasis in diabetes. To clarify the underlying mechanism, glucose-regulated glucagon secretion was studied in mouse pancreatic islets and clonal hamster In-R1-G9 glucagon-releasing cells. Apart from the well-known inhibition of secretion with maximal effect around 7 mmol/l glucose, we discovered that mouse islets showed paradoxical stimulation of glucagon release at 25-30 mmol/l and In-R1-G9 cells at 12-20 mmol/l sugar. Whereas glucagon secretion in the absence of glucose was inhibited by hyperpolarization with diazoxide, this agent tended to further enhance secretion stimulated by high concentrations of the sugar. Because U-shaped dose-response relationships for glucose-regulated glucagon secretion were observed in normal islets and in clonal glucagon-releasing cells, both the inhibitory and stimulatory components probably reflect direct effects on the a-cells. Studies of isolated mouse a-cells indicated that glucose inhibited glucagon secretion by lowering the cytoplasmic Ca2+ concentration. However, stimulation of glucagon release by high glucose concentrations did not require elevation of Ca2+, indicating involvement of novel mechanisms in glucose regulation of glucagon secretion. A U-shaped dose-response relationship for glucose-regulated glucagon secretion may explain why diabetic patients with pronounced hyperglycemia display paradoxical hyperglucagonemia.

  • 36.
    Tengholm, Anders
    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.
    cAMP signalling in insulin and glucagon secretion2017In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 19, p. 42-53Article, review/survey (Refereed)
    Abstract [en]

    The second messenger archetype cAMP is one of the most important cellular signalling molecules with central functions including the regulation of insulin and glucagon secretion from the pancreatic - and -cells, respectively. cAMP is generally considered as an amplifier of insulin secretion triggered by Ca2+ elevation in the -cells. Both messengers are also positive modulators of glucagon release from -cells, but in this case cAMP may be the important regulator and Ca2+ have a more permissive role. The actions of cAMP are mediated by protein kinase A (PKA) and the guanine nucleotide exchange factor Epac. The present review focuses on how cAMP is regulated by nutrients, hormones and neural factors in - and -cells via adenylyl cyclase-catalysed generation and phosphodiesterase-mediated degradation. We will also discuss how PKA and Epac affect ion fluxes and the secretory machinery to transduce the stimulatory effects on insulin and glucagon secretion. Finally, we will briefly describe disturbances of the cAMP system associated with diabetes and how cAMP signalling can be targeted to normalize hypo- and hypersecretion of insulin and glucagon, respectively, in diabetic patients.

  • 37.
    Thore, Sophia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Dyachok, Oleg
    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.
    Feedback activation of phospholipase C via intracellular mobilization and store-operated influx of Ca2+ in insulin-secreting β-cells2005In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 118, no Pt 19, p. 4463-4471Article in journal (Refereed)
    Abstract [en]

    Phospholipase C (PLC) regulates various cellular processes by catalyzing the formation of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol from phosphatidylinositol-4,5-bisphosphate (PIP2). Here, we have investigated the influence of Ca2+ on receptor-triggered PLC activity in individual insulin-secreting β-cells. Evanescent wave microscopy was used to record PLC activity using green fluorescent protein (GFP)-tagged PIP2/IP3-binding pleckstrin homology domain from PLCδ1, and the cytoplasmic Ca2+ concentration ([Ca2+]i) was simultaneously measured using the indicator Fura Red. Stimulation of MIN6 β-cells with the muscarinic-receptor agonist carbachol induced rapid and sustained PLC activation. By contrast, only transient activation was observed after stimulation in the absence of extracellular Ca2+ or in the presence of the non-selective Ca2+ channel inhibitor La3+. The Ca2+-dependent sustained phase of PLC activity did not require voltage-gated Ca2+ influx, as hyperpolarization with diazoxide or direct Ca2+ channel blockade with nifedipine had no effect. Instead, the sustained PLC activity was markedly suppressed by the store-operated channel inhibitors 2-APB and SKF96365. Depletion of intracellular Ca2+ stores with the sarco(endo)plasmic reticulum Ca2+-ATPase inhibitors thapsigargin or cyclopiazonic acid abolished Ca2+ mobilization in response to carbachol, and strongly suppressed the PLC activation in Ca2+-deficient medium. Analogous suppressions were observed after loading cells with the Ca2+ chelator BAPTA. Stimulation of primary mouse pancreatic β-cells with glucagon elicited pronounced [Ca2+]i spikes, reflecting protein kinase A-mediated activation of Ca2+-induced Ca2+ release via IP3 receptors. These [Ca2+]i spikes were found to evoke rapid and transient activation of PLC. Our data indicate that receptor-triggered PLC activity is enhanced by positive feedback from Ca2+ entering the cytoplasm from intracellular stores and via store-operated channels in the plasma membrane. Such amplification of receptor signalling should be important in the regulation of insulin secretion by hormones and neurotransmitters.

  • 38.
    Tian, Geng
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sandler, Stellan
    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- and Hormone-Induced cAMP Oscillations in α- and β-Cells Within Intact Pancreatic Islets2011In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 5, p. 1535-1543Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE

    cAMP is a critical messenger for insulin and glucagon secretion from pancreatic beta- and alpha-cells, respectively. Dispersed beta-cells show cAMP oscillations, but the signaling kinetics in cells within intact islets of Langerhans is unknown.

    RESEARCH DESIGN AND METHODS

    The subplasma-membrane cAMP concentration ([cAMP](pm)) was recorded in alpha-and beta-cells in the mantle of intact mouse pancreatic islets using total internal reflection microscopy and a fluorescent translocation biosensor. Cell identification was based on the opposite effects of adrenaline on cAMP in alpha- and beta-cells.

    RESULTS

    In islets exposed to 3 mmol/L glucose, [cAMP](pm) was low and stable. Glucagon and glucagon-like peptide-1(7-36)-amide (GLP-1) induced dose-dependent elevation of [cAMP](pm), often with oscillations synchronized among beta-cells. Whereas glucagon also induced [cAMP](pm) oscillations in most alpha-cells, < 20% of the alpha-cells responded to GLP-1. Elevation of the glucose concentration to 11-30 mmol/L in the absence of hormones induced slow [cAMP](pm) oscillations in both alpha- and beta-cells. These cAMP oscillations were coordinated with those of the cytoplasmic Ca2+ concentration ([Ca2+](i)) in the beta-cells but not caused by the changes in [Ca2+](i) . The transmembrane adenylyl cyclase (AC) inhibitor 2'5'-dideoxyadenosine suppressed the glucose- and hormone-induced [cAMP](pm) elevations, whereas the preferential inhibitors of soluble AC, KH7, and 1,3,5(10)-estratrien-2,3,17-beta-triol perturbed cell metabolism and lacked effect, respectively.

    CONCLUSIONS

    Oscillatory [cAMP](pm) signaling in secretagogue-stimulated beta-cells is maintained within intact islets and depends on transmembrane AC activity. The discovery of glucose- and glucagon-induced [cAMP](pm) oscillations in alpha-cells indicates the involvement of cAMP in the regulation of pulsatile glucagon secretion.

  • 39.
    Tian, Geng
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tepikin, Alexei V.
    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.
    cAMP Induces Stromal Interaction Molecule 1 (STIM1) Puncta but neither Orai1 Protein Clustering nor Store-operated Ca2+ Entry (SOCE) in Islet Cells2012In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, no 13, p. 9862-9872Article in journal (Refereed)
    Abstract [en]

    The events leading to the activation of store-operated Ca2+ entry (SOCE) involve Ca2+ depletion of the endoplasmic reticulum (ER) resulting in translocation of the transmembrane Ca2+ sensor protein, stromal interaction molecule 1 (STIM1), to the junctions between ER and the plasma membrane where it binds to the Ca2+ channel protein Orai1 to activate Ca2+ influx. Using confocal and total internal reflection fluorescence microscopy, we studied redistribution kinetics of fluorescence-tagged STIM1 and Orai1 as well as SOCE in insulin-releasing beta-cells and glucagon-secreting alpha-cells within intact mouse and human pancreatic islets. ER Ca2+ depletion triggered accumulation of STIM1 puncta in the subplasmalemmal ER where they co-clustered with Orai1 in the plasma membrane and activated SOCE. Glucose, which promotes Ca2+ store filling and inhibits SOCE, stimulated retranslocation of STIM1 to the bulk ER. This effect was evident at much lower glucose concentrations in alpha-than in beta-cells consistent with involvement of SOCE in the regulation of glucagon secretion. Epinephrine stimulated subplasmalemmal translocation of STIM1 in beta-cells and retranslocation in beta-cells involving raising and lowering of cAMP, respectively. The cAMP effect was mediated both by protein kinase A and exchange protein directly activated by cAMP. However, the cAMP-induced STIM1 puncta did not co-cluster with Orai1, and there was no activation of SOCE. STIM1 translocation can consequently occur independently of Orai1 clustering and SOCE.

  • 40.
    Vieira, Elaine
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Liu, Yi-Jia
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Involvement of Alfa1 and Beta-adrenoceptors in adrenaline stimulation fo the glucagon-secreting mouse Alfa-cell2004In: Naunyn-Schmiedeberg´s Arch Pharmacol, no 369, p. 179-183Article in journal (Refereed)
  • 41.
    Vieira, Elaine
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Salehi, Albert
    Institutionen för klinisk vetenskap, Malmö universitetssjukhus, Lunds universitet.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells2007In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 50, no 2, p. 370-379Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis The mechanisms by which glucose regulates glucagon release are poorly understood. The present study aimed to clarify the direct effects of glucose on the glucagon-releasing alpha cells and those effects mediated by paracrine islet factors.

    Materials and methods Glucagon, insulin and somatostatin release were measured from incubated mouse pancreatic islets and the cytoplasmic Ca2+ concentration ([Ca2+](i)) recorded in isolated mouse alpha cells.

    Results Glucose inhibited glucagon release with maximal effect at 7 mmol/l. Since this concentration corresponded to threshold stimulation of insulin secretion, it is unlikely that inhibition of glucagon secretion is mediated by beta cell factors. Although somatostatin secretion data seemed consistent with a role of this hormone in glucose-inhibited glucagon release, a somatostatin receptor type 2 antagonist stimulated glucagon release without diminishing the inhibitory effect of glucose. In islets exposed to tolbutamide plus 8 mmol/l K+, glucose inhibited glucagon secretion without stimulating the release of insulin and somatostatin, indicating a direct inhibitory effect on the alpha cells that was independent of ATP-sensitive K+ channels. lucose lowered [Ca2+](i) of individual alpha cells independently of somatostatin and beta cell factors (insulin, Zn2+ and gamma-aminobutyric acid). Glucose suppression of glucagon release was prevented by inhibitors of the sarco(endo)plasmic reticulum Ca2+-ATPase, which abolished the [Ca2+](i)-lowering effect of glucose on isolated alpha cells.

    Conclusions/interpretation Beta cell factors or somatostatin do not seem to mediate glucose inhibition of glucagon secretion. We instead propose that glucose has a direct inhibitory effect on mouse alpha cells by suppressing a depolarising Ca2+ store-operated current.

  • 42.
    Yang, Mingyu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Idevall-Hagren, Olof
    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.
    A genetically encoded low-affinity Ca2+ sensor unmasks autocrine purinergic signalling in beta cells2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, p. S196-S197Article in journal (Other academic)
  • 43.
    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.))
  • 44.
    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)
  • 45.
    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)
  • 46.
    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.

  • 47.
    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.))
  • 48.
    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 - 48 of 48
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