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  • 1.
    Birnir, Bryndis
    et al.
    Department of Physiology, UCLA School of Medicine.
    Loo, D D
    Wright, E M
    Voltage-clamp studies of the Na+/glucose cotransporter cloned from rabbit small intestine.1991In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 418, no 1-2, p. 79-85Article in journal (Refereed)
    Abstract [en]

    Inward Na+ currents associated with the cloned intestinal Na+/glucose cotransporter expressed in Xenopus oocytes have been studied using the two-microelectrode voltage-clamp method. The steady-state current/voltage relations showed voltage-dependent (Vm from +20 to -75 mV) and relatively voltage-independent (Vm from -75 to -150 mV) regions. The apparent Imax for Na+ and glucose increased with negative membrane potentials, and the apparent K0.5 for glucose (K(Glc)0.5) depended on Vm and [Na]o. Increasing [Na]o from 7 to 110 mmol/l had the same effect in decreasing K(Glc)0.5 from 0.44 to 0.03 mmol/l as increasing the Vm from -40 to -150 mV. The I/V curves under saturating conditions (20 mmol/l external sugars and 110 mmol/l [Na]o) were identical for D-glucose, D-galactose, alpha-methyl D-glucopyranoside and 3-O-methyl D-glucoside. The specificity of the cotransporter for sugars was: D-glucose, D-galactose, alpha-methyl D-glucopyranoside greater than 3-O-methyl D-glucoside much greater than D-xylose greater than D-allose much greater than D-mannose. Ki for phlorizin (approximately 10 mumol/l) was independent of Vm at saturating [Na]o. We conclude that a variety of sugars are transported by the cloned Na+/glucose cotransporter at the same maximal rate and that membrane potential affects both the maximal current and the apparent K0.5 of the cotransporter for Na+ and glucose.

  • 2.
    Broman, Lars Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Karolinska Univ Hosp, Dept Pediat Perioperat Med & Intens Care, ECMO Ctr Karolinska, S-17176 Stockholm, Sweden.; Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden .
    Carlström, Mattias
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden.
    Källskog, Örjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Wolgast, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Effect of nitric oxide on renal autoregulation during hypothermia in the rat.2017In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 469, no 5-6, p. 669-680Article in journal (Refereed)
    Abstract [en]

    Hypothermia-induced reduction of metabolic rate is accompanied by depression of both glomerular perfusion and filtration. The present study investigated whether these changes are linked to changes in renal autoregulation and nitric oxide (NO) signalling. During hypothermia, renal blood flow (RBF) and glomerular filtration rate (GFR) were reduced and urine production was increased, and this was linked with reduced plasma cGMP levels and increased renal vascular resistance. Although stimulation of NO production decreased vascular resistance, blood pressure and urine flow, intravenous infusion of the NO precursor L-arginine or the NO donor sodium nitroprusside did not alter RBF or GFR. In contrast, inhibition of NO synthesis by N(w)-nitro-L-arginine led to a further decline in both parameters. Functional renal autoregulation was apparent at both temperatures. Below the autoregulatory range, RBF in both cases increased in proportion to the perfusion ±pressure, although, the slope of the first ascending limb of the pressure-flow relationship was lower during hypothermia. The main difference was rather that the curves obtained during hypothermia levelled off already at a RBF of 3.9 ± 0.3 mL/min then remained stable throughout the autoregulatory pressure range, compared to 7.6 ± 0.3 mL/min during normothermia. This was found to be due to a threefold increase in, primarily, the afferent arteriolar resistance from 2.6 to 7.5 mmHg min mL(-1). Infusion of sodium nitroprusside did not significantly affect RBF during hypothermia, although a small increase at pressures below the autoregulatory range was observed. In conclusion, cold-induced rise in renal vascular resistance results from afferent arteriolar vasoconstriction by the autoregulatory mechanism, setting RBF and GFR in proportion to the metabolic rate, which cannot be explained by reduced NO production alone.

  • 3. Eckhard, A
    et al.
    Dos Santos, A
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Bassiouni, M
    Arnold, H
    Gleiser, C
    Hirt, B
    Harteneck, C
    Müller, M
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Löwenheim, H
    Regulation of the perilymphatic-endolymphatic water shunt in the cochlea by membrane translocation of aquaporin-52015In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 467, no 12, p. 2571-2588Article in journal (Refereed)
    Abstract [en]

    Volume homeostasis of the cochlear endolymph depends on radial and longitudinal endolymph movements (LEMs). LEMs measured in vivo have been exclusively recognized under physiologically challenging conditions, such as experimentally induced alterations of perilymph osmolarity or endolymph volume. The regulatory mechanisms that adjust LEMs to the physiological requirements of endolymph volume homeostasis remain unknown. Here, we describe the formation of an aquaporin (AQP)-based "water shunt" during the postnatal development of the mouse cochlea and its regulation by different triggers. The final complementary expression pattern of AQP5 (apical membrane) and AQP4 (basolateral membrane) in outer sulcus cells (OSCs) of the cochlear apex is acquired at the onset of hearing function (postnatal day (p)8-p12). In vitro, hyperosmolar perfusion of the perilymphatic fluid spaces or the administration of the muscarinic agonist pilocarpine in cochlear explants (p14) induced the translocation of AQP5 channel proteins into the apical membranes of OSCs. AQP5 membrane translocation was blocked by the muscarinic antagonist atropine. The muscarinic M3 acetylcholine (ACh) receptor (M3R) was identified in murine OSCs via mRNA expression, immunolabeling, and in vitro binding studies using an M3R-specific fluorescent ligand. Finally, the water shunt elements AQP4, AQP5, and M3R were also demonstrated in OSCs of the human cochlea. The regulation of the AQP4/AQP5 water shunt in OSCs of the cochlear apex provides a molecular basis for regulated endolymphatic volume homeostasis. Moreover, its dysregulation or disruption may have pathophysiologic implications for clinical conditions related to endolymphatic hydrops, such as Ménière's disease.

  • 4. Eckhard, A
    et al.
    Müller, M
    Salt, A
    Smolders, J
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Löwenheim, H
    Water permeability of the mammalian cochlea: functional features of an aquaporin-facilitated water shunt at the perilymph-endolymph barrier2014In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 466, no 10, p. 1963-1985Article in journal (Refereed)
    Abstract [en]

    The cochlear duct epithelium (CDE) constitutes a tight barrier that effectively separates the inner ear fluids, endolymph and perilymph, thereby maintaining distinct ionic and osmotic gradients that are essential for auditory function. However, in vivo experiments have demonstrated that the CDE allows for rapid water exchange between fluid compartments. The molecular mechanism governing water permeation across the CDE remains elusive. We computationally determined the diffusional (P D) and osmotic (P f) water permeability coefficients for the mammalian CDE based on in silico simulations of cochlear water dynamics integrating previously derived in vivo experimental data on fluid flow with expression sites of molecular water channels (aquaporins, AQPs). The P D of the entire CDE (P D = 8.18 × 10(-5) cm s(-1)) and its individual partitions including Reissner's membrane (P D = 12.06 × 10(-5) cm s(-1)) and the organ of Corti (P D = 10.2 × 10(-5) cm s(-1)) were similar to other epithelia with AQP-facilitated water permeation. The P f of the CDE (P f = 6.15 × 10(-4) cm s(-1)) was also in the range of other epithelia while an exceptionally high P f was determined for an epithelial subdomain of outer sulcus cells in the cochlear apex co-expressing AQP4 and AQP5 (OSCs; P f = 156.90 × 10(-3) cm s(-1)). The P f/P D ratios of the CDE (P f/P D = 7.52) and OSCs (P f/P D = 242.02) indicate an aqueous pore-facilitated water exchange and reveal a high-transfer region or "water shunt" in the cochlear apex. This "water shunt" explains experimentally determined phenomena of endolymphatic longitudinal flow towards the cochlear apex. The water permeability coefficients of the CDE emphasise the physiological and pathophysiological relevance of water dynamics in the cochlea in particular for endolymphatic hydrops and Ménière's disease.

  • 5. Gromada, J
    et al.
    Ding, W G
    Barg, S
    Renström, E
    Rorsman, P
    Multisite regulation of insulin secretion by cAMP-increasing agonists: evidence that glucagon-like peptide 1 and glucagon act via distinct receptors.1997In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 434, no 5, p. 515-24Article in journal (Refereed)
    Abstract [en]

    The mechanisms by which glucagon-like peptide 1(7-36)amide (GLP-1[7-36]amide) potentiates insulin secretion were investigated by measurements of whole-cell K+ and Ca2+ currents, membrane potential, the cytoplasmic Ca2+ concentration ([Ca2+]i) and exocytosis in mouse pancreatic B-cells. GLP-1(7-36)amide (10 nM) stimulated glucose-induced (10 mM) electrical activity in intact pancreatic islets. The effect was manifested as a 34% increase in the duration of the bursts of action potentials and a corresponding 28% shortening of the silent intervals. GLP-1(7-36)amide had no effect on the electrical activity at subthreshold glucose concentrations (< or = 6.5 mM). In cultured B-cells, GLP-1(7-36)amide produced a decrease of the whole-cell ATP-sensitive K+ (KATP) conductance remaining at 5 mM glucose by approximately 30%. This effect was associated with membrane depolarization and the initiation of electrical activity. GLP-1(7-36)amide produced a protein-kinase-A-(PKA-) and glucose-dependent fourfold potentiation of Ca(2+)-induced exocytosis whilst only increasing the Ca2+ current marginally. The stimulatory action of GLP-1(7-36)amide on exocytosis was mimicked by the pancreatic hormone glucagon and exendin-4, a GLP-1 receptor agonist. Whereas the stimulatory action of GLP-1(7-36)amide could be antagonized by exendin-(9-39), this peptide did not interfere with the ability of glucagon to stimulate exocytosis. We suggest that GLP-1(7-36)amide and glucagon stimulate insulin secretion by binding to distinct receptors. The GLP-1(7-36)amide-induced stimulation of electrical activity and Ca2+ influx can account for (maximally) a doubling of insulin secretion. The remainder of its stimulatory action results from a cAMP/PKA-dependent potentiation of Ca(2+)-dependent exocytosis exerted at a stage distal to the elevation of [Ca2+]i.

  • 6.
    Norman, Holly
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Nordquist, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Andersson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Ansved, Tor
    Tang, Xiaorui
    Dworkin, Barry
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Impact of post-synaptic block of neuromuscular transmission, muscle unloading and mechanical ventilation on skeletal muscle protein and mRNA expression2006In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 453, no 1, p. 53-66Article in journal (Refereed)
    Abstract [en]

    To analyse mechanisms of muscle wasting in intensive care unit patients, we developed an experimental model where rats were pharmacologically paralysed by post-synaptic block of neuromuscular transmission (NMB) and mechanically ventilated for 9 2 days. Specific interest was focused on the effects on protein and mRNA expression of sarcomeric proteins, i.e., myosin heavy chain (MyHC), actin, myosin-binding protein C (MyBP-C) and myosin-binding protein H (MyBP-H) in fast- and slow-twitch limb, respiratory and masticatory muscles. Muscle-specific differences were observed in response to NMB at both the protein and mRNA levels. At the protein level, a decreased MyHC-to-actin ratio was observed in all muscles excluding the diaphragm, whereas at the mRNA level a decreased expression of the dominating MyHC isoform(s) was observed in the hind limb and intercostal muscles, but not in the diaphragm and masseter muscles. MyBP-C mRNA expression was decreased in the limb muscles, but it otherwise remained unaffected. MyBP-H conversely increased in all muscles. Furthermore, we found myofibrillar protein and mRNA expression to be affected differently when comparing NMB; animals with peripherally denervated (DEN) ambulatory rats. We report that NMB; has both a larger and different impact on muscle, at the protein and mRNA levels, than DEN has.

  • 7.
    Ochala, Julien
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology. Muscle Cell Physiology Laboratory, Department of Physical Medicine and RehabilitationSpaulding Rehabilitation Hospital and Harvard Medical School.; Equipe INSERM- ERM 207 Motricité-Plasticité, Faculté des Sciences du SportUniversité de Bourgogne .
    Dorer, D. J.
    Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA.
    Frontera, W. R.
    Muscle Cell Physiology Laboratory, Department of Physical Medicine and RehabilitationSpaulding Rehabilitation Hospital and Harvard Medical School.
    Krivickas, L. S.
    Muscle Cell Physiology Laboratory, Department of Physical Medicine and RehabilitationSpaulding Rehabilitation Hospital and Harvard Medical School.
    Single skeletal muscle fiber behavior after a quick stretch in young and older men: a possible explanation of the relative preservation of eccentric force in old age2006In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 452, no 4, p. 464-470Article in journal (Refereed)
    Abstract [en]

    The origins of the smaller age-related decrease in eccentric force compared to isometric and concentric conditions in vivo remain unclear. Could this originate from contractile elements of muscle cells? The main intent of the current investigation was to assess the force behavior of muscle cells with aging, during lengthening. Chemically skinned single muscle fibers (n=235) from m. vastus lateralis of six young (mean age 31.6 years) and six older men (mean age 66.1 years) were maximally activated with pCa 4.5 at 15 degrees C. Maximal isometric force and cross-sectional area were measured allowing the calculation of the tension (T-0). A quick stretch (2 nm per half-sarcomere length) was applied and caused an immediate increase in tension followed by a decrease and a secondary delayed and transient rise in tension (phase 3); finally, the tension recovered a steady state value (phase 4). The tension enhancements during phase 3 (Delta T (3)) and phase 4 (Delta T (4)) were evaluated. The myosin heavy-chain isoform composition of each single fiber was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Delta T (3) and Delta T (4) were preserved in older men for both type I and IIa fibers despite a reduction in T-0. Therefore, the age-related preservation of the tension increments after a quick stretch in single muscle fibers could explain in part the smaller decrease in force during eccentric contractions compared to isometric and concentric conditions in vivo with aging usually observed.

  • 8.
    Ochala, Julien
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Radell, Peter J
    Eriksson, Lars I
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    EMD 57033 partially reverses ventilator-induced diaphragm muscle fibre calcium desensitisation2010In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 459, no 3, p. 475-483Article in journal (Refereed)
    Abstract [en]

    In critically ill patients, ventilator-induced diaphragm muscle fibre dysfunction (VIDD) contributes to weaning problems, increasing hospitalisation time and related costs. VIDD pathophysiology remains partially unknown, especially the characterisation of the contractile dysfunction. In the present study, it was hypothesised that Ca(2+) activation is affected during VIDD. Ca(2+) sensitivity of contraction was therefore evaluated at the single skinned diaphragm muscle fibre level in piglets randomised into sham operation or 5-day mechanical ventilation. Ca(2+) sensitivities of force and stiffness in fibres were significantly impaired in all mechanically ventilated piglets compared with sham-operated controls, suggesting a less efficient Ca(2+) activation of cells, i.e. a lower relative number of strongly attached cross-bridges for each sub-maximal concentration of Ca(2+). In an attempt to test whether this negative effect of VIDD is reversible, single muscle fibres were exposed to the EMD 57033 Ca(2+) sensitiser. EMD 57033 (30 microM) improved the Ca(2+) sensitivity of force and stiffness in fibres from animals that were mechanically ventilated for 5 days as well as in sham-operated piglets. Thus, EMD 57033 partly restored the Ca(2+) activation of cells, reducing VIDD. This finding offers a strong basis for evaluating the effect of Ca(2+) sensitisers on diaphragm function in vivo.

  • 9. Olofsson, Charlotta S
    et al.
    Göpel, Sven O
    Barg, Sebastian
    Galvanovskis, Juris
    Ma, Xiaosong
    Salehi, Albert
    Rorsman, Patrik
    Eliasson, Lena
    Fast insulin secretion reflects exocytosis of docked granules in mouse pancreatic B-cells.2002In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 444, no 1-2, p. 43-51Article in journal (Refereed)
    Abstract [en]

    A readily releasable pool (RRP) of granules has been proposed to underlie the first phase of insulin secretion. In the present study we combined electron microscopy, insulin secretion measurements and recordings of cell capacitance in an attempt to define this pool ultrastructurally. Mouse pancreatic B-cells contain approximately 9,000 granules, of which 7% are docked below the plasma membrane. The number of docked granules was reduced by 30% (200 granules) during 10 min stimulation with high K+. This stimulus depolarized the cell to -10 mV, elevated cytosolic [Ca2+] ([Ca2+](i)) from a basal concentration of 130 nM to a peak of 1.3 microM and released 0.5 ng insulin/islet, corresponding to 200-300 granules/cell. The Ca2+ transient decayed towards the prestimulatory concentration within approximately 200 s, presumably reflecting Ca2+ channel inactivation. Renewed stimulation with high K+ failed to stimulate insulin secretion when applied in the absence of glucose. The size of the RRP, derived from the insulin measurements, is similar to that estimated from the increase in cell capacitance elicited by photolytic release of caged Ca2+. We propose that the RRP represents a subset of the docked pool of granules and that replenishment of RRP can be accounted for largely by chemical modification of granules already in place or situated close to the plasma membrane.

  • 10. Persson, A E
    et al.
    Schnermann, J
    Ågerup, B
    Eriksson, Nils-Einar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology and Medical Biophysics.
    The hydraulic conductivity of the rat proximal tubular wall determined with colloidal solutions1975In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 360, no 1, p. 25-44Article in journal (Refereed)
    Abstract [en]

    The hydraulic conductivity of the rat proximal tubular wall was determined using colloidal solutions perfused in short (50--200 mum) (SMP) or long (90--200 mum) (LMP) proximal tubular segments. In SMP human serum albumin (HSA) or polyvinylpyrrolidone (PVP) was added to raffinose solutions. A Lp of 0.019 nl-min-1-mm-1-mm Hg-1 was found when high colloid concentrations were used while values of 0.055--0.092 were found when low colloid concentrations were used. In other experiments, the Lp was determined by perfusing short tubular segments with pure raffinose solutions. A value of 0.015 nl-min-1-mm-1-mm Hg-1 was found. This is twice the value found when raffinose solutions were perfused through long tubular segments and it is concluded that the short microperfusion technique overestimates Lp with a factor of two. When microperfusions of long tubular segments were conducted, PVP was added to an equilibrium solution consisting of NaCl (110 mM) and raffinose (80 mM). Lp was found to be 0.018--0.021 when high colloid concentrations were used, while a value of 0.029 was found when a low colloid concentration was used. As found in both SMP and LMP a decrease in Lp's with increasing colloid concentrations indicates that a significant influence of radial concentration differences is highly probable. It is therefore suggested that the highest Lp derived when using the lowest colloid concentrations represents the best estimate. With this Lp value (0.03--0.05 nl-min-1-mm-1-mm Hg-1) and the existing transtubular hydrostatic and oncotic pressure difference it can be calculated that these passive forces might constitute the driving force for 1/3 of the fluid reabsorbed in the proximal tubule.

  • 11.
    Shuai, Hongyan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Xu, Yunjian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Yu, Qian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Fluorescent protein vectors for pancreatic islet cell identification in live-cell imaging2016In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 468, no 10, p. 1765-1777Article in journal (Refereed)
    Abstract [en]

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

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