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Alterations in Net Glucose Uptake and in the Pancreatic B-Cell GLUT2 Transporter Induced by Diazoxide and by Secretory Stimuli

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Alterations in Net Glucose Uptake and in the Pancreatic B-Cell GLUT2 Transporter Induced by Diazoxide and by Secretory Stimuli 291 Alterations in net glucose uptake and in the pancreatic B-cell GLUT2 transporter induced by diazoxide and by secretory stimuli L Zhao, Z Li, M Kullin,LAHBorg1 and F A Karlsson Department of Medical Sciences, University Hospital, SE-751 85 Uppsala, Sweden 1Department of Medical Cell Biology, University of Uppsala, PO Box 571, SE-751 23 Uppsala, Sweden (Requests for offprints should be addressed to L A H Borg; Email: [email protected]) Abstract The pancreatic B-cell GLUT2 transporter and glucose which may reflect a lowered energy requirement. Con- metabolism were examined in isolated rat islets subjected versely, islets subjected to a stimulated insulin secretion to treatments affecting insulin secretion. Diazoxide was with glipizide or a high extracellular K+ concentration used to inhibit, while glipizide or depolarization of the showed a reduced staining of the GLUT2 transporter. The plasma membrane with a high extracellular K+ concen- net glucose uptake and glucose oxidation were also tration were used to stimulate insulin release in short-term reduced. In islets exposed to the high K+ concentration no experiments. Islet GLUT2 and insulin were determined change in the molecular weight or phosphorylation of by quantitative immunohistochemistry and GLUT2 was GLUT2 was observed but a lesser amount of the trans- also determined by Western blot analysis. Islet net glucose porter was found by Western blot analysis. Thus, GLUT2 uptake and glucose oxidation were measured using radio- and glucose uptake in the pancreatic B-cell are modified actively labelled glucose. Exposure of the islets to diaz- by the secretory process, which suggests that changes in oxide was associated with a marked increase in the B-cell the glucose transporter have a functional role in normal plasma membrane staining for GLUT2 and increased net B-cell physiology. glucose uptake. Glucose oxidation was not changed, Journal of Endocrinology (2005) 185, 291–299 Introduction therapy may lead to reduced destruction of the pancreatic B-cells. Indeed, B-cell secretory rest has been induced The metabolic and secretory activities of the pancreatic with promising results in a trial in which 3 months of B-cells are of importance for their susceptibility to damage. supplementary treatment with diazoxide, which is an Chronic hyperglycaemia can have a glucotoxic effect and inhibitor of insulin release, was given to patients with impair B-cell function and survival (Yki-Järvinen 1992). newly onset type I diabetes (Björk et al.1996). Treatment High glucose concentrations in vitro also sensitize the with diazoxide has also been reported to prolong improve- B-cells to direct damage by diabetogenic agents such as ment of B-cell function in rat islets transplanted to a streptozotocin (Eizirik et al. 1988) and cytokines such as diabetic environment (Hiramatsu et al. 2000). Altogether, interleukin-1 (Palmer et al. 1989). B-cell secretory rest these observations indicate that the sensitivity of the (Karlsson & Björk 1997) induced by prophylactic insulin B-cells to destruction is dependent upon their func- treatment can, on the other hand, delay or prevent the tional activity and seems to be linked to the process of onset of autoimmune diabetes in experimental models glucose-stimulated insulin release. such as the NOD mouse (Atkinson et al. 1990) and the BB Insulin secretion is stimulated by a sequence of events in rat (Gotfredsen et al. 1985). In humans, insulin treatment which glucose is metabolized by the pancreatic B-cell to at the clinical onset of type I diabetes commonly improves generate an increase in ATP, followed by closure of B-cell function. The remission of the disease may reflect ATP-dependent K+ channels and subsequent depolariz- B-cell recovery from glucotoxic effects or reduced ation of the B-cell plasma membrane. This leads to the immune-mediated impairments. We and others have opening of voltage-dependent Ca2+ channels, an increase shown that the ambient glucose concentration regulates in cytosolic Ca2+ concentration and reactions terminat- islet cell auto-antigen expression (Kämpe et al. 1989, ing with the exocytosis of insulin-containing secretory Hagopian et al. 1993) and that this expression is linked to granules. Diazoxide inhibits insulin secretion by opening insulin secretion per se (Björk et al. 1992). Therefore, a ATP-dependent K+ channels and hyperpolarizing the normalization of blood glucose brought about by insulin B-cell plasma membrane. We have found that diazoxide Journal of Endocrinology (2005) 185, 291–299 DOI: 10.1677/joe.1.05701 0022–0795/05/0185–291 2005 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/30/2021 02:39:26AM via free access 292 L ZHAO and others · Alterations in the B-cell GLUT2 transporter and another opener of ATP-dependent K+ channels, glucose. Also, isolated islets were incubated with 5 mM NNC-0118, protect rat islets against streptozotocin dam- glucose for 1 h and then for another 30 min in the age (Kullin et al. 2000). Streptozotocin is a well-known presence or absence of 50 mM potassium chloride at the experimental B-cell toxin (Kolb 1987). It contains a same glucose concentration. After these incubations glucose moiety and is taken up into the B-cells by the low the islets were subjected to morphological examination, affinity transporter GLUT2. The transporter is thus Western blot analysis, determination of GLUT2 phos- needed for streptozotocin toxicity. Cells lacking GLUT2 phorylation or measurements of net glucose uptake or are, dose-dependently, rendered sensitive to the toxin by glucose oxidation in media of the same compositions. transgenic expression of the transporter (Schnedl et al. 1994). Morphological examination Although diazoxide has been reported not to alter islet oxidation of glucose (Ashcroft & Randle 1970, Bergsten To determine GLUT2 and insulin content in islet B-cells et al. 1988, Malaisse et al. 1999), the beneficial effect of by immunohistochemistry and to measure immuno- B-cell rest caused by this drug at exposure to streptozo- fluorescence, 150 islets from the various incubations were tocin or under other diabetogenic conditions might transferred to conical glass tubes and sedimented at 800 involve changes in GLUT2 function. Therefore, we r.p.m. for 2 min. The incubation medium was removed, studied the effects of diazoxide on GLUT2 in isolated rat leaving about 200 µl, before the islets were fixed in 8 ml islets. To do this, confocal microscopy and quantitative Bouin’s solution and dehydrated in a graded series of immunohistochemistry were used in conjunction with ethanol. The islet pellets were embedded in paraffinor measurements of islet net uptake of glucose and glucose frozen in liquid nitrogen. Double immunofluoresence oxidation. For comparison, we also examined the effects of staining for GLUT2 and insulin was performed on 5-µm stimulated insulin release on GLUT2 by exposure of thick sections. For this purpose a rabbit antibody raised isolated islets to glipizide, which inhibits ATP-dependent against peptide 512–522 of rat GLUT2 (a generous gift K+ channel activity in pancreatic B-cells, and by exposure from Prof. B Thorens, Lausanne, Switzerland) at a dilution of islets to a high extracellular K+ concentration, which of 1:200, followed by CY 3-conjugated donkey anti-rabbit directly induces a depolarization of the B-cell plasma IgG (Jackson Immunoresearch Laboratories, West Grove, membrane. PA, USA), and a guinea-pig anti-insulin antibody (DAKO, Glostrup, Denmark) at a dilution of 1:400 followed by FITC-conjugated rabbit anti-guinea-pig IgG Materials and Methods (Jackson Immunoresearch Laboratories) were used. Morphological analysis and measurements of the aver- Islet preparation and incubation age fluorescence intensities of insulin and GLUT2 per unit Pancreatic islets were isolated from adult male Sprague– islet section area were performed by a confocal microscope Dawley rats (bred in a local colony at the Biomedical (Laser Scan Microscope 410; Carl Zeiss, Jena, Germany) at Centre, Uppsala, Sweden) by a collagenase digestion excitation wavelengths of 543 and 488 nm. For each of the procedure (Schnell et al. 1988). The experiments were incubation conditions, 20–45 islets were examined in each performed in accordance with principles of laboratory of three experiments. To standardize the measurements of animal care, and the research protocol including all immunofluorescence, brightness and contrast were set for experimental procedures involving animals was approved islets incubated without diazoxide, glipizide or 50 mM by the Regional Animal Ethical Committee. Groups of potassium chloride, and exactly the same settings were also 150 islets were cultured free floating for 6–7 days in 5 ml used for the islets exposed to the substances in each RPMI 1640 medium (Sigma Chemical Co., St Louis, experiment. MO, USA) containing 11 mM glucose and supplemented with 10% (v/v) fetal calf serum (Sigma Chemical K+-stimulated insulin release and islet content of insulin Co.), 0·17 mM sodium benzylpenicillinate and 0·17 mM streptomycin. The islet cultures were maintained in an After exposure to a high concentration of potassium atmosphere of humidified air and 5% (v/v) carbon dioxide chloride as described above, triplicates of fifteen islets from at 37 C. The medium was changed every second day. the control and experimental groups were transferred to Subsequent to culture, the islets were incubated 200 µl redistilled
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