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1
Sjoholm, A. "Nitric oxide donor SIN-1 inhibits insulin release." American Journal of Physiology-Cell Physiology 271, no. 4 (October 1, 1996): C1098—C1102. http://dx.doi.org/10.1152/ajpcell.1996.271.4.c1098.
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Preceding the onset of insulin-dependent diabetes mellitus, pancreatic islets are infiltrated by macrophages secreting interleukin-1 beta, which exerts cytotoxic and inhibitory actions on islet beta-cell insulin secretion through induction of nitric oxide (NO) synthesis. The influence of the NO donor 3-morpholinosydnonimine (SIN-1) on insulin secretion from isolated pancreatic islets in response to various secretagogues was investigated. Stimulation of insulin release evoked by glucose, phospholipase C activation with carbachol, and protein kinase C activation with phorbol ester were obtained by SIN-1, whereas the response to adenylyl cyclase activation or K(+)-induced depolarization was not affected. It is concluded that enzymes involved in glucose catabolism, phospholipase C or protein kinase C, may be targeted by NO. Reversal of SIN-1 inhibition of glucose-stimulated insulin release by dithiothreitol suggests that NO may inhibit insulin secretion partly by S-nitrosylation of thiol residues in key proteins in the stimulus-secretion coupling. These adverse effects of NO on the beta-cell stimulus-secretion coupling may be of importance for the development of the impaired insulin secretion characterizing diabetes mellitus.
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Fernández-Díaz, Cristina M., Beatriz Merino, José F. López-Acosta, Pilar Cidad, Miguel A. de la Fuente, Carmen D. Lobatón, Alfredo Moreno, Malcolm A. Leissring, Germán Perdomo, and Irene Cózar-Castellano. "Pancreatic β-cell-specific deletion of insulin-degrading enzyme leads to dysregulated insulin secretion and β-cell functional immaturity." American Journal of Physiology-Endocrinology and Metabolism 317, no. 5 (November 1, 2019): E805—E819. http://dx.doi.org/10.1152/ajpendo.00040.2019.
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Inhibition of insulin-degrading enzyme (IDE) has been proposed as a possible therapeutic target for type 2 diabetes treatment. However, many aspects of IDE's role in glucose homeostasis need to be clarified. In light of this, new preclinical models are required to elucidate the specific role of this protease in the main tissues related to insulin handling. To address this, here we generated a novel line of mice with selective deletion of the Ide gene within pancreatic beta-cells, B-IDE-KO mice, which have been characterized in terms of multiple metabolic end points, including blood glucose, plasma C-peptide, and intraperitoneal glucose tolerance tests. In addition, glucose-stimulated insulin secretion was quantified in isolated pancreatic islets and beta-cell differentiation markers and insulin secretion machinery were characterized by RT-PCR. Additionally, IDE was genetically and pharmacologically inhibited in INS-1E cells and rodent and human islets, and insulin secretion was assessed. Our results show that, in vivo, life-long deletion of IDE from beta-cells results in increased plasma C-peptide levels. Corroborating these findings, isolated islets from B-IDE-KO mice showed constitutive insulin secretion, a hallmark of beta-cell functional immaturity. Unexpectedly, we found 60% increase in Glut1 (a high-affinity/low- Km glucose transporter), suggesting increased glucose transport into the beta-cell at low glucose levels, which may be related to constitutive insulin secretion. In parallel, IDE inhibition in INS-1E and islet cells resulted in impaired insulin secretion after glucose challenge. We conclude that IDE is required for glucose-stimulated insulin secretion. When IDE is inhibited, insulin secretion machinery is perturbed, causing either inhibition of insulin release at high glucose concentrations or constitutive secretion.
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Dela, F., K. J. Mikines, B. Tronier, and H. Galbo. "Diminished arginine-stimulated insulin secretion in trained men." Journal of Applied Physiology 69, no. 1 (July 1, 1990): 261–67. http://dx.doi.org/10.1152/jappl.1990.69.1.261.
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Glucose-stimulated insulin secretion is depressed by training. To further elucidate the beta-cell adaptation to training, a nonglucose secretagogue was applied. Arginine was infused for 90 min to seven trained and seven untrained young men. Arginine and glucose concentrations increased identically in the groups. The insulin response was biphasic and waned despite increasing arginine concentrations. Both these phases as well as C-peptide responses were reduced in trained subjects, whereas proinsulin responses were similar in the groups. Identical increases were found in glucagon, growth hormone, catecholamines, and production and disappearance of glucose; identical decreases were found in free fatty acids, glycerol, and beta-hydroxybutyrate. In conclusion, in men training diminishes both arginine- and glucose-stimulated insulin secretion, indicating a profound beta-cell adaptation. Being enhanced, the effects of insulin on both production and disposal of glucose are changed in the opposite direction to beta-cell secretion by training. The responses of glucagon- and growth hormone-secreting cells to arginine do not change with training.
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Karimova, Mariana V., Inessa G. Gvazava, and Ekaterina A. Vorotelyak. "Overcoming the Limitations of Stem Cell-Derived Beta Cells." Biomolecules 12, no. 6 (June 9, 2022): 810. http://dx.doi.org/10.3390/biom12060810.
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Great advances in type 1 diabetes (T1D) and type 2 diabetes (T2D) treatment have been made to this day. However, modern diabetes therapy based on insulin injections and cadaveric islets transplantation has many disadvantages. That is why researchers are developing new methods to regenerate the pancreatic hormone-producing cells in vitro. The most promising approach is the generation of stem cell-derived beta cells that could provide an unlimited source of insulin-secreting cells. Recent studies provide methods to produce beta-like cell clusters that display glucose-stimulated insulin secretion—one of the key characteristics of the beta cell. However, in comparison with native beta cells, stem cell-derived beta cells do not undergo full functional maturation. In this paper we review the development and current state of various protocols, consider advantages, and propose ways to improve them. We examine molecular pathways, epigenetic modifications, intracellular components, and the microenvironment as a possible leverage to promote beta cell functional maturation. A possibility to create islet organoids from stem cell-derived components, as well as their encapsulation and further transplantation, is also examined. We try to combine modern research on beta cells and their crosstalk to create a holistic overview of developing insulin-secreting systems.
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Karatug Kacar, A., S. Gezginci-Oktayoglu, and S. Bolkent. "4-Methylcatechol stimulates apoptosis and reduces insulin secretion by decreasing betacellulin and inhibin beta-A in INS-1 beta-cells." Human & Experimental Toxicology 37, no. 11 (February 23, 2018): 1123–30. http://dx.doi.org/10.1177/0960327118758365.
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Insulinoma INS-1 cell line is a pancreatic beta cell tumor which is characterized with high insulin content and secretion in response to increasing glucose levels. 4-Methylcatechol (4-MC) is a metabolite of quercetin, which is known as a potential drug for inhibition of tumorigenesis. The aim of this study was to determine the applying doses of 4-methylcatechol (4-MC) for triggening cell death and decreasing the cell function of rat insulinoma INS-1 beta cells. The rate of apoptosis and the amount of insulin in the cell and the secretions were determined by the ELISA method. Betacellulin (BTC) and inhibin beta-A amounts in both the cell and the glucose induced secretion were investigated by Western blotting. Furthermore, BTC, Inhibin beta-A, Ins1, Ins2, and GLUT2 gene expression levels were determined by the by the real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) method. We noted a significant decrease in cell viability, while an increase in apoptotic cell death by 4-MC treatment. It caused a decrease in the secretion of BTC, expressions of both BTC and inhibin beta-A. We showed a decrease in the expressions of Ins1 and GLUT2, while there is no alteration in the level of insulin protein. Insulin secretion levels increased in INS-1 cells given 4-MC by basal glucose concentration while they did not response to high concentration of glucose, which indicates that 4-MC disrupts the functionality of INS-1 cells. These results revealed that 4-MC induces apoptosis and decreases insulin secretion by reducing BTC and inhibin beta-A in insulinoma INS-1 cells. Thus, 4-MC may be offered as a potential molecule for treatment of insulinoma.
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Corbett, J. A., and M. L. McDaniel. "Intraislet release of interleukin 1 inhibits beta cell function by inducing beta cell expression of inducible nitric oxide synthase." Journal of Experimental Medicine 181, no. 2 (February 1, 1995): 559–68. http://dx.doi.org/10.1084/jem.181.2.559.
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Cytokines, released in and around pancreatic islets during insulitis, have been proposed to participate in beta-cell destruction associated with autoimmune diabetes. In this study we have evaluated the hypothesis that local release of the cytokine interleukin 1 (IL-1) by nonendocrine cells of the islet induce the expression of inducible nitric oxide synthase (iNOS) by beta cells which results in the inhibition of beta cell function. Treatment of rat islets with a combination of tumor necrosis factor (TNF) and lipopolysaccharide (LPS), conditions known to activate macrophages, stimulate the expression of iNOS and the formation of nitrite. Although TNF+LPS induce iNOS expression and inhibit insulin secretion by intact islets, this combination does not induce the expression of iNOS by beta or alpha cells purified by fluorescence activated cell sorting (Facs). In contrast, IL-1 beta induces the expression of iNOS and also inhibits insulin secretion by both intact islets and Facs-purified beta cells, whereas TNF+LPS have no inhibitory effects on insulin secretion by purified beta cells. Evidence suggests that TNF+LPS inhibit insulin secretion from islets by stimulating the release of IL-1 which subsequently induces the expression of iNOS by beta cells. The IL-1 receptor antagonist protein completely prevents TNF+LPS-induced inhibition of insulin secretion and attenuates nitrite formation from islets, and neutralization of IL-1 with antisera specific for IL-1 alpha and IL-1 beta attenuates TNF+LPS-induced nitrite formation by islets. Immunohistochemical localization of iNOS and insulin confirm that TNF+LPS induce the expression of iNOS by islet beta cells, and that a small percentage of noninsulin-containing cells also express iNOS. Local release of IL-1 within islets appears to be required for TNF+LPS-induced inhibition of insulin secretion because TNF+LPS do not stimulate nitrite formation from islets physically separated into individual cells. These findings provide the first evidence that a limited number of nonendocrine cells can release sufficient quantities of IL-1 in islets to induce iNOS expression and inhibit the function of the beta cell, which is selectively destroyed during the development of autoimmune diabetes.
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Brüning, Dennis, Kathrin Hatlapatka, Verena Lier-Glaubitz, Vincent Andermark, Stephan Scherneck, Ingo Ott, and Ingo Rustenbeck. "Pharmacological inhibition of thioredoxin reductase increases insulin secretion and diminishes beta cell viability." Naunyn-Schmiedeberg's Archives of Pharmacology 394, no. 6 (January 19, 2021): 1133–42. http://dx.doi.org/10.1007/s00210-020-02046-2.
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AbstractApparently, both a decrease in beta cell function and in beta cell mass contribute to the progressive worsening of type 2 diabetes. So, it is of particular interest to define factors which are relevant for the regulation of insulin secretion and at the same time for the maintenance of beta cell mass. The NADPH-thioredoxin system has a candidate role for such a dual function. Here, we have characterized the effects of a highly specific inhibitor of thioredoxin reductase, AM12, on the viability and function of insulin-secreting MIN6 cells and isolated NMRI mouse islets. Viability was checked by MTT testing and the fluorescent live-dead assay. Apoptosis was assessed by annexin V assay. Insulin secretion of perifused islets was measured by ELISA. The cytosolic Ca2+ concentration was measured by the Fura technique. Acute exposure of perifused pancreatic islets to 5 μM AM12 was without significant effect on insulin secretion. Islets cultured for 24 h in 0.5 or 5 μM AM12 showed unchanged basal secretion during perifusion, but the response to 30 mM glucose was significantly enhanced by 5 μM. Twenty-four-hour exposure to 5 μM AM12 proved to be without effect on the viability of MIN6 cells, whereas longer exposure was clearly toxic. Islets were more susceptible, showing initial signs of apoptosis after 24-h exposure to 5 μM AM12. The activity of the NADPH-thioredoxin system is indispensable for beta cell viability but may have a limiting effect on glucose-induced insulin secretion.
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Sjoholm, A., and C. Hellerstrom. "TGF-beta stimulates insulin secretion and blocks mitogenic response of pancreatic beta-cells to glucose." American Journal of Physiology-Cell Physiology 260, no. 5 (May 1, 1991): C1046—C1051. http://dx.doi.org/10.1152/ajpcell.1991.260.5.c1046.
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The long-term influence of transforming growth factor-beta (TGF-beta) on replication and insulin secretion by insulin-producing pancreatic beta-cells was investigated. For this purpose, fetal rat pancreatic islets containing a high proportion of beta-cells were isolated and maintained in tissue culture for 3 days at different concentrations of TGF-beta. TGF-beta (5-500 pM) at a glucose concentration of 11.1 mM did not affect the replication of the beta-cells or their insulin content but enhanced secretion of insulin from these cells. TGF-beta (500 pM) counter-acted the mitogenic action of 16.7 mM glucose but failed to affect the glucose-induced increase in islet insulin content or secretion. Growth hormone (GH) also stimulated beta-cell DNA synthesis and insulin secretion, but TGF-beta was unable to prevent these effects. It was found, moreover, that TGF-beta did not prevent the increase in islet polyamine content which occurred in response to glucose or GH, indicating that the effects of TGF-beta are not mediated through this pathway. Addition of neutralizing antibodies to TGF-beta did not affect the mitogenic or secretory responses to glucose or GH, suggesting that TGF-beta does not exert any autocrine or paracrine function in islets.
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Dumortier, Olivier, Gaia Fabris, Didier F. Pisani, Virginie Casamento, Nadine Gautier, Charlotte Hinault, Patricia Lebrun, et al. "microRNA-375 regulates glucose metabolism-related signaling for insulin secretion." Journal of Endocrinology 244, no. 1 (January 2020): 189–200. http://dx.doi.org/10.1530/joe-19-0180.
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Enhanced beta cell glycolytic and oxidative metabolism are necessary for glucose-induced insulin secretion. While several microRNAs modulate beta cell homeostasis, miR-375 stands out as it is highly expressed in beta cells where it regulates beta cell function, proliferation and differentiation. As glucose metabolism is central in all aspects of beta cell functioning, we investigated the role of miR-375 in this process using human and rat islets; the latter being an appropriate model for in-depth investigation. We used forced expression and repression of mR-375 in rat and human primary islet cells followed by analysis of insulin secretion and metabolism. Additionally, miR-375 expression and glucose-induced insulin secretion were compared in islets from rats at different developmental ages. We found that overexpressing of miR-375 in rat and human islet cells blunted insulin secretion in response to glucose but not to α-ketoisocaproate or KCl. Further, miR-375 reduced O2 consumption related to glycolysis and pyruvate metabolism, but not in response to α-ketoisocaproate. Concomitantly, lactate production was augmented suggesting that glucose-derived pyruvate is shifted away from mitochondria. Forced miR-375 expression in rat or human islets increased mRNA levels of pyruvate dehydrogenase kinase-4, but decreased those of pyruvate carboxylase and malate dehydrogenase1. Finally, reduced miR-375 expression was associated with maturation of fetal rat beta cells and acquisition of glucose-induced insulin secretion function. Altogether our findings identify miR-375 as an efficacious regulator of beta cell glucose metabolism and of insulin secretion, and could be determinant to functional beta cell developmental maturation.
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Scullion, S. M. J., E. Gurgul-Convey, M. Elsner, S. Lenzen, P. R. Flatt, and N. H. McClenaghan. "Enhancement of homocysteine toxicity to insulin-secreting BRIN-BD11 cells in combination with alloxan." Journal of Endocrinology 214, no. 2 (May 11, 2012): 233–38. http://dx.doi.org/10.1530/joe-11-0461.
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Previous studies have shown that homocysteine (HC) has a detrimental impact on insulin secretion and pancreatic beta cell function. The aim of the present study was to determine the role of reactive oxygen species (ROS) in the in vitro toxic effects of HC on insulin secretion and function of BRIN-BD11 insulin-secreting cells. In this study, insulin secretion from BRIN-BD11 cells was determined radioimmunologically, cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and glucokinase activity by a glucose phosphorylation assay following culture with HC plus alloxan (Alx). Treatment with HC resulted in concentration-dependent inhibition of insulin secretion induced by glucose and other insulinotropic agents. HC in combination with Alx resulted in a more pronounced decline in insulin secretion, including that induced by 20 mM alanine, by 43% (P<0.001) and 30 mM KCl by 60% (P<0.001), compared with control culture. The glucokinase phosphorylating capacity in cells cultured with HC plus Alx was significantly lower, compared with control cells. The cells also displayed a significant 84% (P<0.001) decline in cell viability. Prolonged, 72-h culture of insulin-secreting cells with HC followed by 18-h culture without HC did not result in full restoration of beta cell responses to insulinotropic agents. In vitro oxygen consumption was enhanced by a combination of Alx with HC. The study arrived at the conclusion that HC generates ROS in a redox-cycling reaction with Alx that explains the decline in viability of insulin-secreting cells, leading to reduced glucokinase phosphorylating ability, diminished insulin secretory responsiveness and cell death.
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Aspinwall, Craig A., Jonathan R. T. Lakey, and Robert T. Kennedy. "Insulin-stimulated Insulin Secretion in Single Pancreatic Beta Cells." Journal of Biological Chemistry 274, no. 10 (March 5, 1999): 6360–65. http://dx.doi.org/10.1074/jbc.274.10.6360.
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Edlund, A., M. Barghouth, M. Hühn, M. Abels, J. S. E. Esguerra, I. G. Mollet, E. Svedin, et al. "Defective exocytosis and processing of insulin in a cystic fibrosis mouse model." Journal of Endocrinology 241, no. 1 (April 2019): 45–57. http://dx.doi.org/10.1530/joe-18-0570.
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Cystic fibrosis-related diabetes (CFRD) is a common complication for patients with cystic fibrosis (CF), a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). The cause of CFRD is unclear, but a commonly observed reduction in first-phase insulin secretion suggests defects at the beta cell level. Here we aimed to examine alpha and beta cell function in the Cftr tm1 EUR/F508del mouse model (C57BL/6J), which carries the most common human mutation in CFTR, the F508del mutation. CFTR expression, beta cell mass, insulin granule distribution, hormone secretion and single cell capacitance changes were evaluated using islets (or beta cells) from F508del mice and age-matched wild type (WT) mice aged 7–10 weeks. Granular pH was measured with DND-189 fluorescence. Serum glucose, insulin and glucagon levels were measured in vivo, and glucose tolerance was assessed using IPGTT. We show increased secretion of proinsulin and concomitant reduced secretion of C-peptide in islets from F508del mice compared to WT mice. Exocytosis and number of docked granules was reduced. We confirmed reduced granular pH by CFTR stimulation. We detected decreased pancreatic beta cell area, but unchanged beta cell number. Moreover, the F508del mutation caused failure to suppress glucagon secretion leading to hyperglucagonemia. In conclusion, F508del mice have beta cell defects resulting in (1) reduced number of docked insulin granules and reduced exocytosis and (2) potential defective proinsulin cleavage and secretion of immature insulin. These observations provide insight into the functional role of CFTR in pancreatic islets and contribute to increased understanding of the pathogenesis of CFRD.
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Grubelnik, Vladimir, Jan Zmazek, Matej Završnik, and Marko Marhl. "Lipotoxicity in a Vicious Cycle of Pancreatic Beta Cell Exhaustion." Biomedicines 10, no. 7 (July 7, 2022): 1627. http://dx.doi.org/10.3390/biomedicines10071627.
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Hyperlipidemia is a common metabolic disorder in modern society and may precede hyperglycemia and diabetes by several years. Exactly how disorders of lipid and glucose metabolism are related is still a mystery in many respects. We analyze the effects of hyperlipidemia, particularly free fatty acids, on pancreatic beta cells and insulin secretion. We have developed a computational model to quantitatively estimate the effects of specific metabolic pathways on insulin secretion and to assess the effects of short- and long-term exposure of beta cells to elevated concentrations of free fatty acids. We show that the major trigger for insulin secretion is the anaplerotic pathway via the phosphoenolpyruvate cycle, which is affected by free fatty acids via uncoupling protein 2 and proton leak and is particularly destructive in long-term chronic exposure to free fatty acids, leading to increased insulin secretion at low blood glucose and inadequate insulin secretion at high blood glucose. This results in beta cells remaining highly active in the “resting” state at low glucose and being unable to respond to anaplerotic signals at high pyruvate levels, as is the case with high blood glucose. The observed fatty-acid-induced disruption of anaplerotic pathways makes sense in the context of the physiological role of insulin as one of the major anabolic hormones.
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Skrzypek, Katarzyna, Yazmin Brito Barrera, Thomas Groth, and Dimitrios Stamatialis. "Endothelial and beta cell composite aggregates for improved function of a bioartificial pancreas encapsulation device." International Journal of Artificial Organs 41, no. 3 (February 20, 2018): 152–59. http://dx.doi.org/10.1177/0391398817752295.
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Introduction: Encapsulation of pancreatic islets or beta cells is a promising strategy for treatment of type 1 diabetes by providing an immune isolated environment and allowing for transplantation in a different location than the liver. However, islets used for encapsulation often show lower functionality due to the damaging of islet endothelial cells during the isolation procedure. Factors produced by endothelial cells have great impact on beta cell insulin secretion. Therefore, mutual signaling between endothelial cells and beta cells should be considered for the development of encapsulation systems to achieve high insulin secretion and maintain beta cell viability. Here, we investigate whether co-culture of beta cells with endothelial cells could improve beta cell function within encapsulation devices. Materials and methods: Mouse insulinoma MIN6 cells and human umbilical vein endothelial cells were used for creating composite aggregates on agarose microwell platform. The composite aggregates were encapsulated within flat poly(ether sulfone)/polyvinylpyrrolidone device. Their functionality was assessed by glucose-induced insulin secretion test and compared to non-encapsulated free-floating aggregates. Results: We created composite aggregates of 80–100 µm in diameter, closely mimicking pancreatic islets. Upon glucose stimulation, their insulin secretion is improved in comparison to aggregates consisting of only MIN6 cells. Moreover, the composite aggregates encapsulated within a device secrete more insulin than aggregates consisting of only MIN6 cells. Conclusion: Composite aggregates of MIN6 cells with human umbilical vein endothelial cells have improved insulin secretion in comparison to MIN6 aggregates showing that the interaction of beta cell and endothelial cell is crucial for a functional encapsulation system.
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Meglasson, M. D., K. M. Smith, D. Nelson, and M. Erecinska. "alpha-Glycerophosphate shuttle in a clonal beta-cell line." American Journal of Physiology-Endocrinology and Metabolism 256, no. 1 (January 1, 1989): E173—E178. http://dx.doi.org/10.1152/ajpendo.1989.256.1.e173.
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It has been proposed that the alpha-glycerophosphate (alpha-GOP) shuttle plays a crucial role in regulation of glycolysis in beta-cells by linking reoxidation of cytosolic NADH to formation of ATP in the electron transport chain (J. Biol. Chem. 265: 8287, 1981). Direct evidence for this suggestion is still lacking, however. In this work the operation of the alpha-GOP shuttle was investigated in the insulin-secreting cell line HIT-T15. The constituent enzymes of the pathway were found to be present in HIT cells. Flavin-linked alpha-GOP dehydrogenase was associated with the mitochondrial fraction, whereas NAD+-dependent alpha-GOP dehydrogenase was localized in the cytosol. In the presence of amobarbital (used to preserve the function of the alpha-GOP shuttle under conditions where oxidation of NADH by the respiratory chain was blocked), glucose increased insulin secretion, O2 consumption, and the cell [ATP]/[ADP] when compared with amobarbital alone. These results indicate that the alpha-GOP shuttle contributes to ATP generation in HIT cells and that its activation may be necessary for the initiation of insulin secretion by glucose.
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Leiter, E. H. "Murine macrophages and pancreatic beta cells. Chemotactic properties of insulin and beta-cytostatic action of interleukin 1." Journal of Experimental Medicine 166, no. 4 (October 1, 1987): 1174–79. http://dx.doi.org/10.1084/jem.166.4.1174.
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This study has used in vitro techniques to investigate the potential interactions between mouse pancreatic islet cells and syngeneic macrophages (M phi). Islets strongly stimulated M phi migration from agarose microdroplets; insulin was the only one of four islet cell hormones tested that was effective individually. Chronic exposure of islet monolayers to recombinant mouse IL-1, an M phi secretory product, was not cytolytic, but inhibited insulin secretion, reduced intracellular insulin content, and produced beta cell-specific degranulation. These effects were unique to IL-1; another monokine, tumor necrosis factor, as well as the lymphokine IL-2, and lymphotoxin were all without effect on insulin secretion or monolayer viability at the concentrations tested. The potential pathological consequences of the chemoattractive action of insulin on M phi, and the inhibitory effect of IL-1 on insulin secretion, are discussed.
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Gaus, Bastian, Dennis Brüning, Kathrin Hatlapatka, and Ingo Rustenbeck. "Changes in granule mobility and age contribute to changes in insulin secretion after desensitization or rest." BMJ Open Diabetes Research & Care 9, no. 1 (October 2021): e002394. http://dx.doi.org/10.1136/bmjdrc-2021-002394.
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IntroductionFunctional impairment of the stimulus secretion coupling in pancreatic beta cells is an essential component of type 2 diabetes. It is known that prolonged stimulation desensitizes the secretion of insulin and thus contributes to beta cell dysfunction. Beta cell rest, in contrast, was shown to enhance the secretory response. Here, the underlying mechanisms were investigated.Research design and methodsTo characterize the consequences of desensitization or rest for the number and mobility of submembrane granules, insulin-secreting MIN6 cells were desensitized by 18-hour culture with 500 µM tolbutamide or rested by 18-hour culture with 1 µM clonidine. The granules were labeled by hIns-EGFP or hIns-DsRed E5, imaged by TIRF microscopy of the cell footprint area and analyzed with an observer-independent program. Additionally, the insulin content and secretion were measured.ResultsConcurrent with the insulin content, submembrane granules were only slightly reduced after desensitization but markedly increased after rest. Both types of pretreatment diminished arrivals and departures of granules in the submembrane space and increased the proportion of immobile long-term resident granules, but desensitization lowered and rest increased the number of exocytoses, in parallel with the effect on insulin secretion. Labeling with hIns-DsRed E5 (‘timer’) showed that desensitization did not affect the proportion of aged granules, whereas rest increased it. Aged granules showed a high mobility and made up only a minority of long-term residents. Long-term resident granules were more numerous after rest and had a lower lateral mobility, suggesting a firmer attachment to the membrane.ConclusionThe number, mobility and age of submembrane granules reflect the preceding functional states of insulin-secreting cells. Representing the pool of releasable granules, their quantity and quality may thus form part of the beta cell memory on renewed stimulation.
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Bandisode, Madhukar S. "Insulin secretion from isolated pure beta cells." Biochemical and Biophysical Research Communications 128, no. 1 (April 1985): 396–401. http://dx.doi.org/10.1016/0006-291x(85)91692-4.
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Shcherbina, L., A. Edlund, J. L. S. Esguerra, M. Abels, Y. Zhou, E. Ottosson-Laakso, C. B. Wollheim, O. Hansson, L. Eliasson, and N. Wierup. "Endogenous beta-cell CART regulates insulin secretion and transcription of beta-cell genes." Molecular and Cellular Endocrinology 447 (May 2017): 52–60. http://dx.doi.org/10.1016/j.mce.2017.02.027.
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Cerf, Marlon E. "Beta Cell Physiological Dynamics and Dysfunctional Transitions in Response to Islet Inflammation in Obesity and Diabetes." Metabolites 10, no. 11 (November 10, 2020): 452. http://dx.doi.org/10.3390/metabo10110452.
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Beta cells adapt their function to respond to fluctuating glucose concentrations and variable insulin demand. The highly specialized beta cells have well-established endoplasmic reticulum to handle their high metabolic load for insulin biosynthesis and secretion. Beta cell endoplasmic reticulum therefore recognize and remove misfolded proteins thereby limiting their accumulation. Beta cells function optimally when they sense glucose and, in response, biosynthesize and secrete sufficient insulin. Overnutrition drives the pathogenesis of obesity and diabetes, with adverse effects on beta cells. The interleukin signaling system maintains beta cell physiology and plays a role in beta cell inflammation. In pre-diabetes and compromised metabolic states such as obesity, insulin resistance, and glucose intolerance, beta cells biosynthesize and secrete more insulin, i.e., hyperfunction. Obesity is entwined with inflammation, characterized by compensatory hyperinsulinemia, for a defined period, to normalize glycemia. However, with chronic hyperglycemia and diabetes, there is a perpetual high demand for insulin, and beta cells become exhausted resulting in insufficient insulin biosynthesis and secretion, i.e., they hypofunction in response to elevated glycemia. Therefore, beta cell hyperfunction progresses to hypofunction, and may progressively worsen towards failure. Preserving beta cell physiology, through healthy nutrition and lifestyles, and therapies that are aligned with beta cell functional transitions, is key for diabetes prevention and management.
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Persaud, SJ, H. Al-Majed, A. Raman, and PM Jones. "Gymnema sylvestre stimulates insulin release in vitro by increased membrane permeability." Journal of Endocrinology 163, no. 2 (November 1, 1999): 207–12. http://dx.doi.org/10.1677/joe.0.1630207.
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To determine whether extracts of Gymnema sylvestre may have therapeutic potential for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), we examined the effects of an alcoholic extract of G. sylvestre (GS4) on insulin secretion from rat islets of Langerhans and several pancreatic beta-cell lines. GS4 stimulated insulin release from HIT-T15, MIN6 and RINm5F beta-cells and from islets in the absence of any other stimulus, and GS4-stimulated insulin secretion was inhibited in the presence of 1 mM EGTA. Blockade of voltage-operated Ca(2+) channels with 10 microM isradipine did not significantly affect GS4-induced secretion, and insulin release in response to GS4 was independent of incubation temperature. Examination of islet and beta-cell integrity after exposure to GS4, by trypan blue exclusion, indicated that concentrations of GS4 that stimulated insulin secretion also caused increased uptake of dye. Two gymnemic acid-enriched fractions of GS4, obtained by size exclusion and silica gel chromatography, also caused increases in insulin secretion concomitant with increased trypan blue uptake. These results confirm the stimulatory effects of G. sylvestre on insulin release, but indicate that GS4 acts by increasing cell permeability, rather than by stimulating exocytosis by regulated pathways. Thus the suitability of GS4 as a potential novel treatment for NIDDM can not be assessed by direct measurements of beta-cell function in vitro.
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Mao, Xuhua, Hucheng Chen, Junmin Tang, Liangliang Wang, and Tingting Shu. "Hepcidin links gluco-toxicity to pancreatic beta cell dysfunction by inhibiting Pdx-1 expression." Endocrine Connections 6, no. 3 (April 2017): 121–28. http://dx.doi.org/10.1530/ec-16-0115.
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Objective Gluco-toxicity is a term used to convey the detrimental effect of hyperglycemia on β-cell function through impaired insulin synthesis. Although it is known that the expression and activity of several key insulin transcription regulators is inhibited, other molecular mechanisms that mediate gluco-toxicity are poorly defined. Our objective was to explore the role of hepcidin in β-cell gluco-toxicity. Design We first confirmed that high glucose levels inhibited hepcidin expression in the mouse insulinoma cell line, MIN6. The downregulation of hepcidin decreased Pdx-1 expression, which reduced insulin synthesis. Methods MIN6 cells were exposed to high glucose concentrations (33.3 mmol/L). Glucose-stimulated insulin secretion (GSIS) and serum hepcidin levels were measured by ELISA. The mRNA levels of insulin1, insulin2, Pdx-1 and hepcidin were measured by real-time polymerase chain reaction. Western blot analysis was used to detect the changes in PDX-1 expression. Transient overexpression with hepcidin was used to reverse the downregulation of Pdx-1 and insulin synthesis induced by gluco-toxicity. Results Exposure of MIN6 cells to high glucose significantly decreased GSIS and inhibited insulin synthesis as well as Pdx-1 transcriptional activity and expression at both the mRNA and protein levels. High glucose also decreased hepcidin expression and secretion. Hepcidin overexpression in MIN6 cells partially reversed the gluco-toxicity-induced downregulation of Pdx-1 and insulin expression and improved GSIS. The restoration of insulin synthesis by transfection of a hepcidin overexpression plasmid confirmed the role of hepcidin in mediating the gluco-toxic inhibition of insulin synthesis. Conclusions Our observations suggest that hepcidin is associated with gluco-toxicity-reduced pancreatic β-cell insulin synthesis in type 2 diabetes by inhibiting Pdx-1 expression.
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Zhang, Irina X., Jianhua Ren, Suryakiran Vadrevu, Malini Raghavan, and Leslie S. Satin. "ER stress increases store-operated Ca2+ entry (SOCE) and augments basal insulin secretion in pancreatic beta cells." Journal of Biological Chemistry 295, no. 17 (March 16, 2020): 5685–700. http://dx.doi.org/10.1074/jbc.ra120.012721.
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Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose-stimulated insulin secretion and increased peripheral insulin resistance. Unremitting endoplasmic reticulum (ER) stress can lead to beta-cell apoptosis and has been linked to type 2 diabetes. Although many studies have attempted to link ER stress and T2DM, the specific effects of ER stress on beta-cell function remain incompletely understood. To determine the interrelationship between ER stress and beta-cell function, here we treated insulin-secreting INS-1(832/13) cells or isolated mouse islets with the ER stress–inducer tunicamycin (TM). TM induced ER stress as expected, as evidenced by activation of the unfolded protein response. Beta cells treated with TM also exhibited concomitant alterations in their electrical activity and cytosolic free Ca2+ oscillations. As ER stress is known to reduce ER Ca2+ levels, we tested the hypothesis that the observed increase in Ca2+ oscillations occurred because of reduced ER Ca2+ levels and, in turn, increased store-operated Ca2+ entry. TM-induced cytosolic Ca2+ and membrane electrical oscillations were acutely inhibited by YM58483, which blocks store-operated Ca2+ channels. Significantly, TM-treated cells secreted increased insulin under conditions normally associated with only minimal release, e.g. 5 mm glucose, and YM58483 blocked this secretion. Taken together, these results support a critical role for ER Ca2+ depletion–activated Ca2+ current in mediating Ca2+-induced insulin secretion in response to ER stress.
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Yamato, Eiji. "High dose of histone deacetylase inhibitors affects insulin secretory mechanism of pancreatic beta cell line." Endocrine Regulations 52, no. 1 (January 1, 2018): 21–26. http://dx.doi.org/10.2478/enr-2018-0004.
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Abstract Objective. Histone deacytylase inhibitors (HDACis) inhibit the deacetylation of the lysine residue of proteins, including histones, and regulate the transcription of a variety of genes. Recently, HDACis have been used clinically as anti-cancer drugs and possible anti-diabetic drugs. Even though HDACis have been proven to protect the cytokine-induced damage of pancreatic beta cells, evidence also shows that high doses of HDACis are cytotoxic. In the present study, we, therefore, investigated the eff ect of HDACis on insulin secretion in a pancreatic beta cell line. Methods. Pancreatic beta cells MIN6 were treated with selected HDACis (trichostatin A, TSA; valproic acid, VPA; and sodium butyrate, NaB) in medium supplemented with 25 mM glucose and 13% heat-inactivated fetal bovine serum (FBS) for indicated time intervals. Protein expression of Pdx1 and Mafa in MIN6 cells was demonstrated by immunohistochemistry and immunocytochemistry, expression of Pdx1 and Mafa genes was measured by quantitative RT-PCR method. Insulin release from MIN6 cells and insulin cell content were estimated by ELISA kit. Superoxide production in MIN6 cells was measured using a Total ROS/Superoxide Detection System. Results. TSA, VPA, and NaB inhibited the expression of Pdx1 and Mafa genes and their products. TSA treatment led to beta cell malfunction, characterized by enhanced insulin secretion at 3 and 9 mM glucose, but impaired insulin secretion at 15 and 25 mM glucose. Th us, TSA induced dysregulation of the insulin secretion mechanism. TSA also enhanced reactive oxygen species production in pancreatic beta cells. Conclusions. Our results showed that HDACis caused failure to suppress insulin secretion at low glucose concentrations and enhance insulin secretion at high glucose concentrations. In other words, when these HDACis are used clinically, high doses of HDACis may cause hypoglycemia in the fasting state and hyperglycemia in the fed state. When using HDACis, physicians should, therefore, be aware of the capacity of these drugs to modulate the insulin secretory capacity of pancreatic beta cells.
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Ladwa, Meera, Oluwatoyosi Bello, Olah Hakim, Fariba Shojaee-Moradie, Maria Linda Boselli, Geoff Charles-Edwards, Janet Peacock, et al. "Ethnic differences in beta cell function occur independently of insulin sensitivity and pancreatic fat in black and white men." BMJ Open Diabetes Research & Care 9, no. 1 (March 2021): e002034. http://dx.doi.org/10.1136/bmjdrc-2020-002034.
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IntroductionIt is increasingly recognized that type 2 diabetes (T2D) is a heterogenous disease with ethnic variations. Differences in insulin secretion, insulin resistance and ectopic fat are thought to contribute to these variations. Therefore, we aimed to compare postprandial insulin secretion and the relationships between insulin secretion, insulin sensitivity and pancreatic fat in men of black West African (BA) and white European (WE) ancestry.Research design and methodsA cross-sectional, observational study in which 23 WE and 23 BA men with normal glucose tolerance, matched for body mass index, underwent a mixed meal tolerance test with C peptide modeling to measure beta cell insulin secretion, an MRI to quantify intrapancreatic lipid (IPL), and a hyperinsulinemic-euglycemic clamp to measure whole-body insulin sensitivity.ResultsPostprandial insulin secretion was lower in BA versus WE men following adjustment for insulin sensitivity (estimated marginal means, BA vs WE: 40.5 (95% CI 31.8 to 49.2) × 103 vs 56.4 (95% CI 48.9 to 63.8) × 103 pmol/m2 body surface area × 180 min, p=0.008). There was a significantly different relationship by ethnicity between IPL and insulin secretion, with a stronger relationship in WE than in BA (r=0.59 vs r=0.39, interaction p=0.036); however, IPL was not a predictor of insulin secretion in either ethnic group following adjustment for insulin sensitivity.ConclusionsEthnicity is an independent determinant of beta cell function in black and white men. In response to a meal, healthy BA men exhibit lower insulin secretion compared with their WE counterparts for their given insulin sensitivity. Ethnic differences in beta cell function may contribute to the greater risk of T2D in populations of African ancestry.
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Mikines, K. J., F. Dela, B. Tronier, and H. Galbo. "Effect of 7 days of bed rest on dose-response relation between plasma glucose and insulin secretion." American Journal of Physiology-Endocrinology and Metabolism 257, no. 1 (July 1, 1989): E43—E48. http://dx.doi.org/10.1152/ajpendo.1989.257.1.e43.
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Physical training decreases glucose-stimulated insulin secretion. To further explore the influence of the level of daily physical activity on beta-cell secretion, the effect of 7 days of bed rest was studied in six young, healthy men by sequential hyperglycemic clamp technique (7, 11, and 20 mM glucose, each step lasting 90 min). At 11 and 20 mM glucose, insulin concentrations in plasma were higher after (87 +/- 11 and 303 +/- 63 microU/ml) than before (63 +/- 5 and 251 +/- 50 microU/ml, P less than 0.05) bed rest. Also C-peptide levels were higher after bed rest than before during glucose stimulation. The responses of other hormones, metabolites, or electrolytes influencing beta-cell secretion were not influenced by bed rest. In spite of increased insulin levels after bed rest, glucose disposal at 20 mM of glucose was significantly lower after bed rest than before. It is concluded that bed rest for 7 days increases the glucose-stimulated insulin response, at least partly due to a beta-cell adaptation increasing glucose-stimulated insulin secretion. However, the insulin secretion does not increase adequately compared with the peripheral insulin resistance induced by bed rest.
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Chen, Xi, Enrique Maldonado, Ralph A. DeFronzo, and Devjit Tripathy. "Impaired Suppression of Glucagon in Obese Subjects Parallels Decline in Insulin Sensitivity and Beta-Cell Function." Journal of Clinical Endocrinology & Metabolism 106, no. 5 (February 1, 2021): 1398–409. http://dx.doi.org/10.1210/clinem/dgab019.
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Abstract Aim To examine the relationship between plasma glucagon levels and insulin sensitivity and insulin secretion in obese subjects. Methods Suppression of plasma glucagon was examined in 275 obese Hispanic Americans with varying glucose tolerance. All subjects received a 2-hour oral glucose tolerance test (OGTT) and a subset (n = 90) had euglycemic hyperinsulinemic clamp. During OGTT, we quantitated suppression of plasma glucagon concentration, Matsuda index of insulin sensitivity, and insulin secretion/insulin resistance (disposition) index. Plasma glucagon suppression was compared between quartiles of insulin sensitivity and beta-cell function. Results Fasting plasma glucagon levels were similar in obese subjects with normal glucose tolerance (NGT), prediabetes, and type 2 diabetes (T2D), but the fasting glucagon/insulin ratio decreased progressively from NGT to prediabetes to T2D (9.28 ± 0.66 vs 6.84 ± 0.44 vs 5.84 ± 0.43; P < 0.001). Fasting and 2-hour plasma glucagon levels during OGTT progressively increased and correlated positively with severity of insulin resistance (both Matsuda index and euglycemic hyperinsulinemic clamp). The fasting glucagon/insulin ratio declined with worsening insulin sensitivity and beta-cell function, and correlated with whole-body insulin sensitivity (Matsuda index, r = 0.81; P < 0.001) and beta-cell function (r = 0.35; P < 0.001). The glucagon/insulin ratio also correlated and with beta-cell function during OGTT at 60 and 120 minutes (r = −0.47; P < 0.001 and r = −0.32; P < 0.001). Conclusion Insulin-mediated suppression of glucagon secretion in obese subjects is impaired with increasing severity of glucose intolerance and parallels the severity of insulin resistance and beta-cell dysfunction.
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Perilhou, Anaïs, Cécile Tourrel-Cuzin, Ilham Kharroubi, Carole Henique, Véronique Fauveau, Tadahiro Kitamura, Christophe Magnan, Catherine Postic, Carina Prip-Buus, and Mireille Vasseur-Cognet. "The Transcription Factor COUP-TFII Is Negatively Regulated by Insulin and Glucose via Foxo1- and ChREBP-Controlled Pathways." Molecular and Cellular Biology 28, no. 21 (September 2, 2008): 6568–79. http://dx.doi.org/10.1128/mcb.02211-07.
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ABSTRACT COUP-TFII has an important role in regulating metabolism in vivo. We showed this previously by deleting COUP-TFII from pancreatic beta cells in heterozygous mutant mice, which led to abnormal insulin secretion. Here, we report that COUP-TFII expression is reduced in the pancreas and liver of mice refed with a carbohydrate-rich diet and in the pancreas and liver of hyperinsulinemic and hyperglycemic mice. In pancreatic beta cells, COUP-TFII gene expression is repressed by secreted insulin in response to glucose through Foxo1 signaling. Ex vivo COUP-TFII reduces insulin production and secretion. Our results suggest that beta cell insulin secretion is under the control of an autocrine positive feedback loop by alleviating COUP-TFII repression. In hepatocytes, both insulin, through Foxo1, and high glucose concentrations repress COUP-TFII expression. We demonstrate that this negative glucose effect involves ChREBP expression. We propose that COUP-TFII acts in a coordinate fashion to control insulin secretion and glucose metabolism.
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Langin, Dominique. "Diabetes, Insulin Secretion, and the Pancreatic Beta-Cell Mitochondrion." New England Journal of Medicine 345, no. 24 (December 13, 2001): 1772–74. http://dx.doi.org/10.1056/nejm200112133452412.
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Van Schravendijk, C. F., R. Kiekens, and D. G. Pipeleers. "Pancreatic beta cell heterogeneity in glucose-induced insulin secretion." Journal of Biological Chemistry 267, no. 30 (October 1992): 21344–48. http://dx.doi.org/10.1016/s0021-9258(19)36615-3.
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Turk, John, Haowei Song, Mary Wohltmann, Cheryl Frankfater, Xiaoyong Lei, and Sasanka Ramanadham. "Metabolic Effects of Selective Deletion of Group VIA Phospholipase A2 from Macrophages or Pancreatic Islet Beta-Cells." Biomolecules 10, no. 10 (October 17, 2020): 1455. http://dx.doi.org/10.3390/biom10101455.
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To examine the role of group VIA phospholipase A2 (iPLA2β) in specific cell lineages in insulin secretion and insulin action, we prepared mice with a selective iPLA2β deficiency in cells of myelomonocytic lineage, including macrophages (MØ-iPLA2β-KO), or in insulin-secreting β-cells (β-Cell-iPLA2β-KO), respectively. MØ-iPLA2β-KO mice exhibited normal glucose tolerance when fed standard chow and better glucose tolerance than floxed-iPLA2β control mice after consuming a high-fat diet (HFD). MØ-iPLA2β-KO mice exhibited normal glucose-stimulated insulin secretion (GSIS) in vivo and from isolated islets ex vivo compared to controls. Male MØ-iPLA2β-KO mice exhibited enhanced insulin responsivity vs. controls after a prolonged HFD. In contrast, β-cell-iPLA2β-KO mice exhibited impaired glucose tolerance when fed standard chow, and glucose tolerance deteriorated further when introduced to a HFD. β-Cell-iPLA2β-KO mice exhibited impaired GSIS in vivo and from isolated islets ex vivo vs. controls. β-Cell-iPLA2β-KO mice also exhibited an enhanced insulin responsivity compared to controls. These findings suggest that MØ iPLA2β participates in HFD-induced deterioration in glucose tolerance and that this mainly reflects an effect on insulin responsivity rather than on insulin secretion. In contrast, β-cell iPLA2β plays a role in GSIS and also appears to confer some protection against deterioration in β-cell functions induced by a HFD.
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Gatford, K. L. "059. POOR GROWTH BEFORE BIRTH IMPAIRS INSULIN SECRETION - WHAT WE HAVE LEARNT ABOUT THE MECHANISMS FROM THE PLACENTALLY-RESTRICTED SHEEP." Reproduction, Fertility and Development 21, no. 9 (2009): 14. http://dx.doi.org/10.1071/srb09abs059.
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Diabetes occurs when insulin secretion fails to increase sufficiently to compensate for developing insulin resistance. This implies that the increased risk of diabetes in adults who were small at birth reflects impaired insulin secretion as well as their well-known insulin resistance. More recently, direct evidence has been obtained that adults and children who were growth-restricted before birth secrete less insulin than they should, given their level of insulin resistance. Our research group is using the placentally-restricted (PR) sheep to investigate the mechanisms underlying impaired insulin action (sensitivity and secretion) induced by poor growth before birth. Like the intra-uterine growth-restricted (IUGR) human, the PR sheep develops impaired insulin action by adulthood, but has enhanced insulin sensitivity in infancy, associated with neonatal catch-up growth1, 2. Impaired insulin action begins to develop in early postnatal life, where although basal insulin action is high due to enhanced insulin sensitivity, maximal glucose-stimulated insulin action is already impaired in males3. Our cellular and molecular studies have identified impaired beta-cell function rather than mass as the likely cause of impaired insulin secretion, and we have reported a novel molecular defect in the calcium channels involved in the insulin secretion pathway in the pancreas of these lambs3. Upregulation of IGF-II and insulin receptor are implicated as key molecular regulators of beta-cell mass in the PR lamb3. By adulthood, both basal and maximal insulin action are profoundly impaired in the male lamb who was growth-restricted at birth2. These studies suggest therapies to prevent diabetes in the individual who grew poorly before birth should target beta-cell function, possibly in addition to further increasing beta-cell mass, to improve insulin secretion capacity, and its ability to increase in response to development of insulin resistance. We are now using the PR sheep to test potential therapies, since the timing of pancreatic development and hence exposure to a growth-restricting environment, is similar to that of the human.
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Alán, Lukáš, Tomáš Olejár, Monika Cahová, Jaroslav Zelenka, Zuzana Berková, Magdalena Smětáková, František Saudek, Radoslav Matěj, and Petr Ježek. "Delta Cell Hyperplasia in Adult Goto-Kakizaki (GK/MolTac) Diabetic Rats." Journal of Diabetes Research 2015 (2015): 1–16. http://dx.doi.org/10.1155/2015/385395.
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Reduced beta cell mass in pancreatic islets (PI) of Goto-Kakizaki (GK) rats is frequently observed in this diabetic model, but knowledge on delta cells is scarce. Aiming to compare delta cell physiology/pathology of GK to Wistar rats, we found that delta cell number increased over time as did somatostatin mRNA and delta cells distribution in PI is different in GK rats. Subtle changes in 6-week-old GK rats were found. With maturation and aging of GK rats, disturbed cytoarchitecture occurred with irregular beta cells accompanied by delta cell hyperplasia and loss of pancreatic polypeptide (PPY) positivity. Unlike the constant glucose-stimulation index for insulin PI release in Wistar rats, this index declined with GK age, whereas for somatostatin it increased with age. A decrease of GK rat PPY serum levels was found. GK rat body weight decreased with increasing hyperglycemia. Somatostatin analog octreotide completely blocked insulin secretion, impaired proliferation at low autocrine insulin, and decreased PPY secretion and mitochondrial DNA in INS-1E cells. In conclusion, in GK rats PI, significant local delta cell hyperplasia and suspected paracrine effect of somatostatin diminish beta cell viability and contribute to the deterioration of beta cell mass. Altered PPY-secreting cells distribution amends another component of GK PI’s pathophysiology.
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Schütt, M., J. Zhou, M. Meier, and H. H. Klein. "Long-term effects of HIV-1 protease inhibitors on insulin secretion and insulin signaling in INS-1 beta cells." Journal of Endocrinology 183, no. 3 (December 2004): 445–54. http://dx.doi.org/10.1677/joe.1.05620.
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The mechanism by which chronic treatment with HIV (human immunodeficiency virus)-1 protease inhibitors leads to a deterioration of glucose metabolism appears to involve insulin resistance, and may also involve impaired insulin secretion. Here we investigated the long-term effects of HIV-1 protease inhibitors on glucose-stimulated insulin secretion from beta cells and explored whether altered insulin secretion might be related to altered insulin signaling. INS-1 cells were incubated for 48 h with different concentrations of amprenavir, indinavir, nelfinavir, ritonavir or saquinavir, stimulated with 20 mM d-glucose, and insulin determined in the supernatant. To evaluate insulin signaling, cells were stimulated with 100 nM insulin for 2 min, and insulin-receptor substrate (IRS)-1, -2 and Akt phosphorylation determined. Incubation for 48 h with ritonavir, nelfinavir and saquinavir resulted in impaired glucose-induced insulin secretion at 2.5, 5 and 5 μM respectively, whereas amprenavir or indinavir had no effects even at 20 and 100 μM respectively. The impaired insulin secretion by ritonavir, nelfinavir and saquinavir was associated with decreased insulin-stimulated IRS-2 phosphorylation, and, for nelfinavir and saquinavir, with decreased insulin-stimulated IRS-1 and Thr308-Akt phosphorylation. No such effects on signaling were observed with amprenavir or indinavir. In conclusion, certain HIV-1 protease inhibitors, such as ritonavir, nelfinavir and saquinavir, not only induce peripheral insulin resistance, but also impair glucose-stimulated insulin secretion from beta cells. With respect to the long-term effect on beta-cell function there appear to be differences between the protease inhibitors that may be clinically relevant. Finally, these effects on insulin secretion after a 48 h incubation with protease inhibitor were associated with a reduction of the insulin-stimulated phosphorylation of insulin signaling parameters, particularly IRS-2, suggesting that protease inhibitor-induced alterations in the insulin signaling pathway may contribute to the impaired beta-cell function.
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Mikines, K. J., P. A. Farrell, B. Sonne, B. Tronier, and H. Galbo. "Postexercise dose-response relationship between plasma glucose and insulin secretion." Journal of Applied Physiology 64, no. 3 (March 1, 1988): 988–99. http://dx.doi.org/10.1152/jappl.1988.64.3.988.
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To investigate whether exertion changes beta-cell reactivity to glucose stimulation and to characterize the beta-cell response to glucose in humans, we performed four sequential 90-min hyperglycemic clamps (7, 11, 20, and 35 mM). Concentrations of hormones and metabolites involved in glucoregulation were measured. Metabolic rate and substrate utilization were studied by indirect calorimetry. Studies were performed without prior exercise, as well as 2 and 48 h after 60 min of bicycle exercise at 150 W. We found 1) a progressive increase in insulin concentrations reaching 1,092 ± 135 microU/ml with increasing glucose levels, 2) linear relationships between glucose concentrations and concentrations of C-peptide (r = 0.931 ± 0.008) and proinsulin (r = 0.952 ± 0.009),3) increased glucose oxidation with increasing glucose uptake, 4) increased plasma norepinephrine, O2 uptake, and beta-hydroxybutyrate at greater than or equal to 20 mM glucose, and 5) no change in beta-cell response or glucose-induced thermogenesis after one bout of exercise despite no compensating changes in plasma concentrations of hormones or metabolites. We conclude that the beta-cell has a very large secretory potential. Secretion of the beta-cell increases linearly with prolonged, graded hyperglycemia. The processing of proinsulin is unchanged during prolonged beta-cell stimulation. In addition, hyperglycemia and sympathetic nervous activity induced by hyperinsulinemia enhance metabolic rate and ketone body production. Finally, a single bout of exercise does not influence either the beta-cell response to intravenous glucose or glucose-induced thermogenesis.
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Bułdak, Łukasz, Estera Skudrzyk, Grzegorz Machnik, Aleksandra Bołdys, Rafał Jakub Bułdak, and Bogusław Okopień. "Exenatide improves antioxidant capacity and reduces the expression of LDL receptors and PCSK9 in human insulin-secreting 1.1E7 cell line subjected to hyperglycemia and oxidative stress." Postępy Higieny i Medycyny Doświadczalnej 76, no. 1 (January 1, 2022): 16–23. http://dx.doi.org/10.2478/ahem-2021-0037.
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Abstract Introduction GLP-1 receptor agonists (e.g., exenatide) are novel drugs used in the treatment of diabetes. These drugs, working with other mechanisms of action, improve glycemic control by increasing secretion of insulin and improving survival of pancreatic islet beta cells. Alterations in the oxidative stress level or the expression of proteins associated with cholesterol uptake might be responsible for those findings. Currently, there are few in vitro studies on the impact of exenatide antioxidant capacity in human islet beta cell lines and none that assess the influence of exenatide on LDL receptors and PCSK9 under hyperglycemia and oxidative stress. Therefore, we evaluated the impact of exenatide on antioxidant capacity, insulin secretion, and proteins involved in cholesterol metabolism. Materials and Method An in vitro culture of insulin-secreting cells 1.1E7 was subjected to hyperglycemia and oxidative stress. Assessment was made of the expression of enzymes associated with oxidative stress (NADPH oxidase, catalase, glutathione peroxidase, superoxide dismutase, iNOS) and cholesterol uptake (LDL receptors, PCSK9). Additionally, insulin and nitrite levels in culture media were quantified. Results We showed that exenatide improves expression of catalase and reduces the amount of nitrite in cell cultures in a protein kinase A–dependent manner. Those results were accompanied by a drop in the expression of LDL receptors and PCSK9. Insulin secretion was modestly increased in the culture condition. Conclusions Our findings show potential protective mechanisms exerted by exenatide in human insulin-secreting pancreatic beta cell line (1.1E7), which may be exerted through increased antioxidant capacity and reduced accumulation of cholesterol.
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So, Wing Yan, Wai Nam Liu, Adrian Kee Keong Teo, Guy A. Rutter, and Weiping Han. "Paired box 6 programs essential exocytotic genes in the regulation of glucose-stimulated insulin secretion and glucose homeostasis." Science Translational Medicine 13, no. 600 (June 30, 2021): eabb1038. http://dx.doi.org/10.1126/scitranslmed.abb1038.
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The paired box 6 (PAX6) transcription factor is crucial for normal pancreatic islet development and function. Heterozygous mutations of PAX6 are associated with impaired insulin secretion and early-onset diabetes mellitus in humans. However, the molecular mechanism of PAX6 in controlling insulin secretion in human beta cells and its pathophysiological role in type 2 diabetes (T2D) remain ambiguous. We investigated the molecular pathway of PAX6 in the regulation of insulin secretion and the potential therapeutic value of PAX6 in T2D by using human pancreatic beta cell line EndoC-βH1, the db/db mouse model, and primary human pancreatic islets. Through loss- and gain-of-function approaches, we uncovered a mechanism by which PAX6 modulates glucose-stimulated insulin secretion (GSIS) through a cAMP response element–binding protein (CREB)/Munc18-1/2 pathway. Moreover, under diabetic conditions, beta cells and pancreatic islets displayed dampened PAX6/CREB/Munc18-1/2 pathway activity and impaired GSIS, which were reversed by PAX6 replenishment. Adeno-associated virus–mediated PAX6 overexpression in db/db mouse pancreatic beta cells led to a sustained amelioration of glycemic perturbation in vivo but did not affect insulin resistance. Our study highlights the pathophysiological role of PAX6 in T2D-associated beta cell dysfunction in humans and suggests the potential of PAX6 gene transfer in preserving and restoring beta cell function.
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Kim, Yong Kyung, Lori Sussel, and Howard W. Davidson. "Inherent Beta Cell Dysfunction Contributes to Autoimmune Susceptibility." Biomolecules 11, no. 4 (March 30, 2021): 512. http://dx.doi.org/10.3390/biom11040512.
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The pancreatic beta cell is a highly specialized cell type whose primary function is to secrete insulin in response to nutrients to maintain glucose homeostasis in the body. As such, the beta cell has developed unique metabolic characteristics to achieve functionality; in healthy beta cells, the majority of glucose-derived carbons are oxidized and enter the mitochondria in the form of pyruvate. The pyruvate is subsequently metabolized to induce mitochondrial ATP and trigger the downstream insulin secretion response. Thus, in beta cells, mitochondria play a pivotal role in regulating glucose stimulated insulin secretion (GSIS). In type 2 diabetes (T2D), mitochondrial impairment has been shown to play an important role in beta cell dysfunction and loss. In type 1 diabetes (T1D), autoimmunity is the primary trigger of beta cell loss; however, there is accumulating evidence that intrinsic mitochondrial defects could contribute to beta cell susceptibility during proinflammatory conditions. Furthermore, there is speculation that dysfunctional mitochondrial responses could contribute to the formation of autoantigens. In this review, we provide an overview of mitochondrial function in the beta cells, and discuss potential mechanisms by which mitochondrial dysfunction may contribute to T1D pathogenesis.
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Hivelin, Céline, Sophie Béraud-Dufour, Christelle Devader, Amar Abderrahmani, Sébastien Moreno, Hamid Moha ou Maati, Alaeddine Djillani, et al. "Potentiation of Calcium Influx and Insulin Secretion in Pancreatic Beta Cell by the Specific TREK-1 Blocker Spadin." Journal of Diabetes Research 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/3142175.
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Inhibition of the potassium channels TREK-1 by spadin (SPA) is currently thought to be a promising therapeutic target for the treatment of depression. Since these channels are expressed in pancreatic β-cells, we investigated their role in the control of insulin secretion and glucose homeostasis. In this study, we confirmed the expression of TREK-1 channels in the insulin secreting MIN6-B1 β-cell line and in mouse islets. We found that their blockade by SPA potentiated insulin secretion induced by potassium chloride dependent membrane depolarization. Inhibition of TREK-1 by SPA induced a decrease of the resting membrane potential (ΔVm~12 mV) and increased the cytosolic calcium concentration. In mice, administration of SPA enhanced the plasma insulin level stimulated by glucose, confirming its secretagogue effect observed in vitro. Taken together, this work identifies SPA as a novel potential pharmacological agent able to control insulin secretion and glucose homeostasis.
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Allen, Jack G., and Jeffery S. Tessem. "Ca2+ Sensors Assemble: Function of the MCU Complex in the Pancreatic Beta Cell." Cells 11, no. 13 (June 22, 2022): 1993. http://dx.doi.org/10.3390/cells11131993.
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The Mitochondrial Calcium Uniporter Complex (MCU Complex) is essential for β-cell function due to its role in sustaining insulin secretion. The MCU complex regulates mitochondrial Ca2+ influx, which is necessary for increased ATP production following cellular glucose uptake, keeps the cell membrane K+ channels closed following initial insulin release, and ultimately results in sustained insulin granule exocytosis. Dysfunction in Ca2+ regulation results in an inability to sustain insulin secretion. This review defines the functions, structure, and mutations associated with the MCU complex members mitochondrial calcium uniporter protein (MCU), essential MCU regulator (EMRE), mitochondrial calcium uptake 1 (MICU1), mitochondrial calcium uptake 2 (MICU2), and mitochondrial calcium uptake 3 (MICU3) in the pancreatic β-cell. This review provides a framework for further evaluation of the MCU complex in β-cell function and insulin secretion.
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Conroy, SJ, YH Abdel-Wahab, EM Caraher, PM Byrne, E. Murphy, J. Nolan, PR Flatt, and P. Newsholme. "Evidence for complement-dependent and -independent inhibition of insulin secretion from clonal beta-cells incubated in the presence of sera of newly diagnosed IDDM patients." Journal of Endocrinology 164, no. 2 (February 1, 2000): 139–47. http://dx.doi.org/10.1677/joe.0.1640139.
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There are conflicting reports on the effect of serum from patients with insulin-dependent diabetes mellitus (IDDM) or normal human serum on beta-cell function and insulin secretion. Here, we report that the sera of newly diagnosed IDDM patients potently suppresses insulin secretion from a clonal rat pancreatic beta-cell line (BRIN-BD11), but do not alter cell viability. Indeed, the viability of the beta-cells was not significantly different between cells cultured in 10% (v/v) IDDM sera, normal human sera, or fetal calf serum after 24, 48 and 72 h. Alanine-stimulated insulin secretion from cells cultured for 24 h in (10% v/v) IDDM patient sera was reduced to 48% of that secreted from cells cultured in (10% v/v) normal human sera. After depletion of the complement components C1q and C3, the inhibition of insulin secretion induced by IDDM patient sera was significantly reversed (no significant difference was observed between cells cultured in complement-depleted IDDM patient sera and cells cultured in normal human sera or complement-depleted normal human sera). The concentration of glutamic acid decarboxylase (GAD) autoantibodies was markedly increased in the sera of six out of nine newly diagnosed IDDM patients in this study, whereas insulin auto-antibodies (IAA) were detected in the sera of three of the nine patients and islet-cell antibodies (ICA) in the sera of five of them. In addition, the concentration of soluble terminal complement complexes (SC5-9) was greater in some of the beta-cell culture media samples after 24 h incubation when the incubation medium was supplemented with IDDM patient sera than when supplementation was with normal human sera. We propose that the mechanism of sera-induced inhibition of insulin secretion from clonal beta-cells may involve complement- and cytokine-stimulated intracellular events that attenuate the metabolite-induced secretory process.
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Josefsen, K., J. P. Stenvang, H. Kindmark, P.-O. Berggren, T. Horn, T. Kjær, and K. Buschard. "Fluorescence-activated cell sorted rat islet cells and studies of the insulin secretory process." Journal of Endocrinology 149, no. 1 (April 1996): 145–54. http://dx.doi.org/10.1677/joe.0.1490145.
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Abstract Studies of individual cell types in the islets of Langerhans are complicated by the cells' functional coupling by gap junctions and paracrine interaction. Access to purified alpha and beta cells is therefore desirable. We present a simplified and optimized method for fluorescence-activated cell sorting of endocrine pancreatic rat islets. For dispersion of the islets, dispase was superior to trypsin, as the number of vital single cells was higher (1·1 ± 0·1 × 103 vs 0·6 ± 0·1 × 103/islet, P<0·05). The purity of the sorted cells was 96·7 ± 1·2% for the non-beta cells and 97·8 ± 0·6% for the beta cells (numbers in percentages of endocrine cells). In culture, isolated beta cells, non-beta cells and mixtures of beta and non-beta cells formed aggregates, but not at low temperature (4 °C) and not in medium with low serum content (2%). Finally, in pure beta cell aggregates, glucose stimulated changes in cytoplasmic free Ca2+ concentration although both glucose- and arginine-induced insulin secretion was much reduced. We conclude that alpha cells are necessary for insulin secretion but not for glucose sensing. Journal of Endocrinology (1996) 149, 145–154
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Sakuma, Nobuko, San-e. Ishikawa, Koji Okada, Jun-ichi Miyazaki, and Toshikazu Saito. "Glucose induces calcium-dependent and calcium-independent insulin secretion from the pancreatic beta cell line MIN6." European Journal of Endocrinology 133, no. 2 (August 1995): 227–34. http://dx.doi.org/10.1530/eje.0.1330227.
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Sakuma N, Ishikawa S, Okada K, Miyazaki J, Saito T, Glucose induces calcium-dependent and calcium-independent insulin secretion from the pancreatic beta cell line MIN6. Eur J Endocrinol 1995;133:227–34. ISSN 0804–4643 The present study was undertaken to determine whether there are Ca2+-dependent and -independent pathways of glucose-induced insulin secretion from the pancreatic beta cell line MIN6. Glucose at a concentration of 16.7 mmol/l caused marked increases in cellular free calcium [Ca2+]1) and insulin secretion, which depended on glucose metabolism. When cells were pretreated with 20 mmol/l mannoheptulose, an inhibitor of glucokinase, the 16.7 mmol/l glucose induced a rise in [Ca2+]1 and insulin secretion disappeared. Also, l-leucine and l-arginine increased [Ca2+]1 and induced insulin secretion. Under Ca2+-free conditions, insulin release was still induced, without any change in [Ca2+]1, by these three different stimulants. The cumulative values of insulin secretion were 13.7–29.3% of the control, which were significantly less than that in the presence of Ca2+. Cellular alkalinization occurred in response to all these stimulants, irrespective of the presence or absence of Ca2+. Forskolin, a diterpene activator of adenylate cyclase, produced insulin secretion independently of [Ca2+]1, which accompanied cellular alkalinization. Also, a high glucose level increased cellular cyclic AMP (cAMP) production in the presence and absence of Ca2+, and the effect was diminished by approximately 73% in Ca2+-free conditions. These results indicate that a high glucose level stimulates both Ca2+-dependent and -independent insulin secretion from pancreatic beta cells. We suggest that the cAMP production and the cellular alkalinization participate in the Ca2+-independent mechanism. Nobuko Sakuma, Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical School, 3311-1 Yakushiji Minamikawachi-machi, Tochigi 329-04, Japan
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Radosavljevic, Tatjana, Vera Todorovic, and Branka Sikic. "Insulin secretion: mechanisms of regulation." Medical review 57, no. 5-6 (2004): 249–53. http://dx.doi.org/10.2298/mpns0406249r.
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Regulation of insulin secretion Beta cells are unique endocrine cells. They respond positively, in terms of insulin secretion, not only to changes in the extracellular glucose concentration, but also to activators of the phospholipase C (cholecystokinin or acetylcholine), and to activators of adenylate cyclase (glucagon, glucagon-like peptide-1, or gastric inhibitory polypeptide). Major messengers which mediate glucose action for insulin release are Ca2%, adenosine triphosphate (ATP) and diacylglycerol (DAG). Major pathways of insulin release stimulation There are four major pathways involved in stimulation of insulin release. The first pathway is KATP channel-dependent pathway in which increased blood glucose concentrations and increased b-cell metabolism result in a change in intracellular ATP/ADP ratio. This is a contributory factor in closure of ATP-dependent K% channels, depolarization of b-cell membrane, in increased voltage-dependent L-type Ca2%channel activity. Increased Ca2% influx results in increased intracellular Ca2% and stimulated insulin release. KATP channel-independent pathway augments Ca2%-stimulated insulun secretion of KATP channel-dependent pathway. Major potentiation of release results from hormonal and peptidergic activation of receptors linked to adenylyl cyclase. Adenylyl cyclase activity is stimulated by hormones such as vasoactive intestinal peptide (VIP), glucagon-like peptide-1 (GLP-1), and so on. These hormones, acting via G protein, stimulate adenylyl cyclase, thus causing a rise in cyclic adenosine monophosphate (cAMP) and activation of protein kinase A (PKA). Increased activity of PKA results in potentiation of insulin secretion.
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Simoni, Ariella D., Holly A. Huber, Senta K. Georgia, and Stacey D. Finley. "Phosphatases are predicted to govern prolactin-mediated JAK–STAT signaling in pancreatic beta cells." Integrative Biology 14, no. 2 (February 2022): 37–48. http://dx.doi.org/10.1093/intbio/zyac004.
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Abstract Patients with diabetes are unable to produce a sufficient amount of insulin to properly regulate their blood glucose levels. One potential method of treating diabetes is to increase the number of insulin-secreting beta cells in the pancreas to enhance insulin secretion. It is known that during pregnancy, pancreatic beta cells proliferate in response to the pregnancy hormone, prolactin (PRL). Leveraging this proliferative response to PRL may be a strategy to restore endogenous insulin production for patients with diabetes. To investigate this potential treatment, we previously developed a computational model to represent the PRL-mediated JAK–STAT signaling pathway in pancreatic beta cells. Here, we applied the model to identify the importance of particular signaling proteins in shaping the response of a population of beta cells. We simulated a population of 10 000 heterogeneous cells with varying initial protein concentrations responding to PRL stimulation. We used partial least squares regression to analyze the significance and role of each of the varied protein concentrations in producing the response of the cell. Our regression models predict that the concentrations of the cytosolic and nuclear phosphatases strongly influence the response of the cell. The model also predicts that increasing PRL receptor strengthens negative feedback mediated by the inhibitor suppressor of cytokine signaling. These findings reveal biological targets that can potentially be used to modulate the proliferation of pancreatic beta cells to enhance insulin secretion and beta cell regeneration in the context of diabetes.
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Sjoholm, A., N. Welsh, and C. Hellerstrom. "Lithium increases DNA replication, polyamine content, and insulin secretion by rat pancreatic beta-cells." American Journal of Physiology-Cell Physiology 262, no. 2 (February 1, 1992): C391—C395. http://dx.doi.org/10.1152/ajpcell.1992.262.2.c391.
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The impact of long-term lithium exposure on the replication, polyamine content, and insulin production of rat pancreatic beta-cells was examined. Fetal rat pancreatic islets enriched in beta-cells were isolated and cultured for 3 days in the presence of different concentrations of LiCl. It was found that lithium dose dependently stimulated beta-cell replication, evoking a 40% increase in beta-cell replication at 1 mM, which was further increased to 70% at 10 mM of the ion. In contrast, the islet contents of insulin mRNA and insulin and insulin biosynthesis rates remained unaltered. The long-term insulin accumulation in the culture medium was nevertheless increased in LiCl-treated groups. In addition, neither the mitogenic effect nor the increased insulin accumulation in the medium by lithium was further augmented by growth hormone, which itself stimulated these functions. Lithium was also found to elevate the islet content of polyamines. Treatment with enzymatic inhibitors of polyamine synthesis failed to preclude the mitogenic and secretagogic impact of lithium, suggesting that the increased contents of polyamines did not convey the lithium effect. We conclude that lithium treatment stimulates rat beta-cell replication and long-term insulin secretion in vitro. These direct effects of the ion on the beta-cell may contribute to the antidiabetic effect of lithium encountered in animal models and patients.
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Larsen, S., J. Hilsted, B. Tronier, and H. Worning. "Pancreatic hormone secretion in chronic pancreatitis without residual beta-cell function." Acta Endocrinologica 118, no. 3 (July 1988): 357–64. http://dx.doi.org/10.1530/acta.0.1180357.
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Abstract. Hormonal responses (glucagon, pancreatic polypeptide and somatostatin) to iv glucagon, iv arginine, and ingestion of a mixed meal were investigated in 6 patients with insulin-dependent diabetes secondary to chronic pancreatitis without beta-cell function, in 8 Type I (insulin-dependent) diabetics without beta-cell function, and 8 healthy subjects. No significant differences were found between the two diabetic groups regarding glucagon responses to arginine and meal ingestion. In the patients with diabetes secondary to chronic pancreatitis compared with Type I diabetics and normal controls, the pancreatic polypeptide concentrations were significantly lower and somatostatin concentrations were significantly higher after glucagon, arginine and a mixed meal. Thus, pancreatic glucagon secretion was preserved in patients with insulin-dependent diabetes secondary to chronic pancreatitis, having no residual beta-cell function. These findings suggest that pancreatic glucagon deficiency is not absolute in insulin-dependent diabetes secondary to chronic pancreatitis. A high level of somatostatin may contribute to a lower blood glucose level in patients with chronic pancreatitis.
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Bendayan, M., D. Malide, E. Ziv, E. Levy, R. Ben-Sasson, R. Kalman, H. Bar-On, M. Chrétien, and N. Seidah. "Immunocytochemical investigation of insulin secretion by pancreatic beta-cells in control and diabetic Psammomys obesus." Journal of Histochemistry & Cytochemistry 43, no. 8 (August 1995): 771–84. http://dx.doi.org/10.1177/43.8.7622840.
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Hyperproinsulinemia is a characteristic feature of non-insulin-dependent diabetes mellitus (NIDDM) caused by pancreatic beta-cell dysfunction through a secretion-related alteration or impaired proinsulin processing. We have investigated the insulin processing and secretion in Psammomys obesus fed with low- and high-energy diets, which represent a model for diet-induced NIDDM. With a high-energy diet the animals develop hyperglycemia and hyperinsulinemia, whereas those maintained on a low-energy diet remain normoglycemic. Although a large amount of insulin immunoreactivity was detected in beta-cells of the normoglycemic compared to hyperglycemic animals, in situ hybridization for insulin mRNA demonstrated a particularly high signal in the beta-cells of the hyperglycemic animals. By electron microscopy, the beta-cells of normoglycemic animals displayed large accumulations of secretory granules, whereas those of the hyperglycemic animals contained very few granules and large deposits of glycogen. These results reflect a secretory resting condition for the cells of the normoglycemic animals in contrast to stimulated synthetic and secretory activities in the cells of the hyperglycemic ones. Using colloidal gold immunocytochemistry at the electron microscopic level, we have examined subcellular proinsulin processing in relation to the convertases PC1 and PC2. Immunolabeling of proinsulin, insulin, C-peptide, PC1, and PC2 in different cell compartments involved in beta-cell secretion were evaluated. Both PC1 and PC2 antigenic sites were detected in beta-cells of hyperglycemic Psammomys, but their labeling intensity was weak compared to the cells of normoglycemic animals. In both groups of animals, higher levels of PC2 were found in the Golgi apparatus than in the immature granules. Major decreases in proinsulin, insulin, PC1, and PC2 immunoreactivity were recorded in beta-cells of the hyperglycemic Psammomys. In addition, all these antigenic sites were detected in lysosome-like structures, revealing a major degradation process. These results suggest that the insulin-secreting cells in hyperglycemic Psammomys obesus are in a chronic secretory state during which impaired processing of proinsulin appears to take place.
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Rastogi, D. P., A. C. Saxena, and Sunil Kumar. "Pancreatic beta-cell regeneration." British Homeopathic Journal 77, no. 03 (July 1988): 147–51. http://dx.doi.org/10.1016/s0007-0785(88)80071-1.
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Abstract Cephalendra, indica ∅ (41% v/v alcoholic extract of the wild variety of Cephalendra indica Naud.), on regular administration in doses ranging from 25 μml to 75 μml/100 g of body weight (gbw) by the oral or intraperitoneal (ip) route produced a significant fall in blood sugar level in alloxan-induced diabetic rats. Biochemical studies showed stabilization of blood sugar level in 70% of cases of fourteen to twenty days after withdrawal of the drug. Histopathological studies revealed regeneration of pancreatic β cells. The hypothesis is that the drug acts through the hypothalamo-hypophysial-pancreatic axis, producing selective regeneration of β cells. The drug may indirectly release inhibitory factors from hypothalamic neurons, inhibiting the secretion of growth hormone and triggering insulin secretion from β cells. The therapeutic action of the drug on pancreatic β cells and lack of acute and subacute toxicity may open up new prospects in the treatment of diabetes mellitus.
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Sehlin, J. "Effect of perchlorate on calcium uptake and insulin secretion in mouse pancreatic islets." Biochemical Journal 248, no. 1 (November 15, 1987): 109–15. http://dx.doi.org/10.1042/bj2480109.
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Microdissected beta-cell-rich pancreatic islets of non-inbred ob/ob mice were used in studies of how perchlorate (CIO4-) affects stimulus-secretion coupling in beta-cells. CIO4- at 16 mM potentiated D-glucose-induced insulin release, without inducing secretion at non-stimulatory glucose concentrations. The potentiation mainly applied to the first phase of stimulated insulin release. In the presence of 20 mM-glucose, the half-maximum effect of CIO4- was reached at 5.5 mM and maximum effect at 12 mM of the anion. The potentiation was reversible and inhibitable by D-mannoheptulose (20 mM) or Ca2+ deficiency. CIO4- at 1-8 mM did not affect glucose oxidation. The effects on secretion were paralleled by a potentiation of glucose-induced 45Ca2+ influx during 3 min. K+-induced insulin secretion and 45Ca2+ uptake were potentiated by 8-16 mM-CIO4-. The spontaneous inactivation of K+-induced (20.9 mM-K+) insulin release was delayed by 8 mM-CIO4-. The anion potentiated the 45Ca2+ uptake induced by glibenclamide, which is known to depolarize the beta-cell. Insulin release was not affected by 1-10 mM-trichloroacetate. It is suggested that CIO4- stimulates the beta-cell by affecting the gating of voltage-controlled Ca2+ channels.