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1
Miralles, Francisco, Tadej Battelino, Paul Czernichow, and Raphael Scharfmann. "TGF-β Plays a Key Role in Morphogenesis of the Pancreatic Islets of Langerhans by Controlling the Activity of the Matrix Metalloproteinase MMP-2." Journal of Cell Biology 143, no. 3 (November 2, 1998): 827–36. http://dx.doi.org/10.1083/jcb.143.3.827.
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Islets of Langerhans are microorgans scattered throughout the pancreas, and are responsible for synthesizing and secreting pancreatic hormones. While progress has recently been made concerning cell differentiation of the islets of Langerhans, the mechanism controlling islet morphogenesis is not known. It is thought that these islets are formed by mature cell association, first differentiating in the primitive pancreatic epithelium, then migrating in the extracellular matrix, and finally associating into islets of Langerhans. This mechanism suggests that the extracellular matrix has to be degraded for proper islet morphogenesis. We demonstrated in the present study that during rat pancreatic development, matrix metalloproteinase 2 (MMP-2) is activated in vivo between E17 and E19 when islet morphogenesis occurs. We next demonstrated that when E12.5 pancreatic epithelia develop in vitro, MMP-2 is activated in an in vitro model that recapitulates endocrine pancreas development (Miralles, F., P. Czernichow, and R. Scharfmann. 1998. Development. 125: 1017–1024). On the other hand, islet morphogenesis was impaired when MMP-2 activity was inhibited. We next demonstrated that exogenous TGF-β1 positively controls both islet morphogenesis and MMP-2 activity. Finally, we demonstrated that both islet morphogenesis and MMP-2 activation were abolished in the presence of a pan-specific TGF-β neutralizing antibody. Taken together, these observations demonstrate that in vitro, TGF-β is a key activator of pancreatic MMP-2, and that MMP-2 activity is necessary for islet morphogenesis.
2
Da Silva Xavier, Gabriela. "The Cells of the Islets of Langerhans." Journal of Clinical Medicine 7, no. 3 (March 12, 2018): 54. http://dx.doi.org/10.3390/jcm7030054.
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Islets of Langerhans are islands of endocrine cells scattered throughout the pancreas. A number of new studies have pointed to the potential for conversion of non-β islet cells in to insulin-producing β-cells to replenish β-cell mass as a means to treat diabetes. Understanding normal islet cell mass and function is important to help advance such treatment modalities: what should be the target islet/β-cell mass, does islet architecture matter to energy homeostasis, and what may happen if we lose a particular population of islet cells in favour of β-cells? These are all questions to which we will need answers for islet replacement therapy by transdifferentiation of non-β islet cells to be a reality in humans. We know a fair amount about the biology of β-cells but not quite as much about the other islet cell types. Until recently, we have not had a good grasp of islet mass and distribution in the human pancreas. In this review, we will look at current data on islet cells, focussing more on non-β cells, and on human pancreatic islet mass and distribution.
3
Bucher, Mathe, Bosco, Andres, Bühler, Morel, and Berney. "Islet of Langerhans Transplantation for the Treatment of Type 1 Diabetes." Swiss Surgery 9, no. 5 (October 1, 2003): 242–46. http://dx.doi.org/10.1024/1023-9332.9.5.242.
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Islet of Langerhans transplantation is gaining recognition as a therapy for type 1 diabetes. The procedure involves enzymatic digestion of the pancreatic tissue, purification of the islets from the exocrine tissue, infusion of the islets into the portal vein and implantation in the liver. Until 1999, an overall rate of insulin independence of 14% at one year was reported in the International Islet Transplant Registry. The results of the "Edmonton protocol" since 2000 were a breakthrough in the field, with reports of 80% insulin independence at 1-year after solitary islet transplantation in non uremic patients with brittle type 1 diabetes. A rapamycin-based, steroid-free, islet-sparing immunosuppressive regimen was designed and the problem of the insufficient islet mass was tackled by sequential infusions of islets isolated from at least two pancreata. The University of Geneva has been involved in clinical islet transplantation since 1992, and has performed 51 allogeneic and 17 autologous. Twenty-one patients have been transplanted in Geneva since 2002. They were five solitary islet transplants, 14 islet after kidney transplants and two simultaneous islet-kidney (SIK) recipients. Insulin independence was achieved in 67%.
4
Goess, Ruediger, Ayse Mutgan, Umut Çalışan, Yusuf Erdoğan, Lei Ren, Carsten Jäger, Okan Safak, et al. "Patterns and Relevance of Langerhans Islet Invasion in Pancreatic Cancer." Cancers 13, no. 2 (January 11, 2021): 249. http://dx.doi.org/10.3390/cancers13020249.
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Background: Pancreatic cancer‐associated diabetes mellitus (PC‐DM) is present in most patients with pancreatic cancer, but its pathogenesis remains poorly understood. Therefore, we aimed to characterize tumor infiltration in Langerhans islets in pancreatic cancer and determine its clinical relevance. Methods: Langerhans islet invasion was systematically analyzed in 68 patients with pancreatic ductal adenocarcinoma (PDAC) using histopathological examination and 3D in vitro migration assays were performed to assess chemoattraction of pancreatic cancer cells to islet cells. Results: Langerhans islet invasion was present in all patients. We found four different patterns of islet invasion: (Type I) peri‐insular invasion with tumor cells directly touching the boundary, but not penetrating the islet; (Type II) endo‐insular invasion with tumor cells inside the round islet; (Type III) distorted islet structure with complete loss of the round islet morphology; and (Type IV) adjacent cancer and islet cells with solitary islet cells encountered adjacent to cancer cells. Pancreatic cancer cells did not exhibit any chemoattraction to islet cells in 3D assays in vitro. Further, there was no clinical correlation of islet invasion using the novel Islet Invasion Severity Score (IISS), which includes all invasion patterns with the occurrence of diabetes mellitus. However, Type IV islet invasion was related to worsened overall survival in our cohort. Conclusions: We systematically analyzed, for the first time, islet invasion in human pancreatic cancer. Four different main patterns of islet invasion were identified. Diabetes mellitus was not related to islet invasion. However, more research on this prevailing feature of pancreatic cancer is needed to better understand underlying principles.
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Goess, Ruediger, Ayse Ceren Mutgan, Umut Çalışan, Yusuf Ceyhun Erdoğan, Lei Ren, Carsten Jäger, Okan Safak, et al. "Patterns and Relevance of Langerhans Islet Invasion in Pancreatic Cancer." Cancers 13, no. 2 (January 11, 2021): 249. http://dx.doi.org/10.3390/cancers13020249.
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Background: Pancreatic cancer‐associated diabetes mellitus (PC‐DM) is present in most patients with pancreatic cancer, but its pathogenesis remains poorly understood. Therefore, we aimed to characterize tumor infiltration in Langerhans islets in pancreatic cancer and determine its clinical relevance. Methods: Langerhans islet invasion was systematically analyzed in 68 patientswith pancreatic ductal adenocarcinoma (PDAC) using histopathological examination and 3D in vitro migration assays were performed to assess chemoattraction of pancreatic cancer cells to isletcells. Results: Langerhans islet invasion was present in all patients. We found four different patterns of islet invasion: (Type I) peri‐insular invasion with tumor cells directly touching the boundary, but not penetrating the islet; (Type II) endo‐insular invasion with tumor cells inside the round islet; (Type III) distorted islet structure with complete loss of the round islet morphology; and (Type IV)adjacent cancer and islet cells with solitary islet cells encountered adjacent to cancer cells. Pancreatic cancer cells did not exhibit any chemoattraction to islet cells in 3D assays in vitro. Further, there was no clinical correlation of islet invasion using the novel Islet Invasion Severity Score (IISS), which includes all invasion patterns with the occurrence of diabetes mellitus. However, Type IV islet invasion was related to worsened overall survival in our cohort. Conclusions: We systematically analyzed, for the first time, islet invasion in human pancreatic cancer. Four different main patterns of islet invasion were identified. Diabetes mellitus was not related to islet invasion. However, moreresearch on this prevailing feature of pancreatic cancer is needed to better understand underlying principles.
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Crowther, N. J., C. F. Gotfredsen, A. J. Moody, and I. C. Green. "Immunological and insulin secretory studies on isolated porcine islets of Langerhans." Journal of Endocrinology 126, no. 1 (July 1990): 43–49. http://dx.doi.org/10.1677/joe.0.1260043.
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ABSTRACT Since porcine islets are considered a likely tissue source for islet transplantation we have studied the insulin secretory responses to stimuli and some of the cell surface antigen characteristics of porcine islet cells. In a static incubation system, the threshold level of glucose required for the stimulation of insulin secretion from freshly isolated porcine islets was found to be between 2·8 and 4·2 mmol glucose/l. Arginine (5 mmol/l) and 3-isobutyl-1-methylxanthine (1 mmol/l) potentiated insulin release induced by 8·3 mmol glucose/l. Leucine (5 mmol/l) initiated release in the presence of 2 mmol glucose/l. Neither β-hydroxybutyrate (10 mmol/l) nor octanoate (5 mmol/l) potentiated insulin release induced by 8·3 mmol glucose/l, but β-hydroxybutyrate initiated release in the presence of 2 mmol glucose/l while octanoate did not. A 125I-labelled protein A binding assay and an enzyme-linked immunosorbent assay system were used to detect antibody binding to islet and non-islet cells. Monoclonal antibodies raised against intact rat islets were shown to bind to both porcine and rat islet cells but not to rat hepatoma tissue culture cells or rat insulinoma cells. The serum from recently diagnosed type I diabetics was shown to bind to rat islet cells in a 125I-labelled protein A binding assay, while serum from control subjects showed little, if any, binding. Porcine islet cells were unable to distinguish between the sera of recently diagnosed type I diabetics and controls in a similar assay. In conclusion, porcine islets respond to many of the major insulin secretagogues to which human islets are sensitive. However, they have a lower secretory response to these compounds compared with that reported for human islets. Monoclonal antibody and human sera binding studies show that rat and porcine islets share some cell surface antigens but it remains to be seen whether the inability of porcine islets to discriminate between diabetic and non-diabetic sera is an advantage for transplantation, indicating less likelihood of an islet-specific autoimmune-like humoral attack. Journal of Endocrinology (1990) 126, 43–4
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Van Der Burg, Michael P. M., Onno R. Guicherit, Marijke Frölich, Frans A. Prins, Jan Anthonie Bruijn, and Hein G. Gooszen. "Cell Preservation in University of Wisconsin Solution during Isolation of Canine Islets of Langerhans." Cell Transplantation 3, no. 4 (July 1994): 315–24. http://dx.doi.org/10.1177/096368979400300408.
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Allogeneic islet transplantation in Type I diabetic patients is considerably hampered by the variable outcome of islet isolation and purification. After collagenase digestion of the pancreas, islet isolation is traditionally performed under hypothermic conditions in physiological solutions such as Hanks and RPMI. The University of Wisconsin solution (UWS) has been shown superior for hypothermic preservation of the pancreas. We, therefore, compared the UWS and RPMI for canine islet isolation and subsequent purification in either a conventional hyperosmotic density gradient of dextran in Hanks, or a novel normosmotic density gradient of Percoll in UWS. The isolation solution did not affect islet yield before purification (51% of the native islet mass). Loss of amylase (30%) and swelling of the acinar cells were observed in RPMI. In contrast, no loss of amylase and slight shrinkage of the acinar cells were observed in the UWS. Cell swelling affected the density separation and viability of the cells. Dextran density separation resulted in a 15% purity and 41% recovery of the islets isolated in RPMI, as compared to a 93% purity and 52% recovery of islets isolated in UWS. Percoll density separation improved the purity (99%) and recovery (74%) of islets isolated in UWS. Islets isolated in UWS demonstrated a superior basal and glucose stimulated insulin release during perifusion. Electron microscopy demonstrated a well-preserved islet ultrastructure after isolation in both solutions — except for slightly swollen mitochondria after isolation in RPMI. Autotransplantation of islets in pancreatectomised dogs was successful both after isolation in UWS and RPMI. We conclude that prevention of cell swelling during isolation and purification in the UWS resulted in an improved yield of viable and consistent virtually pure islets. Prevention of cell swelling during islet isolation should facilitate the analysis and control of other factors affecting outcome in man.
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Samejima, Tadashi, Kenji Yamaguchi, Hiroo Iwata, Noriyuki Morikawa, and Yoshito Ikada. "Gelatin Density Gradient for Isolation of Islets of Langerhans." Cell Transplantation 7, no. 1 (January 1998): 37–45. http://dx.doi.org/10.1177/096368979800700106.
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Isolation of islets of Langerhans (islets) has been performed by means of collagenase digestion of the pancreatic tissue combined with density gradient separation of islets from unwanted exocrine tissues. An enormous number of islets are necessary for clinical islet transplantation. The density gradient used for isolation of a large number of islets should satisfy several requirements in addition to those for the conventional density gradients, such as high viscosity for creating fine interfaces with a large area, easy sterilization, and low cost. This study is concerned with the development of a new density gradient made of low-molecular-weight gelatin. We isolated islets from the hamster pancreatic tissue using the gelatin density gradients. The yield and purity of islet and its insulin release function were compared with those of islets isolated using Ficoll and Ficoll-Conray density gradients that have been conventionally used. The new gelatin density gradient can separate islets from the unwanted exocrine tissue as effectively as the Ficoll density gradient and more effectively than the Ficoll-Conray density gradients. The islets collected using the gelatin gradient retain ability of insulin release increase in response to glucose stimulation, similar to those isolated by the Ficoll-Conray gradient and more than those collected by the Ficoll gradient. In addition, the gelatin effectively inhibited enzyme activities, that is, collagenase and proteolytic enzymes released from the exocrine tissue, and thus it can inhibit overdigestion of islets during their density gradient isolation. The gelatin gradient satisfies most of the additional requirements for islet isolation from the pancreatic tissue of large animals mentioned above. Although several factors, such as molecular weight of gelatin, osmolality of the gradient, and centrifugal conditions, still remain to be optimized, our results suggest that the gelatin gradient has potentiality to isolate islets from the pancreatic tissue of a large animal.
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Westermark, Gunilla T., and Per Westermark. "Transthyretin and Amyloid in the Islets of Langerhans in Type-2 Diabetes." Experimental Diabetes Research 2008 (2008): 1–7. http://dx.doi.org/10.1155/2008/429274.
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Transthyretin (TTR) is a major amyloid fibril protein in certain systemic forms of amyloidosis. It is a plasma protein, mainly synthesized by the liver but expression occurs also at certain minor locations, including the endocrine cells in the islets of Langerhans. With the use of immunohistochemistry and in situ hybridization, we have studied the distribution of transthyretin-containing cells in islets of Langerhans in type-2 diabetic and nondiabetic individuals. TTR expression was particularly seen in alpha (glucagon) cells. Islets from type-2 diabetic patients had proportionally more transthyretin-reactive islet cells, including beta cells. A weak transthyretin immunoreaction in IAPP-derived amyloid occurred in some specimens. In seeding experiments in vitro, we found that TTR fibrils did not seed IAPP while IAPP fibrils seeded TTR. It is suggested that islet expression of transthyretin may be altered in type-2 diabetes.
10
Hurst, R. D., S. L. F. Chan, and N. G. Morgan. "Effects of benextramine on the adrenergic inhibition of insulin secretion in isolated rat pancreatic islets." Journal of Molecular Endocrinology 2, no. 2 (March 1989): 99–105. http://dx.doi.org/10.1677/jme.0.0020099.
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ABSTRACT Insulin secretion from isolated rat islets of Langerhans in the presence of 4 mm glucose averaged 2·26 ± 0·20 (s.e.m.) ng/islet per 90 min and was significantly (P<0·001; n=30) increased to 3·28 ± 0·21 ng/islet per 90 min by the covalent α-adrenoceptor antagonist benextramine (10 μm). Glucose (20 mm) also increased the secretion rate (to 6·24 ± 6·0 ng/islet per 90 min) but, under these conditions, the response was not further enhanced by benextramine. Clonidine and noradrenaline (1 nm–10 μm) each caused dose-dependent inhibition of glucose-induced insulin secretion which was maximal at 1 μm. Benextramine, when added simultaneously with the agonist, relieved, in a dosedependent manner, the inhibition of secretion induced by either clonidine or noradrenaline with similar sensitivity. Even after a 30-min preincubation with benextramine the antagonist failed to differentiate between noradrenaline, adrenaline and clonidine with respect to inhibition of insulin secretion. In contrast to its effects on adrenergic responses, short-term treatment with benextramine did not significantly affect muscarinic—cholinergic receptor-mediated 45Ca2+ efflux from rat islets of Langerhans perifused in Ca2+-depleted medium. These data suggest that benextramine does not differentiate between clonidine and noradrenaline in rat islets of Langerhans but that it does show preference for α-adrenoceptors in this tissue.
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Sadykova, R. Ye, N. N. Skaletsky, A. V. Dreval, L. A. Kirsanova, and P. I. Shishko. "Effect of islet cell culture xenotransplantation on alloxan diabetes course in rats fed diets with different protein content." Problems of Endocrinology 40, no. 4 (December 15, 1994): 45–47. http://dx.doi.org/10.14341/probl12146.
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The authors present data- on the protective effect of newborn rabbits pancreatic islet cell culture xenotransplantation of Langerhans islets P-cells of rats with alloxan diabetes. This effect was the most marked in rats fed diets with normal or increased protein content. The authors discuss a possible stimulating effect of rabbit islet cell culture xenooransplantation on regeneration processes in recipient rat pancreatic islets. This effect was better pronounced in rats kept on rations with increased protein content. Further experiments will help more accuretaly define the indications for therapy of insulindependent diabetes mellitus by xenokansplantations of islet cell cultures.
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Lavoie, Elise G., Michel Fausther, Gilles Kauffenstein, Filip Kukulski, Beat M. Künzli, Helmut Friess, and Jean Sévigny. "Identification of the ectonucleotidases expressed in mouse, rat, and human Langerhans islets: potential role of NTPDase3 in insulin secretion." American Journal of Physiology-Endocrinology and Metabolism 299, no. 4 (October 2010): E647—E656. http://dx.doi.org/10.1152/ajpendo.00126.2010.
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Extracellular nucleotides and adenosine regulate endocrine pancreatic functions such as insulin secretion by Langerhans islet β-cells via the activation of specific P2 and P1 receptors. Membrane-bound ectonucleotidases regulate the local concentration of these ligands and consequently control the activation of their receptors. The objective of this study was to identify and localize the major ectonucleotidases, namely NTPDases and ecto-5′-nucleotidase, present in the endocrine pancreas. In addition, the potential implication of ecto-ATPase activity on insulin secretion was investigated in the rat β-cell line INS-1 (832/13). The localization of ectonucleotidase activity and protein was carried out in situ by enzyme histochemistry and immunolocalization in mouse, rat, and human pancreas sections. NTPDase1 was localized in all blood vessels and acini, and NTPDase2 was localized in capillaries of Langerhans islets and in peripheral conjunctive tissue, whereas NTPDase3 was detected in all Langerhans islet cell types. Interestingly, among the mammalian species tested, ecto-5′-nucleotidase was present only in rat Langerhans islet cells, where it was coexpressed with NTPDase3. Notably, the inhibition of NTPDase3 activity by BG0136 and NF279 facilitated insulin release from INS-1 (832/13) cells under conditions of low glycemia, probably by affecting P2 receptor activation. NTPDase3 activity also regulated the inhibitory effect of exogenous ATP in the presence of a high glucose concentration most likely by controlling adenosine production. In conclusion, all pancreatic endocrine cells express NTPDase3 that was shown to modulate insulin secretion in rat INS-1 (832/13) β-cells. Ecto-5′-nucleotidase is expressed in rat Langerhans islet cells but absent in human and mouse endocrine cells.
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Pakhomov, Oleg, Jiry Honiger, Edouard Gouin, Roland Cariolet, Gerard Reach, and Sylviane Darquy. "Insulin Treatment of Mice Recipients Preserves β-Cell Function in Porcine Islet Transplantation." Cell Transplantation 11, no. 7 (October 2002): 721–28. http://dx.doi.org/10.3727/000000002783985422.
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Encapsulation of islets of Langerhans confers protection against cell-mediated immune destruction and so should allow the transplantation of islets without immunosuppression. Xenotransplantation of encapsulated islets of Langerhans might therefore help overcome problems of human organ donor shortage. Given that islets exposed to sustained hyperglycemia show impaired β-cell function, we set out to determine whether recipient treatment with insulin could improve transplantation success rate. Islets of Langerhans were obtained from Specific Germ-Free (SPF) pig pancreas and cultured overnight. Islets were encapsulated in AN69 fibers and implanted into the peritoneal cavity of diabetic mice. A group of implanted mice was treated with exogenous insulin from day 3 to day 7 after grafting. Islet implantation depressed plasma glucose in all the mice, both insulin treated and untreated. Glycemia slowly increased in the non-insulin-treated mice, whereas the decrease observed in the insulin-treated mice was maintained until day 29 of follow-up. We found significant differences between the two groups (p < 0.05 at day 18 and day 20, p < 0.001 at day 23 and day 29). No improvement of hyperglycemia was observed in diabetic mice implanted with empty fibers. When islet-containing fibers were removed from the peritoneal cavity of mice 1 month after the graft plasma glucose increased markedly. We demonstrate that treatment of recipients with exogenous insulin in the immediate posttransplantation period has a positive effect on β-cell function in transplanted macroencapsulated porcine islets.
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Winter, William E., and Desmond A. Schatz. "Autoimmune Markers in Diabetes." Clinical Chemistry 57, no. 2 (February 1, 2011): 168–75. http://dx.doi.org/10.1373/clinchem.2010.148205.
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BACKGROUND Type 1 diabetes (T1DM) results from cell-mediated autoimmune destruction of the β cells of the islets of Langerhans. Autoantibodies directed against the islets are useful clinical tools that allow the recognition and confirmation of β-cell autoimmunity. CONTENT In this review we define the term “islet autoantibody,” describe the pathogenesis of autoantibody generation, and explain the uses of islet autoantibodies in clinical medicine and in research studies that concern the interruption or prevention of T1DM. We also discuss the biology of islet autoantibodies and their rates of appearance at the time of onset of T1DM and their appearance before the development of T1DM. SUMMARY The presence of islet autoantibodies in persons with diabetes confirms an autoimmune etiology. In nondiabetic individuals, islet autoantibodies are strong predictors of the later development of T1DM.
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Bertera, Suzanne, Angela M. Alexander, Megan L. Crawford, Glenn Papworth, Simon C. Watkins, Paul D. Robbins, and Massimo Trucco. "Gene Combination Transfer to Block Autoimmune Damage in Transplanted Islets of Langerhans." Experimental Diabesity Research 5, no. 3 (2004): 201–10. http://dx.doi.org/10.1080/15438600490486822.
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Islet transplantation therapy would be applicable to a wider range of diabetic patients if donor islet acceptance and protection were possible without systemic immunosuppression of the recipient. To this aim, gene transfer to isolated donor islets ex vivo is one method that has shown promise. This study examines the combined effect of selected immunomodulatory and anti-inflammatory genes known to extend the functional viability of pancreatic islet grafts in an autoimmune system. These genes, indoleamine 2,3-dioxygenase (IDO), manganese superoxide dismutase (MnSOD), and interleukin (IL)-1 receptor antagonist protein (IRAP), were transferred to isolated NOD donor islets ex vivo then transplanted to NODscidrecipients and evaluated in vivo after diabetogenic T-cell challenge. The length of time the recipient remained euglycemic was used to measure the ability of the transgenes to protect the graft from autoimmune destruction. Although the results of these cotransfections gave little evidence of a synergistic relationship, they were useful to show that gene combinations can be used to more efficiently protect islet grafts from diabetogenic T cells.
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Seiron, Peter, Anton Stenwall, Anders Hedin, Louise Granlund, Jonathan Lou S. Esguerra, Petr Volkov, Erik Renström, Olle Korsgren, Marcus Lundberg, and Oskar Skog. "Transcriptional analysis of islets of Langerhans from organ donors of different ages." PLOS ONE 16, no. 3 (March 12, 2021): e0247888. http://dx.doi.org/10.1371/journal.pone.0247888.
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Insulin secretion is impaired with increasing age. In this study, we aimed to determine whether aging induces specific transcriptional changes in human islets. Laser capture microdissection was used to extract pancreatic islet tissue from 37 deceased organ donors aged 1–81 years. The transcriptomes of the extracted islets were analysed using Ion AmpliSeq sequencing. 346 genes that co-vary significantly with age were found. There was an increased transcription of genes linked to senescence, and several aspects of the cell cycle machinery were downregulated with increasing age. We detected numerous genes not linked to aging in previous studies likely because earlier studies analysed islet cells isolated by enzymatic digestion which might affect the islet transcriptome. Among the novel genes demonstrated to correlate with age, we found an upregulation of SPP1 encoding osteopontin. In beta cells, osteopontin has been seen to be protective against both cytotoxicity and hyperglycaemia. In summary, we present a transcriptional profile of aging in human islets and identify genes that could affect disease course in diabetes.
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Lakey, Jonathan R. T., Garth L. Warnock, Ziliang Ao, and Ray V. Rajotte. "Bulk Cryopreservation of Isolated Islets of Langerhans." Cell Transplantation 5, no. 3 (May 1996): 395–404. http://dx.doi.org/10.1177/096368979600500306.
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Current methods to isolate human islets of Langerhans are limited and multiple donors are required for successful reversal of longstanding Type 1 diabetes mellitus. Cryopreservation of isolated islets is an effective method of storing and pooling islets. Current cryopreservation protocols are cumbersome due to current practices of placing small aliquots of islets per individual freezer tube. In the present study, we examined the application of a blood freezer bag for the cryopreservation of isolated islets by slow cooling and rapid thawing. Freezing and thawing profiles generated using thermocouples placed inside a 500 mL Cryocyte (Baxter) blood freezer bag showed that a longer equilibration period at −7.4°C was necessary to consistently achieve nucleation and cooling profiles similar to those observed in glass tubes. When known numbers of rat islets were placed in the freezer bag and the cryoprotectant dimethyl sulfoxide (DMSO) was added in a stepwise fashion and removed using a sucrose dilution, the islet recovery compared with glass tubes was 92 ± 4.8 vs. 90 ± 2.3% (n = 4, p = ns, Mann-Whitney U-test). When purified canine islets were cryopreserved in a single freezer bag or in multiple glass tubes, the recovery was similar (78.8 ± 12.5% recovery for freezer bag vs. 82.3 ± 5.3% for glass tubes; n = 6, p = ns). In vitro function was equivalent for both groups. The stimulation index of insulin release during glucose perifusion (stimulated over basal insulin secretion) for canine islets cryopreserved in a freezer bag vs. glass tubes was 3.2 ± 1.0 and 2.3 ± 1.3, respectively (n = 6, p = ns). These values were significantly lower than the nonfrozen control islets (6.9 ± 2.4, p < 0.05). When 2000 canine islets cryopreserved in either a freezer bag, or glass tubes were transplanted into diabetic nude mice, the animals became and remained normoglycemic posttransplant. We conclude that the survival of freshly isolated canine islets cryopreserved in a single freezer bag is equivalent to the glass tube method. Bulk cryopreservation of islets in a single freezer bag will facilitate effective low temperature tissue banking to support ongoing clinical trials of islet transplantation.
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Skaletskiy, N. N., L. A. Kirsanova, G. N. Bubentsova, N. V. Baranova, G. N. Skaletskaya, and V. I. Sevastianov. "IDENTIFICATION OF ISLET CAPACITY IN DONOR’S PANCREAS USING IMMUNOMORPHOLOGICAL ANALYSIS." Russian Journal of Transplantology and Artificial Organs 18, no. 1 (April 16, 2016): 32–37. http://dx.doi.org/10.15825/1995-1191-2016-1-32-37.
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The aimof the work was detailed morphological investigations of donor pancreas (DP) for the study of possibilities of maximal selection of islet tissue suitable for transplantation to a patient of diabetes mellitus type 1.Materials and methods.Eight DPs were received as a result of multiorgan donation. Morphological investigations were performed by means of histological and special immunohistochemical methods.Results.The Majority of islets were revealed in the tail part of the DP. Besides typical Langerhans islets with predominance of mosaically located beta cells, the accumulations of islet cells forming so-called interlobular (perilobular) islets were revealed in the layers of interlobular connecting tissue. In addition, in the cells of ductal epithelium nestin which is a marker of progenitor cells was revealed.Conclusion.To obtain the maximal potential of islet tissue from DP it is necessary to use interlobular located islets as well as to use progenitor cells of pancreas, which have the ability to transdifferentiate into islet cells.
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Zekorn, T. D. C., A. Horcher, J. Mellert, U. Siebers, T. Altug, A. Emre, H.-J. Hahn, and K. Federlin. "Biocompatibility and Immunology in the Encapsulation of Islets of Langerhans (Bioartificial Pancreas)." International Journal of Artificial Organs 19, no. 4 (April 1996): 251–57. http://dx.doi.org/10.1177/039139889601900408.
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Successful transplantation of encapsulated islets (bioartificial pancreas) would circumvent problems of islet availability and rejection in the treatment of insulin-dependent diabetes with biological organ replacement. Alginates are widely used as a hydrogel matrix or membrane for immunoprotected transplantation. A major problem in the use of diffusion-based devices is the biocompatibility of the material used. The foreign body reaction after implantation of empty microcapsules into different compartments in rats, dogs and pigs is evaluated in this article. However, biocompatibility of the bioartificial pancreas has three different aspects: reaction of the entrapped islet to the encapsulation technique and material; reaction of the recipient against the incorporated device (= foreign body reaction); and finally the reaction of the recipient against the encapsulated islet (= immunology of bioartificial pancreas). It is obvious from different experiments that even if foreign body reactions (reactions against material) are almost abolished the recipient may react against material released from the encapsulated islet. In conclusion, transplantation of encapsulated islets induces various morphological reactions (i.e. inflammation and fibrosis) as a result of a variety of donor and recipient related factors. Therefore, the use of an adequate animal model that reflects the human situation is essential for progress in the development of a bioartificial pancreas.
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Berrow, N. S., G. Milligan, and N. G. Morgan. "Immunological characterization of the guanine-nucleotide binding proteins Gi and Go in rat islets of Langerhans." Journal of Molecular Endocrinology 8, no. 2 (April 1992): 103–8. http://dx.doi.org/10.1677/jme.0.0080103.
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ABSTRACT Inhibition of insulin secretion from rat islets of Langerhans is known to involve at least one pertussis toxin-sensitive guanine-nucleotide binding (G) protein. We have used antisera raised against unique antigenic determinants of different members of the family of pertussis toxin-sensitive G proteins to identify these proteins in rat islets. Antiserum SG1, which recognizes both Gi1 and Gi2, reacted with an islet protein having an approximate Mr of 40 000. Antiserum IlC (Gi1 specific) failed to recognize any islet proteins, suggesting that Gi2 is present in much greater amounts than Gi1. Indeed, Gi1 levels were below the detection limit of a sensitive immunogold/silver-staining method, indicating that it may be absent from the cells of rat islets. Two different antisera were used to identify Go-like G proteins in rat islet homogenates. Both antisera reacted with a protein band which, under appropriate conditions, could be resolved to reveal two separate proteins of Mr 39–40 000. Thus, at least two molecular forms of Go are present in rat islets. Subcellular fractionation indicated that all three G proteins identified in this study (Gi2 and two forms of Go) are localized to islet membranes. No immunoreactivity could be detected in the cytosolic fraction.
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Quesada, Ivan, Esther Fuentes, Etelvina Andreu, Paolo Meda, Angel Nadal, and Bernat Soria. "On-line analysis of gap junctions reveals more efficient electrical than dye coupling between islet cells." American Journal of Physiology-Endocrinology and Metabolism 284, no. 5 (May 1, 2003): E980—E987. http://dx.doi.org/10.1152/ajpendo.00473.2002.
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Pancreatic β-cells constitute a well-communicating multicellular network that permits a coordinated and synchronized signal transmission within the islet of Langerhans that is necessary for proper insulin release. Gap junctions are the molecular keys that mediate functional cellular connections, which are responsible for electrical and metabolic coupling in the majority of cell types. Although the role of gap junctions in β-cell electrical coupling is well documented, metabolic communication is still a matter of discussion. Here, we have addressed this issue by use of a fluorescence recovery after photobleaching (FRAP) approach. This technique has been validated as a reliable and noninvasive approach to monitor functional gap junctions in real time. We show that control pancreatic islet cells did not exchange a gap junction-permeant molecule in either clustered cells or intact islets of Langerhans under conditions that allowed cell-to-cell exchange of current-carrying ions. Conversely, we have detected that the same probe was extensively transferred between islet cells of transgenic mice expressing connexin 32 (Cx32) that have enhanced junctional coupling properties. The results indicate that the electrical coupling of native islet cells is more extensive than dye communication. Dye-coupling domains in islet cells appear more restricted than previously inferred with other methods.
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Katzman, S. M., M. A. Messerli, D. T. Barry, A. Grossman, T. Harel, J. D. Wikstrom, B. E. Corkey, P. J. S. Smith, and O. S. Shirihai. "Mitochondrial metabolism reveals a functional architecture in intact islets of Langerhans from normal and diabetic Psammomys obesus." American Journal of Physiology-Endocrinology and Metabolism 287, no. 6 (December 2004): E1090—E1099. http://dx.doi.org/10.1152/ajpendo.00044.2004.
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The cells within the intact islet of Langerhans function as a metabolic syncytium, secreting insulin in a coordinated and oscillatory manner in response to external fuel. With increased glucose, the oscillatory amplitude is enhanced, leading to the hypothesis that cells within the islet are secreting with greater synchronization. Consequently, non-insulin-dependent diabetes mellitus (NIDDM; type 2 diabetes)-induced irregularities in insulin secretion oscillations may be attributed to decreased intercellular coordination. The purpose of the present study was to determine whether the degree of metabolic coordination within the intact islet was enhanced by increased glucose and compromised by NIDDM. Experiments were performed with isolated islets from normal and diabetic Psammomys obesus. Using confocal microscopy and the mitochondrial potentiometric dye rhodamine 123, we measured mitochondrial membrane potential oscillations in individual cells within intact islets. When mitochondrial membrane potential was averaged from all the cells in a single islet, the resultant waveform demonstrated clear sinusoidal oscillations. Cells within islets were heterogeneous in terms of cellular synchronicity (similarity in phase and period), sinusoidal regularity, and frequency of oscillation. Cells within normal islets oscillated with greater synchronicity compared with cells within diabetic islets. The range of oscillatory frequencies was unchanged by glucose or diabetes. Cells within diabetic (but not normal) islets increased oscillatory regularity in response to glucose. These data support the hypothesis that glucose enhances metabolic coupling in normal islets and that the dampening of oscillatory insulin secretion in NIDDM may result from disrupted metabolic coupling.
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Westermark, Per, Arne Andersson, and Gunilla T. Westermark. "Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus." Physiological Reviews 91, no. 3 (July 2011): 795–826. http://dx.doi.org/10.1152/physrev.00042.2009.
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Islet amyloid polypeptide (IAPP, or amylin) is one of the major secretory products of β-cells of the pancreatic islets of Langerhans. It is a regulatory peptide with putative function both locally in the islets, where it inhibits insulin and glucagon secretion, and at distant targets. It has binding sites in the brain, possibly contributing also to satiety regulation and inhibits gastric emptying. Effects on several other organs have also been described. IAPP was discovered through its ability to aggregate into pancreatic islet amyloid deposits, which are seen particularly in association with type 2 diabetes in humans and with diabetes in a few other mammalian species, especially monkeys and cats. Aggregated IAPP has cytotoxic properties and is believed to be of critical importance for the loss of β-cells in type 2 diabetes and also in pancreatic islets transplanted into individuals with type 1 diabetes. This review deals both with physiological aspects of IAPP and with the pathophysiological role of aggregated forms of IAPP, including mechanisms whereby human IAPP forms toxic aggregates and amyloid fibrils.
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Leibiger, Barbara, Tilo Moede, Ismael Valladolid-Acebes, Meike Paschen, Montse Visa, Ingo B. Leibiger, and Per-Olof Berggren. "Ectopic Leptin Production by Intraocular Pancreatic Islet Organoids Ameliorates the Metabolic Phenotype of ob/ob Mice." Metabolites 11, no. 6 (June 14, 2021): 387. http://dx.doi.org/10.3390/metabo11060387.
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The pancreatic islets of Langerhans consist of endocrine cells that secrete peptide hormones into the blood circulation in response to metabolic stimuli. When transplanted into the anterior chamber of the eye (ACE), pancreatic islets engraft and maintain morphological features of native islets as well as islet-specific vascularization and innervation patterns. In sufficient amounts, intraocular islets are able to maintain glucose homeostasis in diabetic mice. Islet organoids (pseudo-islets), which are formed by self-reassembly of islet cells following disaggregation and genetic manipulation, behave similarly to native islets. Here, we tested the hypothesis that genetically engineered intraocular islet organoids can serve as production sites for leptin. To test this hypothesis, we chose the leptin-deficient ob/ob mouse as a model system, which becomes severely obese, hyperinsulinemic, hyperglycemic, and insulin resistant. We generated a Tet-OFF-based beta-cell-specific adenoviral expression construct for mouse leptin, which allowed efficient transduction of native beta-cells, optical monitoring of leptin expression by co-expressed fluorescent proteins, and the possibility to switch-off leptin expression by treatment with doxycycline. Intraocular transplantation of islet organoids formed from transduced islet cells, which lack functional leptin receptors, to ob/ob mice allowed optical monitoring of leptin expression and ameliorated their metabolic phenotype by improving bodyweight, glucose tolerance, serum insulin, and C-peptide levels.
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Kakimoto, Tetsuhiro, Hirotaka Kimata, Satoshi Iwasaki, Atsushi Fukunari, and Hiroyuki Utsumi. "Automated recognition and quantification of pancreatic islets in Zucker diabetic fatty rats treated with exendin-4." Journal of Endocrinology 216, no. 1 (October 22, 2012): 13–20. http://dx.doi.org/10.1530/joe-12-0456.
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Type 2 diabetes is characterized by impaired insulin secretion from pancreatic β-cells. Quantification of the islet area in addition to the insulin-positive area is important for detailed understanding of pancreatic islet histopathology. Here we show computerized automatic recognition of the islets of Langerhans as a novel high-throughput method to quantify islet histopathology. We utilized state-of-the-art tissue pattern recognition software to enable automatic recognition of islets, eliminating the need to laboriously trace islet borders by hand. After training by a histologist, the software successfully recognized even irregularly shaped islets with depleted insulin immunostaining, which were quite difficult to automatically recognize. The results from automated image analysis were highly correlated with those from manual image analysis. To establish whether this automated, rapid, and objective determination of islet area will facilitate studies of islet histopathology, we showed the beneficial effect of chronic exendin-4, a glucagon-like peptide-1 analog, treatment on islet histopathology in Zucker diabetic fatty (ZDF) rats. Automated image analysis provided qualitative and quantitative evidence that exendin-4 treatment ameliorated the loss of pancreatic insulin content and gave rise to islet hypertrophy. We also showed that glucagon-positive α-cell area was decreased significantly in ZDF rat islets with disorganized structure. This study is the first to demonstrate the utility of automatic quantification of digital images to study pancreatic islet histopathology. The proposed method will facilitate evaluations in preclinical drug efficacy studies as well as elucidation of the pathophysiology of diabetes.
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Gerő, László. "Őssejtterápia, β-sejt- és Langerhans-sziget-neogenezis: a jövő lehetséges terápiái 1-es típusú diabetesben?" Orvosi Hetilap 157, no. 19 (May 2016): 740–45. http://dx.doi.org/10.1556/650.2016.30440.
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In type 1 diabetic patients perfect normoglycaemia can only be achieved by successful transplantation of the pancreas or Langerhans’ islets. Surgical transplantation of the whole pancreas is an invasive operation exerting great burden on the patients. Transplantation of the islets of Langerhans does not burden the patients but the survival of the islet grafts is limited. Both interventions are hampered by the lack of donor organs. However, much of these difficulties could be overcome by the use of “artificial β-cells” which ought to have an ultrastructure identical with that of natural β-cells and produce and secrete insulin in a glucose dependent manner. At present three such methods are at our disposal: transformation of the ductal cells of the exocrine pancreas into β-cells, development of β-cells from stem-cells, and neogenesis of Langerhans’ islets induced by viral delivery of transcription factors. The author summarises the experience and experimental results obtained with the use of the three methods. Orv. Hetil., 2016, 157(19), 740–745.
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Kinasiewicz, J., M. Sabat, M. Antosiak-Iwańska, E. Godlewska, E. Sitarek, and T. Orłowski. "The influence of porcine pancreas digestion parameters and islet histomorphology on islet isolation outcome." Polish Journal of Veterinary Sciences 14, no. 2 (May 1, 2011): 227–30. http://dx.doi.org/10.2478/v10181-011-0034-7.
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The influence of porcine pancreas digestion parameters and islet histomorphology on islet isolation outcomeTransplantation of the pig islets of Langerhans is considered as the future treatment for patients suffering from type Idiabetes mellitus. Despite the adaptation of modified Ricordi method and highly purified collagenase, the results of pancreas digestions are precarious. Selection of proper donor and optimal digestion procedure are fundamental. The aim of this study was to assess the impact of pancreas procuring parameters on pig islets yield. The pancreata were harvested from 69 market sows weighting over 150 kg. After intraductal injection of cold collagenase solution pancreata were transported in UW solution or under conditions of two layer method (TLM). In laboratory pancreata were digested at 37°C according to Ricordi isolation method or stationary in the bottle. The particular parameters of isolation procedure were considered as substantial. Pig weight, volume of infused collagenase solution, TLM application and pancreas dividing before digestion positively affected islet yield. Additionally, the influence of pancreatic islet tissue histomorphology on isolation outcome was studied. Proper donor selection as well as adequate digestion parameters could improve pig islet recovery during islet isolation.
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Wang, R., J. Li, and L. Rosenberg. "Factors mediating the transdifferentiation of islets of Langerhans to duct epithelial-like structures." Journal of Endocrinology 171, no. 2 (November 1, 2001): 309–18. http://dx.doi.org/10.1677/joe.0.1710309.
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We have previously shown that isolated islets embedded in type 1 collagen gel in the presence of a defined medium undergo transdifferentiation within 96 h to duct epithelial structures. The aim of this study was to identify the factors implicated in this process. Freshly isolated canine islets were embedded in type 1 collagen gel, Matrigel or agarose for up to 120 h and cultured in (i) Dulbecco's modified Eagle's medium (DMEM)/F12 plus cholera toxin (CT), (ii) medium CMRL1066 plus CT, (iii) CMRL1066 plus forskolin and (iv) CMRL1066 alone. At 16 h, intracellular levels of cAMP (fmol/10(3) islets) were increased in groups i-iii (642+/-17, 338+/-48, 1128+/-221) compared with group iv (106+/-19, P<0.01). Epithelial differentiation correlated with the total amount of intracellular cAMP measured over 120 h. Islet-epithelial transformation during the initial 36 h was associated with a wave of apoptosis which was followed by a wave of cell proliferation. During epithelial differentiation there was a progressive loss of all islet hormones and the concomitant expression of cytoskeletal proteins characteristic of duct epithelial cells. Islets in collagen and Matrigel demonstrated high rates of epithelial differentiation (63+/-2% and 71+/-4% respectively) compared with those in agarose gel (0+/-0%, P<0.001). Islets suspended in DMEM/F12 plus CT supplemented with soluble laminin or fibronectin did not undergo transformation. Prior incubation of freshly isolated islets with an integrin-binding arginine-glycine-aspartate motif-presenting synthetic peptide also reduced islet transformation. These studies confirm the biological potential of islets of Langerhans to differentiate to duct epithelial structures. cAMP-mediated signal transduction and an appropriate integrin-matrix interaction are necessary for this process to proceed.
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Nurdin, Sarah M., Nuniek Nugraheni, and Mei Wulan. "Moderate Intensity of Physical Exercise increased Β (Beta) Cell and Size of Langerhans Islets in Streptozotocin Induced Diabetes Mellitus Rats." Surabaya Physical Medicine and Rehabilitation Journal 1, no. 2 (December 24, 2019): 52. http://dx.doi.org/10.20473/spmrj.v1i2.16176.
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Background: The death of β cells Langerhans islets in Diabetes Mellitus (DM) can cause loss of Langerhans islet function and worsen the progression of DM. Physical exercise plays a major part in DM treatment.Aim: to observe the effect of moderate intensity exercise to β (beta) cell numbers and Langerhans islets area size in Streptozotocin (STZ) induced diabetes in rats.Methods: Thirty adult male Wistar rats (Rattusnorvegicus) divided into 3, Group 1 as the control, Group 2 received 35 mg/kg streptozotocin induction treatment, Group 3 received 35 mg/kg streptozotocin induction and physical exercise, swimming, with moderate intensity 70% from the swimming maximal ability, 9% of body weight load, 4 times a week for 4 weeks. Datas collected were in the form of histopathology slide of pancreatic tissue after receiving treatment for 28 days.Results: There are significant differences of β-cell pancreas number between group K1 and K2 (p<0,001), group K2 and to K3 (p<0,001). No significant difference between group K1 and K3 (p=0,102). The Langerhans islets area sizes of pancreas tissue between group K1, K2, and K3 are significantly different (p<0,001).Conclusion: This study shows moderate-intensity physical exercise can increase the number of β cell and average area size of Langerhans islets. The effect of physical exercise depends on the intensity of exercise and the capacity of pancreatic function left of the diabetic.
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Nurdin, Sarah M., Nuniek Nugraheni, and Mei Wulan. "Moderate Intensity of Physical Exercise increased Β (Beta) Cell and Size of Langerhans Islets in Streptozotocin Induced Diabetes Mellitus Rats." Surabaya Physical Medicine and Rehabilitation Journal 1, no. 2 (December 24, 2019): 52. http://dx.doi.org/10.20473/spmrj.v1i2.2019.52-58.
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Background: The death of β cells Langerhans islets in Diabetes Mellitus (DM) can cause loss of Langerhans islet function and worsen the progression of DM. Physical exercise plays a major part in DM treatment.Aim: to observe the effect of moderate intensity exercise to β (beta) cell numbers and Langerhans islets area size in Streptozotocin (STZ) induced diabetes in rats.Methods: Thirty adult male Wistar rats (Rattusnorvegicus) divided into 3, Group 1 as the control, Group 2 received 35 mg/kg streptozotocin induction treatment, Group 3 received 35 mg/kg streptozotocin induction and physical exercise, swimming, with moderate intensity 70% from the swimming maximal ability, 9% of body weight load, 4 times a week for 4 weeks. Datas collected were in the form of histopathology slide of pancreatic tissue after receiving treatment for 28 days.Results: There are significant differences of β-cell pancreas number between group K1 and K2 (p<0,001), group K2 and to K3 (p<0,001). No significant difference between group K1 and K3 (p=0,102). The Langerhans islets area sizes of pancreas tissue between group K1, K2, and K3 are significantly different (p<0,001).Conclusion: This study shows moderate-intensity physical exercise can increase the number of β cell and average area size of Langerhans islets. The effect of physical exercise depends on the intensity of exercise and the capacity of pancreatic function left of the diabetic.
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Doliba, Nicolai M., Wei Qin, Habiba Najafi, Chengyang Liu, Carol W. Buettger, Johanna Sotiris, Heather W. Collins, et al. "Glucokinase activation repairs defective bioenergetics of islets of Langerhans isolated from type 2 diabetics." American Journal of Physiology-Endocrinology and Metabolism 302, no. 1 (January 1, 2012): E87—E102. http://dx.doi.org/10.1152/ajpendo.00218.2011.
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It was reported previously that isolated human islets from individuals with type 2 diabetes mellitus (T2DM) show reduced glucose-stimulated insulin release. To assess the possibility that impaired bioenergetics may contribute to this defect, glucose-stimulated respiration (V̇o2), glucose usage and oxidation, intracellular Ca2+, and insulin secretion (IS) were measured in pancreatic islets isolated from three healthy and three type 2 diabetic organ donors. Isolated mouse and rat islets were studied for comparison. Islets were exposed to a “staircase” glucose stimulus, whereas IR and V̇o2 were measured. V̇o2 of human islets from normals and diabetics increased sigmoidally from equal baselines of 0.25 nmol/100 islets/min as a function of glucose concentration. Maximal V̇o2 of normal islets at 24 mM glucose was 0.40 ± 0.02 nmol·min−1·100 islets−1, and the glucose S0.5 was 4.39 ± 0.10 mM. The glucose stimulation of respiration of islets from diabetics was lower, Vmax of 0.32 ± 0.01 nmol·min−1·100 islets−1, and the S0.5 shifted to 5.43 ± 0.13 mM. Glucose-stimulated IS and the rise of intracellular Ca2+ were also reduced in diabetic islets. A clinically effective glucokinase activator normalized the defective V̇o2, IR, and free calcium responses during glucose stimulation in islets from type 2 diabetics. The body of data shows that there is a clear relationship between the pancreatic islet energy (ATP) production rate and IS. This relationship was similar for normal human, mouse, and rat islets and the data for all species fitted a single sigmoidal curve. The shared threshold rate for IS was ∼13 pmol·min−1·islet−1. Exendin-4, a GLP-1 analog, shifted the ATP production-IS curve to the left and greatly potentiated IS with an ATP production rate threshold of ∼10 pmol·min−1·islet−1. Our data suggest that impaired β-cell bioenergetics resulting in greatly reduced ATP production is critical in the molecular pathogenesis of type 2 diabetes mellitus.
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Henningsson, R., P. Alm, and I. Lundquist. "Occurrence and putative hormone regulatory function of a constitutive heme oxygenase in rat pancreatic islets." American Journal of Physiology-Cell Physiology 273, no. 2 (August 1, 1997): C703—C709. http://dx.doi.org/10.1152/ajpcell.1997.273.2.c703.
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Recent observations suggest that carbon monoxide (CO) may serve as a neuroendocrine modulator in hypothalamus. Here we provide evidence, for the first time, that the islets of Langerhans contain the constitutive isoform of the CO-producing enzyme heme oxygenase (HO-2), the activity of which was found to modulate islet hormone release. Most insulin and glucagon cells in the rat endocrine pancreas expressed strong immunoreactivity for HO-2. In the exocrine parenchyma, scattered HO-2-positive ganglionic cell bodies were occasionally observed. Furthermore, Western blot analysis revealed the presence of HO-2 in isolated islets but not in acinar cells. Islet homogenates displayed a comparatively high HO-2 enzymatic activity measured as CO formation (approximately 600 pmol CO.min-1.mg islet protein-1). This HO-2 enzymatic activity was greatly suppressed by zincprotoporphyrin-IX (ZnPP-IX), a recognized inhibitor of HO activity. Neither ZnPP-IX nor the HO activator, hemin, influenced basal insulin release from isolated rat islets at low (1 mM) glucose. However, glucagon release at 1 mM glucose was increased by hemin and inhibited by ZnPP-IX. The hemin-induced increase in glucagon secretion was abolished by ZnPP-IX. Furthermore, a series of experiments at high glucose (16.7 mM) revealed that hemin induced a dose-dependent potentiation of glucose-stimulated insulin release. Moreover, glucose-induced insulin release was dose-dependently suppressed by ZnPP-IX but unaffected by protoporphyrin-IX, a compound known not to influence HO-2 activity in other tissues. Similarly, glucagon release at high glucose was dose-dependently increased by hemin and suppressed by ZnPP-IX. Finally, the hemin-induced increase in islet hormone release at high glucose was totally abolished by ZnPP-IX. The data strongly suggest that CO production positively modulates both glucagon and insulin secretion. We propose that CO may serve as a novel messenger molecule within the islets of Langerhans.
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Portis, Andrew J., Ray V. Rajotte, and Teresa L. Krukoff. "Reinnervation of Isolated Islets of Langerhans Transplanted beneath the Kidney Capsule in the Rat." Cell Transplantation 3, no. 2 (March 1994): 163–70. http://dx.doi.org/10.1177/096368979400300204.
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Neural regulation of islets of Langerhans mediates responses to stress and food ingestion. Transplantation of isolated islets offers hope to patients with insulin dependent diabetes mellitus but denervation of isolated islets may affect the capacity for appropriate metabolic control. Previous examination of the endocrine response to stress in islet autografted dogs revealed differences consistent with loss of neural regulation. Therefore, in the present study, islets grafted in rats were examined for extent and nature of reinnervation. Islets isolated from syngeneic donors were grafted under the kidney capsule of Wistar-Furth rats (n = 7) after 3 wk of streptozotocin induced diabetes. After 4 mo, graft-bearing kidneys were recovered and processed for double immunofluorescence. Antibodies were directed against (a) neuron associated proteins: synapsin (SYN) and L1; (b) neurotransmitters; tyrosine hydroxylase (TH), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), and calcitonin gene-related peptide (CGRP); and (c) islet hormones: insulin and somatostatin. SYN and L1 immunoreactivities in nerve fibres suggested reinnervation of the grafted islets although fibres were not associated with structures within the transplanted islets as in intact islets. CGRP immunoreactivity was observed in fibres and in a subpopulation of cells within intact islets but only in cells of the grafted islets. VIP, TH, and NPY immunoreactivities were found in nerve fibres of intact islets but only VIP was observed in fibres of grafted islets suggesting an absence of sympathetic reinnervation. In conclusion, transplanted islets of Langerhans become reinnervated but with a distribution and complement of neurotransmitters distinct from intact islets.
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Slee, D. J., P. M. Jones, and S. L. Howell. "Proinsulin processing in electrically permeabilized rat islets of Langerhans." Journal of Molecular Endocrinology 5, no. 3 (December 1990): 275–80. http://dx.doi.org/10.1677/jme.0.0050275.
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ABSTRACT Proinsulin conversion to insulin was studied using electrically permeabilized rat islets of Langerhans. Using high-performance liquid chromotography separation of radiolabelled islet proteins, we have demonstrated that conversion was dependent upon temperature, sensitive to pH and regulated by MgATP. Ammonium acetate was used to collapse the granular pH gradient, over a pH range of 3·5–7·4. Conversion was optimum at pH 4·5–5·5 and was reduced, but not abolished, at pH 7·4. Ca2+ (10 μm) and 4β-phorbol 12-myristate 13-acetate (500 nm), which are insulin secretagogues in permeabilized islets, caused no significant stimulation of conversion.
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Penfornis, Alfred. "Langerhans islet preparation in cell transplantation." Transfusion Science 18, no. 2 (June 1997): 235–41. http://dx.doi.org/10.1016/s0955-3886(97)00016-7.
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Spence, Allyson, Whitney Purtha, Janice Tam, Shen Dong, Youmin Kim, Chia-Hsin Ju, Teague Sterling, et al. "Revealing the specificity of regulatory T cells in murine autoimmune diabetes." Proceedings of the National Academy of Sciences 115, no. 20 (April 30, 2018): 5265–70. http://dx.doi.org/10.1073/pnas.1715590115.
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Regulatory T cells (Tregs) control organ-specific autoimmunity in a tissue antigen-specific manner, yet little is known about their specificity in a natural repertoire. In this study, we used the nonobese diabetic (NOD) mouse model of autoimmune diabetes to investigate the antigen specificity of Tregs present in the inflamed tissue, the islets of Langerhans. Compared with Tregs present in spleen and lymph node, Tregs in the islets showed evidence of antigen stimulation that correlated with higher proliferation and expression of activation markers CD103, ICOS, and TIGIT. T cell receptor (TCR) repertoire profiling demonstrated that islet Treg clonotypes are expanded in the islets, suggesting localized antigen-driven expansion in inflamed islets. To determine their specificity, we captured TCRαβ pairs from islet Tregs using single-cell TCR sequencing and found direct evidence that some of these TCRs were specific for islet-derived antigens including insulin B:9–23 and proinsulin. Consistently, insulin B:9–23 tetramers readily detected insulin-specific Tregs in the islets of NOD mice. Lastly, islet Tregs from prediabetic NOD mice were effective at preventing diabetes in Treg-deficient NOD.CD28−/− recipients. These results provide a glimpse into the specificities of Tregs in a natural repertoire that are crucial for opposing the progression of autoimmune diabetes.
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Persaud, S. J., P. M. Jones, D. Sugden, and S. L. Howell. "The role of protein kinase C in cholinergic stimulation of insulin secretion from rat islets of Langerhans." Biochemical Journal 264, no. 3 (December 15, 1989): 753–58. http://dx.doi.org/10.1042/bj2640753.
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The role of the Ca2+/phospholipid-dependent protein kinase C (PKC) in cholinergic potentiation of insulin release was investigated by measuring islet PKC activity and insulin secretion in response to carbachol (CCh), a cholinergic agonist. CCh caused a dose-dependent increase in insulin secretion from cultured rat islets at stimulatory glucose concentrations (greater than or equal to 7 mM), with maximal effects observed at 100 microM. Short-term exposure (5 min) of islets to 500 microM-CCh at 2 mM- or 20 mM-glucose resulted in redistribution of islet PKC activity from a predominantly cytosolic location to a membrane-associated form. Prolonged exposure (greater than 20 h) of islets to 200 nM-phorbol myristate acetate caused a virtual depletion of PKC activity associated with the islet cytosolic fraction. Under these conditions of PKC down-regulation, the potentiation of glucose-stimulated insulin secretion by CCh (500 microM) was significantly decreased, but not abolished. CCh stimulated the hydrolysis of inositol phospholipids in both normal and PKC-depleted islets, as assessed by the generation of radiolabelled inositol phosphates. These results suggest that the potentiation of glucose-induced insulin secretion by cholinergic agonists is partly mediated by activation of PKC as a consequence of phospholipid hydrolysis.
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Katdare, MR, RR Bhonde, and PB Parab. "Analysis of morphological and functional maturation of neoislets generated in vitro from pancreatic ductal cells and their suitability for islet banking and transplantation." Journal of Endocrinology 182, no. 1 (July 1, 2004): 105–12. http://dx.doi.org/10.1677/joe.0.1820105.
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The pancreatic ductal stem cells are known to differentiate into islets of Langerhans; however, their yield is limited and the islet population is not defined. Therefore, the aims of the present study were to improvise a methodology for obtaining large numbers of islets in vitro and to characterize their morphological and functional status for islet cell banking and transplantation. Pancreatic ductal epithelial cell cultures were set in serum-free medium. Monolayers of epithelial cells in culture gave rise to islet-like clusters within 3-4 weeks. The identity of neoislets was confirmed by dithizone staining and analysis of the gene expression for endocrine markers by reverse transcriptase-polymerase chain reaction (RT-PCR). The islet population obtained was analysed by image analysis and insulin secretion in response to secretagogues. The cellular extracts from neoislets were immunoreactive to anti-insulin antibody and expressed insulin, glucagon, GLUT-2, PDX-1 and Reg-1 genes. The islets generated within 3-4 weeks exhibited a mixed population of large- and small-sized islets with clear cut dichotomy in the pattern of their insulin secretion in response to L-arginine and glucose. These neoislets maintained their structural and functional integrity on cryopreservation and transplantation indicating their suitability for islet cell banking. Thus, the present study describes an improved method for obtaining a constant supply of large numbers of islets from pancreatic ductal stem cell cultures. The newly generated islets undergo functional maturation indicating their suitability for transplantation.
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English, Andrew, and Nigel Irwin. "Nonclassical Islet Peptides: Pancreatic and Extrapancreatic Actions." Clinical Medicine Insights: Endocrinology and Diabetes 12 (January 2019): 117955141988887. http://dx.doi.org/10.1177/1179551419888871.
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The pancreas has physiologically important endocrine and exocrine functions; secreting enzymes into the small intestine to aid digestion and releasing multiple peptide hormones via the islets of Langerhans to regulate glucose metabolism, respectively. Insulin and glucagon, in combination with ghrelin, pancreatic polypeptide and somatostatin, are the main classical islet peptides critical for the maintenance of blood glucose. However, pancreatic islets also synthesis numerous ‘nonclassical’ peptides that have recently been demonstrated to exert fundamental effects on overall islet function and metabolism. As such, insights into the physiological relevance of these nonclassical peptides have shown impact on glucose metabolism, insulin action, cell survival, weight loss, and energy expenditure. This review will focus on the role of individual nonclassical islet peptides to stimulate pancreatic islet secretions as well as regulate metabolism. In addition, the more recognised actions of these peptides on satiety and energy regulation will also be considered. Furthermore, recent advances in the field of peptide therapeutics and obesity-diabetes have focused on the benefits of simultaneously targeting several hormone receptor signalling cascades. The potential for nonclassical islet hormones within such combinational approaches will also be discussed.
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Hart, Nathaniel J., Craig Weber, Nicholas Price, Alma Banuelos, Madison Schultz, Barry Huey, Emily Harnois, et al. "Insulinoma-derived pseudo-islets for diabetes research." American Journal of Physiology-Cell Physiology 321, no. 2 (August 1, 2021): C247—C256. http://dx.doi.org/10.1152/ajpcell.00466.2020.
Full textAbstract:
The islets of Langerhans of the pancreas are the primary endocrine organ responsible for regulating whole body glucose homeostasis. The use of isolated primary islets for research development and training requires organ resection, careful digestion, and isolation of the islets from nonendocrine tissue. This process is time consuming, expensive, and requires substantial expertise. For these reasons, we sought to develop a more rapidly obtainable and consistent model system with characteristic islet morphology and function that could be employed to train personnel and better inform experiments prior to using isolated rodent and human islets. Immortalized β cell lines reflect several aspects of primary β cells, but cell propagation in monolayer cell culture limits their usefulness in several areas of research, which depend on islet morphology and/or functional assessment. In this manuscript, we describe the propagation and characterization of insulinoma pseudo-islets (IPIs) from a rat insulinoma cell line INS832/3. IPIs were generated with an average diameter of 200 μm, consistent with general islet morphology. The rates of oxygen consumption and mitochondrial oxidation-reduction changes in response to glucose and metabolic modulators were similar to isolated rat islets. In addition, the dynamic insulin secretory patterns of IPIs were similar to primary rat islets. Thus, INS832/3-derived IPIs provide a valuable and convenient model for accelerating islet and diabetes research.
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Garry, D. J., H. D. Coulter, T. J. McIntee, J. Y. Wu, and R. L. Sorenson. "Immunoreactive GABA transaminase within the pancreatic islet is localized in mitochondria of the B-cell." Journal of Histochemistry & Cytochemistry 35, no. 8 (August 1987): 831–36. http://dx.doi.org/10.1177/35.8.3298424.
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Subcellular localization of gamma aminobutyrate-alpha-ketoglutarate transaminase (GABA-T) in the pancreatic islets of Langerhans was determined by use of an electron microscopic, immunogold post-embedding protocol. The objective of this study was to define the islet cell distribution and subcellular localization of GABA-T. Within the islet, GABA-T was found only in the B-cells and was localized in mitochondria; 78 mitochondria contained 336 gold particles, whereas 245 secretory granules contained only 18 gold particles. Although studies utilizing either the isolated perfused pancreas or cultured islets have shown that exogenous GABA modulates D-cell secretion, in this study immunoreactive GABA-T, the catabolic enzyme for GABA, was not detectable in A- and D-cells of the islet. Control studies substituting normal rabbit serum for the GABA-T antiserum resulted in absence of labeling. These results indicate that the high concentration of GABA present in islet B-cells is catabolized by GABA-T in the mitochondrial compartment, consistent with the possibility that GABA functions as a mediator of B-cell activity.
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Bedoya, F. J., J. C. Oberholtzer, and F. M. Matschinsky. "Glucokinase in B-cell-depleted islets of Langerhans." Journal of Histochemistry & Cytochemistry 35, no. 10 (October 1987): 1089–93. http://dx.doi.org/10.1177/35.10.3305701.
Full textAbstract:
Glucose phosphorylation was studied in B-cell-enriched or in B-cell-depleted pancreatic islets from normal or streptozotocin-diabetic rats, respectively, using quantitative histochemical procedures. The data indicate that B-cell-enriched preparations from normal animals and whole islets from normals, diabetics, and insulin-treated diabetic animals have comparable glucokinase activities. Average maximum velocities were (mmol/kg dry tissue/hr) 134.1 +/- 7.3 for whole islets and 125.6 +/- 10.7 for the B-cell-enriched preparations from normal rats, 143.1 +/- 13.6 for B-cell-depleted islets from diabetic rats, and 124.4 +/- 10.7 for B-cell-depleted islets from insulin-treated diabetic animals. The Kmax for glucose of the enzyme in islets from untreated diabetic rats was 16 mM, comparable to the Kmax found for glucokinase from normal rat islets. Mannoheptulose, previously shown to be a competitive inhibitor of glucokinase from liver and normal islets, also inhibited glucokinase in B-cell-depleted islets from diabetic rats. The data indicate that glucokinase is not selectively located in the B-cell, as was previously assumed, but is also found in A- and/or D-cells of diabetic rats. This observation raises significant questions about the functional role of islet glucokinase under control and diabetic conditions.
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Hogan, Janita P., and Bradford E. Peercy. "Flipping the switch on the hub cell: Islet desynchronization through cell silencing." PLOS ONE 16, no. 4 (April 8, 2021): e0248974. http://dx.doi.org/10.1371/journal.pone.0248974.
Full textAbstract:
Pancreatic β cells, responsible for secreting insulin into the bloodstream and maintaining glucose homeostasis, are organized in the islets of Langerhans as clusters of electrically coupled cells. Gap junctions, connecting neighboring cells, coordinate the behavior of the islet, leading to the synchronized oscillations in the intracellular calcium and insulin secretion in healthy islets. Recent experimental work has shown that silencing special hub cells can lead to a disruption in the coordinated behavior, calling into question the democratic paradigm of islet insulin secretion with more or less equal input from each β cell. Islets were shown to have scale-free functional connectivity and a hub cell whose silencing would lead to a loss of functional connectivity and activity in the islet. A mechanistic model representing the electrical and calcium dynamics of β cells during insulin secretion was applied to a network of cells connected by gap junctions to test the hypothesis of hub cells. Functional connectivity networks were built from the simulated calcium traces, with some networks classified as scale-free, confirming experimental results. Potential hub cells were identified using previously defined centrality measures, but silencing them was unable to desynchronize the islet. Instead, switch cells, which were able to turn off the activity of the islet but were not highly functionally connected, were found via systematically silencing each cell in the network.
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Westermark, Gunilla T., Donald F. Steiner, Samuel Gebre-Medhin, Ulla Engström, and Per Westermark. "Pro Islet Amyloid Polypeptide (ProIAPP) Immunoreactivity in the Islets of Langerhans." Upsala Journal of Medical Sciences 105, no. 2 (January 2000): 97–106. http://dx.doi.org/10.1517/03009734000000057.
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Gebre-Medhin, S., C. Olofsson, and H. Mulder. "Islet amyloid polypeptide in the islets of Langerhans: friend or foe?" Diabetologia 43, no. 6 (June 5, 2000): 687–95. http://dx.doi.org/10.1007/s001250051364.
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Denijn, M., R. A. De Weger, A. D. M. Van Mansfeld, J. A. M. van Unnik, and C. J. M. Lips. "Islet amyloid polypeptide (IAPP) is synthesized in the islets of Langerhans." Histochemistry 97, no. 1 (January 1992): 33–37. http://dx.doi.org/10.1007/bf00271279.
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Morgan, N. G., G. M. Rumford, and W. Montague. "Mechanisms involved in intracellular calcium mobilization in isolated rat islets of Langerhans." Biochemical Journal 244, no. 3 (June 15, 1987): 669–74. http://dx.doi.org/10.1042/bj2440669.
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1. The rate of 45Ca2+ efflux from prelabelled rat islets of Langerhans was stimulated by carbachol in a dose-dependent manner. 2. Significant stimulation occurred in the presence of 0.2 microM-carbachol; the response was half-maximal at 3-5 microM and was maximal at 20 microM. 3. Stimulation of 45Ca2+ efflux by carbachol was not dependent on the presence of extracellular Ca2+ and was enhanced in Ca2+-depleted medium. 4. Stimulation of 45Ca2+ efflux by 5 microM-carbachol occurred independently of any change in [3H]arachidonic acid release in prelabelled islets, and probably reflected generation of inositol trisphosphate in the cells. 5. The amphipathic peptide melittin failed to increase islet-cell 45Ca2+ efflux at a concentration of 1 microgram/ml, and caused only a modest increase at 10 micrograms/ml. 6. Despite its failure to increase 45Ca2+ efflux, melittin at 1 microgram/ml caused a marked enhancement of 3H release from islets that had been prelabelled with [3H]arachidonic acid. 7. The stimulation of 3H efflux caused by melittin correlated with a dose-dependent increase in the unesterified [3H]arachidonic acid content of prelabelled islets and with a corresponding decrease in the extent of labelling of islet phospholipids. 8. Combined addition of melittin (1 microgram/ml) and 5 microM-carbachol to perifused islets failed to augment 45Ca2+ efflux relative to that elicited by carbachol alone. 9. The data indicate that melittin promotes an increase in arachidonic acid availability in intact rat islets. They do not, however, support the proposal that this can either directly reproduce or subsequently modify the extent of intracellular Ca2+ mobilization induced by agents that cause an increase in inositol trisphosphate.
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Pandey, Shashank, Zdenek Tuma, Tereza Smrhova, Miroslava Cedikova, Tereza Macanova, and Magdalena Chottova Dvorakova. "Laser Capture Microdissection Coupled Capillary Immunoassay to Study the Expression of PCK-2 on Spatially-Resolved Islets of Rat Langerhans." Pharmaceutics 13, no. 6 (June 15, 2021): 883. http://dx.doi.org/10.3390/pharmaceutics13060883.
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The platform for precise proteomic profiling of targeted cell populations from heterogeneous tissue sections is developed. We demonstrate a seamless and systematic integration of LCM with an automated cap-IA for the handling of a very small-sized dissected tissues section from the kidney, liver and pancreatic Langerhans islet of rats. Our analysis reveals that the lowest LCM section area ≥ 0.125 mm2 with 10 µm thickness can be optimized for the detection of proteins through LCM-cap-IA integration. We detect signals ranging from a highly-abundant protein, β-actin, to a low-abundance protein, LC-3AB, using 0.125 mm2 LCM section from rat kidney, but, so far, a relatively large section is required for good quality of results. This integration is applicable for a highly-sensitive and accurate assessment of microdissected tissue sections to decipher hidden proteomic information of pure targeted cells. To validate this integration, PCK2 protein expression is studied within Langerhans islets of normal and diabetic rats. Our results show significant overexpression of PCK2 in Langerhans islets of rats with long-term diabetes.
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Ferris, Stephen T., Pavel N. Zakharov, Xiaoxiao Wan, Boris Calderon, Maxim N. Artyomov, Emil R. Unanue, and Javier A. Carrero. "The islet-resident macrophage is in an inflammatory state and senses microbial products in blood." Journal of Experimental Medicine 214, no. 8 (June 19, 2017): 2369–85. http://dx.doi.org/10.1084/jem.20170074.
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We examined the transcriptional profiles of macrophages that reside in the islets of Langerhans of 3-wk-old non-obese diabetic (NOD), NOD.Rag1−/−, and B6.g7 mice. Islet macrophages expressed an activation signature with high expression of Tnf, Il1b, and MHC-II at both the transcript and protein levels. These features are common with barrier macrophages of the lung and gastrointestinal tract. Moreover, injection of lipopolysaccharide induced rapid inflammatory gene expression, indicating that blood stimulants are accessible to the macrophages and that these macrophages can sense them. In NOD mice, the autoimmune process imparted an increased inflammatory signature, including elevated expression of chemokines and chemokine receptors and an oxidative response. The elevated inflammatory signature indicates that the autoimmune program was active at the time of weaning. Thus, the macrophages of the islets of Langerhans are poised to mount an immune response even at steady state, while the presence of the adaptive immune system elevates their activation state.
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Morgan, N. G., and W. Montague. "Studies on the mechanism of inhibition of glucose-stimulated insulin secretion by noradrenaline in rat islets of Langerhans." Biochemical Journal 226, no. 2 (March 1, 1985): 571–76. http://dx.doi.org/10.1042/bj2260571.
Full textAbstract:
Noradrenaline (norepinephrine) was shown to be a potent inhibitor of glucose-induced insulin release from rat pancreatic islets, with half-maximal inhibition of the secretory response to 20 mM-glucose occurring at approx. 0.3 microM, and complete suppression of the response occurring at 4 microM-noradrenaline. Inhibition of insulin secretion by noradrenaline was antagonized by the alpha 2-adrenergic antagonist yohimbine (half maximally effective dose approximately 1 microM), but was largely unaffected by the alpha 1-adrenergic antagonist prazosin at concentrations up to 50 microM, suggesting that the response was mediated by alpha 2-adrenergic receptors. Noradrenaline significantly reduced the extent of 45Ca2+ accumulation in glucose-stimulated islets, although as much as 5 microM-noradrenaline was required for 50% inhibition of this response. The ability of noradrenaline to inhibit islet-cell 45Ca2+ uptake was totally abolished in media containing 1 mM-dibutyryl cyclic AMP, suggesting that the response may have been secondary to lowering of islet cyclic AMP. Under these conditions, however, noradrenaline was still able to inhibit insulin secretion maximally. The data suggest that the site(s) at which noradrenaline acts to mediate inhibition of insulin secretion in rat islets lies distal to both islet-cell cyclic AMP accumulation and Ca2+ uptake.