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1
Santangelo, Carmela, Angela Scipioni, Lorella Marselli, Piero Marchetti, and Francesco Dotta. "Suppressor of cytokine signaling gene expression in human pancreatic islets: modulation by cytokines." European Journal of Endocrinology 152, no. 3 (March 2005): 485–89. http://dx.doi.org/10.1530/eje.1.01856.
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Objective: Suppressor of cytokine signaling (SOCS) proteins negatively regulate signal transduction of several cytokines. Since cytokines participate in the pancreatic islet damage in type 1 diabetes, the aim of our study was to investigate the expression of SOCS-1, -2 and -3 in isolated human islets, in basal conditions and after exposure, in vitro, to a combination of interferon (IFN)-γ, interleukin (IL)-1β and tumor necrosis factor (TNF)-α cytokines and in control and in type 1 diabetic human pancreata, to establish (i) whether SOCS molecules are constitutively expressed in human pancreatic islets and (ii) whether their expression can be modulated in vitro by proinflammatory cytokines or ex vivo by an islet inflammatory process. Methods: Gene expression of SOCS-1, -2 and -3 was evaluated by RT-PCR in untreated and cytokine-treated isolated human pancreatic islets and their protein expression by immunohistochemistry in control and in type 1 diabetic human pancreata paraffin-embedded sections. Results: We found that SOCS-1, -2 and -3 mRNA is constitutively, although weakly, expressed in human pancreatic islets, similar to the expression observed in control pancreata by immunohistochemistry. SOCS-1, -2 and -3 mRNA expression was strongly increased in human islets after exposure, in vitro, to IFN-γ, IL-1β and TNF-α. Accordingly, an intense and islet-specific immunohistochemical staining for all three SOCS was detected in pancreata from type 1 diabetic patients. Conclusion: SOCS-1, -2 and -3 genes are constitutively expressed in human pancreatic islets; their expression increases after exposure to proinflammatory cytokines and during an autoimmune inflammatory process, raising the possibility that these molecules act as key regulators of cytokine signaling in pancreatic islets.
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Omori, Keiko, Eiji Kobayashi, Hirotake Komatsu, Jeffrey Rawson, Garima Agrawal, Mounika Parimi, Alina R. Oancea, et al. "Involvement of a proapoptotic gene (BBC3) in islet injury mediated by cold preservation and rewarming." American Journal of Physiology-Endocrinology and Metabolism 310, no. 11 (June 1, 2016): E1016—E1026. http://dx.doi.org/10.1152/ajpendo.00441.2015.
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Long-term pancreatic cold ischemia contributes to decreased islet number and viability after isolation and culture, leading to poor islet transplantation outcome in patients with type 1 diabetes. In this study, we examined mechanisms of pancreatic cold preservation and rewarming-induced injury by interrogating the proapoptotic gene BBC3/Bbc3, also known as Puma (p53 upregulated modulator of apoptosis), using three experimental models: 1) bioluminescence imaging of isolated luciferase-transgenic (“Firefly”) Lewis rat islets, 2) cold preservation of en bloc-harvested pancreata from Bbc3-knockout (KO) mice, and 3) cold preservation and rewarming of human pancreata and isolated islets. Cold preservation-mediated islet injury occurred during rewarming in “Firefly” islets. Silencing Bbc3 by transfecting Bbc3 siRNA into islets in vitro prior to cold preservation improved postpreservation mitochondrial viability. Cold preservation resulted in decreased postisolation islet yield in both wild-type and Bbc3 KO pancreata. However, after culture, the islet viability was significantly higher in Bbc3-KO islets, suggesting that different mechanisms are involved in islet damage/loss during isolation and culture. Furthermore, Bbc3-KO islets from cold-preserved pancreata showed reduced HMGB1 (high-mobility group box 1 protein) expression and decreased levels of 4-hydroxynonenal (4-HNE) protein adducts, which was indicative of reduced oxidative stress. During human islet isolation, BBC3 protein was upregulated in digested tissue from cold-preserved pancreata. Hypoxia in cold preservation increased BBC3 mRNA and protein in isolated human islets after rewarming in culture and reduced islet viability. These results demonstrated the involvement of BBC3/Bbc3 in cold preservation/rewarming-mediated islet injury, possibly through modulating HMGB1- and oxidative stress-mediated injury to islets.
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Norman, Daniel, Carl Johan Drott, Per-Ola Carlsson, and Daniel Espes. "Irisin—A Pancreatic Islet Hormone." Biomedicines 10, no. 2 (January 25, 2022): 258. http://dx.doi.org/10.3390/biomedicines10020258.
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Irisin is a myokine involved in glucose homeostasis. It is primarily expressed in skeletal muscle, but also in the pancreas. This study aimed to elucidate its presence and role in the islets of Langerhans—i.e., its effect on insulin and glucagon secretion as well as on blood flow in the pancreas. The precursor of irisin, fibronectin type III domain-containing protein 5 (FNDC5), was identified in rat and human islets by both qPCR and immunohistochemistry. Both α- and β-cells stained positive for FNDC5. In human islets, we found that irisin was secreted in a glucose-dependent manner. Neither irisin nor an irisin-neutralizing antibody affected insulin or glucagon secretion from human or rat islets in vitro. The insulin and glucagon content in islets was not altered by irisin. The intravenous infusion of irisin in Sprague Dawley rats resulted in nearly 50% reduction in islet blood flow compared to the control. We conclude that irisin is an islet hormone that has a novel role in pancreatic islet physiology, exerting local vascular effects by diminishing islet blood flow without affecting insulin secretion per se.
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Chadwick, D. R., G. S. M. Robertson, P. Toomey, H. Contractor, S. Rose, R. F. L. James, P. R. F. Bell, and N. J. M. London. "Pancreatic Islet Purification Using Bovine Serum Albumin: The Importance of Density Gradient Temperature and Osmolality." Cell Transplantation 2, no. 4 (July 1993): 355–61. http://dx.doi.org/10.1177/096368979300200419.
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Euro-Ficoll and bovine serum albumin (BSA) are two of the most commonly used density gradient media for the purification of pancreatic islets. Euro-Ficoll is based upon Euro-Collins, a cold storage medium, and must, therefore, be used at 4°C. The ionic composition of BSA, however, is likely to contribute to hypothermic cellular swelling, and this may influence the efficiency of islet purification using this medium at 4°C. Experience in this laboratory also suggested that batch-to-batch variation in islet purity using BSA was related to differences in BSA osmolality. The aim of this study was to assess the effect of gradient medium temperature and osmolality on the purification of human and porcine islets using BSA. Pancreata were collagenase-digested, and islets were purified on continuous linear density gradients of BSA. The distribution of insulin and amylase in each gradient was assayed, and used to calculate the median density of islets and exocrine tissue, and the efficiency of islet purification (%amylase contamination at a fixed insulin yield), using: 1) gradient osmolalities of 300, 400, and 500 mOsm/kg H2O (seven porcine pancreata), and 2) gradients at 4°C and at 22°C (eight human and seven porcine pancreata). Increase in density gradient osmolality produced increases in porcine exocrine tissue density which exceeded changes in islet density, resulting in improved islet purity, maximal at a BSA osmolality of 400 mOsm/kg H2O. For human pancreata there was no significant change in pancreatic tissue densities nor islet purity with temperature. For porcine pancreata the densities of exocrine tissue and islets were lower at 4°C than at 22°C. This reduction in density with temperature was greater for exocrine tissue, resulting in lesser islet purity at 4°C compared to 22°C (p = 0.036). In conclusion, islet purification using BSA is influenced by density gradient temperature and osmolality. For porcine pancreata, a temperature of 22°C, and an osmolality of 400 mOsm/kg H2O are optimal.
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Graves, Leo, Mine Aksular, Riyadh Alakeely, Daniel Ruiz Buck, Adam Chambers, Fernanda Murguia-Meca, Juan-Jose Plata-Muñoz, et al. "Improved Baculovirus Vectors for Transduction and Gene Expression in Human Pancreatic Islet Cells." Viruses 10, no. 10 (October 20, 2018): 574. http://dx.doi.org/10.3390/v10100574.
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Pancreatic islet transplantation is a promising treatment for type 1 diabetes mellitus offering improved glycaemic control by restoring insulin production. Improved human pancreatic islet isolation has led to higher islet transplantation success. However, as many as 50% of islets are lost after transplantation due to immune responses and cellular injury, gene therapy presents a novel strategy to protect pancreatic islets for improved survival post-transplantation. To date, most of the vectors used in clinical trials and gene therapy studies have been derived from mammalian viruses such as adeno-associated or retrovirus. However, baculovirus BacMam vectors provide an attractive and safe alternative. Here, a novel BacMam was constructed containing a frameshift mutation within fp25, which results in virus stocks with higher infectious titres. This improved in vitro transduction when compared to control BacMams. Additionally, incorporating a truncated vesicular stomatitis virus G protein increased transduction efficacy and production of EGFP and BCL2 in human kidney (HK-2) and pancreatic islet β cells (EndoC βH3). Lastly, we have shown that our optimized BacMam vector can deliver and express egfp in intact pancreatic islet cells from human cadaveric donors. These results confirm that BacMam vectors are a viable choice for providing delivery of transgenes to pancreatic islet cells.
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Brissova, Marcela, Michael J. Fowler, Wendell E. Nicholson, Anita Chu, Boaz Hirshberg, David M. Harlan, and Alvin C. Powers. "Assessment of Human Pancreatic Islet Architecture and Composition by Laser Scanning Confocal Microscopy." Journal of Histochemistry & Cytochemistry 53, no. 9 (May 27, 2005): 1087–97. http://dx.doi.org/10.1369/jhc.5c6684.2005.
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The recent success of pancreatic islet transplantation has generated considerable enthusiasm. To better understand the quality and characteristics of human islets used for transplantation, we performed detailed analysis of islet architecture and composition using confocal laser scanning microscopy. Human islets from six separate isolations provided by three different islet isolation centers were compared with isolated mouse and non-human primate islets. As expected from histological sections of murine pancreas, in isolated murine islets α and δ cells resided at the periphery of the β-cell core. However, human islets were markedly different in that α, β, and δ cells were dispersed throughout the islet. This pattern of cell distribution was present in all human islet preparations and islets of various sizes and was also seen in histological sections of human pancreas. The architecture of isolated non-human primate islets was very similar to that of human islets. Using an image analysis program, we calculated the volume of α, β, and δ cells. In contrast to murine islets, we found that populations of islet cell types varied considerably in human islets. The results indicate that human islets not only are quite heterogeneous in terms of cell composition but also have a substantially different architecture from widely studied murine islets.
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Liggins, C., D. J. Orlicky, L. A. Bloomquist, and Roberto Gianani. "Developmentally Regulated Expression of Survivin in Human Pancreatic Islets." Pediatric and Developmental Pathology 6, no. 5 (September 2003): 392–97. http://dx.doi.org/10.1007/s10024-003-2014-0.
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Islet cell apoptosis plays a role in both normal development of the endocrine pancreas and in the pathogenesis of Type I and Type II diabetes. The molecular mechanisms regulating islet cell death and survival in both normal and pathological situations are still not completely elucidated. The inhibitor of apoptosis protein (IAP) Survivin has an anti-apoptotic function mediated by several mechanisms; these include inhibiting caspase 3 and caspase 7. Survivin expression has been reported in human fetal islets and it may play a role in pancreatic remodeling and islet homeostasis. However, there are no data concerning either its expression in neonate or adult islets or its expression in any specific subtype of islet cells. We identified Survivin expression by immunohistochemistry in alpha cells and beta islet cells of 5/5 fetal pancreases. In contrast, fetal delta cells failed to demonstrate any detectable level of Survivin expression. Survivin expression was subsequently lost in the beta cells but not the alpha cells of 5/5 newborns and 5/5 adult subjects. Neonatal and adult delta cells maintained the lack of Survivin expression seen in fetal islets. These data show that different subtypes of islet cells differ in their pattern of Survivin expression. Furthermore, expression of Survivin in the beta cells is developmentally regulated.
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Forbes, Shareen, Andrew R. Bond, Kayleigh L. Thirlwell, Paul Burgoyne, Kay Samuel, June Noble, Gary Borthwick, et al. "Human umbilical cord perivascular cells improve human pancreatic islet transplant function by increasing vascularization." Science Translational Medicine 12, no. 526 (January 15, 2020): eaan5907. http://dx.doi.org/10.1126/scitranslmed.aan5907.
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Islet transplantation is an efficacious therapy for type 1 diabetes; however, islets from multiple donor pancreata are required, and a gradual attrition in transplant function is seen. Here, we manufactured human umbilical cord perivascular mesenchymal stromal cells (HUCPVCs) to Good Manufacturing Practice (GMP) standards. HUCPVCs showed a stable phenotype while undergoing rapid ex vivo expansion at passage 2 (p2) to passage 4 (p4) and produced proregenerative factors, strongly suppressing T cell responses in the resting state and in response to inflammation. Transplanting an islet equivalent (IEQ):HUCPVC ratio of 1:30 under the kidney capsule in diabetic NSG mice demonstrated the fastest return to normoglycemia by 3 days after transplant: Superior glycemic control was seen at both early (2.7 weeks) and later stages (7, 12, and 16 weeks) versus ratios of 1:0, 1:10, and 1:50, respectively. Syngeneic islet transplantation in immunocompetent mice using the clinically relevant hepatic portal route with a marginal islet mass showed that mice transplanted with an IEQ:HUCPVC ratio of 1:150 had superior glycemic control versus ratios of 1:0, 1:90, and 1:210 up to 6 weeks after transplant. Immunodeficient mice transplanted with human islets (IEQ:HUCPVC ratio of 1:150) exhibited better glycemic control for 7 weeks after transplant versus islet transplant alone, and islets transplanted via the hepatic portal vein in an allogeneic mouse model using a curative islet mass demonstrated delayed rejection of islets when cotransplanted with HUCPVCs (IEQ:HUCPVC ratio of 1:150). The immunosuppressive and proregenerative properties of HUCPVCs demonstrated long-term positive effects on graft function in vivo, indicating that they may improve long-term human islet allotransplantation outcomes.
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Barbieux, Charlotte, Géraldine Parnaud, Vanessa Lavallard, Estelle Brioudes, Jérémy Meyer, Mohamed Alibashe Ahmed, Ekaterine Berishvili, Thierry Berney, and Domenico Bosco. "Asymmetrical distribution of δ and PP cells in human pancreatic islets." Journal of Endocrinology 229, no. 2 (May 2016): 123–32. http://dx.doi.org/10.1530/joe-15-0542.
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The aim of this study was to evaluate the location of PP and δ cells in relation to the vascularization within human pancreatic islets. To this end, pancreas sections were analysed by immunofluorescence using antibodies against endocrine islet and endothelial cells. Staining in different islet areas corresponding to islet cells adjacent or not to peripheral or central vascular channels was quantified by computerized morphometry. As results, α, PP and δ cells were preferentially found adjacent to vessels. In contrast to α cells, which were evenly distributed between islet periphery and intraislet vascular channels, PP and δ cells had asymmetric and opposite distributions: PP staining was higher and somatostatin staining was lower in the islet periphery than in the area around intraislet vascular channels. Additionally, frequencies of PP and δ cells were negatively correlated in the islets. No difference was observed between islets from the head and the tail of the pancreas, and from type 2 diabetic and non-diabetic donors. In conclusion, the distribution of δ cells differs from that of PP cells in human islets, suggesting that vessels at the periphery and at the centre of islets drain different hormonal cocktails.
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Ohsawa, Haruhiko, Azuma Kanatsuka, Yoshiharu Tokuyama, Takahide Yamaguchi, Hideichi Makino, Sho Yoshida, Hiroshi Horie, Atsuo Mikata, and Yoshibumi Kohen. "Amyloid protein in somatostatinoma differs from human islet amyloid polypeptide." Acta Endocrinologica 124, no. 1 (January 1991): 45–53. http://dx.doi.org/10.1530/acta.0.1240045.
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Abstract. Amyloid deposits in somatostatinomas are rare observations. To examine the characteristics of this amyloid, we compared amyloid deposits in a somatostatinoma to those found in pancreatic tissue in patients with Type II diabetes mellitus and in insulinomas, using immunohistochemical techniques and specific antibodies to islet amyloid polypeptide or other pancreatic hormones, as well as electron-microscopy. Antibodies to islet amyloid polypeptide regions 8-17 or 25-37 were confirmed to be specific. Amyloid deposits in patients with Type II diabetes mellitus and in insulinomas, but not those in the somatostatinoma strongly reacted with these antibodies, or to an antibody to amyloid P component. Amyloid deposits in the somatostatinoma were not reactive with antibodies to somatostatin or to other pancreatic hormones. Electron-microscopic examinations revealed that amyloid fibrils in the somatostatinoma were thinner and more randomly distributed than were those in islets from patients with Type II diabetes mellitus. As amyloid in somatostatinomas is unlike that consisting of islet amyloid polypeptide or other mature pancreatic hormones, it may be a novel type of local amyloid in pancreatic islets.
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Jin, L., H. Wang, T. Narita, R. Kikuno, O. Ohara, N. Shihara, T. Nishigori, Y. Horikawa, and J. Takeda. "Expression profile of mRNAs from human pancreatic islet tumors." Journal of Molecular Endocrinology 31, no. 3 (December 1, 2003): 519–28. http://dx.doi.org/10.1677/jme.0.0310519.
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In order to understand the tIssue specificity of the endocrine pancreas, it is important to clarify the expression profile of mRNAs in various states of the tIssue. A total of approximately 9000 non-redundant expressed genes from human pancreatic islets and insulinoma have so far been determined as expressed sequence tags (ESTs) and deposited in public databases. In the present study towards the identification of a complete set of genes expressed in human pancreatic islets, we have determined 3'-ESTs of 21267 clones randomly selected from a cDNA library of human pancreatic islet tumors. Clustering analysis generated 6157 non-redundant sequences comprising 2323 groups and 3834 singletons. Nucleotide and peptide database searches show that 3103 of them represent known human sequences or homologs of genes identified in other species and 58 are new members of structurally related families. The sequences were classified on the basis of the putative protein functions encoded, and were assigned to the respective chromosome by database analysis. The sequences were also compared with the EST databases (dbEST and EPConDB) including ESTs from normal pancreatic islet, insulinoma, and fetal pancreas. Since 3384 genes were newly found to be expressed in human pancreatic islets and 587 of them were unique to the islets, this study has considerably expanded the catalog of genes expressed in the endocrine pancreas. The larger collection of pancreatic islet-related ESTs should provide a better genome source for molecular studies of differentiation, tIssue-specific functions, and tumorigenesis of the endocrine pancreas as well as for genetic studies of diabetes mellitus.
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Atouf, Fouad, Yong Choi, Michael J. Fowler, Greg Poffenberger, Jan Vobecky, Malancha Ta, George B. Chapman, Alvin C. Powers, and Nadya L. Lumelsky. "Generation of Islet-Like Hormone-Producing Cells In Vitro from Adult Human Pancreas." Cell Transplantation 14, no. 10 (November 2005): 735–48. http://dx.doi.org/10.3727/000000005783982602.
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Transplantation of pancreatic islets can provide long-lasting insulin independence for diabetic patients, but the current islet supply is limited. Here we describe a new in vitro system that utilizes adult human pancreatic islet-enriched fractions to generate hormone-producing cells over 3–4 weeks of culture. By labeling proliferating cells with a retrovirus-expressing green fluorescent protein, we show that in this system hormone-producing cells are generated de novo. These hormone-producing cells aggregate to form islet-like cell clusters. The cell clusters, when tested in vitro, release insulin in response to glucose and other secretagogues. After transplantation into immunodeficient, nondiabetic mice, the islet-like cell clusters survive and release human insulin. We propose that this system will be useful as an experimental tool for investigating mechanisms for generating new islet cells from the postnatal pancreas, and for designing strategies to generate physiologically competent pancreatic islet cells ex vivo.
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Wu, Douglas C., Joanna Wieckiewicz, and Kathryn J. Wood. "HUMAN REGULATORY T CELLS PREVENT ISLET ALLOGRAFT REJECTION." Clinical & Investigative Medicine 31, no. 4 (August 1, 2008): 25. http://dx.doi.org/10.25011/cim.v31i4.4832.
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Background: Type 1 diabetes mellitus represents a significant burden on global healthcare. Pancreatic islet transplantation offers an effective means of controlling the disease, but shortage of donor tissue, graft thrombosis, and immunological rejection after transplantation remain obstacles that need to be overcome. Our aim was to assess the ability of ex vivo expanded human regulatory T cells (Treg) in modulating the rejection response against a human islet allograft in a clinically relevant model of human pancreatic islet transplantation. Methods: We studied the rejection response against allogeneic human islets in acohort of 32 immunodeficient mice which had been reconstituted with a functional human immune system. Thirteen subjects were transplanted with human islets without further immunological modification; graft survival was compared with that of thirteen subjects treated additionally with human regulatory T cells. Six controls were given a human islet transplant, but not reconstituted with human immune cells to demonstrate the functionality of the islet graft in the absence of immunological rejection. Graft function was assessed with serial blood glucose measurements, immunohistochemistry,immunoflourescence, and flow cytometry. Findings: Human islet allografts were rapidly rejected in subjects that did notreceive Treg. With Treg treatment, however, human islet allograft rejection was prevented (median survival time (MST) of > 45 days with Treg, as opposed to an MST of 23 days without Treg). Ex vivo expanded Treg homed to the lymphoid tissue draining the graft site where they suppressed the priming, activation, proliferation, and effector cytokine production of alloreactive T cells. Interpretation: These findings in a clinically relevant model of human pancreatic islet transplantation demonstrate the ability of ex vivo expanded human Treg to attenuate acute islet allograft rejection, and provide further support for their use in cellular immunotherapy.
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Jaroch, David B., Jing Lu, Rajtarun Madangopal, Natalie D. Stull, Matthew Stensberg, Jin Shi, Jennifer L. Kahn, et al. "Mouse and human islets survive and function after coating by biosilicification." American Journal of Physiology-Endocrinology and Metabolism 305, no. 10 (November 15, 2013): E1230—E1240. http://dx.doi.org/10.1152/ajpendo.00081.2013.
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Inorganic materials have properties that can be advantageous in bioencapsulation for cell transplantation. Our aim was to engineer a hybrid inorganic/soft tissue construct by inducing pancreatic islets to grow an inorganic shell. We created pancreatic islets surrounded by porous silica, which has potential application in the immunoprotection of islets in transplantation therapies for type 1 diabetes. The new method takes advantage of the islet capsule surface as a template for silica formation. Mouse and human islets were exposed to medium containing saturating silicic acid levels for 9–15 min. The resulting tissue constructs were then cultured for up to 4 wk under normal conditions. Scanning electron microscopy and energy dispersive X-ray spectroscopy was used to monitor the morphology and elemental composition of the material at the islet surface. A cytokine assay was used to assess biocompatibility with macrophages. Islet survival and function were assessed by confocal microscopy, glucose-stimulated insulin release assays, oxygen flux at the islet surface, expression of key genes by RT-PCR, and syngeneic transplant into diabetic mice.
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Suszynski, Thomas M., Efstathios S. Avgoustiniatos, and Klearchos K. Papas. "Oxygenation of the Intraportally Transplanted Pancreatic Islet." Journal of Diabetes Research 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/7625947.
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Intraportal islet transplantation (IT) is not widely utilized as a treatment for type 1 diabetes. Oxygenation of the intraportally transplanted islet has not been studied extensively. We present a diffusion-reaction model that predicts the presence of ananoxiccore and a largerpartly functionalcore within intraportally transplanted islets. Four variables were studied: islet diameter, islet fractional viability, external oxygen partial pressure (P) (in surrounding portal blood), and presence or absence of a thrombus on the islet surface. Results indicate that an islet with average size and fractional viability exhibits an anoxic volume fraction (AVF) of 14% and a function loss of 72% at a low externalP. Thrombus formation increased AVF to 30% and function loss to 92%, suggesting that the effect of thrombosis may be substantial. ExternalPand islet diameter accounted for the greatest overall impact on AVF and loss of function. At our institutions, large human alloislets (>200μm diameter) account for ~20% of total islet number but ~70% of total islet volume; since most of the total transplanted islet volume is accounted for by large islets, most of the intraportal islet cells are likely to be anoxic and not fully functional.
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Cross, Sarah E., Stephen J. Hughes, Anne Clark, Derek W. R. Gray, and Paul R. V. Johnson. "Collagenase does Not Persist in Human Islets following Isolation." Cell Transplantation 21, no. 11 (November 2012): 2531–35. http://dx.doi.org/10.3727/096368912x636975.
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Optimal human islet isolation requires the delivery of bacterial collagenase to the pancreatic islet–exocrine interface. However, we have previously demonstrated the presence of collagenase within human islets immediately following intraductal collagenase administration. This potentially has significant implications for patient safety. The present study aimed to determine if collagenase becomes internalized into islets during the isolation procedure and if it remains within the islet postisolation. Islet samples were taken at various stages throughout 14 clinical human islet isolations: during digest collection, following University of Wisconsin solution incubation, immediately postisolation, and after 24 h of culture. Samples were embedded in agar, cryosectioned, and then assessed by immunolabeling for collagenase and insulin. Immunoreactivity for collagenase was not observed in isolated islets in any preparation. Collagenase labeling was detected in one sample taken at the digest collection phase in one islet preparation only. No collagenase-specific labeling was seen in islets sampled at any of the other time points in any of the 14 islet preparations. Collagenase that enters islets during intraductal administration is washed out of the islets during the collection phase of the isolation process and thus does not remain in islets after isolation. This observation alleviates some of the important safety concerns that collagenase remains within islet grafts.
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Reers, Christina, Saskia Erbel, Irene Esposito, Bruno Schmied, Markus W. Büchler, Peter P. Nawroth, and Robert A. Ritzel. "Impaired islet turnover in human donor pancreata with aging." European Journal of Endocrinology 160, no. 2 (February 2009): 185–91. http://dx.doi.org/10.1530/eje-08-0596.
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ObjectiveThe prevalence of type 2 diabetes mellitus escalates with aging although β-cell mass, a primary parameter of β-cell function, is subject to compensatory regulation. So far it is unclear whether the proliferative capacity of pancreatic islets is restricted by senescence.Materials and methodsHuman pancreatic tissue from n=20 non-diabetic organ donors with a mean age of 50.2±3.5 years (range 7–66 years) and mean body mass index of 25.7±0.9 kg/m2 (17.2–33.1 kg/m2) was morphometrically analyzed to determine β-cell volume, β-cell replication, β-cell apoptosis, islet neogenesis, and pancreatic duodenal homeobox-1 (PDX-1) expression.ResultsRelative β-cell volume in human pancreata (mean 2.3±0.2%) remains constant with aging (r=0.26, P=ns). β-cell replication (r=0.71, P=0.0004) decreases age-dependently, while β-cell apoptosis does not change significantly (r=0.42, P=0.08). Concomitantly, PDX-1 expression is downregulated with age in human pancreatic tissue (r=0.65, P=0.002). The rate of islet neogenesis is not affected by aging (r=0.13, P=ns).ConclusionsIn non-diabetic humans, aging is linked with impaired islet turnover possibly due to reduced PDX-1 expression. As β-cell replication is considered to be the main mechanism responsible for β-cell regeneration, these changes restrict the flexibility of the aging human pancreas to adapt to changing demands for insulin secretion and increase the risk for the development of diabetes mellitus in older subjects.
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Joglekar, Mugdha V., Vinay M. Joglekar, Sheela V. Joglekar, and Anandwardhan A. Hardikar. "Human fetal pancreatic insulin-producing cells proliferate in vitro." Journal of Endocrinology 201, no. 1 (January 26, 2009): 27–36. http://dx.doi.org/10.1677/joe-08-0497.
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There have been considerable efforts towards understanding the potential of human pancreatic endocrine cells to proliferate and transition into mesenchymal cell populations. Since rodent studies have demonstrated that mouse insulin-producing cells do not proliferate in vitro, a similar possibility has been considered for human islet endocrine cells. Considering the inherent differences in mouse and human pancreatic islets, we decided to assess the potential of human fetal pancreatic insulin-producing cells to proliferate in vitro. We studied the proliferative potential of human fetal pancreatic islet-derived populations from second or third trimester fetal pancreas and characterized the cells that grow out during their expansion. We have used seven different approaches including in situ hybridization and immunostaining, quantitative estimation of multiple gene transcripts in populations as well as in single cells, clonal analysis of islet cells, assessment of heritable marks of active insulin promoter, and thymidine analog-based lineage tracing. Our studies demonstrate that human fetal pancreatic insulin-producing cells proliferate in vitro to generate mesenchymal cell populations. Interestingly, epigenetic modifications that mark open chromatin conformation of insulin promoter regions are retained even after a million fold expansion/proliferation in vitro. These findings demonstrate that hormone-producing cells in pancreatic islets proliferate in vitro and retain epigenetic marks that characterize an active insulin promoter. Such in vitro-derived mesenchymal cells may be of potential use in cell-replacement therapy for diabetes.
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Warnock, Garth L., and Ray V. Rajotte. "Human pancreatic islet transplantation." Transplantation Reviews 6, no. 4 (October 1992): 195–208. http://dx.doi.org/10.1016/s0955-470x(10)80005-9.
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Ribeiro, Diana, Istvan Horvath, Nikki Heath, Ryan Hicks, Anna Forslöw, and Pernilla Wittung-Stafshede. "Extracellular vesicles from human pancreatic islets suppress human islet amyloid polypeptide amyloid formation." Proceedings of the National Academy of Sciences 114, no. 42 (October 2, 2017): 11127–32. http://dx.doi.org/10.1073/pnas.1711389114.
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Extracellular vesicles (EVs) are small vesicles released by cells to aid cell–cell communication and tissue homeostasis. Human islet amyloid polypeptide (IAPP) is the major component of amyloid deposits found in pancreatic islets of patients with type 2 diabetes (T2D). IAPP is secreted in conjunction with insulin from pancreatic β cells to regulate glucose metabolism. Here, using a combination of analytical and biophysical methods in vitro, we tested whether EVs isolated from pancreatic islets of healthy patients and patients with T2D modulate IAPP amyloid formation. We discovered that pancreatic EVs from healthy patients reduce IAPP amyloid formation by peptide scavenging, but T2D pancreatic and human serum EVs have no effect. In accordance with these differential effects, the insulin:C-peptide ratio and lipid composition differ between EVs from healthy pancreas and EVs from T2D pancreas and serum. It appears that healthy pancreatic EVs limit IAPP amyloid formation via direct binding as a tissue-specific control mechanism.
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Coulson, Barbara S., Paul D. Witterick, Yan Tan, Marilyn J. Hewish, Joanne N. Mountford, Leonard C. Harrison, and Margo C. Honeyman. "Growth of Rotaviruses in Primary Pancreatic Cells." Journal of Virology 76, no. 18 (September 15, 2002): 9537–44. http://dx.doi.org/10.1128/jvi.76.18.9537-9544.2002.
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ABSTRACT Rotavirus infection in children at risk of developing type 1 diabetes has been temporally associated with development of pancreatic islet autoantibodies. In this study, nonobese diabetic mice were shown to be susceptible to rhesus rotavirus infection and pancreatic islets from nonobese diabetic mice, nonobese diabetes-resistant mice, fetal pigs, and macaque monkeys supported various degrees of rotavirus growth. Human rotaviruses replicated in monkey islets only. This islet susceptibility shows that rotavirus infection of the pancreas in vivo might be possible.
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Kutlu, B., A. G. Kayali, S. Jung, G. Parnaud, D. Baxter, G. Glusman, N. Goodman, L. A. Behie, A. Hayek, and L. Hood. "Meta-analysis of gene expression in human pancreatic islets after in vitro expansion." Physiological Genomics 39, no. 1 (September 2009): 72–81. http://dx.doi.org/10.1152/physiolgenomics.00063.2009.
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Pancreatic islet transplantation as a potential cure for type 1 diabetes (T1D) cannot be scaled up due to a scarcity of human pancreas donors. In vitro expansion of β-cells from mature human pancreatic islets provides an alternative source of insulin-producing cells. The exact nature of the expanded cells produced by diverse expansion protocols and their potential for differentiation into functional β-cells remain elusive. We performed a large-scale meta-analysis of gene expression in human pancreatic islet cells, which were processed using three different previously described protocols for expansion and for which redifferentiation was attempted. All three expansion protocols induced dramatic changes in the expression profiles of pancreatic islets; many of these changes are shared among the three protocols. Attempts at redifferentiation of expanded cells induce a limited number of gene expression changes. Nevertheless, these fail to restore a pancreatic islet-like gene expression pattern. Comparison with a collection of public microarray datasets confirmed that expanded cells are highly comparable to mesenchymal stem cells. Genes induced in expanded cells are also enriched for targets of transcription factors important for pluripotency induction. The present data increase our understanding of the active pathways in expanded and redifferentiated islets. Knowledge of the mesenchymal stem cell potential may help development of drug therapeutics to restore β-cell mass in T1D patients.
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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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Street, CN, K. Seeberger, L. Helms, RV Rajotte, AM Shapiro, and GS Korbutt. "Heterogenous expression of nestin in human pancreatic tissue precludes its use as an islet precursor marker." Journal of Endocrinology 180, no. 2 (February 1, 2004): 213–25. http://dx.doi.org/10.1677/joe.0.1800213.
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The discovery of a pancreatic adult stem cell would have significant implications for cell-based replacement therapies for type 1 diabetes mellitus. Nestin, a marker for neural precursor cells, has been suggested as a possible marker for islet progenitor cells. We have characterized the expression and localization of nestin in both the intact human pancreas and clinical human pancreatic islet grafts. Nestin was found to be expressed at different levels in the acinar component of human pancreatic biopsies depending on donor, as well as in ductal structures and islets to some degree. In islets, insulin-producing beta-cells rarely co-expressed the protein, and in the ducts a small percentage (1-2%) of cells co-expressed nestin and cytokeratin 19 (CK19) while most expressed only CK19 (90%) or nestin (5-10%) alone. Assessment of nestin expression in neonatal pancreatic sections revealed an increased number of islet-associated positive cells as compared with adult islets. Nestin immunoreactivity was also found in cells of the pancreatic vasculature and mesenchyme as evidenced by co-localization with smooth muscle actin and vimentin. Samples from post-islet isolation clinical islet grafts revealed a pronounced heterogeneity in the proportion of nestin-positive cells (<1-72%). Co-localization studies in these grafts showed that nestin is not co-expressed in endocrine cells and rarely (<5%) with cytokeratin-positive ductal cells. However, relatively high levels of co-expression were found with acinar cells and cells expressing the mesenchymal marker vimentin. In conclusion we have shown a diffuse and variable expression of nestin in human pancreas that may be due to a number of different processes, including post-mortem tissue remodeling and cellular differentiation. For this reason nestin may not be a suitable marker solely for the identification of endocrine precursor cells in the pancreas.
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Johannesen, Jesper, Steffen Helqvist, and Jørn Nerup. "Not all insulin secretagogues sensitize pancreatic islets to recombinant human interleukin 1β." Acta Endocrinologica 123, no. 4 (October 1990): 445–52. http://dx.doi.org/10.1530/acta.0.1230445.
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Abstract. The purpose of this study was to test the influence of different insulin secretagogues on interleukin 1β mediated injury to isolated rat pancreatic islets. Islets were exposed to interleukin 1β for 6 days. During exposure, beta-cells were stimulated with glucose ( 11 mmol/l vs 3.3 mmol/l or with non-nutrients as tolbutamide (250 μmol/l), iso-butyl 1-methyl-xanthine (50 μmol/l), or glucagon (10 mg/l). At 3.3 mmol/l of glucose, 60 000 U/l of interleukin 1β caused an inhibition of medium insulin accumulation to 62±5% of control from 48 h to 6 days of exposure, whereas islet DNA content was unaffected. At 11 mmol/l of glucose, interleukin 1β dose-dependently decreased medium insulin accumulation (e.g. 60 000 U/l of interleukin 1β, 12±3% of control) and islet content of DNA (60 000 U/l of interleukin 1β, 60±8% of control). During beta-cell stimulation with tolbutamide, interleukin 1β caused inhibition of insulin accumulation to 36±9% of control. In contrast, on islets stimulated with iso-butyl 1-methyl-xanthine or glucagon, the effects of interleukin 1 β were equivalent to those on non-stimulated islets. These differences were paralleled by differences in the interleukin 1β effect on islet morphology. In conclusion, high beta-cell activity (as measured by islet insulin release) may increase islet susceptibility to interleukin 1β, however, depending upon the intracellular pathway through which insulin secretion is activated.
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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.
Full textAbstract:
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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M., Nithyakalyani,, Reddy, H., Raghavan, S., Sunder, A., Sivamani, G., and Veerabathiran, R. "Isolation of Human Pancreatic Islets from the Indian Population - Unveiling the Synergistic Interplay between different blends of Collagenases and Neutral Proteases." CARDIOMETRY, no. 24 (November 30, 2022): 243–51. http://dx.doi.org/10.18137/cardiometry.2022.24.243251.
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Innovative and effective therapeutic approaches for diabetes such as islet cell transplantation are much needed as diabetes increases the risk of heart failure. In India, the success rate of human clinical islet transplantation (allo-or auto-) mandates sufficiency of functional islets from the pancreas of either brain-dead or chronic pancreatitis donors. Human islet transplantation outcome is significantly affected by collagenases, which decides the yield and quality of isolated pancreatic islet cells. Comparison of collagenase blends carried out in a few islet transplantation centers yields conflicting results for islet quantity and quality. Therefore, we have researched on the right blend of enzymes to achieve an efficient pancreatic islet release, first-ever in Indian population. Our prospective approach evaluated the outcome of islet isolations performed in humans with three different collagenases, namely Serva Collagenase NB1, Roche Liberase and Vitacyte supplemented with Neutral Protease NB. Eight brain-dead humans served as organ donors for pancreatic islet isolation. We modified the islet isolation method to test these three new enzymes using the traditional split pancreas methodology. The islet isolation outcomes were compared for morphological differences, yield, and viability. This was correlated statistically with the donor characteristics using graph-pad prism analysis. Islet yield was substantial in all the three enzyme blends. But post-purification of islets in the Indian population, we found that the yield was better in Serva collagenase NB1 compared to Vitacyte and Roche liberase. For every gram of pancreas, the islet yield, proportion and morphology of islet cells (both free and intact) were higher in Serva collagenase compared to the other two enzyme blends.
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Klymiuk, N., A. Baehr, B. Kessler, M. Kurome, A. Wuensch, N. Herbach, R. Wanke, H. Nagashima, and E. Wolf. "425 HIGH-LEVEL EXPRESSION OF LEA29Y IN PANCREATIC ISLETS OF TRANSGENIC PIGS." Reproduction, Fertility and Development 22, no. 1 (2010): 370. http://dx.doi.org/10.1071/rdv22n1ab425.
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Among the candidate organs or tissues for pig-to-primate xenotransplantation, pancreatic islets are probably closest to clinical application. Rejection of islet xenografts occurs mainly by cellular mechanisms; that is, T cells. A candidate molecule to protect porcine islets against the attack by human T cells is CTLA-4Ig, which represents the T-cell-inactivating extracellular domain of the human CTLA-4 protein linked to a region of the human immunoglobulin (Ig). This recombinant soluble fusion protein binds to CD80 and CD86, blocking their interaction with CD28 and thereby inhibiting T-cell proliferation and T-cell-dependent antibody production. The survival of human, rabbit, and porcine islets after transplantation into streptozotocin-treated diabetic mice was found to be prolonged after treatment with CTLA-4Ig. In order to facilitate local protection of pig-to-primate islet xenografts, we generated transgenic pigs expressing LEA29Y, a modification of the original CTLA-4Ig with higher potency, specifically in the pancreatic islets. In LEA29Y, 2 amino acids in the binding region of CTLA-4 are altered. The LEA29Y coding sequence was placed under the control of the 1.3-kb core promoter from the porcine insulin gene (INS), and the polyadenylation signal from the bovine growth hormone gene (GH) was added. The construct was linked with a floxed neomycin resistance cassette and transfected into porcine fetal fibroblasts. The cells were selected and stable clones were pooled and used as donors for nuclear transfer. After electrofusion and activation, embryos were transferred to 2 synchronized gilts; 8 piglets survived to term with 7 of them carrying the transgene. Southern blot analysis suggested that the founder animals contain 1 or 2 independent integration sites. Four founders were autopsied at the age of 3 months to evaluate expression of LEA29Y in the pancreatic islets by immunohistochemistry. The ratio of immunohistochemically stained islet cell profiles to all islet cell profiles in the islet profiles visible in the sections was estimated. The staining intensity was also estimated qualitatively, by grading from weak to strong immunoreactivity (brown color, using DAB as chromogen). Although 2 founders exhibited single LEA29Y-positive islet cells in some pancreatic islet profiles, the other 2 founders showed a high percentage of strongly positive cells in all islet profiles examined, suggesting beta-cell specific expression. Fibroblasts from the latter 2 founders are currently being used for recloning to generate multiple pigs with constitutive expression of LEA29Y in the pancreatic islets. The protective effect of this strategy will be tested by transplanting LEA29Y-expressing porcine islets in diabetic mouse models with a humanized immune system and in diabetic nonhuman primate models. Supported by the Deutsche Forschungsgemeinschaft (FOR 535).
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Alvarsson, Alexandra, Maria Jimenez-Gonzalez, Rosemary Li, Carolina Rosselot, Nikolaos Tzavaras, Zhuhao Wu, Andrew F. Stewart, Adolfo Garcia-Ocaña, and Sarah A. Stanley. "A 3D atlas of the dynamic and regional variation of pancreatic innervation in diabetes." Science Advances 6, no. 41 (October 2020): eaaz9124. http://dx.doi.org/10.1126/sciadv.aaz9124.
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Understanding the detailed anatomy of the endocrine pancreas, its innervation, and the remodeling that occurs in diabetes can provide new insights into metabolic disease. Using tissue clearing and whole-organ imaging, we identified the 3D associations between islets and innervation. This technique provided detailed quantification of α and β cell volumes and pancreatic nerve fibers, their distribution and heterogeneity in healthy tissue, canonical mouse models of diabetes, and samples from normal and diabetic human pancreata. Innervation was highly enriched in the mouse endocrine pancreas, with regional differences. Islet nerve density was increased in nonobese diabetic mice, in mice treated with streptozotocin, and in pancreata of human donors with type 2 diabetes. Nerve contacts with β cells were preserved in diabetic mice and humans. In summary, our whole-organ assessment allows comprehensive examination of islet characteristics and their innervation and reveals dynamic regulation of islet innervation in diabetes.
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Habart, David, Jan Švihlík, Jan Schier, Monika Cahová, Peter Girman, Klára Zacharovová, Zuzana Berkov, et al. "Automated Analysis of Microscopic Images of Isolated Pancreatic Islets." Cell Transplantation 25, no. 12 (December 2016): 2145–56. http://dx.doi.org/10.3727/096368916x692005.
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Clinical islet transplantation programs rely on the capacities of individual centers to quantify isolated islets. Current computer-assisted methods require input from human operators. Here we describe two machine learning algorithms for islet quantification: the trainable islet algorithm (TIA) and the nontrainable purity algorithm (NPA). These algorithms automatically segment pancreatic islets and exocrine tissue on microscopic images in order to count individual islets and calculate islet volume and purity. References for islet counts and volumes were generated by the fully manual segmentation (FMS) method, which was validated against the internal DNA standard. References for islet purity were generated via the expert visual assessment (EVA) method, which was validated against the FMS method. The TIA is intended to automatically evaluate micrographs of isolated islets from future donors after being trained on micrographs from a limited number of past donors. Its training ability was first evaluated on 46 images from four donors. The pixel-to-pixel comparison, binary statistics, and islet DNA concentration indicated that the TIA was successfully trained, regardless of the color differences of the original images. Next, the TIA trained on the four donors was validated on an additional 36 images from nine independent donors. The TIA was fast (67 s/image), correlated very well with the FMS method ( R 2 = 1.00 and 0.92 for islet volume and islet count, respectively), and had small REs (0.06 and 0.07 for islet volume and islet count, respectively). Validation of the NPA against the EVA method using 70 images from 12 donors revealed that the NPA had a reasonable speed (69 s/image), had an acceptable RE (0.14), and correlated well with the EVA method ( R 2 = 0.88). Our results demonstrate that a fully automated analysis of clinical-grade micrographs of isolated pancreatic islets is feasible. The algorithms described herein will be freely available as a Fiji platform plugin.
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Figueiredo, Hugo, Ana Lucia C. Figueroa, Ainhoa Garcia, Rebeca Fernandez-Ruiz, Christophe Broca, Anne Wojtusciszyn, Rita Malpique, Rosa Gasa, and Ramon Gomis. "Targeting pancreatic islet PTP1B improves islet graft revascularization and transplant outcomes." Science Translational Medicine 11, no. 497 (June 19, 2019): eaar6294. http://dx.doi.org/10.1126/scitranslmed.aar6294.
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Deficient vascularization is a major driver of early islet graft loss and one of the primary reasons for the failure of islet transplantation as a viable treatment for type 1 diabetes. This study identifies the protein tyrosine phosphatase 1B (PTP1B) as a potential modulator of islet graft revascularization. We demonstrate that grafts of pancreatic islets lacking PTP1B exhibit increased revascularization, which is accompanied by improved graft survival and function, and recovery of normoglycemia and glucose tolerance in diabetic mice transplanted with PTP1B-deficient islets. Mechanistically, we show that the absence of PTP1B leads to activation of hypoxia-inducible factor 1α–independent peroxisome proliferator–activated receptor γ coactivator 1α/estrogen-related receptor α signaling and enhanced expression and production of vascular endothelial growth factor A (VEGF-A) by β cells. These observations were reproduced in human islets. Together, these findings reveal that PTP1B regulates islet VEGF-A production and suggest that this phosphatase could be targeted to improve islet transplantation outcomes.
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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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Moin, Abu Saleh Md, Megan Cory, Tatyana Gurlo, Yoshifumi Saisho, Robert A. Rizza, Peter C. Butler, and Alexandra E. Butler. "Pancreatic alpha-cell mass across adult human lifespan." European Journal of Endocrinology 182, no. 2 (February 2020): 219–31. http://dx.doi.org/10.1530/eje-19-0844.
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Aim To establish pancreatic alpha-cell mass in lean, non-diabetic humans over the adult lifespan, performed as a follow-up study to beta-cell mass across the adult human lifespan. Methods We examined human pancreatic autopsy tissue from 66 lean, non-diabetic individuals aged from 30 to 102 years, grouped into deciles: 3rd (30–39 years), 4th (40–49 years), 5th (50–59 years), 6th (60–69 years), 7th (70–79 years), 8th (80–89 years) and 9th deciles (90+ years). Sections of pancreas were immunostained for glucagon and analyzed for fractional alpha-cell area. Population-based pancreatic volume data were used to calculate alpha-cell mass. Results With advanced age, the exocrine pancreas undergoes atrophy demonstrated by increased fat area (as % exocrine area) (0.05 ± 0.01 vs 1.6 ± 0.7% fat area of total exocrine pancreas, 3rd vs 9th decile, P < 0.05). Consequently, islet density increases with age (2.7 ± 0.4 vs 10.5 ± 3.3 islets/mm2, 3rd vs 9th decile, P < 0.05). Alpha-cell fractional area increases with advanced age (0.34 ± 0.05% vs 0.73 ± 0.26%, 3rd vs 9th decile, P < 0.05). However, alpha-cell mass remains constant at ~190 mg throughout the adult lifespan in lean, non-diabetic humans. Within islets, alpha-cell distribution between mantle and core is unchanged across deciles (1862 ± 220 vs 1945 ± 200 vs 1948 ± 139 alpha cells in islet mantle/mm2, 3rd vs 6th vs 9th decile, P = 0.93 and 1912 ± 442 vs 1449 ± 123 vs 1514 ± 168 alpha cells in islet core/mm2, 3rd vs 6th vs 9th decile, P = 0.47), suggesting that human islets retain their structural organization in the setting of age-related exocrine atrophy. Conclusions Consistent with our previous findings for beta-cell mass, alpha-cell mass remains constant in humans, even with advanced age. Pancreatic endocrine cells are much more robustly preserved than exocrine cells in aged humans, and islets maintain their structural integrity throughout life.
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Hanley, Stephen, and Lawrence Rosenberg. "Transforming Growth Factor β Is a Critical Regulator of Adult Human Islet Plasticity." Molecular Endocrinology 21, no. 6 (June 1, 2007): 1467–77. http://dx.doi.org/10.1210/me.2007-0045.
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Abstract Tissue plasticity is well documented in the context of pancreatic regeneration and carcinogenesis, with recent reports implicating dedifferentiated islet cells both as endocrine progenitors and as the cell(s) of origin in pancreatic adenocarcinoma. Accordingly, it is noteworthy that accumulating evidence suggests that TGFβ signaling is essential to pancreatic endocrine development and maintenance, whereas its loss is associated with the progression to pancreatic adenocarcinoma. The aim of this study was to examine the role of TGFβ in an in vitro model of islet morphogenetic plasticity. Human islets were embedded in a collagen gel and cultured under conditions that induced transformation into duct-like epithelial structures (DLS). Addition of TGFβ caused a dose-dependent decrease in DLS formation. Although it was demonstrated that collagen-embedded islets secrete low levels of TGFβ, antibody-mediated neutralization of this endogenously released TGFβ improved DLS formation rates, suggesting local TGFβ concentrations may in fact be higher. Time course studies indicated that TGFβ signaling was associated with an increase in ERK and p38 MAPK phosphorylation, although inhibitor-based studies were consistent with an islet endocrine-stabilizing effect mediated by p38 alone. Localization of TGFβ signaling molecules suggested that the action of TGFβ is directly on the β-cell to inhibit apoptosis and thus stabilize endocrine phenotype.
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Oh, Ju Yun, Yang Hee Kim, Song Lee, Yu Na Lee, Han Se Go, Dae Wook Hwang, Ki Byung Song, et al. "The Outcomes and Quality of Pancreatic Islet Cells Isolated from Surgical Specimens for Research on Diabetes Mellitus." Cells 11, no. 15 (July 29, 2022): 2335. http://dx.doi.org/10.3390/cells11152335.
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Isolating a large quantity of high-quality human islets is a prerequisite for diabetes research. Human islets are typically isolated from the pancreases of brain-dead donors, making research difficult due to low availability. Pancreas tissue discarded after surgical resection may be a good alternative source of islet cells. To test this hypothesis, we isolated islets from discarded surgical specimens and evaluated the islet yield and quality as well as islet cell preparations. Eighty-two segmental pancreases were processed using the Ricordi automated method, and islet yield and quality were investigated. The mean age of patients was 54.6, and the cohort included 32 diabetes patients. After purification, partially resected pancreases yielded an average of 59,593 ± 56,651 islet equivalents (IEQs) and 2546 IEQ/g of digested pancreas, with 71.5 ± 21% purity. Multivariate analysis revealed that diabetes (p = 0.0046) and the lobe used (p = 0.0156) significantly altered islet yield. Islets transplanted into diabetic mice displayed good viability and in vitro glucose responses, DNA/RNA quality, mitochondrial function, and glucose control, even though these results were dependent on islet quality. Isolated cells also maintained high viability and function even after cryopreservation. Our findings indicate that pancreatic tissue discarded after surgery can be a valuable source of islets for diabetes research.
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Reubi, J. C., A. Kappeler, B. Waser, A. Schonbrunn, and J. Laissue. "Immunohistochemical Localization of Somatostatin Receptor sst2A in Human Pancreatic Islets." Journal of Clinical Endocrinology & Metabolism 83, no. 10 (October 1, 1998): 3746–49. http://dx.doi.org/10.1210/jcem.83.10.5314.
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Somatostatin and octreotide inhibit endocrine pancreatic functions in man, via specific somatostatin receptors. However, the cellular distribution of the different somatostatin receptor subtype proteins has not been determined in the human pancreas. Here, the immunohistochemical distribution of the sst2A receptor was investigated using the sst2A receptor specific anti-peptide antibody R2-88 in cryostat as well as in formalin-fixed paraffin-embedded sections of human pancreatic tissue, and compared with insulin, glucagon and somatostatin immunostaining of adjacent sections. All pancreatic islets were immunostained with R2-88. Most islet cells were labeled: the sst2A receptors were present in insulin as well as glucagon producing cells, but were not detected in intra-islet vessels nor in adjacent acinar tissue. Absorption of the sst2A antibody with 100 nM of the antigen peptide abolished specific staining in tissue sections. Immunohistochemical staining with 125I-Tyr3-octreotide. Therefore, the clinical efficacy of octreotide on glucagon and insulin release can be explained by the presence of sst2A receptors in human A and B pancreatic islet cells. Moreover, absence of sst2A receptors in human acinar tissue suggests that the action of somatostatin on pancreatic exocrine secretion is mediated either indirectly or through a different somatostatin receptor subtype on acinar cells.
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Grzesik, Wojciech J., Joseph L. Nadler, Yui Machida, Jerry L. Nadler, Yumi Imai, and Margaret A. Morris. "Expression Pattern of 12-Lipoxygenase in Human Islets With Type 1 Diabetes and Type 2 Diabetes." Journal of Clinical Endocrinology & Metabolism 100, no. 3 (March 1, 2015): E387—E395. http://dx.doi.org/10.1210/jc.2014-3630.
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Context: Inflammation in the pancreas can cause β-cell stress, leading to diabetes development. Access to human pancreas tissues via the Network for Pancreatic Organ Donors with Diabetes (nPOD) has allowed characterization of pathways leading to this inflammation. Objective: 12-Lipoxygenase (12-LO) induces inflammation and has been implicated in diabetes development. Our goal was to determine expression of 12-LO in human islets from control, autoantibody-positive, type 1 diabetic, and type 2 diabetic nPOD pancreas donors. Design: Pancreas tissues from nPOD donors were examined by immunohistochemistry and immunofluorescence for islet expression of 12-LO in different subsets of islet cells. Participants: Donor pancreas samples were obtained from nPOD based on disease status (control, n = 7; autoantibody-positive, n = 8; type 1 diabetic, n = 17; or type 2 diabetic donors, n = 15). Main Outcome Measure: Determination of 12-LO expression within human islets served as the main outcome measure, including distinguishing which types of islet cells expressed 12-LO. Results: Islets from control participants (nondiabetic) lacked islet expression of 12-LO. Of donors in the other groups, 25% to 37% expressed islet 12-LO with a clear inverse relation between the numbers of β-cells and 12-LO+ cells within islets of 12-LO+ cases. 12-LO expression was not seen within macrophages, endothelial cells, α-cells, or β-cells, but only within cells expressing low levels of pancreatic polypeptide (PP) and increased levels of vimentin. Conclusions: 12-LO expression colocalizes within a specific type of islet PP+ cell under prediabetic and diabetic conditions. The costaining of PP and vimentin suggests that 12-LO participates in the process leading to β-cell dedifferentiation in the islet.
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Lebreton, Fanny, Reine Hanna, Charles H. Wassmer, Kevin Bellofatto, Lisa Perez, Véronique Othenin-Girard, Begoña Martinez de Tejada, Marie Cohen, and Ekaterine Berishvili. "Mechanisms of Immunomodulation and Cytoprotection Conferred to Pancreatic Islet by Human Amniotic Epithelial Cells." Stem Cell Reviews and Reports 18, no. 1 (October 6, 2021): 346–59. http://dx.doi.org/10.1007/s12015-021-10269-w.
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AbstractInhibiting pro-inflammatory cytokine activity can reverse inflammation mediated dysfunction of islet grafts. Human amniotic epithelial cells (hAECs) possess regenerative, immunomodulatory and anti-inflammatory properties. We hypothesized that hAECs could protect islets from cellular damage induced by pro-inflammatory cytokines. To verify our hypothesis, hAEC monocultures, rat islets (RI), or RI-hAEC co-cultures where exposed to a pro-inflammatory cytokine cocktail (Interferon γ: IFN-γ, Tumor necrosis factor α: TNF-α and Interleukin-1β: IL-1β). The secretion of anti-inflammatory cytokines and gene expression changes in hAECs and viability and function of RI were evaluated. The expression of non-classical Major Histocompatibility Complex (MHC) class I molecules by hAECs cultured with various IFN-γ concentrations were assessed. Exposure to the pro-inflammatory cocktail significantly increased the secretion of the anti-inflammatory cytokines IL6, IL10 and G-CSF by hAECs, which was confirmed by upregulation of IL6, and IL10 gene expression. HLA-G, HLA-E and PDL-1 gene expression was also increased. This correlated with an upregulation of STAT1, STAT3 and NF-κB1gene expression levels. RI co-cultured with hAECs maintained normal function after cytokine exposure compared to RI cultured alone, and showed significantly lower apoptosis rate. Our results show that exposure to pro-inflammatory cytokines stimulates secretion of anti-inflammatory and immunomodulatory factors by hAECs through the JAK1/2 – STAT1/3 and the NF-κB1 pathways, which in turn protects islets against inflammation-induced damages. Integrating hAECs in islet transplants appears as a valuable strategy to achieve to inhibit inflammation mediated islet damage, prolong islet survival, improve their engraftment and achieve local immune protection allowing reducing systemic immunosuppressive regimens. Graphical Abstract This study focuses on the cytoprotective effect of isolated hAECs on islets exposed to pro-inflammatory cytokines in vitro. Exposure to pro-inflammatory cytokines stimulated secretion of anti-inflammatory and immunomodulatory factors by hAECs putatively through the JAK1/2 – STAT1/3 and the NF-κB1 pathways. This had protective effect on islets against inflammation-induced damages. Taken together our results indicate that incorporating hAECs in islet transplants could be a valuable strategy to inhibit inflammation mediated islet damage, prolong islet survival, improve their engraftment and achieve local immune protection allowing to reduce systemic immunosuppressive regimens.
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Lee, Yu Na, Hye-Jin Yi, Yang Hee Kim, Song Lee, Jooyun Oh, Teruo Okano, In Kyong Shim, and Song Cheol Kim. "Evaluation of Multi-Layered Pancreatic Islets and Adipose-Derived Stem Cell Sheets Transplanted on Various Sites for Diabetes Treatment." Cells 9, no. 9 (August 31, 2020): 1999. http://dx.doi.org/10.3390/cells9091999.
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Islet cell transplantation is considered an ideal treatment for insulin-deficient diabetes, but implantation sites are limited and show low graft survival. Cell sheet technology and adipose-derived stem cells (ADSCs) can be useful tools for improving islet cell transplantation outcomes since both can increase implantation efficacy and graft survival. Herein, the optimal transplantation site in diabetic mice was investigated using islets and stem cell sheets. We constructed multi-layered cell sheets using rat/human islets and human ADSCs. Cell sheets were fabricated using temperature-responsive culture dishes. Islet/ADSC sheet (AI sheet) group showed higher viability and glucose-stimulated insulin secretion than islet-only group. Compared to islet transplantation alone, subcutaneous AI sheet transplantation showed better blood glucose control and CD31+ vascular traits. Because of the adhesive properties of cell sheets, AI sheets were easily applied on liver and peritoneal surfaces. Liver or peritoneal surface grafts showed better glucose control, weight gain, and intraperitoneal glucose tolerance test (IPGTT) profiles than subcutaneous site grafts using both rat and human islets. Stem cell sheets increased the therapeutic efficacy of islets in vivo because mesenchymal stem cells enhance islet function and induce neovascularization around transplanted islets. The liver and peritoneal surface can be used more effectively than the subcutaneous site in future clinical applications.
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Dominguez Gutierrez, Giselle, Jinrang Kim, Ann-Hwee Lee, Jenny Tong, JingJing Niu, Sarah M. Gray, Yi Wei, et al. "Gene Signature of the Human Pancreatic ε Cell." Endocrinology 159, no. 12 (October 30, 2018): 4023–32. http://dx.doi.org/10.1210/en.2018-00833.
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Abstract The ghrelin-producing ε cell represents the fifth endocrine cell type in human pancreatic islets. The abundance of ε cells in adult pancreas is extremely low, which has hampered the investigation on the molecular pathways regulating the development and the function of this cell type. In this study, we explored the molecular features defining the function of pancreatic ε cells isolated from adult nondiabetic donors using single-cell RNA sequencing technology. We focus on transcription factors, cell surface receptors, and genes involved in metabolic pathways that contribute to regulation of cellular function. Furthermore, the genes that separate ε cells from the other islet endocrine cell types are presented. This study expands prior knowledge about the genes important for ε cell functioning during development and provides a resource to interrogate the transcriptome of this rare human islet cell type.
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Novials, A., Y. Sarri, R. Casamitjana, F. Rivera, and R. Gomis. "Regulation of Islet Amyloid Polypeptide in Human Pancreatic Islets." Diabetes 42, no. 10 (October 1, 1993): 1514–19. http://dx.doi.org/10.2337/diab.42.10.1514.
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Novials, A., Y. Sarri, R. Casamitjana, F. Rivera, and R. Gomis. "Regulation of islet amyloid polypeptide in human pancreatic islets." Diabetes 42, no. 10 (October 1, 1993): 1514–19. http://dx.doi.org/10.2337/diabetes.42.10.1514.
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Sundkvist, Göran, Agneta Bergqvist, Henrik Weibull, David Bergqvist, Kaj Fält, Mona Landin Olsson, and Åke Lernmark. "Islet cell antibody reactivity with human fetal pancreatic islets." Diabetes Research and Clinical Practice 14, no. 1 (October 1991): 1–7. http://dx.doi.org/10.1016/0168-8227(91)90046-g.
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Scopsi, Lucio, Salvatore Andreola, Carlo Socci, Federico Bertuzzi, Valerio Di Carlo, Guido Pozza, Franco Rilke, et al. "Immunocytochemical Detection and Characterization of Intrahepatic Human Pancreatic Islets after Combined Liver-Islet Allotransplantation." Cell Transplantation 3, no. 6 (November 1994): 499–508. http://dx.doi.org/10.1177/096368979400300607.
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The unique availability of an explanted liverislet allograft, removed for primary nonfunction of the liver, led us to evaluate distribution and phenotype of exocrine and endocrine components of the pancreatic graft. Immunocytochemistry was used to map patterns of gene products for islet hormones, proprotein processing enzymes, panneuroendocrine markers, and pancreatic exocrine markers. When compared with age-matched control pancreases, insulin-, glucagon-, somatostatin-, and pancreatic polypeptide-producing cells were similarly represented and distributed within the grafted islet. We also demonstrate that the intrahepatic transplanted islets retained the enzyme machinery able to process the hormone precursors into bioactive fragments. In the clinical setting, this resulted in an immediate functioning of the graft and insulin-independence of the patient one month after transplantation. The purity in islets, as assessed by immunocytochemistry with antibodies to tissue constituents of endocrine and exocrine lineages, was around 40%. Despite the massive intraportal presence of pancreatic acinar tissue, no signs or symptoms attributable to ectopic hypersecretion of exocrine enzymes occurred. In fact, when tested with antibodies to such enzymes, low levels of immunoreactivity were observed in the grafted acinar cells.
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Liu, Jun-Li, Karen T. Coschigano, Katie Robertson, Mark Lipsett, Yubin Guo, John J. Kopchick, Ujendra Kumar, and Ye Lauren Liu. "Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice." American Journal of Physiology-Endocrinology and Metabolism 287, no. 3 (September 2004): E405—E413. http://dx.doi.org/10.1152/ajpendo.00423.2003.
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Growth hormone, acting through its receptor (GHR), plays an important role in carbohydrate metabolism and in promoting postnatal growth. GHR gene-deficient (GHR−/−) mice exhibit severe growth retardation and proportionate dwarfism. To assess the physiological relevance of growth hormone actions, GHR−/− mice were used to investigate their phenotype in glucose metabolism and pancreatic islet function. Adult GHR−/− mice exhibited significant reductions in the levels of blood glucose and insulin, as well as insulin mRNA accumulation. Immunohistochemical analysis of pancreatic sections revealed normal distribution of the islets despite a significantly smaller size. The average size of the islets found in GHR−/− mice was only one-third of that in wild-type littermates. Total β-cell mass was reduced 4.5-fold in GHR−/− mice, significantly more than their body size reduction. This reduction in pancreatic islet mass appears to be related to decreases in proliferation and cell growth. GHR−/− mice were different from the human Laron syndrome in serum insulin level, insulin responsiveness, and obesity. We conclude that growth hormone signaling is essential for maintaining pancreatic islet size, stimulating islet hormone production, and maintaining normal insulin sensitivity and glucose homeostasis.
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Chittezhath, Manesh, Cho M. M. Wai, Vanessa S. Y. Tay, Minni Chua, Sarah R. Langley, and Yusuf Ali. "TLR4 signals through islet macrophages to alter cytokine secretion during diabetes." Journal of Endocrinology 247, no. 1 (October 2020): 87. http://dx.doi.org/10.1530/joe-20-0131.
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Toll-like receptors (TLRs), particularly TLR4, may act as immune sensors for metabolic stress signals such as lipids and link tissue metabolic changes to innate immunity. TLR signalling is not only tissue-dependent but also cell-type dependent and recent studies suggest that TLRs are not restricted to innate immune cells alone. Pancreatic islets, a hub of metabolic hormones and cytokines, respond to TLR signalling. However, the source of TLR signalling within the islet remain poorly understood. Uncovering the specific cell source and its role in mediating TLR signalling, especially within type 2 diabetes (T2D) islet will yield new targets to tackle islet inflammation, hormone secretion dysregulation and ultimately diabetes. In the present study, we immuno-characterised TLRs linked to pancreatic islets in both healthy and obese diabetic mice. We found that while TLRs1–4 and TLR9 were expressed in mouse islets, these TLRs did not co-localise with insulin-producing β-cells. β-Cells from obese diabetic mice were also devoid of these TLRs. While TLR immunoreactivity in obese mice islets increased, this was driven mostly by increased islet endothelial cell and islet macrophage presence. Analysis of human islet single-cell RNA-seq databases revealed that macrophages were an important source of islet TLRs. However, only TLR4 and TLR8 showed variation and cell-type specificity in their expression patterns. Cell depletion experiments in isolated mouse islets showed that TLR4 signalled through macrophages to alter islet cytokine secretome. Together, these studies suggest that islet macrophages are a dominant source of TLR4-mediated signalling in both healthy and diabetic islets.
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Olack, Barbara J., Michael Alexander, Carol J. Swanson, Julie Kilburn, Nicole Corrales, Antonio Flores, Jennifer Heng, et al. "Optimal Time to Ship Human Islets Post Tissue Culture to Maximize Islet." Cell Transplantation 29 (January 1, 2020): 096368972097458. http://dx.doi.org/10.1177/0963689720974582.
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Access to functional high-quality pancreatic human islets is critical to advance diabetes research. The Integrated Islet Distribution Program (IIDP), a major source for human islet distribution for over 15 years, conducted a study to evaluate the most advantageous times to ship islets postisolation to maximize islet recovery. For the evaluation, three experienced IIDP Islet Isolation Centers each provided samples from five human islet isolations, shipping 10,000 islet equivalents (IEQ) at four different time periods postislet isolation (no 37°C culture and shipped within 0 to 18 hours; or held in 37°C culture for 18 to 42, 48 to 96, or 144 to 192 hours). A central evaluation center compared samples for islet quantity, quality, and viability for each experimental condition preshipment and postshipment, as well as post 37°C culture 18 to 24 hours after shipment receipt. Additional evaluations included measures of functional potency by static glucose-stimulated insulin release (GSIR), represented as a stimulation index. Comparing the results of the four preshipment holding periods, the greatest IEQ loss postshipment occurred with the shortest preshipment times. Similar patterns emerged when comparing preshipment to postculture losses. In vitro islet function (GSIR) was not adversely impacted by increased tissue culture time. These data indicate that allowing time for islet recovery postisolation, prior to shipping, yields less islet loss during shipment without decreasing islet function.
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Chen, Sing-Young, Ellen M. Olzomer, Martina Beretta, James Cantley, Craig S. Nunemaker, Kyle L. Hoehn, and Frances L. Byrne. "Investigating the Expression and Function of the Glucose Transporter GLUT6 in Obesity." International Journal of Molecular Sciences 23, no. 17 (August 29, 2022): 9798. http://dx.doi.org/10.3390/ijms23179798.
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Obesity-related insulin resistance is a highly prevalent and growing health concern, which places stress on the pancreatic islets of Langerhans by increasing insulin secretion to lower blood glucose levels. The glucose transporters GLUT1 and GLUT3 play a key role in glucose-stimulated insulin secretion in human islets, while GLUT2 is the key isoform in rodent islets. However, it is unclear whether other glucose transporters also contribute to insulin secretion by pancreatic islets. Herein, we show that SLC2A6 (GLUT6) is markedly upregulated in pancreatic islets from genetically obese leptin-mutant (ob/ob) and leptin receptor-mutant (db/db) mice, compared to lean controls. Furthermore, we observe that islet SLC2A6 expression positively correlates with body mass index in human patients with type 2 diabetes. To investigate whether GLUT6 plays a functional role in islets, we crossed GLUT6 knockout mice with C57BL/6 ob/ob mice. Pancreatic islets isolated from ob/ob mice lacking GLUT6 secreted more insulin in response to high-dose glucose, compared to ob/ob mice that were wild type for GLUT6. The loss of GLUT6 in ob/ob mice had no adverse impact on body mass, body composition, or glucose tolerance at a whole-body level. This study demonstrates that GLUT6 plays a role in pancreatic islet insulin secretion in vitro but is not a dominant glucose transporter that alters whole-body metabolic physiology in ob/ob mice.
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Granata, Riccarda, Alessandra Baragli, Fabio Settanni, Francesca Scarlatti, and Ezio Ghigo. "Unraveling the role of the ghrelin gene peptides in the endocrine pancreas." Journal of Molecular Endocrinology 45, no. 3 (July 1, 2010): 107–18. http://dx.doi.org/10.1677/jme-10-0019.
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The ghrelin gene peptides include acylated ghrelin (AG), unacylated ghrelin (UAG), and obestatin (Ob). AG, mainly produced by the stomach, exerts its central and peripheral effects through the GH secretagogue receptor type 1a (GHS-R1a). UAG, although devoid of GHS-R1a-binding affinity, is an active peptide, sharing with AG many effects through an unknown receptor. Ob was discovered as the G-protein-coupled receptor 39 (GPR39) ligand; however, its physiological actions remain unclear. The endocrine pancreas is necessary for glucose homeostasis maintenance. AG, UAG, and Ob are expressed in both human and rodent pancreatic islets from fetal to adult life, and the pancreas is the major source of ghrelin in the perinatal period. GHS-R1a and GPR39 expression has been shown in β-cells and islets, as well as specific binding sites for AG, UAG, and Ob. Ghrelin colocalizes with glucagon in α-islet cells, but is also uniquely expressed in ε-islet cells, suggesting a role in islet function and development. Indeed, AG, UAG, and Ob regulate insulin secretion in β-cells and isolated islets, promote β-cell proliferation and survival, inhibit β-cell and human islet cell apoptosis, and modulate the expression of genes that are essential in pancreatic islet cell biology. They even induce β-cell regeneration and prevent diabetes in streptozotocin-treated neonatal rats. The receptor(s) mediating their effects are not fully characterized, and a signaling crosstalk has been suggested. The present review summarizes the newest findings on AG, UAG, and Ob expression in pancreatic islets and the role of these peptides on β-cell development, survival, and function.
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Cirulli, V., L. Crisa, G. M. Beattie, M. I. Mally, A. D. Lopez, A. Fannon, A. Ptasznik, et al. "KSA Antigen Ep-CAM Mediates Cell–Cell Adhesion of Pancreatic Epithelial Cells: Morphoregulatory Roles in Pancreatic Islet Development." Journal of Cell Biology 140, no. 6 (March 23, 1998): 1519–34. http://dx.doi.org/10.1083/jcb.140.6.1519.
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Cell adhesion molecules (CAMs) are important mediators of cell–cell interactions and regulate cell fate determination by influencing growth, differentiation, and organization within tissues. The human pancarcinoma antigen KSA is a glycoprotein of 40 kD originally identified as a marker of rapidly proliferating tumors of epithelial origin. Interestingly, most normal epithelia also express this antigen, although at lower levels, suggesting that a dynamic regulation of KSA may occur during cell growth and differentiation. Recently, evidence has been provided that this glycoprotein may function as an epithelial cell adhesion molecule (Ep-CAM). Here, we report that Ep-CAM exhibits the features of a morphoregulatory molecule involved in the development of human pancreatic islets. We demonstrate that Ep-CAM expression is targeted to the lateral domain of epithelial cells of the human fetal pancreas, and that it mediates calcium-independent cell–cell adhesion. Quantitative confocal immunofluorescence in fetal pancreata identified the highest levels of Ep-CAM expression in developing islet-like cell clusters budding from the ductal epithelium, a cell compartment thought to comprise endocrine progenitors. A surprisingly reversed pattern was observed in the human adult pancreas, displaying low levels of Ep-CAM in islet cells and high levels in ducts. We further demonstrate that culture conditions promoting epithelial cell growth induce upregulation of Ep-CAM, whereas endocrine differentiation of fetal pancreatic epithelial cells, transplanted in nude mice, is associated with a downregulation of Ep-CAM expression. In addition, a blockade of Ep-CAM function by KS1/4 mAb induced insulin and glucagon gene transcription and translation in fetal pancreatic cell clusters. These results indicate that developmentally regulated expression and function of Ep-CAM play a morphoregulatory role in pancreatic islet ontogeny.