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1
Diana, Julien, Vedran Brezar, Lucie Beaudoin, Marc Dalod, Andrew Mellor, Anna Tafuri, Matthias von Herrath, Christian Boitard, Roberto Mallone, and Agnès Lehuen. "Viral infection prevents diabetes by inducing regulatory T cells through NKT cell–plasmacytoid dendritic cell interplay." Journal of Experimental Medicine 208, no. 4 (March 28, 2011): 729–45. http://dx.doi.org/10.1084/jem.20101692.
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Type 1 diabetes (T1D) is an autoimmune disease resulting from T cell–mediated destruction of insulin-producing β cells, and viral infections can prevent the onset of disease. Invariant natural killer T cells (iNKT cells) exert a regulatory role in T1D by inhibiting autoimmune T cell responses. As iNKT cell–plasmacytoid dendritic cell (pDC) cooperation controls viral replication in the pancreatic islets, we investigated whether this cellular cross talk could interfere with T1D development during viral infection. Using both virus-induced and spontaneous mouse models of T1D, we show that upon viral infection, iNKT cells induce TGF-β–producing pDCs in the pancreatic lymph nodes (LNs). These tolerogenic pDCs convert naive anti-islet T cells into Foxp3+ CD4+ regulatory T cells (T reg cells) in pancreatic LNs. T reg cells are then recruited into the pancreatic islets where they produce TGF-β, which dampens the activity of viral- and islet-specific CD8+ T cells, thereby preventing T1D development in both T1D models. These findings reveal a crucial cooperation between iNKT cells, pDCs, and T reg cells for prevention of T1D by viral infection.
2
Teixeira, Caio Jordão, Junia Carolina Santos-Silva, Dailson Nogueira de Souza, Alex Rafacho, Gabriel Forato Anhe, and Silvana Bordin. "Dexamethasone during pregnancy impairs maternal pancreatic β-cell renewal during lactation." Endocrine Connections 8, no. 2 (February 2019): 120–31. http://dx.doi.org/10.1530/ec-18-0505.
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Pancreatic islets from pregnant rats develop a transitory increase in the pancreatic β-cell proliferation rate and mass. Increased apoptosis during early lactation contributes to the rapid reversal of those morphological changes. Exposure to synthetic glucocorticoids during pregnancy has been previously reported to impair insulin secretion, but its impacts on pancreatic islet morphological changes during pregnancy and lactation have not been described. To address this issue, we assessed the morphological and molecular characteristics of pancreatic islets from rats that underwent undisturbed pregnancy (CTL) or were treated with dexamethasone between the 14th and 19th days of pregnancy (DEX). Pancreatic islets were analyzed on the 20th day of pregnancy (P20) and on the 3rd, 8th, 14th and 21st days of lactation (L3, L8, L14 and L21, respectively). Pancreatic islets from CTL rats exhibited transitory increases in cellular proliferation and pancreatic β-cell mass at P20, which were reversed at L3, when a transitory increase in apoptosis was observed. This was followed by the appearance of morphological features of pancreatic islet neogenesis at L8. Islets from DEX rats did not demonstrate an increase in apoptosis at L3, which coincided with an increase in the expression of M2 macrophage markers relative to M1 macrophage and T lymphocyte markers. Islets from DEX rats also did not exhibit the morphological characteristics of pancreatic islet neogenesis at L8. Our data demonstrate that maternal pancreatic islets undergo a renewal process during lactation that is impaired by exposure to DEX during pregnancy.
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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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Chen, Wei, Salma Begum, Lynn Opare-Addo, Justin Garyu, Thomas F. Gibson, Alfred L. M. Bothwell, Virginia E. Papaioannou, and Kevan C. Herold. "Promotion of β-Cell Differentiation in Pancreatic Precursor Cells by Adult Islet Cells." Endocrinology 150, no. 2 (February 1, 2009): 570–79. http://dx.doi.org/10.1210/en.2008-1009.
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It is thought that differentiation of β-cell precursors into mature cells is largely autonomous, but under certain conditions differentiation can be modified by external factors. The factors that modify β-cell differentiation have not been identified. In this study, we tested whether adult islet cells can affect the differentiation process in mouse and human pancreatic anlage cells. We assessed β-cell proliferation and differentiation in mouse and human pancreatic anlage cells cocultured with adult islet cells or βTC3 cells using cellular, molecular, and immunohistochemical methods. Differentiation of murine anlage cells into β-cells was induced by mature islet cells. It was specific for β-cells and not a general feature of endodermal derived cells. β-Cell differentiation required cell-cell contact. The induced cells acquired features of mature β-cells including increased expression of β-cell transcription factors and surface expression of receptor for stromal cell-derived factor 1 and glucose transporter-2 (GLUT-2). They secreted insulin in response to glucose and could correct hyperglycemia in vivo when cotransplanted with vascular cells. Human pancreatic anlage cells responded in a similar manner and showed increased expression of pancreatic duodenal homeobox 1 and v-maf musculoaponeurotic fibrosarcoma oncogene homolog A and increased production of proinsulin when cocultured with adult islets. We conclude that mature β-cells can modify the differentiation of precursor cells and suggest a mechanism whereby changes in differentiation of β-cells can be affected by other β-cells. Mature β cells affect differentiation of pancreatic anlage cells into functional β cells. The differentiated cells respond to glucose and ameliorate diabetes.
5
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.
6
Honzawa, Norikiyo, and Kei Fujimoto. "The Plasticity of Pancreatic β-Cells." Metabolites 11, no. 4 (April 2, 2021): 218. http://dx.doi.org/10.3390/metabo11040218.
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Type 2 diabetes is caused by impaired insulin secretion and/or insulin resistance. Loss of pancreatic β-cell mass detected in human diabetic patients has been considered to be a major cause of impaired insulin secretion. Additionally, apoptosis is found in pancreatic β-cells; β-cell mass loss is induced when cell death exceeds proliferation. Recently, however, β-cell dedifferentiation to pancreatic endocrine progenitor cells and β-cell transdifferentiation to α-cell was reported in human islets, which led to a new underlying molecular mechanism. Hyperglycemia inhibits nuclear translocation and expression of forkhead box-O1 (FoxO1) and induces the expression of neurogenin-3 (Ngn3), which is required for the development and maintenance of pancreatic endocrine progenitor cells. This new hypothesis (Foxology) is attracting attention because it explains molecular mechanism(s) underlying β-cell plasticity. The lineage tracing technique revealed that the contribution of dedifferentiation is higher than that of β-cell apoptosis retaining to β-cell mass loss. In addition, islet cells transdifferentiate each other, such as transdifferentiation of pancreatic β-cell to α-cell and vice versa. Islet cells can exhibit plasticity, and they may have the ability to redifferentiate into any cell type. This review describes recent findings in the dedifferentiation and transdifferentiation of β-cells. We outline novel treatment(s) for diabetes targeting islet cell plasticity.
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Rodríguez-Comas, Júlia, and Javier Ramón-Azcón. "Islet-on-a-chip for the study of pancreatic β-cell function." In vitro models 1, no. 1 (December 2, 2021): 41–57. http://dx.doi.org/10.1007/s44164-021-00005-6.
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AbstractDiabetes mellitus is a significant public health problem worldwide. It encompasses a group of chronic disorders characterized by hyperglycemia, resulting from pancreatic islet dysfunction or as a consequence of insulin-producing β-cell death. Organ-on-a-chip platforms have emerged as technological systems combining cell biology, engineering, and biomaterial technological advances with microfluidics to recapitulate a specific organ’s physiological or pathophysiological environment. These devices offer a novel model for the screening of pharmaceutical agents and to study a particular disease. In the field of diabetes, a variety of microfluidic devices have been introduced to recreate native islet microenvironments and to understand pancreatic β-cell kinetics in vitro. This kind of platforms has been shown fundamental for the study of the islet function and to assess the quality of these islets for subsequent in vivo transplantation. However, islet physiological systems are still limited compared to other organs and tissues, evidencing the difficulty to study this “organ” and the need for further technological advances. In this review, we summarize the current state of islet-on-a-chip platforms that have been developed so far. We recapitulate the most relevant studies involving pancreatic islets and microfluidics, focusing on the molecular and cellular-scale activities that underlie pancreatic β-cell function.
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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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Kilimnik, German, Abraham Kim, Junghyo Jo, Kevin Miller, and Manami Hara. "Quantification of pancreatic islet distribution in situ in mice." American Journal of Physiology-Endocrinology and Metabolism 297, no. 6 (December 2009): E1331—E1338. http://dx.doi.org/10.1152/ajpendo.00479.2009.
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Tracing changes of specific cell populations in health and disease is an important goal of biomedical research. Precisely monitoring pancreatic β-cell proliferation and islet growth is a challenging area of research. We have developed a method to capture the distribution of β-cells in the intact pancreas of transgenic mice with fluorescence-tagged β-cells with a macro written for ImageJ (rsb.info.nih.gov/ij/). Total β-cell area and islet number and size distribution are quantified with reference to specific parameters and location for each islet and for small clusters of β-cells. The entire distribution of islets can now be plotted in three dimensions, and the information from the distribution on the size and shape of each islet allows a quantitative and a qualitative comparison of changes in overall β-cell area at a glance.
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Parajuli, Keshab R., Yanqing Zhang, Alexander M. Cao, Hongjun Wang, Vivian A. Fonseca, and Hongju Wu. "Pax4 Gene Delivery Improves Islet Transplantation Efficacy by Promoting β Cell Survival and α-to-β Cell Transdifferentiation." Cell Transplantation 29 (January 1, 2020): 096368972095865. http://dx.doi.org/10.1177/0963689720958655.
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The transcription factor Pax4 plays an essential role in the development of insulin-producing β cells in pancreatic islets. Ectopic Pax4 expression not only promotes β cell survival but also induces α-to-β cell transdifferentiation. This dual functionality of Pax4 makes it an appealing therapeutic target for the treatment of insulin-deficient type 1 diabetes (T1D). In this study, we demonstrated that Pax4 gene delivery by an adenoviral vector, Ad5.Pax4, improved β cell function of mouse and human islets by promoting islet cell survival and α-to-β cell transdifferentiation, as assessed by multiple viability assays and lineage-tracing analysis. We then explored the therapeutic benefits of Pax4 gene delivery in the context of islet transplantation using T1D mouse models. Both mouse-to-mouse and human-to-mouse islet transplantation, via either kidney capsule or portal vein, were examined. In all settings, Ad5.Pax4-treated donor islets (mouse or human) showed substantially better therapeutic outcomes. These results suggest that Pax4 gene delivery into donor islets may be considered as an adjunct therapy for islet transplantation, which can either improve the therapeutic outcome of islet transplantation using the same amount of donor islets or allow the use of fewer donor islets to achieve normoglycemia.
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Freemark, Michael, Isabelle Avril, Don Fleenor, Phyllis Driscoll, Ann Petro, Emmanuel Opara, Will Kendall, et al. "Targeted Deletion of the PRL Receptor: Effects on Islet Development, Insulin Production, and Glucose Tolerance." Endocrinology 143, no. 4 (April 1, 2002): 1378–85. http://dx.doi.org/10.1210/endo.143.4.8722.
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Abstract PRL and placental lactogen (PL) stimulate β-cell proliferation and insulin gene transcription in isolated islets and rat insulinoma cells, but the roles of the lactogenic hormones in islet development and insulin production in vivo remain unclear. To clarify the roles of the lactogens in pancreatic development and function, we measured islet density (number of islets/cm2) and mean islet size, β-cell mass, pancreatic insulin mRNA levels, islet insulin content, and the insulin secretory response to glucose in an experimental model of lactogen resistance: the PRL receptor (PRLR)-deficient mouse. We then measured plasma glucose concentrations after ip injections of glucose or insulin. Compared with wild-type littermates, PRLR-deficient mice had 26–42% reductions (P < 0.01) in islet density and β-cell mass. The reductions in islet density and β-cell mass were noted as early as 3 wk of age and persisted through 8 months of age and were observed in both male and female mice. Pancreatic islets of PRLR-deficient mice were smaller than those of wild-type mice at weaning but not in adulthood. Pancreatic insulin mRNA levels were 20–30% lower (P < 0.05) in adult PRLR-deficient mice than in wild-type mice, and the insulin content of isolated islets was reduced by 16–25%. The insulin secretory response to ip glucose was blunted in PRLR-deficient males in vivo (P < 0.05) and in isolated islets of PRLR-deficient females and males in vitro (P < 0.01). Fasting blood glucose concentrations in PRLR-deficient mice were normal, but glucose levels after an ip glucose load were 10–20% higher (P < 0.02) than those in wild-type mice. On the other hand, the glucose response to ip insulin was normal. Our observations establish a physiologic role for lactogens in islet development and function.
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Klein, Dagmar, Valeska Mendoza, Antonello Pileggi, R. Damaris Molano, Florencia M. Barbé-Tuana, Luca Inverardi, Camillo Ricordi, and Ricardo L. Pastori. "Delivery of TAT/PTD-Fused Proteins/Peptides to Islets via Pancreatic Duct." Cell Transplantation 14, no. 5 (May 2005): 241–48. http://dx.doi.org/10.3727/000000005783983016.
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Delivering cytoprotective proteins/peptides into pancreata prior to islet isolation through protein transduction (PT) is a novel strategy to enhance the yield of viable transplantable islets. Previous work has shown that the protein transduction domain PTD-5 efficiently transduced islets via the pancreatic duct. TAT/PTD is a well-characterized PTD with the capability to cross even the hemato–encephalic barrier. In this study, we investigated the utilization of the 11-aa TAT protein transduction domain (TAT/PTD) to deliver peptides or proteins of different sizes ranging from 1.2 to 120 kDa, as the TAT/PTD and TAT/PTD-BH4 peptide, or the TAT/PTD–β-galactosidase fusion protein, into islets through the pancreatic duct. Using flow cytometry analysis we found that TAT/PTD derivatives transduced practically 100% of the islet cell population. Moreover, confocal laser scanning microscopy in live, nonfixed islets confirmed these results assessing transduction of TAT/PTD molecules into intact nondisaggregated islets. TAT–β-galactosidase peptide conjugated to FITC was not compartment selective, as both cytoplasmic and nucleic cellular compartments were positively stained. Furthermore, TAT–β-galactosidase peptide delivery was highly effective, as even cells located in the inner core region of the islets were transduced. Finally, transduced TAT–β-galactosidase fusion protein was biologically active after islet isolation and manipulation, and islet insulin secretion capability was not compromised by peptide transduction. These findings suggest that the transduction of chimeric TAT/PTD proteins can represent an efficient tool of molecular delivery independent of the size, to enhance or modify a specific phenotype at the nuclei or cytoplasmic level.
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Padmasekar, M., N. Lingwal, B. Samikannu, C. Chen, H. Sauer, and T. Linn. "Exendin-4 Protects Hypoxic Islets From Oxidative Stress and Improves Islet Transplantation Outcome." Endocrinology 154, no. 4 (April 1, 2013): 1424–33. http://dx.doi.org/10.1210/en.2012-1983.
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Abstract Oxidative stress produced during pancreatic islet isolation leads to significant β-cell damage. Homeostatic cytokines secreted subsequently to islet transplantation damage β-cells by generating oxygen free radicals. In this study, exendin-4, a glucagon-like peptide-1 analog improved islet transplantation outcome by increasing the survival of diabetic recipient mice from 58% to 100%. We hypothesized that this beneficial effect was due to the ability of exendin-4 to reduce oxidative stress. Further experiments showed that it significantly reduced the apoptotic rate of cultured β-cells subjected to hypoxia or to IL-1β. Reduction of apoptotic events was confirmed in pancreatic islet grafts of exendin-4–treated mice. Exendin-4 enhanced Akt phosphorylation of β-cells and insulin released from them. It even augmented insulin secretion from islets cultivated at hypoxic conditions. Exposure to hypoxia led to a decrease in the activation of Akt, which was reversed when β-cells were pretreated with exendin-4. Moreover, exendin-4 increased the activity of redox enzymes in a hypoxia-treated β-cell line and reduced reactive oxygen species production in isolated pancreatic islets. Recovery from diabetes in mice transplanted with hypoxic islets was more efficient when they received exendin-4. In conclusion, exendin-4 rescued islets from oxidative stress caused by hypoxia or due to cytokine exposure. It improved the outcome of syngenic and xenogenic islet transplantation.
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Miettinen, Päivi, Päivi Ormio, Elina Hakonen, Meenal Banerjee, and Timo Otonkoski. "EGF receptor in pancreatic β-cell mass regulation." Biochemical Society Transactions 36, no. 3 (May 21, 2008): 280–85. http://dx.doi.org/10.1042/bst0360280.
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Pancreatic islet development is impaired in mice lacking EGFRs (epidermal growth factor receptors). Even partial tissue-specific attenuation of EGFR signalling in the islets leads to markedly reduced β-cell proliferation and development of diabetes during the first weeks after birth. Out of the many EGFR ligands, betacellulin has been specifically associated with positive effects on β-cell growth, through both increased proliferation and neogenesis. EGFR action is also necessary for the β-cell mitogenic activity of the gut hormone GLP-1 (glucagon-like peptide 1). Finally, in vitro models demonstrate a central role for EGFR in transdifferentiation of pancreatic acinar and ductal cells into endocrine islet cells. EGFR thus plays an essential role in β-cell mass regulation, but its mechanisms of action remain poorly understood.
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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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Okano, Satoshi, Akira Yasui, Shin-ichiro Kanno, Kennichi Satoh, Masahiko Igarashi, and Osamu Nakajima. "Karyopherin Alpha 2-Expressing Pancreatic Duct Glands and Intra-Islet Ducts in Aged Diabetic C414A-Mutant-CRY1 Transgenic Mice." Journal of Diabetes Research 2019 (April 24, 2019): 1–11. http://dx.doi.org/10.1155/2019/7234549.
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Our earlier studies demonstrated that cysteine414- (zinc-binding site of mCRY1-) alanine mutant mCRY1 transgenic mice (Tg mice) exhibit diabetes characterized by the reduction of β-cell proliferation and by β-cell dysfunction, presumably caused by senescence-associated secretory phenotype- (SASP-) like characters of islets. Earlier studies also showed that atypical duct-like structures in the pancreas developed age-dependently in Tg mice. Numerous reports have described that karyopherin alpha 2 (KPNA2) is highly expressed in cancers of different kinds. However, details of the expression of KPNA2 in pancreatic ductal atypia and in normal pancreatic tissues remain unclear. To assess the feature of the expression of KPNA2 in the development of the ductal atypia and islet architectures, we scrutinized the pancreas of Tg mice histopathologically. Results showed that considerable expression of KPNA2 was observed in pancreatic β-cells, suggesting its importance in maintaining the functions of β-cells. In mature stages, the level of KPNA2 expression was lower in islets of Tg mice than in wild-type controls. At 4 weeks, the expression levels of KPNA2 in islets of Tg mice were the same as those in wild-type controls. These results suggest that the reduction of KPNA2 might contribute to β-cell dysfunction in mature Tg mice. Additionally, the formation of mucin-producing intra-islet ducts, islet fibrosis, and massive T cell recruitment to the islet occurred in aged Tg mice. In exocrine areas, primary pancreatic intraepithelial neoplasias (PanINs) with mucinous pancreatic duct glands (PDGs) emerged in aged Tg mice. High expression of KPNA2 was observed in the ductal atypia. By contrast, KPNA2 expression in normal ducts was quite low. Thus, upregulation of KPNA2 seemed to be correlated with progression of the degree of atypia in pancreatic ductal cells. The SASP-like microenvironment inside islets might play stimulatory roles in the formation of ductal metaplasia inside islets and in islet fibrosis in Tg mice.
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Short, Kurt W., W. Steve Head, and David W. Piston. "Connexin 36 mediates blood cell flow in mouse pancreatic islets." American Journal of Physiology-Endocrinology and Metabolism 306, no. 3 (February 1, 2014): E324—E331. http://dx.doi.org/10.1152/ajpendo.00523.2013.
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The insulin-secreting β-cells are contained within islets of Langerhans, which are highly vascularized. Blood cell flow rates through islets are glucose-dependent, even though there are no changes in blood cell flow within in the surrounding exocrine pancreas. This suggests a specific mechanism of glucose-regulated blood flow in the islet. Pancreatic islets respond to elevated glucose with synchronous pulses of electrical activity and insulin secretion across all β-cells in the islet. Connexin 36 (Cx36) gap junctions between islet β-cells mediate this synchronization, which is lost in Cx36 knockout mice (Cx36−/−). This leads to glucose intolerance in these mice, despite normal plasma insulin levels and insulin sensitivity. Thus, we sought to investigate whether the glucose-dependent changes in intraislet blood cell flow are also dependent on coordinated pulsatile electrical activity. We visualized and quantified blood cell flow using high-speed in vivo fluorescence imaging of labeled red blood cells and plasma. With the use of a live animal glucose clamp, blood cell flow was measured during either hypoglycemia (∼50 mg/dl) or hyperglycemia (∼300 mg/dl). In contrast to the large glucose-dependent islet blood velocity changes observed in wild-type mice, only minimal differences are observed in both Cx36+/− and Cx36−/− mice. This observation supports a novel model where intraislet blood cell flow is regulated by the coordinated electrical activity in the islet β-cells. Because Cx36 expression and function is reduced in type 2 diabetes, the resulting defect in intraislet blood cell flow regulation may also play a significant role in diabetic pathology.
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Rozance, Paul J., Sean W. Limesand, Gary O. Zerbe, and William W. Hay. "Chronic fetal hypoglycemia inhibits the later steps of stimulus-secretion coupling in pancreatic β-cells." American Journal of Physiology-Endocrinology and Metabolism 292, no. 5 (May 2007): E1256—E1264. http://dx.doi.org/10.1152/ajpendo.00265.2006.
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We measured the impact of chronic late gestation hypoglycemia on pancreatic islet structure and function to determine the cause of decreased insulin secretion in this sheep model of fetal nutrient deprivation. Late gestation hypoglycemia did not decrease pancreas weight, insulin content, β-cell area, β-cell mass, or islet size. The pancreatic islet isolation procedure selected a group of islets that were larger and had an increased proportion of β-cells compared with islets measured in pancreatic sections, but there were no morphologic differences between islets isolated from control and hypoglycemic fetuses. The rates of glucose-stimulated pancreatic islet glucose utilization (126.2 ± 25.3 pmol glucose·islet−1·h−1, hypoglycemic, vs. 93.5 ± 5.5 pmol glucose·islet−1·h−1, control, P = 0.47) and oxidation (10.5 ± 1.7 pmol glucose·islet−1·h−1, hypoglycemic, vs. 10.6 ± 1.6 pmol glucose·islet−1·h−1, control) were not different in hypoglycemic fetuses compared with control fetuses. Chronic late gestation hypoglycemia decreased insulin secretion in isolated pancreatic islets by almost 70% in response to direct nonnutrient membrane depolarization and in response to increased extracellular calcium entry. β-Cell ultrastructure was abnormal with markedly distended rough endoplasmic reticulum in three of the seven hypoglycemic fetuses studied, but in vitro analysis of hypoglycemic control islets showed no evidence that these changes represented endoplasmic reticulum stress, as measured by transcription of glucose regulatory protein-78 and processing of X-box binding protein-1. In conclusion, these studies show that chronic hypoglycemia in late gestation decreases insulin secretion by inhibiting the later steps of stimulus-secretion coupling after glucose metabolism, membrane depolarization, and calcium entry.
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Hogh, K.-Lynn N., Michael N. Craig, Christopher E. Uy, Heli Nygren, Ali Asadi, Madeline Speck, Jordie D. Fraser, et al. "Overexpression of PPARγ Specifically in Pancreatic β-Cells Exacerbates Obesity-Induced Glucose Intolerance, Reduces β-Cell Mass, and Alters Islet Lipid Metabolism in Male Mice." Endocrinology 155, no. 10 (October 1, 2014): 3843–52. http://dx.doi.org/10.1210/en.2014-1076.
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Abstract The contribution of peroxisomal proliferator-activated receptor (PPAR)-γ agonism in pancreatic β-cells to the antidiabetic actions of thiazolidinediones has not been clearly elucidated. Genetic models of pancreatic β-cell PPARγ ablation have revealed a potential role for PPARγ in β-cell expansion in obesity but a limited role in normal β-cell physiology. Here we overexpressed PPARγ1 or PPARγ2 specifically in pancreatic β-cells of mice subjected to high-fat feeding using an associated adenovirus (β-PPARγ1-HFD and β-PPARγ2-HFD mice). We show β-cell-specific PPARγ1 or PPARγ2 overexpression in diet-induced obese mice exacerbated obesity-induced glucose intolerance with decreased β-cell mass, increased islet cell apoptosis, and decreased plasma insulin compared with obese control mice (β-eGFP-HFD mice). Analysis of islet lipid composition in β-PPARγ2-HFD mice revealed no significant changes in islet triglyceride content and an increase in only one of eight ceramide species measured. Interestingly β-PPARγ2-HFD islets had significantly lower levels of lysophosphatidylcholines, lipid species shown to enhance insulin secretion in β-cells. Gene expression profiling revealed increased expression of uncoupling protein 2 and genes involved in fatty acid transport and β-oxidation. In summary, transgenic overexpression of PPARγ in β-cells in diet-induced obesity negatively impacts whole-animal carbohydrate metabolism associated with altered islet lipid content, increased expression of β-oxidative genes, and reduced β-cell mass.
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Lei, Xiaoyong, Sheng Zhang, Alan Bohrer, Suzanne E. Barbour, and Sasanka Ramanadham. "Role of calcium-independent phospholipase A2β in human pancreatic islet β-cell apoptosis." American Journal of Physiology-Endocrinology and Metabolism 303, no. 11 (December 1, 2012): E1386—E1395. http://dx.doi.org/10.1152/ajpendo.00234.2012.
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Death of β-cells due to apoptosis is an important contributor to β-cell dysfunction in both type 1 and type 2 diabetes mellitus. Previously, we described participation of the Group VIA Ca2+-independent phospholipase A2 (iPLA2β) in apoptosis of insulinoma cells due to ER stress. To examine whether islet β-cells are similarly susceptible to ER stress and undergo iPLA2β-mediated apoptosis, we assessed the ER stress response in human pancreatic islets. Here, we report that the iPLA2β protein is expressed predominantly in the β-cells of human islets and that thapsigargin-induced ER stress promotes β-cell apoptosis, as reflected by increases in activated caspase-3 in the β-cells. Furthermore, we demonstrate that ER stress is associated with increases in islet iPLA2β message, protein, and activity, iPLA2β-dependent induction of neutral sphingomyelinase and ceramide accumulation, and subsequent loss of mitochondrial membrane potential. We also observe that basal activated caspase-3 increases with age, raising the possibility that β-cells in older human subjects have a greater susceptibility to undergo apoptotic cell death. These findings reveal for the first time expression of iPLA2β protein in human islet β-cells and that induction of iPLA2β during ER stress contributes to human islet β-cell apoptosis. We hypothesize that modulation of iPLA2β activity might reduce β-cell apoptosis and this would be beneficial in delaying or preventing β-cell dysfunction associated with diabetes.
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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.
Full textAbstract:
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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Zhang, Xiongfei, Wei Yong, Jinghuan Lv, Yunxia Zhu, Jingjing Zhang, Fang Chen, Rihua Zhang, Tao Yang, Yujie Sun, and Xiao Han. "Inhibition of Forkhead Box O1 Protects Pancreatic β-Cells against Dexamethasone-Induced Dysfunction." Endocrinology 150, no. 9 (May 14, 2009): 4065–73. http://dx.doi.org/10.1210/en.2009-0343.
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Abstract Forkhead Box O1 (FoxO1) is a key transcription regulator of insulin/IGF-I signaling pathway, and its activity can be increased by dexamethasone (DEX) in several cell types. However, the role of FoxO1 in DEX-induced pancreatic β-cell dysfunction has not been fully understood. Therefore, in this study, we investigated whether FoxO1 could mediate DEX-induced β-cell dysfunction and the possible underlying mechanisms in pancreatic β-cell line RINm5F cells and primary rat islet. We found that DEX markedly increased FoxO1 mRNA and protein expression and decreased FoxO1 phosphorylation through the Akt pathway, which resulted in an increase in active FoxO1 in RINm5F cells and isolated rat islets. Activated FoxO1 subsequently inhibited pancreatic duodenal homeobox-1 expression and induced nuclear exclusion of pancreatic duodenal homeobox-1. Knockdown of FoxO1 by RNA interference restored the expression of pancreatic duodenal homeobox-1 and prevented DEX-induced dysfunction of glucose-stimulated insulin secretion in rat islets. Together, the results of present study demonstrate that FoxO1 is integrally involved in DEX-induced inhibition of pancreatic duodenal homeobox-1 and glucose-stimulated insulin secretion dysfunction in pancreatic islet β-cells. Inhibition of FoxO1 can effectively protect β-cells against DEX-induced dysfunction.
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Yabe, Koichi, Yuka Yamamoto, Takami Suzuki, Sanae Takada, and Kazuhiko Mori. "Functional and Morphological Characteristics of Pancreatic Islet Lesions Induced by Quinolone Antimicrobial Agent Gatifloxacin in Rats." Toxicologic Pathology 47, no. 1 (November 8, 2018): 35–43. http://dx.doi.org/10.1177/0192623318809062.
Full textAbstract:
We characterized pancreatic islet lesions induced by several quinolones using functional and morphological examinations of the pancreatic islets in male rats orally administered gatifloxacin, lomefloxacin, or levofloxacin at 300 mg/kg for 14 consecutive days. Consequently, in contrast to lomefloxacin or levofloxacin, gatifloxacin increased serum glucose and glycosylated albumin on day 14 and elevated serum glucose tended to decrease insulin in the intravenous glucose tolerance test. Microscopically, only gatifloxacin induced cytoplasmic vacuoles containing eosinophilic homogenous contents in islet cells. Immunohistochemical examination revealed that vacuolated islet cells were positively stained for insulin, demonstrating they were pancreatic β cells. Electron microscopy showed that the cytoplasmic vacuoles represented dilated cisterna of the rough endoplasmic reticulum filled with electron-lucent materials in pancreatic β cells. Moreover, insulin secretory granules were drastically decreased in vacuolated islet cells, suggesting impaired insulin synthesis and/or transport. This gatifloxacin-induced pancreatic toxicity in rats was considered to be associated with high pancreatic drug distribution. These results demonstrated that gatifloxacin provoked functional and morphological pancreatic β cell alteration associated with impaired insulin synthesis and/or transport, leading to hyperglycemia.
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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.
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Yang, Kaiyuan, Jonathan Gotzmann, Sharee Kuny, Hui Huang, Yves Sauvé, and Catherine B. Chan. "Five stages of progressive β-cell dysfunction in the laboratory Nile rat model of type 2 diabetes." Journal of Endocrinology 229, no. 3 (June 2016): 343–56. http://dx.doi.org/10.1530/joe-15-0517.
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We compared the evolution of insulin resistance, hyperglycemia, and pancreatic β-cell dysfunction in the Nile rat (Arvicanthis niloticus), a diurnal rodent model of spontaneous type 2 diabetes (T2D), when maintained on regular laboratory chow versus a high-fiber diet. Chow-fed Nile rats already displayed symptoms characteristic of insulin resistance at 2 months (increased fat/lean mass ratio and hyperinsulinemia). Hyperglycemia was first detected at 6 months, with increased incidence at 12 months. By this age, pancreatic islet structure was disrupted (increased α-cell area), insulin secretion was impaired (reduced insulin secretion and content) in isolated islets, insulin processing was compromised (accumulation of proinsulin and C-peptide inside islets), and endoplasmic reticulum (ER) chaperone protein ERp44 was upregulated in insulin-producing β-cells. By contrast, high-fiber-fed Nile rats had normoglycemia with compensatory increase in β-cell mass resulting in maintained pancreatic function. Fasting glucose levels were predicted by the α/β-cell ratios. Our results show that Nile rats fed chow recapitulate the five stages of progression of T2D as occurs in human disease, including insulin-resistant hyperglycemia and pancreatic islet β-cell dysfunction associated with ER stress. Modification of diet alone permits long-term β-cell compensation and prevents T2D.
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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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KONRAD, Robert J., Irina MIKOLAENKO, Joseph F. TOLAR, Kan LIU, and Jeffrey E. KUDLOW. "The potential mechanism of the diabetogenic action of streptozotocin: inhibition of pancreatic β-cell O-GlcNAc-selective N-acetyl-β-d-glucosaminidase." Biochemical Journal 356, no. 1 (May 8, 2001): 31–41. http://dx.doi.org/10.1042/bj3560031.
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Streptozotocin (STZ), an analogue of GlcNAc, inhibits purified rat spleen O-GlcNAc-selective N-acetyl-β-d-glucosaminidase (O-GlcNAcase), the enzyme that removes O-GlcNAc from protein. We have shown previously that STZ increases pancreatic islet O-linked protein glycosylation. In light of these data, we investigated the possibility further that STZ causes β-cell death by inhibiting O-GlcNAcase. In isolated islets, the time course and dose curve of STZ-induced O-glycosylation correlated with β-cell toxicity. STZ inhibition of rat islet O-GlcNAcase activity also paralleled that of its β-cell toxicity, with significant inhibition occurring at a concentration of 1mM. In contrast, STZ inhibition of rat brain O-GlcNAcase and β-TC3 insulinoma cell O-GlcNAcase was significantly right-shifted compared with islets, with STZ only significantly inhibiting activity at a concentration of 5mM, the same concentration required for β-TC3 cell toxicity. In comparison, N-methyl-N-nitrosourea, the nitric oxide-donating portion of STZ, did not cause increased islet O-glycosylation, β-cell toxicity or inhibition of β-cell O-GlcNAcase. Enhanced STZ sensitivity of islet O-GlcNAcase compared with O-GlcNAcase from other tissues or an insulinoma cell line suggests why actual islet β-cells are particularly sensitive to STZ. Confirming this idea, STZ-induced islet β-cell toxicity was completely blocked by GlcNAc, which also prevented STZ-induced O-GlcNAcase inhibition, but was not even partially blocked by glucose, glucosamine or GalNAc. Together, these data demonstrate that STZ's inhibition of β-cell O-GlcNAcase is the mechanism that accounts for its diabetogenic toxicity.
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Hasegawa, Yutaka, Takehide Ogihara, Tetsuya Yamada, Yasushi Ishigaki, Junta Imai, Kenji Uno, Junhong Gao, et al. "Bone Marrow (BM) Transplantation Promotes β-Cell Regeneration after Acute Injury through BM Cell Mobilization." Endocrinology 148, no. 5 (May 1, 2007): 2006–15. http://dx.doi.org/10.1210/en.2006-1351.
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There is controversy regarding the roles of bone marrow (BM)-derived cells in pancreatic β-cell regeneration. To examine these roles in vivo, mice were treated with streptozotocin (STZ), followed by bone marrow transplantation (BMT; lethal irradiation and subsequent BM cell infusion) from green fluorescence protein transgenic mice. BMT improved STZ-induced hyperglycemia, nearly normalizing glucose levels, with partially restored pancreatic islet number and size, whereas simple BM cell infusion without preirradiation had no effects. In post-BMT mice, most islets were located near pancreatic ducts and substantial numbers of bromodeoxyuridine-positive cells were detected in islets and ducts. Importantly, green fluorescence protein-positive, i.e. BM-derived, cells were detected around islets and were CD45 positive but not insulin positive. Then to examine whether BM-derived cell mobilization contributes to this process, we used Nos3−/− mice as a model of impaired BM-derived cell mobilization. In streptozotocin-treated Nos3−/− mice, the effects of BMT on blood glucose, islet number, bromodeoxyuridine-positive cells in islets, and CD45-positive cells around islets were much smaller than those in streptozotocin-treated Nos3+/+ controls. A series of BMT experiments using Nos3+/+ and Nos3−/− mice showed hyperglycemia-improving effects of BMT to correlate inversely with the severity of myelosuppression and delay of peripheral white blood cell recovery. Thus, mobilization of BM-derived cells is critical for BMT-induced β-cell regeneration after injury. The present results suggest that homing of donor BM-derived cells in BM and subsequent mobilization into the injured periphery are required for BMT-induced regeneration of recipient pancreatic β-cells.
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Åvall, Karin, Yusuf Ali, Ingo B. Leibiger, Barbara Leibiger, Tilo Moede, Meike Paschen, Andrea Dicker, et al. "Apolipoprotein CIII links islet insulin resistance to β-cell failure in diabetes." Proceedings of the National Academy of Sciences 112, no. 20 (May 4, 2015): E2611—E2619. http://dx.doi.org/10.1073/pnas.1423849112.
Full textAbstract:
Insulin resistance and β-cell failure are the major defects in type 2 diabetes mellitus. However, the molecular mechanisms linking these two defects remain unknown. Elevated levels of apolipoprotein CIII (apoCIII) are associated not only with insulin resistance but also with cardiovascular disorders and inflammation. We now demonstrate that local apoCIII production is connected to pancreatic islet insulin resistance and β-cell failure. An increase in islet apoCIII causes promotion of a local inflammatory milieu, increased mitochondrial metabolism, deranged regulation of β-cell cytoplasmic free Ca2+ concentration ([Ca2+]i) and apoptosis. Decreasing apoCIII in vivo results in improved glucose tolerance, and pancreatic apoCIII knockout islets transplanted into diabetic mice, with high systemic levels of the apolipoprotein, demonstrate a normal [Ca2+]i response pattern and no hallmarks of inflammation. Hence, under conditions of islet insulin resistance, locally produced apoCIII is an important diabetogenic factor involved in impairment of β-cell function and may thus constitute a novel target for the treatment of type 2 diabetes mellitus.
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Rosendahl, Alexander, Helena Cucak, Chistopher Mayer, and Morten Tonnensen. "Pancreatic β-cells undergo apoptosis in a TLR4 and macrophage cell-dependent manner (P4031)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 131.16. http://dx.doi.org/10.4049/jimmunol.190.supp.131.16.
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Abstract To elucidate the expression and effect of TLR4 on pancreatic β-cells, we studied mouse islets and the murine β-cell line MIN6 in the presence of macrophages (MΦ). Diabetic islets had 40% less TLR4+ β-cells, while twice as many TLR4+ MΦ compared to healthy islets. TLR4 activation with LPS induced a 5-10 fold induction of cytokines in healthy and diabetic islets. MIN6 cells were only weakly TLR4+ and did not produce cytokines in response to LPS. LPS stimulated diabetic systemic MΦ released 3-10 fold more cytokines per cell compared to healthy MΦ. Interestingly, diabetic MΦ co-cultured with MIN6 cells secreted higher levels of cytokines compared to MΦ alone. We also measured apoptosis in healthy and diabetic islets treated with LPS and found no effect. However, a 3-fold induction of MIN6 apoptosis was obtained when co-cultured with diabetic MΦ and 2-fold when cultured with media from LPS activated MΦ. Taken together, our data suggest that the majority of the TLR4 response in the islet appears to be mediated through MΦ. Moreover a cell-dependent MΦ- β-cell interaction appears to contribute to the enhanced local immunity in the islet. Thus targeting either TLR4 or macrophages may provide a novel treatment regime for type 2 diabetes.
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Lavine, Jeremy A., Philipp W. Raess, Donald S. Stapleton, Mary E. Rabaglia, Joshua I. Suhonen, Kathryn L. Schueler, James E. Koltes, et al. "Cholecystokinin Is Up-Regulated in Obese Mouse Islets and Expands β-Cell Mass by Increasing β-Cell Survival." Endocrinology 151, no. 8 (June 9, 2010): 3577–88. http://dx.doi.org/10.1210/en.2010-0233.
Full textAbstract:
An absolute or functional deficit in β-cell mass is a key factor in the pathogenesis of diabetes. We model obesity-driven β-cell mass expansion by studying the diabetes-resistant C57BL/6-Leptinob/ob mouse. We previously reported that cholecystokinin (Cck) was the most up-regulated gene in obese pancreatic islets. We now show that islet cholecystokinin (CCK) is up-regulated 500-fold by obesity and expressed in both α- and β-cells. We bred a null Cck allele into the C57BL/6-Leptinob/ob background and investigated β-cell mass and metabolic parameters of Cck-deficient obese mice. Loss of CCK resulted in decreased islet size and reduced β-cell mass through increased β-cell death. CCK deficiency and decreased β-cell mass exacerbated fasting hyperglycemia and reduced hyperinsulinemia. We further investigated whether CCK can directly affect β-cell death in cell culture and isolated islets. CCK was able to directly reduce cytokine- and endoplasmic reticulum stress-induced cell death. In summary, CCK is up-regulated by islet cells during obesity and functions as a paracrine or autocrine factor to increase β-cell survival and expand β-cell mass to compensate for obesity-induced insulin resistance.
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Korol, Sergiy V., Zhe Jin, and Bryndis Birnir. "GABAA Receptor-Mediated Currents and Hormone mRNAs in Cells Expressing More Than One Hormone Transcript in Intact Human Pancreatic Islets." International Journal of Molecular Sciences 21, no. 2 (January 17, 2020): 600. http://dx.doi.org/10.3390/ijms21020600.
Full textAbstract:
In pancreatic islets, the major cell-types are α, β and δ cells. The γ-aminobutyric acid (GABA) signalling system is expressed in human pancreatic islets. In single hormone transcript-expressing cells, we have previously characterized the functional properties of islet GABAA receptors (iGABAARs). Here, we extended these studies to islet cells expressing mRNAs for more than one hormone and sought for correlation between iGABAAR activity level and relative mRNA expression ratio. The single-cell RT-PCR in combination with the patch-clamp current recordings was used to examine functional properties of iGABAARs in the multiple hormone mRNA-expressing cells. We detected cells expressing double (α/β, α/δ, β/δ cell-types) and triple (α/β/δ cell-type) hormone transcripts. The most common mixed-identity cell-type was the α/β group where the cells could be grouped into β- and α-like subgroups. The β-like cells had low GCG/INS expression ratio (<0.6) and significantly higher frequency of iGABAAR single-channel openings than the α-like cells where the GCG/INS expression ratio was high (>1.2). The hormone expression levels and iGABAAR single-channel characteristics varied in the α/β/δ cell-type. Clearly, multiple hormone transcripts can be expressed in islet cells whereas iGABAAR single-channel functional properties appear to be α or β cell specific.
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Niu, Guoguang, John P. McQuilling, Yu Zhou, Emmanuel C. Opara, Giuseppe Orlando, and Shay Soker. "In VitroProliferation of Porcine Pancreatic Islet Cells forβ-Cell Therapy Applications." Journal of Diabetes Research 2016 (2016): 1–8. http://dx.doi.org/10.1155/2016/5807876.
Full textAbstract:
β-Cell replacement through transplantation is the only curative treatment to establish a long-term stable euglycemia in diabetic patients. Owing to the shortage of donor tissue, attempts are being made to develop alternative sources of insulin-secreting cells. Stem cells differentiation and reprograming as well as isolating pancreatic progenitors from different sources are some examples; however, no approach has yet yielded a clinically relevant solution. Dissociated islet cells that are cultured in cell numbers byin vitroproliferation provide a promising platform for redifferentiation towardsβ-cells phenotype. In this study, we cultured islet-derived cellsin vitroand examined the expression ofβ-cell genes during the proliferation. Islets were isolated from porcine pancreases and enzymatically digested to dissociate the component cells. The cells proliferated well in tissue culture plates and were subcultured for no more than 5 passages. Only 10% of insulin expression, as measured by PCR, was preserved in each passage. High glucose media enhanced insulin expression by about 4–18 fold, suggesting a glucose-dependent effect in the proliferated islet-derived cells. The islet-derived cells also expressed other pancreatic genes such as Pdx1, NeuroD, glucagon, and somatostatin. Taken together, these results indicate that pancreatic islet-derived cells, proliferatedin vitro, retained the expression capacity for key pancreatic genes, thus suggesting that the cells may be redifferentiated into insulin-secretingβ-like cells.
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Pederson, Raymond A., Susan B. Curtis, Connie B. Chisholm, Neil R. A. Gaba, Robert V. Campos, and John C. Brown. "Insulin secretion and islet endocrine cell content at onset and during the early stages of diabetes in the BB rat: effect of the level of glycemic control." Canadian Journal of Physiology and Pharmacology 69, no. 8 (August 1, 1991): 1230–36. http://dx.doi.org/10.1139/y91-180.
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Although it is agreed that autoimmune destruction of pancreatic islets in diabetic BB rats is rapid, reports of endocrine cell content of islets from BB diabetic rats at the time of onset of diabetes vary considerably. Because of the rapid onset of the disease (hours) and the attendant changes in islet morphology and insulin secretion, it was the aim of this study to compare islet β-cell numbers to other islet endocrine cells as close to the time of onset of hyperglycemia as possible (within 12 h). As it has been reported that hyperglycemia renders the β cell insensitive to glucose, the early effects of different levels of insulin therapy (well-controlled vs. poorly controlled glycemia) on islet morphology and insulin secretion were examined. When measured within 12 h of onset, insulin content of BB diabetic islets, measured by morphometric analysis or pancreatic extraction, was 60% of insulin content of control islets. Despite significant amounts of insulin remaining in the pancreas, 1-day diabetic rats exhibited fasting hyperglycemia and were glucose intolerant. The insulin response from the isolated perfused pancreas to glucose and the glucose-dependent insulinotropic hormone, gastric inhibitory polypeptide (GIP), was reduced by 95%. Islet content of other endocrine peptides, glucagon, somatostatin, and pancreatic polypeptide, was normal at onset and at 2 weeks post onset. A group of diabetic animals, maintained in a hyperglycemic state for 7 days with low doses of insulin, were compared with a group kept normoglycemic by appropriate insulin therapy. No insulin could be detected in islets of poorly controlled diabetics, while well-controlled animals had 30% of the normal islet insulin content. Well-controlled diabetic animals were more glucose tolerant and exhibited greater in vivo and in vitro insulin responses to glucose and GIP than poorly controlled animals. These studies indicate that at the onset of diabetes in the BB rat, significant amounts of insulin remain in the islet, although secretion in response to glucose and GIP is severely blunted. Adjusting insulin dosage to achieve normoglycemia has a significant β-cell sparing effect in diabetic animals, which is reflected in only a small increase in glucose-stimulated insulin secretion. These data suggest that impaired glucose recognition by the BB diabetic β cell occurs prior to autoimmune destruction of the islet and may contribute to the onset and severity of the diabetic state in these animals.Key words: diabetes, BB rat, islet endocrine cell content, insulin secretion.
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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.
Full textAbstract:
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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Wu, Chien-Ting, Keren I. Hilgendorf, Romina J. Bevacqua, Yan Hang, Janos Demeter, Seung K. Kim, and Peter K. Jackson. "Discovery of ciliary G protein-coupled receptors regulating pancreatic islet insulin and glucagon secretion." Genes & Development 35, no. 17-18 (August 12, 2021): 1243–55. http://dx.doi.org/10.1101/gad.348261.121.
Full textAbstract:
Multiple G protein-coupled receptors (GPCRs) are expressed in pancreatic islet cells, but the majority have unknown functions. We observed specific GPCRs localized to primary cilia, a prominent signaling organelle, in pancreatic α and β cells. Loss of cilia disrupts β-cell endocrine function, but the molecular drivers are unknown. Using functional expression, we identified multiple GPCRs localized to cilia in mouse and human islet α and β cells, including FFAR4, PTGER4, ADRB2, KISS1R, and P2RY14. Free fatty acid receptor 4 (FFAR4) and prostaglandin E receptor 4 (PTGER4) agonists stimulate ciliary cAMP signaling and promote glucagon and insulin secretion by α- and β-cell lines and by mouse and human islets. Transport of GPCRs to primary cilia requires TULP3, whose knockdown in primary human and mouse islets relocalized ciliary FFAR4 and PTGER4 and impaired regulated glucagon or insulin secretion, without affecting ciliary structure. Our findings provide index evidence that regulated hormone secretion by islet α and β cells is controlled by ciliary GPCRs providing new targets for diabetes.
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Harb, George, and Gregory S. Korbutt. "Effect of prolonged in vitro exposure to high glucose on neonatal porcine pancreatic islets." Journal of Endocrinology 191, no. 1 (October 2006): 37–44. http://dx.doi.org/10.1677/joe.1.06812.
Full textAbstract:
Prolonged exposure to high glucose can influence the function, growth, and survival of pancreatic β-cells. In this study, we examine the effects of prolonged in vitro exposure to high glucose on neonatal porcine β-cells, a potentially useful source of insulin-producing cells for clinical islet transplantation. Neonatal porcine islets were prepared by culturing collagenase-digested pancreases for 1 week in 5.6 mM glucose, followed by an additional week in either 5.6, 10.0, or 28.0 mM glucose. An additional 2 days of culture in 5.6 mM glucose followed for recovery from high glucose. The 7-day culture period in 28.0 mM glucose failed to irreversibly impair glucose responsiveness and also caused a modest increase in β-cell mass. Immunostaining revealed that precursor cell differentiation was responsible for the increase in β-cell mass rather than β-cell proliferation. Islet cell survival was also assessed by a DNA fragmentation assay (TUNEL stain) to determine β-cell susceptibility to apoptosis after exposure to high glucose. Interestingly, although the total number of apoptotic islet cells did not drastically change after a week of culture in either 5.6, 10.0, or 28.0 mM glucose (25% TUNEL-positive), neither did the percentage of apoptotic β-cells. These encouraging results further support the use of neonatal porcine islets for clinical transplantation because of their ability to resist the cytotoxic effects of high glucose on islet function and survival.
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Shigeyama, Yutaka, Toshiyuki Kobayashi, Yoshiaki Kido, Naoko Hashimoto, Shun-ichiro Asahara, Tomokazu Matsuda, Akihiko Takeda, et al. "Biphasic Response of Pancreatic β-Cell Mass to Ablation of Tuberous Sclerosis Complex 2 in Mice." Molecular and Cellular Biology 28, no. 9 (March 3, 2008): 2971–79. http://dx.doi.org/10.1128/mcb.01695-07.
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ABSTRACT Recent studies have demonstrated the importance of insulin or insulin-like growth factor 1 (IGF-1) for regulation of pancreatic β-cell mass. Given the role of tuberous sclerosis complex 2 (TSC2) as an upstream molecule of mTOR (mammalian target of rapamycin), we examined the effect of TSC2 deficiency on β-cell function. Here, we show that mice deficient in TSC2, specifically in pancreatic β cells (βTSC2−/− mice), manifest increased IGF-1-dependent phosphorylation of p70 S6 kinase and 4E-BP1 in islets as well as an initial increased islet mass attributable in large part to increases in the sizes of individual β cells. These mice also exhibit hypoglycemia and hyperinsulinemia at young ages (4 to 28 weeks). After 40 weeks of age, however, the βTSC2−/− mice develop progressive hyperglycemia and hypoinsulinemia accompanied by a reduction in islet mass due predominantly to a decrease in the number of β cells. These results thus indicate that TSC2 regulates pancreatic β-cell mass in a biphasic manner.
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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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Shiota, Chiyo, Krishna Prasadan, Ping Guo, Yousef El-Gohary, John Wiersch, Xiangwei Xiao, Farzad Esni, and George K. Gittes. "α-Cells are dispensable in postnatal morphogenesis and maturation of mouse pancreatic islets." American Journal of Physiology-Endocrinology and Metabolism 305, no. 8 (October 15, 2013): E1030—E1040. http://dx.doi.org/10.1152/ajpendo.00022.2013.
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Glucagon-producing α-cells are the second-most abundant cell type in the islet. Whereas α-cells make up less than 20% of the cells in a mature mouse islet, they occupy a much larger proportion of the pancreatic endocrine cell population during the early postnatal period, the time when morphological and functional maturation occurs to form adult islets. To determine whether α-cells have a role in postnatal islet development, a diphtheria toxin-mediated α-cell ablation mouse model was established. Rapid and persistant depletion of α-cells was achieved by daily injection of the toxin for 2 wk starting at postnatal day 1 (P1). Total pancreatic glucagon content in the α-cell-ablated mice was undetectable at P14 and still less than 0.3% of that of the control mice at 4 mo of age. Histological analyses revealed that formation of spherical islets occurred normally, and the islet size distribution was not changed despite the near-total lack of α-cells. Furthermore, there were no differences in expression of β-cell maturation marker proteins, including urocortin 3 and glucose transporter 2, in the α-cell-ablated islets at P14. Mice lacking α-cells grew normally and appeared healthy. Both glucose and insulin tolerance tests demonstrated that the α-cell-ablated mice had normal glucose homeostasis. These results indicate that α-cells do not play a critical role in postnatal islet morphogenesis or functional maturation of β-cells.
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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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Groen, Nathalie, Floris Leenders, Ahmed Mahfouz, Amadeo Munoz-Garcia, Mauro J. Muraro, Natascha de Graaf, Ton J. Rabelink, et al. "Single-Cell Transcriptomics Links Loss of Human Pancreatic β-Cell Identity to ER Stress." Cells 10, no. 12 (December 19, 2021): 3585. http://dx.doi.org/10.3390/cells10123585.
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The maintenance of pancreatic islet architecture is crucial for proper β-cell function. We previously reported that disruption of human islet integrity could result in altered β-cell identity. Here we combine β-cell lineage tracing and single-cell transcriptomics to investigate the mechanisms underlying this process in primary human islet cells. Using drug-induced ER stress and cytoskeleton modification models, we demonstrate that altering the islet structure triggers an unfolding protein response that causes the downregulation of β-cell maturity genes. Collectively, our findings illustrate the close relationship between endoplasmic reticulum homeostasis and β-cell phenotype, and strengthen the concept of altered β-cell identity as a mechanism underlying the loss of functional β-cell mass.
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Nyman, Lara R., Eric Ford, Alvin C. Powers, and David W. Piston. "Glucose-dependent blood flow dynamics in murine pancreatic islets in vivo." American Journal of Physiology-Endocrinology and Metabolism 298, no. 4 (April 2010): E807—E814. http://dx.doi.org/10.1152/ajpendo.00715.2009.
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Pancreatic islets are highly vascularized and arranged so that regions containing β-cells are distinct from those containing other cell types. Although islet blood flow has been studied extensively, little is known about the dynamics of islet blood flow during hypoglycemia or hyperglycemia. To investigate changes in islet blood flow as a function of blood glucose level, we clamped blood glucose sequentially at hyperglycemic (∼300 mg/dl or 16.8 mM) and hypoglycemic (∼50 mg/dl or 2.8 mM) levels while simultaneously imaging intraislet blood flow in mouse models that express green fluorescent protein in the β-cells or yellow fluorescent protein in the α-cells. Using line scanning confocal microscopy, in vivo blood flow was assayed after intravenous injection of fluorescent dextran or sulforhodamine-labeled red blood cells. Regardless of the sequence of hypoglycemia and hyperglycemia, islet blood flow is faster during hyperglycemia, and apparent blood volume is greater during hyperglycemia than during hypoglycemia. However, there is no change in the order of perfusion of different islet endocrine cell types in hypoglycemia compared with hyperglycemia, with the islet core of β-cells usually perfused first. In contrast to the results in islets, there was no significant difference in flow rate in the exocrine pancreas during hyperglycemia compared with hypoglycemia. These results indicate that glucose differentially regulates blood flow in the pancreatic islet vasculature independently of blood flow in the rest of the pancreas.
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Boehmer, Brit H., Sean W. Limesand, and Paul J. Rozance. "The impact of IUGR on pancreatic islet development and β-cell function." Journal of Endocrinology 235, no. 2 (November 2017): R63—R76. http://dx.doi.org/10.1530/joe-17-0076.
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Placental insufficiency is a primary cause of intrauterine growth restriction (IUGR). IUGR increases the risk of developing type 2 diabetes mellitus (T2DM) throughout life, which indicates that insults from placental insufficiency impair β-cell development during the perinatal period because β-cells have a central role in the regulation of glucose tolerance. The severely IUGR fetal pancreas is characterized by smaller islets, less β-cells, and lower insulin secretion. Because of the important associations among impaired islet growth, β-cell dysfunction, impaired fetal growth, and the propensity for T2DM, significant progress has been made in understanding the pathophysiology of IUGR and programing events in the fetal endocrine pancreas. Animal models of IUGR replicate many of the observations in severe cases of human IUGR and allow us to refine our understanding of the pathophysiology of developmental and functional defects in islet from IUGR fetuses. Almost all models demonstrate a phenotype of progressive loss of β-cell mass and impaired β-cell function. This review will first provide evidence of impaired human islet development and β-cell function associated with IUGR and the impact on glucose homeostasis including the development of glucose intolerance and diabetes in adulthood. We then discuss evidence for the mechanisms regulating β-cell mass and insulin secretion in the IUGR fetus, including the role of hypoxia, catecholamines, nutrients, growth factors, and pancreatic vascularity. We focus on recent evidence from experimental interventions in established models of IUGR to understand better the pathophysiological mechanisms linking placental insufficiency with impaired islet development and β-cell function.
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Rosenberg, Lawrence. "In Vivo Cell Transformation: Neogenesis of Beta Cells from Pancreatic Ductal Cells." Cell Transplantation 4, no. 4 (July 1995): 371–83. http://dx.doi.org/10.1177/096368979500400408.
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During embryogenesis, islet cells differentiate from primitive duct-like cells. This process leads to the formation of islets in the mesenchyme adjacent to the ducts. In the postnatal period, any further expansion of the pancreatic endocrine cell mass will manifest itself either by a limited proliferation of the existing islet cells, or by a reiteration of ontogenetic development. It is the latter, cell transformation by a process of differentiation from a multipotential cell, that will be referred to in this review as islet neogenesis. To better appreciate the mechanisms underlying islet cell neogenesis, some of the basic concepts of developmental biology will be reviewed. Considerable discussion is devoted to the subject of transdifferentiation, a change in a cell or in its progeny from one differentiated phenotype to another, where the change includes both morphological and functional phenotypic markers. While in vitro studies with fetal and neonatal pancreata strongly suggest that new islet tissue is derived from ductal epithelium, what is not established is whether the primary cell is a committed endocrine cell or duct-like cell capable of transdifferentiation. Next, research in the field of β-cell neogenesis is surveyed, in preparation for the examination of whether there is a physiological means of inducing islet cell regeneration, and whether the new islet mass will function in a regulated manner to reverse or stabilize a diabetic state? Our belief is that the pancreas retains the ability to regenerate a functioning islet cell mass in the postnatal period, and that the process of cell transformation leading to islet neogenesis is mediated by growth factors that are intrinsic to the gland. Furthermore, it is our contention that these factors act directly or indirectly on a multipotential cell, probably associated with the ductular epithelium, to induce endocrine cell differentiation. In other words, new islet formation in the postnatal period reiterates the normal ontogeny of islet cell development. These ideas will be fully developed in a discussion of the Partial Duct Obstruction (PDO) Model.
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Machida, Yui, Christine Bruinsma, Daniel R. Hallinger, Stephen M. Roper, Eden Garcia, Michelle B. Trevino, Joseph Nadler, Rexford Ahima, and Yumi Imai. "Pancreatic Islet Neuropeptide Y Overexpression Has Minimal Effect on Islet Morphology and β-Cell Adaptation to High-Fat Diet." Endocrinology 155, no. 12 (December 1, 2014): 4634–40. http://dx.doi.org/10.1210/en.2014-1537.
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Neuropeptide Y (NPY) is highly expressed in the hypothalamus, where it regulates feeding and energy homeostasis. Interestingly, NPY and its receptors are also expressed in peripheral tissues with roles in metabolism, including pancreatic islets. In islets, NPY is known to suppress insulin secretion acutely. In addition, the role of NPY in β-cell de-differentiation has been postulated recently. Therefore, we studied transgenic mice expressing NPY under rat insulin promoter (TG) to determine the effects of chronic up-regulation of NPY on islet morphology and function. NPY levels were 25 times higher in islets of TG mice compared with wild-type (WT) littermates, whereas no differences in NPY expression were noted in the brains of TG and WT mice. Islet NPY secretion was 2.3-fold higher in TG compared with WT mice. There were no significant changes in body weight, glucose tolerance, or insulin sensitivity in TG mice fed regular rodent diet or high-fat diet (HF). Islet β-cell area was comparable between TG and WT mice both on regular rodent and HF diets, indicating that NPY overexpression is insufficient to alter β-cell maturation or the compensatory increase of β-cell area on HF. One abnormality noted was that the glucose-stimulated insulin secretion in islets isolated from TG was reduced compared with those from WT mice on HF diet. Overall, an increase in islet NPY level has little impact on islet function and is insufficient to affect glucose homeostasis in mice.
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Woodland, David C., Wei Liu, Jacky Leong, Mallory L. Sears, Ping Luo, and Xiaojuan Chen. "Short-term high-fat feeding induces islet macrophage infiltration and β-cell replication independently of insulin resistance in mice." American Journal of Physiology-Endocrinology and Metabolism 311, no. 4 (October 1, 2016): E763—E771. http://dx.doi.org/10.1152/ajpendo.00092.2016.
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Short-term high-fat consumption stimulates mouse islet β-cell replication through unknown mechanisms. Resident macrophages (MΦs) are capable of secreting various factors involved in islet development and tissue remodeling. We hypothesized that a short-term high-fat diet (HFD) promotes MΦ infiltration in pancreatic islets and that MΦs serve as a regulator of β-cell replication. To test these hypotheses and dissect mechanisms involved in HFD-induced β-cell replication, adult C57BL/6J mice were fed a HFD for 7 days with or without administration of clodronate-containing liposomes, an MΦ-depleting agent. Mouse body and epididymal fat pad weights, and nonfasting blood glucose and fasting serum insulin levels were measured, and pancreatic islet β-cell replication, oxidative stress, and MΦ infiltration were examined. Short-term HFD promoted an increase in body and epididymal fat pad weight and blood glucose levels, along with an increased fasting serum insulin concentration. β-Cell replication, islet MΦ infiltration, and the percentage of inducible NO synthase positive MΦs in the islets increased significantly in mice fed the HFD. Immunofluorescence staining for 8-oxo-2′-deoxyguanosine or activated caspase-3 revealed no significant induction of DNA damage or apoptosis, respectively. In addition, no change in stromal-derived factor 1-expressing cells was found induced by HFD. Despite continuous elevation of nonfasting blood glucose and fasting serum insulin levels, depletion of MΦs through treatments of clodronate abrogated HFD-induced β-cell replication. These findings demonstrated that HFD-induced MΦ infiltration is responsible for β-cell replication. This study suggests the existence of MΦ-mediated mechanisms in β-cell replication that are independent of insulin resistance.
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Volinic, Jamie L., Jee H. Lee, Kazuhiro Eto, Varinderpal Kaur, and Melissa K. Thomas. "Overexpression of the Coactivator Bridge-1 Results in Insulin Deficiency and Diabetes." Molecular Endocrinology 20, no. 1 (January 1, 2006): 167–82. http://dx.doi.org/10.1210/me.2005-0127.
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Abstract Multiple forms of heritable diabetes are associated with mutations in transcription factors that regulate insulin gene transcription and the development and maintenance of pancreatic β-cell mass. The coactivator Bridge-1 (PSMD9) regulates the transcriptional activation of glucose-responsive enhancers in the insulin gene in a dose-dependent manner via PDZ domain-mediated interactions with E2A transcription factors. Here we report that the pancreatic overexpression of Bridge-1 in transgenic mice reduces insulin gene expression and results in insulin deficiency and severe diabetes. Dysregulation of Bridge-1 signaling increases pancreatic apoptosis with a reduction in the number of insulin-expressing pancreatic β-cells and an expansion of the complement of glucagon-expressing pancreatic α-cells in pancreatic islets. Increased expression of Bridge-1 alters pancreatic islet, acinar, and ductal architecture and disrupts the boundaries between endocrine and exocrine cellular compartments in young adult but not neonatal mice, suggesting that signals transduced through this coactivator may influence postnatal pancreatic islet morphogenesis. Signals mediated through the coactivator Bridge-1 may regulate both glucose homeostasis and pancreatic β-cell survival. We propose that coactivator dysfunction in pancreatic β-cells can limit insulin production and contribute to the pathogenesis of diabetes.
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Kahraman, Sevim, Debasish Manna, Ercument Dirice, Basudeb Maji, Jonnell Small, Bridget K. Wagner, Amit Choudhary, and Rohit N. Kulkarni. "Harnessing reaction-based probes to preferentially target pancreatic β-cells and β-like cells." Life Science Alliance 4, no. 4 (January 29, 2021): e202000840. http://dx.doi.org/10.26508/lsa.202000840.
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Highly sensitive approaches to target insulin-expressing cells would allow more effective imaging, sorting, and analysis of pancreatic β-cells. Here, we introduce the use of a reaction-based probe, diacetylated Zinpyr1 (DA-ZP1), to image pancreatic β-cells and β-like cells derived from human pluripotent stem cells. We harness the high intracellular zinc concentration of β-cells to induce a fluorescence signal in cells after administration of DA-ZP1. Given its specificity and rapid uptake by cells, we used DA-ZP1 to purify live stem cell-derived β-like cells as confirmed by immunostaining analysis. We tested the ability of DA-ZP1 to image transplanted human islet grafts and endogenous mouse pancreatic islets in vivo after its systemic administration into mice. Thus, DA-ZP1 enables purification of insulin-secreting β-like cells for downstream applications, such as functional studies, gene-expression, and cell–cell interaction analyses and can be used to label engrafted human islets and endogenous mouse islets in vivo.
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Delghingaro-Augusto, Viviane, Simon Décary, Marie-Line Peyot, Martin G. Latour, Julien Lamontagne, Nicolas Paradis-Isler, Marianne Lacharité-Lemieux, et al. "Voluntary running exercise prevents β-cell failure in susceptible islets of the Zucker diabetic fatty rat." American Journal of Physiology-Endocrinology and Metabolism 302, no. 2 (January 15, 2012): E254—E264. http://dx.doi.org/10.1152/ajpendo.00360.2011.
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Physical activity improves glycemic control in type 2 diabetes (T2D), but its contribution to preserving β-cell function is uncertain. We evaluated the role of physical activity on β-cell secretory function and glycerolipid/fatty acid (GL/FA) cycling in male Zucker diabetic fatty (ZDF) rats. Six-week-old ZDF rats engaged in voluntary running for 6 wk (ZDF-A). Inactive Zucker lean and ZDF (ZDF-I) rats served as controls. ZDF-I rats displayed progressive hyperglycemia with β-cell failure evidenced by falling insulinemia and reduced insulin secretion to oral glucose. Isolated ZDF-I rat islets showed reduced glucose-stimulated insulin secretion expressed per islet and per islet protein. They were also characterized by loss of the glucose regulation of fatty acid oxidation and GL/FA cycling, reduced mRNA expression of key β-cell genes, and severe reduction of insulin stores. Physical activity prevented diabetes in ZDF rats through sustaining β-cell compensation to insulin resistance shown in vivo and in vitro. Surprisingly, ZDF-A islets had persistent defects in fatty acid oxidation, GL/FA cycling, and β-cell gene expression. ZDF-A islets, however, had preserved islet insulin mRNA and insulin stores compared with ZDF-I rats. Physical activity did not prevent hyperphagia, dyslipidemia, or obesity in ZDF rats. In conclusion, islets of ZDF rats have a susceptibility to failure that is possibly due to altered β-cell fatty acid metabolism. Depletion of pancreatic islet insulin stores is a major contributor to islet failure in this T2D model, preventable by physical activity.