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More than three decades ago, we embarked on a number of bioengineering explorations using the most advanced materials and fabrication methods. In every area we ventured into, it was our intention to ensure fundamental discoveries were deployed into the clinic to benefit patients. When we embarked on this journey, we did so without a road map, not even a compass, and so the path was arduous, sometimes tedious. Now, we can see the doorway to deployment on the near horizon. We now appreciate that overcoming the challenges has made this a rewarding and exciting journey. However, maybe we could have been here a lot sooner, and so maybe the lessons we have learned could benefit others and accelerate progress in clinical translation. Through a number of case studies, including neural regeneration, cartilage regeneration, skin regeneration, the 3D printing of capsules for islet cell transplantation, and the bioengineered cornea, here, we retrace our steps. We will summarise the journey to date, point out the obstacles encountered, and celebrate the translational impact. Then, we will provide a framework for project design with the clinical deployment of bioengineered products as the goal.
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While inflammation is beneficial for insulin secretion during homeostasis, its transformation adversely affects ß cells and contributes to diabetes. However, the regulation of islet inflammation for maintaining glucose homeostasis remains largely unknown. Here, we identified pericytes as pivotal regulators of islet immune and ß cell function in health. Islets and pancreatic pericytes express various cytokines in healthy humans and mice. To interfere with the pericytic inflammatory response, we selectively inhibited the TLR/MyD88 pathway in these cells in transgenic mice. The loss of MyD88 impaired pericytic cytokine production. Furthermore, MyD88-deficient mice exhibited skewed islet inflammation with fewer cells, an impaired macrophage phenotype, and reduced IL-1ß production. This aberrant pericyte-orchestrated islet inflammation was associated with ß cell dedifferentiation and impaired glucose response. Additionally, we found that Cxcl1, a pericytic MyD88-dependent cytokine, promoted immune IL-1ß production. Treatment with either Cxcl1 or IL-1ß restored the mature ß cell phenotype and glucose response in transgenic mice, suggesting a potential mechanism through which pericytes and immune cells regulate glucose homeostasis. Our study revealed pericyte-orchestrated islet inflammation as a crucial element in glucose regulation, implicating this process as a potential therapeutic target for diabetes.
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Inflamación , Interleucina-1beta , Factor 88 de Diferenciación Mieloide , Pericitos , Transducción de Señal , Animales , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Ratones , Pericitos/metabolismo , Pericitos/patología , Pericitos/inmunología , Humanos , Inflamación/patología , Inflamación/metabolismo , Inflamación/genética , Inflamación/inmunología , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Ratones Transgénicos , Receptores Toll-Like/metabolismo , Receptores Toll-Like/genética , Quimiocina CXCL1/metabolismo , Quimiocina CXCL1/genética , Islotes Pancreáticos/inmunología , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Ratones Noqueados , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Células Secretoras de Insulina/inmunología , Masculino , Glucosa/metabolismoRESUMEN
AIMS: To evaluate the cell proliferation and death, and structural morphology of the pancreatic islet cells of the rats with hyperglycemia in the first month of life and compare to those of the control rats. MAIN METHODS: Female Sprague-Dawley newborn rats received Streptozotocin (a beta-cytotoxic drug) at birth for diabetes induction. Control and hyperglycemic animals were euthanized on different days of life: 5, 10, 15, and 30. The pancreas was collected and processed for immunohistochemical analysis of cleaved Caspase-3 (cell death), Ki-67 (cell proliferation), PDX-1 (transcription factor responsible for insulin synthesis), and endocrine hormones (insulin, glucagon, and somatostatin). KEY FINDINGS: Control females showed a higher percentage (%) of Ki-67-positive(+) cells on D10 and D15, a higher % of insulin+ and somatostatin+ cells on D15 and D30, a lower % of PDX-1+ cells on D10, and a higher % of glucagon+ cells on D10 and D30. Hyperglycemic females showed a lower % of Ki-67+ cells on D15, a higher % of cleaved Caspase-3+ cells on D15, and insulin+ cells on D15 and D30. In the comparison among the experimental groups, the hyperglycemic females showed an increased % of cleaved Caspase-3+ and Ki-67+ cells and a lower % of PDX-1+ cells. SIGNIFICANCE: This study enabled a better understanding of the abnormal pancreas development regarding cellular proliferation, apoptosis, and hormonal synthesis in the neonatal period. Thus, the pancreatic islets of hyperglycemic rats do not reestablish the normal endocrine cell population, and cellular apoptosis overcame the proliferative activity of these cells.
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Animales Recién Nacidos , Proliferación Celular , Hiperglucemia , Islotes Pancreáticos , Ratas Sprague-Dawley , Animales , Femenino , Hiperglucemia/metabolismo , Hiperglucemia/patología , Ratas , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/metabolismo , Muerte Celular , Glucagón/metabolismo , Insulina/metabolismo , Antígeno Ki-67/metabolismo , Caspasa 3/metabolismo , Somatostatina/metabolismo , Apoptosis , Transactivadores , Proteínas de HomeodominioRESUMEN
AIMS: The existence of insulin- or glucagon-expressing extra-islet endocrine cells scattered in the pancreas is well-known, but they have been sparsely characterized. The aim of this study was to examine their density, distribution, transcription-factor expression, and mitotic activity in young non-diabetic subjects. METHODS: Multispectral imaging was used to examine PDX1, ARX, Ki67, insulin and glucagon in extra-islet endocrine cells in pancreatic tissue from organ donors aged 1-25 years. RESULTS: Extra-islet insulin- or glucagon-positive cells were frequent in all donors (median 17.3 and 22.9 cells/mm2 respectively), with an insulin:glucagon cell ratio of 0.9. The density was similar regardless of age. PDX1 localized mainly to insulin-, and ARX mainly to glucagon-positive cells but, interestingly, many of the cells were negative for both transcription factors. Double-hormone-positive cells were rare but found in all age groups, as were insulin-positive cells expressing ARX and glucagon-positive cells expressing PDX1. Extra-islet endocrine cells with Ki67 expression were present but rare (0-2%) in all age groups. CONCLUSIONS: Extra-islet endocrine cells are more frequent than islets. The preserved extra-islet cell density during pancreas volume-expansion from childhood- to adulthood indicates that new cells are formed, possibly from replication as cells with mitotic activity were discovered. The lack of transcription-factor expression in many cells indicates that they are immature, newly formed or plastic. This, together with the mitotic activity, suggests that these cells could play an important role in the expansion of beta-cell mass in situations of increasing demand, or in the turnover of the endocrine cell population.
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Glucagón , Proteínas de Homeodominio , Insulina , Páncreas , Donantes de Tejidos , Humanos , Glucagón/metabolismo , Insulina/metabolismo , Adolescente , Niño , Adulto , Preescolar , Adulto Joven , Lactante , Masculino , Páncreas/metabolismo , Páncreas/citología , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Femenino , Transactivadores/metabolismo , Transactivadores/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Islotes Pancreáticos/metabolismo , Antígeno Ki-67/metabolismoRESUMEN
The presence of remaining insulin-positive cells in type 1 diabetes (T1D) is well-known. These cells are part of islets or appear as extra-islet insulin-positive cells scattered in the exocrine parenchyma. The latter are poorly described, and the presence of scattered endocrine cells expressing other islet hormones than insulin has not been explored. This study aimed to compare the extra-islet insulin- or glucagon-positive cells concerning their frequency, transcription-factor expression, and mitotic activity in subjects with and without T1D. Multispectral imaging was used to examine extra-islet cells by staining for insulin, glucagon, ARX, PDX1, and Ki67. This was done in well-preserved pancreatic tissue obtained from heart-beating organ donors with or without T1D. In three T1D donors, lobes with insulin-containing islets (ICI) were found. Within these, a higher frequency of extra-islet insulin-positive cells was observed compared to lobes with insulin-deficient islets (IDI). Increased frequency of glucagon-positive extra-islet cells was observed in donors with T1D (median 53 cells/mm2) when compared with non-diabetic donors (11 cells/mm2, p = 0.004). Proliferating endocrine cells were present in donors with, and without T1D, as demonstrated by Ki67-positive staining (0-3% of the cells expressing insulin or glucagon). The reduced frequency of extra-islet insulin-positive cells in lobes with IDI in donors with T1D suggests that the pathological mechanism causing beta cell demise in T1D affects entire lobes. The presence of an increased frequency of glucagon-positive extra-islet cells supports the notion of a preserved capacity to regenerate the endocrine pancreas in donors with T1D.
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BACKGROUND: It was reported that rikkunshito (TJ-43) improved the cisplatin-induced decreases in the active form of ghrelin in plasma; however, other effects on gastrointestinal hormones have not been investigated. AIM: To investigate the effects of TJ-43 on peripheral levels of incretin hormones, including gastric inhibitory polypeptide (GIP) and glucagon-like polypeptide-1 (GLP-1), in humans and rats. METHODS: Patients were divided into two groups, namely patients who received TJ-43 immediately following surgery [TJ-43(+) group] and those who received TJ-43 on postoperative day 21 [TJ-43(-) group], and the plasma levels of active GIP and active GLP-1 were assessed. In animal experiments, rats were treated with TJ-43 [rat (r)TJ-43(+) group] or without [rTJ-43(-) group] by gavage for 4 wk, and the plasma active GIP and active GLP-1 levels were measured. The expression of incretin hormones in the gastrointestinal tract and insulin in the pancreas were investigated by immunohistochemistry. Furthermore, the cyclic adenosine monophosphate activities were assessed in pancreatic tissues from rats treated with or without TJ-43 in vivo, and the blood glucose levels and plasma insulin levels were measured in rats treated with or without TJ-43 in oral glucose tolerance tests. RESULTS: In humans, the active incretin hormone levels increased, and values were significantly greater in the TJ-43(+) group compared those in the TJ-43(-) group. In rats, the plasma active incretin levels significantly increased in the rTJ-43(+) group compared with those in the rTJ-43(-) group. GIP and GLP-1 expressions were enhanced by TJ-43 treatment. Moreover, plasma insulin levels increased and blood glucose levels were blunted in the rTJ-43(+) group. CONCLUSION: The results show that TJ-43 may be beneficial for patients who undergo pancreatic surgery.
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Human allogeneic pancreatic islet transplantation is a life-changing treatment for patients with severe Type 1 Diabetes (T1D) who suffer from hypoglycemia unawareness and high risk of severe hypoglycemia. However, intensive immunosuppression is required to prevent immune rejection of the graft, that may in turn lead to undesirable side effects such as toxicity to the islet cells, kidney toxicity, occurrence of opportunistic infections, and malignancies. The shortage of cadaveric human islet donors further limits islet transplantation as a treatment option for widespread adoption. Alternatively, porcine islets have been considered as another source of insulin-secreting cells for transplantation in T1D patients, though xeno-transplants raise concerns over the risk of endogenous retrovirus transmission and immunological incompatibility. As a result, technological advancements have been made to protect transplanted islets from immune rejection and inflammation, ideally in the absence of chronic immunosuppression, to improve the outcomes and accessibility of allogeneic islet cell replacement therapies. These include the use of microencapsulation or macroencapsulation devices designed to provide an immunoprotective environment using a cell-impermeable layer, preventing immune cell attack of the transplanted cells. Other up and coming advancements are based on the use of stem cells as the starting source material for generating islet cells 'on-demand'. These starting stem cell sources include human induced pluripotent stem cells (hiPSCs) that have been genetically engineered to avoid the host immune response, curated HLA-selected donor hiPSCs that can be matched with recipients within a given population, and multipotent stem cells with natural immune privilege properties. These strategies are developed to provide an immune-evasive cell resource for allogeneic cell therapy. This review will summarize the immunological challenges facing islet transplantation and highlight recent bio-engineering and cell-based approaches aimed at avoiding immune rejection, to improve the accessibility of islet cell therapy and enhance treatment outcomes. Better understanding of the different approaches and their limitations can guide future research endeavors towards developing more comprehensive and targeted strategies for creating a more tolerogenic microenvironment, and improve the effectiveness and sustainability of islet transplantation to benefit more patients.
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Diabetes Mellitus Tipo 1 , Rechazo de Injerto , Trasplante de Islotes Pancreáticos , Trasplante de Islotes Pancreáticos/métodos , Humanos , Animales , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/terapia , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Ingeniería Biomédica/métodos , Islotes Pancreáticos/inmunologíaRESUMEN
Differentiation of pancreatic endocrine cells from human pluripotent stem cells (PSCs) has been thoroughly investigated for application in cell therapy against diabetes. In the context of induced pancreatic endocrine cell implantation, previous studies have reported graft enlargement resulting from off-target pancreatic lineage cells. However, there is currently no documented evidence of proliferative off-target cells beyond the pancreatic lineage in existing studies. Here, we show that the implantation of seven-stage induced PSC-derived pancreatic islet cells (s7-iPICs) leads to the emergence of unexpected off-target cells with proliferative capacity via in vivo maturation. These cells display characteristics of both mesenchymal stem cells (MSCs) and smooth muscle cells (SMCs), termed proliferative MSC- and SMC-like cells (PMSCs). The frequency of PMSC emergence was found to be high when 108 s7-iPICs were used. Given that clinical applications involve the use of a greater number of induced cells than 108, it is challenging to ensure the safety of clinical applications unless PMSCs are adequately addressed. Accordingly, we developed a detection system and removal methods for PMSCs. To detect PMSCs without implantation, we implemented a 4-wk-extended culture system and demonstrated that putative PMSCs could be reduced by compound treatment, particularly with the taxane docetaxel. When docetaxel-treated s7-iPICs were implanted, the PMSCs were no longer observed. This study provides useful insights into the identification and resolution of safety issues, which are particularly important in the field of cell-based medicine using PSCs.
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Células Madre Pluripotentes Inducidas , Islotes Pancreáticos , Humanos , Docetaxel , Diferenciación Celular , Implantación del EmbriónRESUMEN
Single-cell sequencing is a novel and rapidly advancing high-throughput technique that can be used to investigating genomics, transcriptomics, and epigenetics at a single-cell level. Currently, single-cell sequencing can not only be used to draw the pancreatic islet cells map and uncover the characteristics of cellular heterogeneity in type 2 diabetes, but can also be used to label and purify functional beta cells in pancreatic stem cells, improving stem cells and islet organoids therapies. In addition, this technology helps to analyze islet cell dedifferentiation and can be applied to the treatment of type 2 diabetes. In this review, we summarize the development and process of single-cell sequencing, describe the potential applications of single-cell sequencing in the field of type 2 diabetes, and discuss the prospects and limitations of single-cell sequencing to provide a new direction for exploring the pathogenesis of type 2 diabetes and finding therapeutic targets.
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Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Islotes Pancreáticos , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Islotes Pancreáticos/metabolismo , Páncreas/metabolismo , Células Secretoras de Insulina/metabolismo , Perfilación de la Expresión GénicaRESUMEN
Recent studies have implicated pre-beta and beta lipoproteins (VLDL and LDL) in the etiopathogenesis of complications of diabetes mellitus (DM). In contrast, alpha lipoprotein (HDL) is protective of the beta cells of the pancreas. This study examined the distribution of HDL in the islets of Langerhans of murine models of type 1 diabetic rats (streptozotocin (STZ)-induced DM in Wistar rats) and type 2 models of DM rats (Goto-Kakizaki (GK), non-diabetic Zucker lean (ZL), and Zucker diabetic and fatty (ZDF)). The extent by which HDL co-localizes with insulin or glucagon in the islets of the pancreas was also investigated. Pancreatic tissues of Wistar non-diabetic, diabetic Wistar, GK, ZL, and ZDF rats were processed for immunohistochemistry. Pancreatic samples of GK rats fed with either a low-fat or a high-fat diet were prepared for transmission immune-electron microscopy (TIEM) to establish the cytoplasmic localization of HDL in islet cells. HDL was detected in the core and periphery of pancreatic islets of Wistar non-diabetic and diabetic, GK, ZL, and ZDF rats. The average total of islet cells immune positive for HDL was markedly (<0.05) reduced in GK and ZDF rats in comparison to Wistar controls. The number of islet cells containing HDL was also remarkably (p < 0.05) reduced in Wistar diabetic rats and GK models fed on high-fat food. The co-localization study using immunofluorescence and TIEM techniques showed that HDL is detected alongside insulin within the secretory granules of ß-cells. HDL did not co-localize with glucagon. This observation implies that HDL may contribute to the metabolism of insulin.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Islotes Pancreáticos , Ratas , Ratones , Animales , Insulina/metabolismo , Glucagón/metabolismo , Diabetes Mellitus Experimental/metabolismo , Roedores , Lipoproteínas HDL/metabolismo , Ratas Wistar , Ratas Zucker , Islotes Pancreáticos/metabolismo , Hormonas Pancreáticas/metabolismo , Diabetes Mellitus Tipo 2/metabolismoRESUMEN
Ghrelin exerts key effects on islet hormone secretion to regulate blood glucose levels. Here, we sought to determine whether ghrelin's effects on islets extend to the alteration of islet size and ß cell mass. We demonstrate that reducing ghrelin - by ghrelin gene knockout (GKO), conditional ghrelin cell ablation, or high-fat diet (HFD) feeding - was associated with increased mean islet size (up to 62%), percentage of large islets (up to 854%), and ß cell cross-sectional area (up to 51%). In GKO mice, these effects were more apparent in 10- to 12-week-old mice than in 4-week-old mice. Higher ß cell numbers from decreased ß cell apoptosis drove the increase in ß cell cross-sectional area. Conditional ghrelin cell ablation in adult mice increased the ß cell number per islet by 40% within 4 weeks. A negative correlation between islet size and plasma ghrelin in HFD-fed plus chow-fed WT mice, together with even larger islet sizes in HFD-fed GKO mice than in HFD-fed WT mice, suggests that reduced ghrelin was not solely responsible for diet-induced obesity-associated islet enlargement. Single-cell transcriptomics revealed changes in gene expression in several GKO islet cell types, including upregulation of Manf, Dnajc3, and Gnas expression in ß cells, which supports decreased ß cell apoptosis and/or increased ß cell proliferation. These effects of ghrelin reduction on islet morphology might prove useful when designing new therapies for diabetes.
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Células Secretoras de Insulina , Islotes Pancreáticos , Ratones , Animales , Glucemia/metabolismo , Ghrelina/genética , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Células Secretoras de Insulina/metabolismo , Ratones Noqueados , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BLRESUMEN
PURPOSE: Previous research has highlighted the impact of X-ray irradiation-induced organ damage, on cancer patients after radiation therapy. The ionizing radiation-induced oxidative stress causes injury to the pancreatic islet cells of Langerhans. We used histopathological, immunohistochemical, and biochemical analyses to examine α- and ß-cells in the islets of Langerhans in rats undergoing whole-body x-ray ionizing radiation, a group of which was treated with NAC. MATERIAL AND METHODS: Twenty-four male rats were randomly divided into 3 groups, one control, and two experimental groups. Group I (Control) was administered only saline solution (0.09% NaCl) by oral gavage for 7 days. Group II (IR) was administrated whole body single dose 6 Gray ionizing radiation (IR) and saline solution (0.09% NaCl) by oral gavage for 7 days. Group III (IR + NAC) was administered 300 mg/kg NAC (N-acetylcysteine) by oral gavage for 7 days, 5 days before, and 2 days after 6 Gray IR application. RESULTS: In the X-ray irradiation group, we observed diffuse necrotic endocrine cells in the islets of Langerhans. In addition, we found that Caspase-3, malondialdehyde (MDA) levels increased, and insulin, glucagon, and glutathione (GSH) levels decreased in the IR group compared to the control group. In contrast, we observed a decrease in Caspase-3, and MDA levels in necrotic endocrine cells, and an increase in insulin, glucagon, and GSH levels in the IR + NAC group compared to the IR group. CONCLUSION: This study provides evidence for the beneficial effects of N-acetyl cysteine on islets of Langerhans cells with X-ray ionizing-radiation-induced damage in a rat model.
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Insulinas , Islotes Pancreáticos , Traumatismos por Radiación , Humanos , Masculino , Ratas , Animales , Antioxidantes/farmacología , Acetilcisteína/farmacología , Rayos X , Caspasa 3/metabolismo , Glucagón , Solución Salina/farmacología , Cloruro de Sodio/farmacología , Estrés Oxidativo , Glutatión/metabolismo , Radiación Ionizante , Traumatismos por Radiación/tratamiento farmacológico , Traumatismos por Radiación/prevención & control , Islotes Pancreáticos/metabolismoRESUMEN
Pancreatic islet ß cells preferentially secrete insulin toward the plasma membrane, making contact with the capillary extracellular matrix (ECM). Isolated islets separated from the exocrine acinar cells are the best system for cell biology studies of primary ß cells, whereas isolated islets lose their capillary network during ex vivo culture. Providing the appropriate extracellular signaling by attaching islets to vascular ECM-coated surfaces can restore the polarized insulin secretion toward the ECM. The guided secretion toward ECM-coated glass coverslips provides a good model for recording insulin secretion in real time to study its regulation. Additionally, ß cells attached to the ECM-coated coverslips are suitable for confocal live imaging of subcellular components including adhesion molecules, cytoskeleton, and ion channels. This procedure is also compatible for total internal reflection fluorescence (TIRF) microscopy, which provides optimal signal-to-noise ratio and high spatial precision of structures close to the plasma membrane. In this article, we describe the optimized protocol for vascular ECM-coating of glass coverslips and the process of attachment of isolated mouse islets on the coverslip. This preparation is compatible with any high-resolution microscopy of live primary ß cells. Key features ⢠Optimized coating procedure to attach isolated islets, compatible for both confocal and TIRF microscopy. ⢠The ECM-coated glass coverslip functions as the artificial capillary surface to guide secretion toward the coated surface for optimal imaging of secretion events. ⢠Shows the process of islets attachment to the ECM-coated surface in a 6-day ex vivo culture.
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Pancreatic ß cells are specialized for coupling glucose metabolism to insulin peptide production and secretion. Acute glucose exposure robustly and coordinately increases translation of proinsulin and proteins required for secretion of mature insulin peptide. By contrast, chronically elevated glucose levels that occur during diabetes impair ß cell insulin secretion and have been shown experimentally to suppress insulin translation. Whether translation of other genes critical for insulin secretion is similarly downregulated by chronic high glucose is unknown. Here, we used high-throughput ribosome profiling and nascent proteomics in MIN6 insulinoma cells to elucidate the genome-wide impact of sustained high glucose on ß cell mRNA translation. Before induction of ER stress or suppression of global translation, sustained high glucose suppressed glucose-stimulated insulin secretion and downregulated translation of not only insulin, but also mRNAs related to insulin secretory granule formation, exocytosis, and metabolism-coupled insulin secretion. Translation of these mRNAs was also downregulated in primary rat and human islets following ex vivo incubation with sustained high glucose and in an in vivo model of chronic mild hyperglycemia. Furthermore, translational downregulation decreased cellular abundance of these proteins. Our study uncovered a translational regulatory circuit during ß cell glucose toxicity that impairs expression of proteins with critical roles in ß cell function.
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Hiperglucemia , Células Secretoras de Insulina , Islotes Pancreáticos , Neoplasias Pancreáticas , Ratas , Humanos , Animales , Secreción de Insulina , ARN Mensajero/metabolismo , Insulina/metabolismo , Hiperglucemia/genética , Hiperglucemia/metabolismo , Glucosa/metabolismo , Células Secretoras de Insulina/metabolismo , Péptidos/metabolismo , Neoplasias Pancreáticas/metabolismo , Islotes Pancreáticos/metabolismoRESUMEN
INTRODUCTION: Recent studies have shown that a decline in isletß cells quality is due to ß-cell dedifferentiation, not only ß-cell apoptosis. Angiotensin (1-7) [Ang(1-7)] could attenuate high glucose-induced apoptosis and dedifferentiation of pancreaticß cells by combining with MAS receptors. However, the mechanism of such action has not been elucidated. Recent studies have revealed that Wnt/ß-catenin and forkhead box transcription factor O1 (FoxO1) are associated with ß-cell dedifferentiation. Our study aims to explore whether the effects of Ang(1-7)on islet b cell dedifferentiation are mediated through the Wnt/ß-catenin/FoxO1 pathway. MATERIAL AND METHODS: Isletß cells were divided into 6 groups: a control group, a high-glucose group, high glucose with Ang(1-7) group, high-glucose with Ang(1-7) and A779 group, high-glucose with angiotensin(1-7) and CHIR99021 group, and high-glucose with CHIR99021 group. A779 is a kind of MAS receptor antagonist that blocks the action of Ang(1-7), and CHIR99021 is a Wnt pathway activator. The morphology of pancreaticß cells was observed in each group after 48 hours of intervention. ß-cell insulin secretory function and expressions of relevant factors were measured. RESULTS: Compared with the control group, the cell morphology became degraded in the high-glucose group and the capability of insulin secretion was reduced. Meanwhile, the expressions of matureß cells markers [pancreatic and duodenal homeobox 1 (Pdx1) and MAF BZIP transcription factor A (MafA)] were reduced, while the expressions of endocrine progenitor cells makers [octamer-binding transcription factor 4 (Oct4) and Nanog] were increased. The addition of CHIR99021 resulted in profound deep destruction ofß cells compared with the high-glucose group. However, such changes were dramatically reversed following the treatment of Ang(1-7). The addition of A779 significantly inhibited the improvement caused by Ang(1-7). CONCLUSION: Ang(1-7) can effectively reverseß cell dedifferentiation through Wnt/ß-catenin/FoxO1 pathway. It might be a new strategy for preventing and treating diabetes.
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Glucosa , Células Secretoras de Insulina , Humanos , Glucosa/farmacología , Glucosa/metabolismo , Vía de Señalización Wnt , Desdiferenciación Celular , beta Catenina/metabolismo , beta Catenina/farmacología , Células Secretoras de Insulina/metabolismoRESUMEN
Type 1 diabetes (T1D) is an autoimmune disease that destroys pancreatic beta cells, which produce insulin in the islets of Langerhans. The risk of developing T1D is influenced by environmental factors, genetics, and autoantibodies. Latent autoimmune diabetes in adults (LADA) is a type of T1D that is genetically and phenotypically distinct from classic T1D. This review summarizes the accumulated information on the risk factors for T1D and LADA, and immunotherapy trials that offer insights into potential future combined therapeutic interventions for both T1D and LADA to slow the rate of islet cell loss and preserve beta cell function. Future research should also focus on improving intervention doses, conducting more thorough examinations of intervention responders, and/or combining minimally effective single-target immunotherapies to slow the rate of islet cell loss and preserve beta cell function.
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The metabolic health trajectory of an individual is shaped as early as prepregnancy, during pregnancy, and lactation period. Both maternal nutrition and metabolic health status are critical factors in the programming of offspring toward an increased propensity to developing type 2 diabetes in adulthood. Pancreatic beta-cells, part of the endocrine islets, which are nutrient-sensitive tissues important for glucose metabolism, are primed early in life (the first 1000 days in humans) with limited plasticity later in life. This suggests the high importance of the developmental window of programming in utero and early in life. This review will focus on how changes to the maternal milieu increase offspring's susceptibility to diabetes through changes in pancreatic beta-cell mass and function and discuss potential mechanisms by which placental-driven nutrient availability, hormones, exosomes, and immune alterations that may impact beta-cell development in utero, thereby affecting susceptibility to type 2 diabetes in adulthood.
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Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Humanos , Embarazo , Femenino , Placenta , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Fenómenos Fisiologicos Nutricionales Maternos , LactanciaRESUMEN
Transplantation of microencapsulated islet cells remains a promising strategy for the normalization of glucose metabolism control in type 1 diabetes mellitus. However, vigorous host immunologic rejection, fibrotic overgrowth around the microcapsules, and poor oxygen supply often lead to graft failure. Herein, a bioartificial pancreas is constructed, which incorporates the "stealth effect" based on polyethylene glycol copolymers and the high oxygen-carrying performance of fluorinated nanoparticles. Polycationic poly(l-lysine)-grafted-poly(ethylene glycol) is successfully coated on the surface of alginate microcapsules through electrostatic interaction, which can not only resist fibrinogen adhesion and avoid excessive fibrosis around the microcapsules but also isolate the host immune system from attacking, achieving a "stealth effect" of microencapsulated islet cells. Furthermore, the coloading of fluoride-based O2 nanocarriers gives them enhanced oxygen-carrying and continuous oxygen supply capabilities, thereby effectively prolonging the survival of islet cells. The intracapsular islet cells still display similar cell viability and almost normal insulin secretion function even in long-term culture under hypoxic conditions. Collectively, here a new approach is opened for microencapsulated islets to efficiently evade host immune attack and improve oxygen supply and a promising strategy is provided for islet transplantation in type 1 diabetes mellitus.
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Diabetes Mellitus Tipo 1 , Trasplante de Islotes Pancreáticos , Humanos , Cápsulas , Diabetes Mellitus Tipo 1/terapia , Insulina , Oxígeno , Páncreas/metabolismo , Polietilenglicoles , Cationes/químicaRESUMEN
Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet ß cells, characterized by inappropriate production of other islet cell-enriched hormones. Here, we examined how hormone misexpression was influenced by the MAFA and MAFB transcription factors, closely related proteins that maintain islet cell function. Mice specifically lacking MafA in ß cells demonstrated broad, population-wide changes in hormone gene expression with an overall gene signature closely resembling islet gastrin+ (Gast+) cells generated under conditions of chronic hyperglycemia and obesity. A human ß cell line deficient in MAFB, but not one lacking MAFA, also produced a GAST+ gene expression pattern. In addition, GAST was detected in human T2D ß cells with low levels of MAFB. Moreover, evidence is provided that human MAFB can directly repress GAST gene transcription. These results support a potentially novel, species-specific role for MafA and MAFB in maintaining adult mouse and human ß cell identity, respectively. Here, we discuss the possibility that induction of Gast/GAST and other non-ß cell hormones, by reduction in the levels of these transcription factors, represents a dysfunctional ß cell signature.