Pancreatic Endocrine Tissue Research Articles

Human Stem Cell Therapy for the Cure of Type 1 Diabetes Mellitus (T1D): A Hurdle Course between Lights and Shadows

Background: T1D is a severe metabolic disorder due to selective autoimmune pancreatic islet β-cell killing, which results in complete abrogation of endogenous insulin secretion. The affected patients, once the disease is clinically overt, must immediately undertake insulin supplementation according to intensive therapy regimens to prevent the onset of acute and chronic complications, some of them potentially lethal. Replacement of the destroyed β-cells with fresh and vital pancreatic endocrine tissue, either of the whole organ or isolated islets transplantation, started a few decades ago with progressively encouraging results, although exogenous insulin withdrawal was obtained in a minor cohort of the treated patients. The restricted availability of donor organs coupled with general immunosuppression treatment of recipients to avoid graft immune rejection may, at least partially, explain the limited success achieved by these procedures. Results: The introduction of pluripotent stem cells (either of human embryonic origin or adult cells genetically induced to pluripotency) that can be differentiated toward insulin secretory β-like cells could provide an indefinite resource for insulin-producing cells (IPCs). Conclusions: Because the use of human embryos may encounter ethical problems, employment of adult multipotent mesenchymal stem cells (MSCs) extracted from several tissues may represent an alternative option. MSCs are associated with strong immunoregulatory properties that can alter early stages of β-cell-directed autoimmunity in T1D, other than holding the potential to differentiate themselves into β-like cells. Lights and shadows of these new strategies for the potential cure of T1D and their advancement state are reviewed.

Reduced Nephrin Tyrosine Phosphorylation Enhances Insulin Secretion and Increases Glucose Tolerance With Age.

Nephrin is a transmembrane protein with well-established signaling roles in kidney podocytes, and a smaller set of secretory functions in pancreatic β cells are implicated in diabetes. Nephrin signaling is mediated in part through its 3 cytoplasmic YDxV motifs, which can be tyrosine phosphorylated by high glucose and β cell injuries. Although in vitro studies demonstrate these phosphorylated motifs can regulate β cell vesicle trafficking and insulin release, in vivo evidence of their role in this cell type remains to be determined. To further explore the role of nephrin YDxV phosphorylation in β cells, we used a mouse line with tyrosine to phenylalanine substitutions at each YDxV motif (nephrin-Y3F) to inhibit phosphorylation. We assessed islet function via primary islet glucose-stimulated insulin secretion assays and oral glucose tolerance tests. Nephrin-Y3F mice successfully developed pancreatic endocrine and exocrine tissues with minimal structural differences. Unexpectedly, male and female nephrin-Y3F mice showed elevated insulin secretion, with a stronger increase observed in male mice. At 8 months of age, no differences in glucose tolerance were observed between wild-type (WT) and nephrin-Y3F mice. However, aged nephrin-Y3F mice (16 months of age) demonstrated more rapid glucose clearance compared to WT controls. Taken together, loss of nephrin YDxV phosphorylation does not alter baseline islet function. Instead, our data suggest a mechanism linking impaired nephrin YDxV phosphorylation to improved islet secretory ability with age. Targeting nephrin phosphorylation could provide novel therapeutic opportunities to improve β cell function.

Comparative study of endocrine pancreatic tissue in bats: Assessing variations among frugivorous, insectivorous, and nectarivorous diets

Whether the endocrine pancreas exhibits structural features to couple with dietary patterns is not fully explored. Considering the lack of data comparing endocrine pancreas and islet cell distribution among different bat species in the same study, we considered this an opportunity to explore the topic, including five species within three different predominant diets. For this, we applied morphometric techniques to compare the islets of frugivorous Artibeus lituratus and Carollia perspicillata, insectivorous Molossus molossus and Myotis nigricans, and nectarivorous Glossophaga soricina bats. Data for islet size, cellularity, and mass were equivalent between frugivorous A. lituratus and nectarivorous G. soricina, which differed from insectivorous bats. The frugivorous C. perspicillata bat exhibited morphometric islet values between A. lituratus and the insectivorous species. A. lituratus and G. soricina but not C. perspicillata bats had higher islet mass than insectivorous species due to larger size, instead of a higher number of islets per area. Insectivorous bats, on the other hand, had a higher proportion of α-cells per islet. These differences in the endocrine pancreas across species with different eating habits indicate the occurrence of species-specific adjustments along the years of evolution, with the demand for α-cells higher in bats with higher protein intake.

Understanding molecular differences in endocrine and exocrine pancreatic tissue in healthy and unhealthy metabolic states

Type II diabetes (T2D) is a metabolic disorder characterized by hyperglycemia largely due the development of insulin-resistance, and in some cases, due to insuffcient insulin secretion. The endocrine portion of the pancreas, the islets of Langerhans, is composed of a diverse population of cells (beta, alpha, delta) that play vital roles in glucose homeostasis. Intercellular signaling events that occur within this diverse cell population play an active role in T2D progression. Therefore, to properly understand the progression of T2D it is critical to understand the how both the cellular neighborhoods and cell-cell communications within the islet of Langerhans and the surrounding exocrine (non-Islet) tissue contribute to the development of T2D. As the pancreas is a heterogenous organ, techniques allowing for the identification of cellular subpopulations within the tissue, such as single-cell RNA sequencing (scRNAseq), have been critical to answering questions about the pathogenesis of T2D. However, these techniques provide no insight into the anatomical and spatial context of cells, and therefore lack the ability to determine the influence of cellular neighborhoods in T2D pathogenesis. To begin to fill the gap in our understanding of how cellular neighborhoods and cell-cell communication impacts the progression of T2D, we utilized cutting edge technology that allows for the identification of RNA and protein within tissue at cellular and subcellular level, the Nanostring CosMx Spatial Molecular Imager. In this study, we aimed to determine if the location of individual cells within the islet (exocrine adjacent versus endocrine adjacent) contributes to gene expression changes that direct disease progression. To answer this question, we collected 200 human donor pancreases and analyzed them for 1000 RNA targets using the CosMX Spatial Molecular Imager. Ig. We then performed an analysis of RNA expression of exocrine cells bordering the islets of Langerhans and endocrine cells surrounding pancreatic vasculature was compared between healthy, metabolically heathy obese (MHO), and obese T2D groups. Preliminary analysis of these data yield novel insights into the transcriptomic profile of metabolically unhealthy tissues that may play a role in the progression of T2D. In particular, we observed an upregulation of mRNA transcripts associated with pro-inflammatory IL-21 and IL-22 signaling in the alpha cells from MHO donor pancreases. Furthermore, this upregulation is primarily observed in alpha cells in close proximity to acinar cells. Overall, these data will help pave the way to addressing previously unanswered questions in the context of T2D pathogenesis and unexplored cell-cell interactions that occur between the endocrine and exocrine spaces of the pancreas. Funding: Saint Louis University. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Mixed-Lineage Leukaemia Gene Regulates Glucose-Sensitive Gene Expression and Insulin Secretion in Pancreatic Beta Cells.

The escalating prevalence of diabetes mellitus underscores the need for a comprehensive understanding of pancreatic beta cell function. Interest in glucose effectiveness has prompted the exploration of novel regulatory factors. The myeloid/lymphoid or mixed-lineage leukaemia gene (MLL) is widely recognised for its role in leukemogenesis and nuclear regulatory mechanisms through its histone methyltransferase activity in active chromatin. However, its function within pancreatic endocrine tissues remains elusive. Herein, we unveil a novel role of MLL in glucose metabolism and insulin secretion. MLL knockdown in βHC-9 pancreatic beta cells diminished insulin secretion in response to glucose loading, paralleled by the downregulation of the glucose-sensitive genes SLC2a1 and SLC2a2. Similar observations were made in MLL heterozygous knockout mice (MLL+/-), which exhibited impaired glucose tolerance and reduced insulin secretion without morphological anomalies in pancreatic endocrine cells. The reduction in insulin secretion was independent of changes in beta cell mass or insulin granule morphology, suggesting the regulatory role of MLL in glucose-sensitive gene expression. The current results suggest that MLL interacts with circadian-related complexes to modulate the expression of glucose transporter genes, thereby regulating glucose sensing and insulin secretion. Our findings shed light on insulin secretion control, providing potential avenues for therapeutics against diabetes.

Dopamine signalling in pancreatic islet cells and role in adaptations to metabolic stress.

Dopamine and related receptors are evidenced in pancreatic endocrine tissue, but the impact on islet β-cell stimulus-secretion as well as (patho)physiological role are unclear. The present study has evaluated islet cell signalling pathways and biological effects of dopamine, as well as alterations of islet dopamine in rodent models of diabetes of different aetiology. The dopamine precursor l-DOPA partially impaired glucose tolerance in mice and attenuated glucose-, exendin-4, and alanine-induced insulin secretion. The latter effect was echoed by the attenuation of glucose-induced [Ca2+]i dynamics and elevation of ATP levels in individual mouse islet cells. l-DOPA significantly decreased β-cell proliferation rates, acting predominantly via the D2 receptor, which was most abundant at the mRNA level. The administration of streptozotocin (STZ) or high-fat diet (HFD) in mice significantly elevated numbers of dopamine-positive islet cells, with HFD also increasing colocalization of dopamine with insulin. At the same time, colocalization of dopamine with glucagon was increased in STZ-treated and pregnant mice, but unaffected by HFD. These findings highlight a role for dopamine receptor signalling in islet cell biology adaptations to various forms of metabolic stress.

Microphysiological pancreas-on-chip platform with integrated sensors to model endocrine function and metabolism.

Pancreatic in vitro research is of major importance to advance mechanistic understanding and development of treatment options for diseases such as diabetes mellitus. We present a thermoplastic-based microphysiological system aiming to model the complex microphysiological structure and function of the endocrine pancreas with concurrent real-time read-out capabilities. The specifically tailored platform enables self-guided trapping of single islets at defined locations: β-cells are assembled to pseudo-islets and injected into the tissue chamber using hydrostatic pressure-driven flow. The pseudo-islets can further be embedded in an ECM-like hydrogel mimicking the native microenvironment of pancreatic islets in vivo. Non-invasive real-time monitoring of the oxygen levels on-chip is realized by the integration of luminescence-based optical sensors to the platform. To monitor insulin secretion kinetics in response to glucose stimulation in a time-resolved manner, an automated cycling of different glucose conditions is implemented. The model's response to glucose stimulation can be monitored via offline analysis of insulin secretion and via specific changes in oxygen consumption due to higher metabolic activity of pseudo-islets at high glucose levels. To demonstrate applicability for drug testing, the effects of antidiabetic medications are assessed and changes in dynamic insulin secretion are observed in line with the respective mechanism of action. Finally, by integrating human pancreatic islet microtissues, we highlight the flexibility of the platform and demonstrate the preservation of long-term functionality of human endocrine pancreatic tissue.

Recent advances in the development of bioartificial pancreas using 3D bioprinting for the treatment of type 1 diabetes: a review

Type 1 diabetes is a chronic condition that results from the destruction of insulin-producing β-cells in the pancreas. Current treatments for type 1 diabetes, such as insulin therapy and pancreatic islet transplantation, have several limitations and, hence not quite effective in the long run. As current therapy methods fail to slow disease development, novel strategies such as the development of a bioartificial pancreas are being seriously considered. Over the last decade, research has focused on tissue engineering, which aids in the design of biological alternatives for the repair and replacement of non-functional or damaged organs. Three dimensional (3D) bioprinting technology which employs 3D printing technology to generate 3D tissue-like structures from biomaterials and cells, offers a promising solution for the treatment of type 1 diabetes by providing the ability to generate functional endocrine pancreatic tissue. Bioprinted structures are therefore an important aspect of tissue engineering because they have been found to replicate the native extracellular matrix, promoting cell survival and proliferation. In this review, recent developments in 3D bioprinting of endocrine pancreas for the treatment of type 1 diabetes particularly focussing on the choice of cells, biomaterials, growth factors, and essential considerations have been discussed in detail. Additionally, the key challenges and perspectives towards recapitulation of the pancreatic function of the pancreatic organ engineering technologies have also been discussed.

The melatonin receptor agonist agomelatine protects against acute pancreatitis induced by cadmium by attenuating inflammation and oxidative stress and modulating Nrf2/HO-1 pathway

Pancreatitis is a serious effect of the heavy metal cadmium (Cd) and inflammation and oxidative stress (OS) are implicated in Cd-induced pancreatic injury. This study evaluated the effect of the melatonin receptor agonist agomelatine (AGM) on Cd-induced acute pancreatitis (AP), pointing to its modulatory effect on inflammation, OS, and Nrf2/HO-1 pathway. Rats were supplemented with AGM orally for 14 days and a single injection of cadmium chloride (CdCl2) on day 7. Cd increased serum amylase and lipase and caused pancreatic endocrine and exocrine tissue injury. Malondialdehyde (MDA), nitric oxide (NO) and myeloperoxidase (MPO) were elevated, nuclear factor (NF)-kB p65, inducible NO synthase (iNOS), interleukin (IL)-6, tumor necrosis factor (TNF)-α and CD40 were upregulated, and antioxidants were decreased in the pancreas of Cd-administered rats. AGM ameliorated serum amylase and lipase and pancreatic OS, NF-kB p65, CD40, pro-inflammatory mediators and caspase-3, prevented tissue injury and enhanced antioxidants. AGM downregulated Keap1 and enhanced Nrf2 and HO-1 in the pancreas of Cd-administered rats. In silico findings revealed the binding affinity of AGM with Keap1, HO-1, CD40L and caspase-3. In conclusion, AGM protected against AP induced by Cd by preventing inflammation, OS and apoptosis and modulating Nrf2/HO-1 pathway.

Rare Solid Pancreatic Lesions on Cross-Sectional Imaging.

Several solid lesions can be found within the pancreas mainly arising from the exocrine and endocrine pancreatic tissue. Among all pancreatic malignancies, the most common subtype is pancreatic ductal adenocarcinoma (PDAC), to a point that pancreatic cancer and PDAC are used interchangeably. But, in addition to PDAC, and to the other most common and well-known solid lesions, either related to benign conditions, such as pancreatitis, or not so benign, such as pancreatic neuroendocrine neoplasms (pNENs), there are solid pancreatic lesions considered rare due to their low incidence. These lesions may originate from a cell line with a differentiation other than exocrine/endocrine, such as from the nerve sheath as for pancreatic schwannoma or from mesenchymal cells as for solitary fibrous tumour. These rare solid pancreatic lesions may show a behaviour that ranges in a benign to highly aggressive malignant spectrum. This review includes cases of an intrapancreatic accessory spleen, pancreatic tuberculosis, solid serous cystadenoma, solid pseudopapillary tumour, pancreatic schwannoma, purely intraductal neuroendocrine tumour, pancreatic fibrous solitary tumour, acinar cell carcinoma, undifferentiated carcinoma with osteoclastic-like giant cells, adenosquamous carcinoma, colloid carcinoma of the pancreas, primary leiomyosarcoma of the pancreas, primary and secondary pancreatic lymphoma and metastases within the pancreas. Therefore, it is important to determine the correct diagnosis to ensure optimal patient management. Because of their rarity, their existence is less well known and, when depicted, in most cases incidentally, the correct diagnosis remains challenging. However, there are some typical imaging features present on cross-sectional imaging modalities that, taken into account with the clinical and biological context, contribute substantially to achieve the correct diagnosis.

Thrombospondin-1, CD47, and SIRPα display cell-specific molecular signatures in human islets and pancreata.

Thrombospondin-1 (TSP1) is a secreted protein minimally expressed in health but increased in disease and age. TSP1 binds to the cell membrane receptor CD47, which itself engages signal regulatory protein α (SIRPα), and the latter creates a checkpoint for immune activation. Individuals with cancer administered checkpoint-blocking molecules developed insulin-dependent diabetes. Relevant to this, CD47 blocking antibodies and SIRPα fusion proteins are in clinical trials. We characterized the molecular signature of TSP1, CD47, and SIRPα in human islets and pancreata. Fresh islets and pancreatic tissue from nondiabetic individuals were obtained. The expression of THBS1, CD47, and SIRPA was determined using single-cell mRNA sequencing, immunofluorescence microscopy, Western blot, and flow cytometry. Islets were exposed to diabetes-affiliated inflammatory cytokines and changes in protein expression were determined. CD47 mRNA was expressed in all islet cell types. THBS1 mRNA was restricted primarily to endothelial and mesenchymal cells, whereas SIRPA mRNA was found mostly in macrophages. Immunofluorescence staining showed CD47 protein expressed by β cells and present in the exocrine pancreas. TSP1 and SIRPα proteins were not seen in islets or the exocrine pancreas. Western blot and flow cytometry confirmed immunofluorescent expression patterns. Importantly, human islets produced substantial quantities of secreted TSP1. Human pancreatic exocrine and endocrine tissue expressed CD47, whereas fresh islets displayed cell surface CD47 and secreted TSP1 at baseline and in inflammation. These findings suggest unexpected effects on islets from agents that intersect TSP1-CD47-SIRPα.NEW & NOTEWORTHY CD47 is a cell surface receptor with two primary ligands, soluble thrombospondin-1 (TSP1) and cell surface signal regulatory protein alpha (SIRPα). Both interactions provide checkpoints for immune cell activity. We determined that fresh human islets display CD47 and secrete TSP1. However, human islet endocrine cells lack SIRPα. These gene signatures are likely important given the increasing use of CD47 and SIRPα blocking molecules in individuals with cancer.

Biomaterial-mediated strategies for accurate and convenient diagnosis, and effective treatment of diabetes: advantages, current progress and future perspectives.

As a kind of widespread chronic disease, diabetes potentially triggers serious complications, thereby severely threatening patients' life and health. To achieve the goal of more accurate and convenient diagnosis, and effective treatment of diabetes that what could be achieved based on traditional methods, many biomaterial-mediated strategies have been launched in recent studies, and have shown promising application potentials. In this review, we have systematically summarized the biomaterial-mediated diagnosis strategies in three parts including combined use of biomedical nanomaterials or organometallic compounds and Raman spectroscopy, utilization of gas sensors made of biomedical metal-oxides to detect glucose in exhaled gas, and detection of glucose by wearable sensors made of biomaterials with high sensitivity and conductivity, and the biomaterial-mediated treatment strategies in four parts including antidiabetic drug delivery by nanoparticles, transdermal drug delivery systems, gels and vesicles, and achieving insulin secretion by transplantation of pancreatic endocrine cells or tissue engineered islets. In particular, advantages of every strategy, current research progress, as well as the challenges and perspectives are elaborated. This review will certainly help to spark new ideas and possibilities for accurate and convenient diagnosis, and effective treatment of diabetes.

Research Advancements on Fluorinated and Non-Fluorinated 4- Phenyl(thio)ureido-Substituted 2,2-Dimethylchromans Acting as Inhibitors of Insulin Release and Smooth Muscle Relaxants.

The present study aimed at characterizing the impact of the presence or absence of fluorine atoms on the phenyl and benzopyran rings of 4-phenyl(thio)ureido-substituted 2,2- dimethylchromans on their ability to inhibit insulin release from pancreatic β-cells or to relax vascular smooth muscle cells. Most compounds were found to inhibit insulin secretion and to provoke a marked myorelaxant activity. The lack of a fluorine or chlorine atom at the 6-position of the 2,2-dimethylchroman core structure reduced the inhibitory activity on the pancreatic endocrine tissue. One of the most active compounds on both tissues, compound 11h (BPDZ 678), was selected for further pharmacological investigations. The biological data suggested that 11h mainly expressed the profile of a KATP channel opener on pancreatic β-cells, although a calcium entry blockade effect was also observed. On vascular smooth muscle cells, 11h behaved as a calcium entry blocker.

241.3: Generation of Prevascularized Endocrine Constructs to Treat Type 1 Diabetes

Introduction: The goal of our study was to generate a functional, prevascularized endocrine constructs utilizing amniotic membrane derived hydrogel, islets and blood outgrowth endothelial cells (BOECs) to be transplanted in diabetic hosts. Methods: Human amniotic membranes were dissected from placentas decellularized, lyophilized, and solubilized to obtain hydrogels. DNA quantification and scanning electron microscopy showed complete removal of cellular components and preserved extracellular matrix. Characterization studies demonstrated widespread distribution of all essential structural proteins, including collagen, GAGs and laminin. The islets and BOECs were admixed in amnion derived hydrogels and cultured in specially designed media to enhance endothelial cell assembly into tubular, vascular-like structures. Constructs were kept under culture for 3 days. Glucose stimulated insulin secretion (GSIS) tests showed an adequate insulin secretion in response to high glucose stimulation, confirming the functional activity of the prevascularized endocrine constructs. Results: To test in vivo biocompatibility and function, the vascularized constructs generated from 500 IEQ rat islets and 2× 105 human derived BOECs were implanted under the skin of the diabetic NSG mice. Transplantation of the constructs led to rapid and long-term (90 days) normalization of blood glucose levels. Removal of the grafts led to recurrence of hyperglycemia within 24 hours, indicating that the transplanted constructs was responsible for normalized glucose levels. Histological analysis of the explanted grafts revealed healthy islet morphology and perfect revascularization. Grafts stained positive for insulin and human specific CD 31 indicating presence of human endothelial cells in newly formed intra-islet micro vessels. Conclusion: Our findings show that amnion derived hydrogel seeded with endocrine pancreatic tissue and endothelial cells could be used for functional, preveascularized endocrine construct bioengineering. This work is supported by grants from the European Commission (Horizon 2020 Framework Program; VANGUARD grant 874700), the European Foundation for the Study of Diabetes (EFSD), the Juvenile Diabetes Research Foundation (JDRF; grant 3-SRA-2020-926-S-B) and the Shota Rustaveli National Science Foundation (grant FR-19-19760).

In mouse chronic pancreatitis CD25+FOXP3+ regulatory T cells control pancreatic fibrosis by suppression of the type 2 immune response

Chronic pancreatitis (CP) is characterized by chronic inflammation and the progressive fibrotic replacement of exocrine and endocrine pancreatic tissue. We identify Treg cells as central regulators of the fibroinflammatory reaction by a selective depletion of FOXP3-positive cells in a transgenic mouse model (DEREG-mice) of experimental CP. In Treg-depleted DEREG-mice, the induction of CP results in a significantly increased stroma deposition, the development of exocrine insufficiency and significant weight loss starting from day 14 after disease onset. In CP, FOXP3+CD25+ Treg cells suppress the type-2 immune response by a repression of GATA3+ T helper cells (Th2), GATA3+ innate lymphoid cells type 2 (ILC2) and CD206+ M2-macrophages. A suspected pathomechanism behind the fibrotic tissue replacement may involve an observed dysbalance of Activin A expression in macrophages and of its counter regulator follistatin. Our study identified Treg cells as key regulators of the type-2 immune response and of organ remodeling during CP. The Treg/Th2 axis could be a therapeutic target to prevent fibrosis and preserve functional pancreatic tissue.

Symptomatic heterotopic pancreas of the jejunum: A case report

Introduction: Heterotopic pancreatic (HP) tissue defined as tissue that is found outside the anatomical location of the pancreas. It can occur anywhere in the gastrointestinal tract with the stomach and small bowel being the most common sites. The diagnosis of HP is considered difficult and usually discovered as an incidental finding in laparotomy. However, it can present as a case of intussusception or even perforation. Case Presentation: In this case, we report a 23-year-old male with a history of abdominal pain with vomiting that lasted for 7 days. Computed tomography (CT) scan was suggestive of intussusception. Laparotomy was done and a mass was found adherent to the jejunal wall. Partial resection of the jejunum was performed including the mass. The histopathological analysis confirmed it to be mixed exocrine and endocrine heterotopic pancreatic tissue. Conclusion: Heterotopic pancreatic tissue in the jejunum is rare. However, it should be considered in the differential diagnosis of jejunal masses.

Emerging Classes of Small Non-Coding RNAs With Potential Implications in Diabetes and Associated Metabolic Disorders.

Most of the sequences in the human genome do not code for proteins but generate thousands of non-coding RNAs (ncRNAs) with regulatory functions. High-throughput sequencing technologies and bioinformatic tools significantly expanded our knowledge about ncRNAs, highlighting their key role in gene regulatory networks, through their capacity to interact with coding and non-coding RNAs, DNAs and proteins. NcRNAs comprise diverse RNA species, including amongst others PIWI-interacting RNAs (piRNAs), involved in transposon silencing, and small nucleolar RNAs (snoRNAs), which participate in the modification of other RNAs such as ribosomal RNAs and transfer RNAs. Recently, a novel class of small ncRNAs generated from the cleavage of tRNAs or pre-tRNAs, called tRNA-derived small RNAs (tRFs) has been identified. tRFs have been suggested to regulate protein translation, RNA silencing and cell survival. While for other ncRNAs an implication in several pathologies is now well established, the potential involvement of piRNAs, snoRNAs and tRFs in human diseases, including diabetes, is only beginning to emerge. In this review, we summarize fundamental aspects of piRNAs, snoRNAs and tRFs biology. We discuss their biogenesis while emphasizing on novel sequencing technologies that allow ncRNA discovery and annotation. Moreover, we give an overview of genomic approaches to decrypt their mechanisms of action and to study their functional relevance. The review will provide a comprehensive landscape of the regulatory roles of these three types of ncRNAs in metabolic disorders by reporting their differential expression in endocrine pancreatic tissue as well as their contribution to diabetes incidence and diabetes-underlying conditions such as inflammation. Based on these discoveries we discuss the potential use of piRNAs, snoRNAs and tRFs as promising therapeutic targets in metabolic disorders.

Hyperlipasemia and Potential Pancreatic Injury Patterns in COVID-19: A Marker of Severity or Innocent Bystander?

Hyperlipasemia and Potential Pancreatic Injury Patterns in COVID-19: A Marker of Severity or Innocent Bystander?

Potentials and Safety of Date Palm Fruit against Diabetes: A Critical Review.

Diabetes is a chronic metabolic disorder triggered by disturbances in carbohydrate, protein, and lipid metabolisms, where either reduced secretion or sensitivity of insulin is observed coupled with poor glucose control. Date palm fruits are one of the fruits reported to have good potential in diabetes treatment due to its presence of polyphenols exerting strong antioxidant activities. Other possible mechanisms of action include the polyphenolic compounds, which can inhibit enzymes like α-amylase and α-glucosidase. Flavonoids in dates can stimulate β-cells by increasing the number of islets and β-cells, recovering endocrine pancreatic tissues, reducing β-cell apoptosis, activating insulin receptors following the increase in insulin secretion, in addition to improving diabetes-induced complications. In this review, the in vitro, in vivo, and human study-based evidence of date palm as an anti-diabetic fruit is summarised.

Rb and p53 Execute Distinct Roles in the Development of Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PanNET) were classified into grades (G) 1 to 3 by the World Health Organization in 2017, but the precise mechanisms of PanNET initiation and progression have remained unclear. In this study, we used a genetically engineered mouse model to investigate the mechanisms of PanNET formation. Although pancreas-specific deletion of the Rb gene (Pdx1-Cre;Rbf/f ) in mice did not affect pancreatic exocrine cells, the α-cell/β-cell ratio of islet cells was decreased at 8 months of age. During long-term observation (18-20 months), mice formed well-differentiated PanNET with a Ki67-labeling index of 2.7%. In contrast, pancreas-specific induction of a p53 mutation (Pdx1-Cre;Trp53R172H ) had no effect on pancreatic exocrine and endocrine tissues, but simultaneous induction of a p53 mutation with Rb gene deletion (Pdx1-Cre;Trp53R172H;Rb f/f ) resulted in the formation of aggressive PanNET with a Ki67-labeling index of 24.7% over the short-term (4 months). In Pdx1-Cre;Trp53R172H;Rbf/f mice, mRNA expression of Pten and Tsc2, negative regulators of the mTOR pathway, significantly decreased in the islet cells, and activation of the mTOR pathway was confirmed in subsequently formed PanNET. Thus, by manipulating Rb and p53 genes, we established a multistep progression model from dysplastic islet to indolent PanNET and aggressive metastatic PanNET in mice. These observations suggest that Rb and p53 have distinct roles in the development of PanNET. SIGNIFICANCE: Pancreas-specific manipulation of Rb and p53 genes induced malignant transformation of islet cells, reproducing stepwise progression from microadenomas to indolent (grade 1) and subsequent aggressive PanNETs (grade 2-3).