Fic-mediated AMPylation tempers the unfolded protein response during physiological stress.

The proper balance of synthesis, folding, modification, and degradation of proteins, also known as protein homeostasis, is vital to cellular health and function. The unfolded protein response (UPR) is activated when the mechanisms maintaining protein homeostasis in the endoplasmic reticulum become overwhelmed. However, prolonged or strong UPR responses can result in elevated inflammation and cellular damage. Previously, we discovered that the enzyme filamentation induced by cyclic-AMP (Fic) can modulate the UPR response via posttranslational modification of binding immunoglobulin protein (BiP) by AMPylation during homeostasis and deAMPylation during stress. Loss of fic in Drosophila leads to vision defects and altered UPR activation in the fly eye. To investigate the importance of Fic-mediated AMPylation in a mammalian system, we generated a conditional null allele of Fic in mice and characterized the effect of Fic loss on the exocrine pancreas. Compared to controls, Fic-/- mice exhibit elevated serum markers for pancreatic dysfunction and display enhanced UPR signaling in the exocrine pancreas in response to physiological and pharmacological stress. In addition, both fic-/- flies and Fic-/- mice show reduced capacity to recover from damage by stress that triggers the UPR. These findings show that Fic-mediated AMPylation acts as a molecular rheostat that is required to temper the UPR response in the mammalian pancreas during physiological stress. Based on these findings, we propose that repeated physiological stress in differentiated tissues requires this rheostat for tissue resilience and continued function over the lifetime of an animal.

Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease.

Maturity-onset diabetes of the young type 5 (MODY5) is due to heterozygous mutations or deletion of HNF1B. No mouse models are currently available to recapitulate the human MODY5 disease. Here, we investigate the pancreatic phenotype of a unique MODY5 mouse model generated by heterozygous insertion of a human HNF1B splicing mutation at the intron-2 splice donor site in the mouse genome. This Hnf1bsp2/+ model generated with targeted mutation of Hnf1b mimicking the c.544+1G>T (T) mutation identified in humans, results in alternative transcripts and a 38% decrease of native Hnf1b transcript levels. As a clinical feature of MODY5 patients, the hypomorphic mouse model Hnf1bsp2/+ displays glucose intolerance. Whereas Hnf1bsp2/+ isolated islets showed no altered insulin secretion, we found a 65% decrease in pancreatic insulin content associated with a 30% decrease in total large islet volume and a 20% decrease in total ß-cell volume. These defects were associated with a 30% decrease in expression of the pro-endocrine gene Neurog3 that we previously identified as a direct target of Hnf1b, showing a developmental etiology. As another clinical feature of MODY5 patients, the Hnf1bsp2/+ pancreases display exocrine dysfunction with hypoplasia. We observed chronic pancreatitis with loss of acinar cells, acinar-to-ductal metaplasia, and lipomatosis, with upregulation of signaling pathways and impaired acinar cell regeneration. This was associated with ductal cell deficiency characterized by shortened primary cilia. Importantly, the Hnf1bsp2/+ mouse model reproduces the pancreatic features of the human MODY5/HNF1B disease, providing a unique in vivo tool for molecular studies of the endocrine and exocrine defects and to advance basic and translational research. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Pancreatic fat cells of humans with type 2 diabetes display reduced adipogenic and lipolytic activity.

Obesity, especially visceral fat accumulation, increases the risk of type 2 diabetes (T2D). The purpose of this study was to investigate the impact of T2D on the pancreatic fat depot. Pancreatic fat pads from 17 partial pancreatectomized patients (PPP) were collected, pancreatic preadipocytes isolated, and in vitro differentiated. Patients were grouped using HbA1c into normal glucose tolerant (NGT), prediabetic (PD), and T2D. Transcriptome profiles of preadipocytes and adipocytes were assessed by RNAseq. Insulin sensitivity was estimated by quantifying AKT phosphorylation on Western blots. Lipogenic capacity was assessed with oil red O staining, lipolytic activity via fatty acid release. Secreted factors were measured using ELISA. Comparative transcriptome analysis of preadipocytes and adipocytes indicates defective upregulation of genes governing adipogenesis (NR1H3), lipogenesis (FASN, SCD, ELOVL6, and FADS1), and lipolysis (LIPE) during differentiation of cells from T2D-PPP. In addition, the ratio of leptin/adiponectin mRNA was higher in T2D than in NGT-PPP. Preadipocytes and adipocytes of NGT-PPP were more insulin sensitive than T2D-PPP cells in regard to AKT phosphorylation. Triglyceride accumulation was similar in NGT and T2D adipocytes. Despite a high expression of the receptors NPR1 and NPR2 in NGT and T2D adipocytes, lipolysis was stimulated by ANP 1.74-fold in NGT cells only. This stimulation was further increased by the PDE5 inhibitor dipyridamole (3.09-fold). Dipyridamole and forskolin increased lipolysis receptor independently 1.88-fold and 1.48-fold, respectively, solely in NGT cells. In conclusion, the metabolic status persistently affects differentiation and lipolysis of pancreatic adipocytes. These alterations could aggravate the development of T2D.

Chronic binge alcohol and ovariectomy-mediated impaired insulin responsiveness in SIV-infected female rhesus macaques.

Aging people living with HIV (PLWH), especially postmenopausal women may be at higher risk of comorbidities associated with HIV, antiretroviral therapy (ART), hypogonadism, and at-risk alcohol use. Our studies in simian immunodeficiency virus (SIV)-infected male macaques demonstrated that chronic binge alcohol (CBA) reduced acute insulin response to glucose (AIRG), and at-risk alcohol use decreased HOMA-ß in PLWH. The objective of this study was to examine the impact of ovariectomy (OVX) on glucose-insulin dynamics and integrity of pancreatic endocrine function in CBA/SIV-infected female macaques. Female macaques were administered CBA (12-15 g/kg/wk) or isovolumetric water (VEH) intragastrically. Three months after initiation of CBA/VEH administration, all macaques were infected with SIVmac251, and initiated on antiretroviral therapy (ART) 2.5 mo postinfection. After 1 mo of ART, macaques were randomized to OVX or sham surgeries (n = 7 or 8/group), and euthanized 8 mo post-OVX (study endpoint). Frequently sampled intravenous glucose tolerance tests (FSIVGTT) were performed at selected time points. Pancreatic gene expression and islet morphology were determined at study endpoint. There was a main effect of CBA to decrease AIRG at Pre-SIV and study endpoint. There were no statistically significant OVX effects on AIRG (P = 0.06). CBA and OVX decreased the expression of pancreatic markers of insulin docking and release. OVX increased endoplasmic stress markers. CBA but not OVX impaired glucose-insulin expression dynamics in SIV-infected female macaques. Both CBA and OVX altered integrity of pancreatic endocrine function. These findings suggest increased vulnerability of PLWH to overt metabolic dysfunction that may be exacerbated by alcohol use and ovarian hormone loss.

The course and prognostic value of increased pancreas stiffness detected by ultrasound elastography during acute pancreatitis.

BACKGROUND: In this study, we determined the pancreatic stiffness (PS) changes in the course of acute pancreatitis (AP) by ultrasound elastography and evaluated its relation with prognosis. MATERIAL/METHODS: Pancreatic shear wave velocity measurements (SWM) were evaluated at the time of admission to the hospital, following clinical improvement, and one-month after for AP patients and compared to healthy volunteers. Its relationship with clinical severity indexes was evaluated. RESULTS: The pancreatic SWM value in the healthy group was 7.72 ± 2.50 kPa, and in AP group was 10.97 ± 2.26 kPa (p = 0.000). There was no difference between mild and severe pancreatitis. The mean SWM was 8.96 ± 1.53 kPa after disease remission, and 8.83 ± 1.24 kPa after 1-month. CONCLUSIONS: PS increases significantly during AP and decreases with clinical improvement, but this was still higher than controls, and it kept its elevation after 1-month. We think that larger, long-term studies are needed to determine the clinicopathological significance of this.

Acute pancreatitis in COVID-19 patients: true risk?

BACKGROUND: A relation between coronavirus disease 2019 (COVID-19) and acute pancreatitis has been suggested. However, the incidence and clinical relevance of this relation remain unclear. OBJECTIVE: We aimed to investigate the incidence, severity and clinical impact of acute pancreatitis in patients with COVID-19. METHODS: This is a cross-sectional study of a prospective, observational cohort concerning all COVID-19 patients admitted to two Dutch university hospitals between 4 March 2020 and 26 May 2020. Primary outcome was acute pancreatitis potentially related to COVD-19 infection. Acute pancreatitis was defined according to the revised Atlanta Classification. Potential relation with COVID-19 was defined as the absence of a clear aetiology of acute pancreatitis. RESULTS: Among 433 patients with COVID-19, five (1.2%) had potentially related acute pancreatitis according to the revised Atlanta Classification. These five patients suffered from severe COVID-19 infection; all had (multiple) organ failure and 60% died. None of the patients developed necrotizing pancreatitis. Moreover, development of acute pancreatitis did not lead to major treatment consequences. CONCLUSIONS: In contrast with previous research, our study demonstrated that COVID-19 related acute pancreatitis is rare and of little clinical impact. It is therefore debatable if acute pancreatitis in COVID-19 patients requires specific screening. We hypothesize that acute pancreatitis occurs in patients with severe illness due to COVID-19 infection as a result of transient hypoperfusion and pancreatic ischemia, not as a direct result of the virus.

A 2-Year Experience With Enhanced Recovery After Surgery: Evaluation of Compliance and Outcomes in Pancreatic Surgery.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) programs reduce recovery time, length of stay (LOS), and complications after major surgical procedures. PURPOSE: We evaluated our 2-year experience with a newly implemented comprehensive ERAS program at a high-volume center after pancreatic surgery. METHODS: Outcomes, cost, and compliance metrics were assessed in 215 patients who underwent elective pancreatic surgery (pre-ERAS; n = 99; post-ERAS: n = 116). Mann-Whitney U and χ2 tests were used to evaluate continuous and categorical variables. RESULTS: There were significant decreases in LOS and cost in the post-ERAS cohorts. There were significant increases in compliance with ERAS implementation. Postoperative complication, readmission, and survival rates did not increase. CONCLUSIONS: Implementation of ERAS at a large-volume hospital may improve compliance and reduce costs and LOS without increasing adverse outcomes.

Organisation of the human pancreas in health and in diabetes.

For much of the last century, our knowledge regarding the pancreas in type 1 and type 2 diabetes was largely derived from autopsy studies of individuals with these disorders or investigations utilising rodent models of either disease. While many important insights emanated from these efforts, the mode for investigation has increasingly seen change due to the availability of transplant-quality organ-donor tissues, improvements in pancreatic imaging, advances in metabolic assessments of living patients, genetic analyses, technological advances for laboratory investigation and more. As a result, many long-standing notions regarding the role for and the changes that occur in the pancreas in individuals with these disorders have come under question, while, at the same time, new issues (e.g., beta cell persistence, disease heterogeneity, exocrine contributions) have arisen. In this article, we will consider the vital role of the pancreas in human health and physiology, including discussion of its anatomical features and dual (exocrine and endocrine) functions. Specifically, we convey changes that occur in the pancreas of those with either type 1 or type 2 diabetes, with careful attention to the facets that may contribute to the pathogenesis of either disorder. Finally, we discuss the emerging unknowns with the belief that understanding the role of the pancreas in type 1 and type 2 diabetes will lead to improvements in disease diagnosis, understanding of disease heterogeneity and optimisation of treatments at a personalised level. Graphical abstract.

Angiotensin-converting enzyme 2 influences pancreatic and renal function in diabetic mice.

Type 1 diabetes is a T-cell mediated autoimmune disease characterized by pancreatic beta cells destruction. Angiotensin-converting enzyme 2 (ACE2), a component of renin-angiotensin system (RAS) has been identified in pancreas from type 2 diabetic mice and its overexpression prevents beta cell dysfunction. We studied the effect of ACE2 deletion on pancreatic and renal function in the nonobese diabetic mice, a model that mimics type 1 diabetes. ACE2-deficient NOD mice and the respective controls were generated. Pancreas function and immunohistochemistry studies were performed. Renal function and RAS gene expression were also analyzed. Renal proximal tubular cells were obtained from these animals to dissect the effect of ACE2 deficiency in these cells. In NOD mice, ACE2 deletion significantly worsened glucose homeostasis, decreased islet insulin content, increased beta cell oxidative stress, and RIPK1-positive islets as compared with control mice. Angiotensin-converting enzyme and angiotensin II type 1 receptor (AT1R) were also increased in ACE2-deficient mice. In kidneys of 30-day diabetic mice, ACE2 deletion decreased podocyte number within the glomeruli, and altered renal RAS gene expression in tubules. ACE2 deletion influenced the expression of fibrosis-related genes in isolated primary renal proximal tubular cells before diabetes onset in NOD mice. Our findings suggest that ACE2 deletion may have a deleterious impact on beta cell and renal function, by promoting oxidative stress and increasing necroptosis mediators. In addition, this effect is accompanied by RAS alterations in both pancreas and renal proximal tubular cells, indicating that ACE2 may exert a renopancreatic protective effect on type 1 diabetes, which is activated before diabetes starts.

Impaired Exocrine Pancreatic Function Associates With Changes in Intestinal Microbiota Composition and Diversity.

BACKGROUND & AIMS: Changes in intestinal microbiome composition are associated with inflammatory, metabolic, and malignant disorders. We studied how exocrine pancreatic function affects intestinal microbiota. METHODS: We performed 16S ribosomal RNA gene sequencing analysis of stool samples from 1795 volunteers from the population-based Study of Health in Pomerania who had no history of pancreatic disease. We also measured fecal pancreatic elastase by enzyme-linked immunosorbent assay and performed quantitative imaging of secretin-stimulated pancreatic fluid secretion. Associations of exocrine pancreatic function with microbial diversity or individual genera were calculated by permutational analysis of variance or linear regression, respectively. RESULTS: Differences in pancreatic elastase levels associated with significantly (P < .0001) greater changes in microbiota diversity than with participant age, body mass index, sex, smoking, alcohol consumption, or dietary factors. Significant changes in the abundance of 30 taxa, such as an increase in Prevotella (q < .0001) and a decrease of Bacteroides (q < .0001), indicated a shift from a type-1 to a type-2 enterotype. Changes in pancreatic fluid secretion alone were also associated with changes in microbial diversity (P = .0002), although to a lesser degree. CONCLUSIONS: In an analysis of fecal samples from 1795 volunteers, pancreatic acinar cell, rather than duct cell, function is presently the single most significant host factor to be associated with changes in intestinal microbiota composition.

Genetics, Cell Biology, and Pathophysiology of Pancreatitis.

Since the discovery of the first trypsinogen mutation in families with hereditary pancreatitis, pancreatic genetics has made rapid progress. The identification of mutations in genes involved in the digestive protease-antiprotease pathway has lent additional support to the notion that pancreatitis is a disease of autodigestion. Clinical and experimental observations have provided compelling evidence that premature intrapancreatic activation of digestive proteases is critical in pancreatitis onset. However, disease course and severity are mostly governed by inflammatory cells that drive local and systemic immune responses. In this article, we review the genetics, cell biology, and immunology of pancreatitis with a focus on protease activation pathways and other early events.

Central Pancreatectomy Versus Distal Pancreatectomy and Pancreaticoduodenectomy for Benign and Low-Grade Malignant Neoplasms: A Retrospective and Propensity Score-Matched Study with Long-Term Functional Outcomes and Pancreas Volumetry.

BACKGROUND: It remains controversial whether central pancreatectomy (CP) can preserve the exocrine and endocrine function of the pancreas or not. This study aimed to evaluate the safety and efficacy of CP compared with distal pancreatectomy (DP) and pancreaticoduodenectomy (PD) for benign and low-grade malignant neoplasms. METHODS: This retrospective study enrolled 219 patients who underwent elective CP (n = 55), DP (n = 70), or PD (n = 94) for benign and low-malignant neoplasms in a single university hospital between January 2000 and December 2015. Patients who underwent CP were propensity score matched to patients who underwent DP or PD at a 1:1 ratio, respectively. Peri- and postoperative outcomes, long-term endocrine/exocrine function, and pancreatic volume change 12 months postoperatively were prospectively evaluated. RESULTS: Of the 165 patients, 55 were included in each of the CP, DP, and PD groups. Significant differences between the CP and DP groups were observed in overall morbidity (CP: n = 18, 33% vs DP: n = 8, 14%; P = 0.041), clinically relevant postoperative pancreatic fistula (CP: n = 13, 24% vs DP: n = 4, 7%; P = 0.022), stool elastase level 12 months after surgery (CP: 151 µg/g vs DP: 245 µg/g; P = 0.003), and percentage change in the remnant pancreatic volume 12 months after surgery (CP: - 9.4% vs DP: + 7.5%; P < 0.001). CONCLUSIONS: The indications for CP to treat benign and low-grade malignant pancreatic neoplasms should be limited to cases in which the distal pancreatic volume can be considerably saved and PD can be prevented because CP has a higher postoperative morbidity without a marked functional superiority over DP.

Zinc: Roles in pancreatic physiology and disease.

Zinc is an essential trace element. Deficiencies are frequently seen with gastrointestinal diseases, including chronic pancreatitis, nutritional deficiency, and reduced intestinal absorption. Additionally, reduced zinc levels have been linked to cellular changes associated with acute pancreatitis such as enhanced inflammation with increased macrophage activation and production of inflammatory cytokines such as IL-1ß, impaired autophagy, and modulation of calcium homeostasis. Preliminary data suggest that zinc deficiency may lead to pancreatic injury in animal models. The purpose of this review is to explore the biologic effects of zinc deficiency that could impact pancreatic disease. MESH KEYWORDS: Malnutrition, inflammation, trace element.

Two cases of agenesis of the dorsal pancreas and a review of the literature.

BACKGROUND: Agenesis of the dorsal pancreas (ADP) is a very rare disease with no specific symptoms, and the pathogenesis is not clear. Some patients will be accompanied by other diseases, such as pancreatic tumor or pancreatitis. But most cases are very atypical and difficult to distinguish. Some syndromes of pancreatic exocrine insufficiency are common in patients with ADP. Here, we report two cases of ADP and summarize the clinical features, diagnosis, and treatment of ADP. CASE PRESENTATION: Case A is a 65-year-old Chinese woman who presented with abdominal pain accompanied by nausea, bloating and acid reflux. The enhanced abdominal CT scan found nothing meaningful except the absence of the body and tail of the pancreas. The diagnosis was considered as gastrointestinal dysfunction cause by exocrine pancreatic insufficiency and recovered after symptomatic treatment. Case B is a 61-year-old Chinese woman who presented with abdominal pain accompanied by fever, vomiting and bloating. The abdominal CT showed multiple stones in the gallbladder, and the body and tail of the patient's pancreas were absent. She was diagnosed with cholelithiasis and recovered after laparoscopic cholecystectomy. CONCLUSION: Agenesis of the dorsal pancreas (ADP) is a rare congenital disease with an unclear pathogenesis that presents multiple symptoms. It should be considered when the patients have non-specific, persistent and unexplained symptoms such as bloating or uncontrolled blood sugar. Imaging examination is helpful for diagnosis. And it does not require surgical intervention unless it accompanies other diseases, EPI need to be considered when the non-specific gastrointestinal symptoms appear.

Pancreatic Extracts for the Treatment of Diabetes (1889-1914): Acomatol.

BACKGROUND: Historical review on the early development of organotherapy for diabetes [pancreatic extracts (PE)] and its relationship with the social and political circumstances. AREAS OF UNCERTAINTY: The diagnosis of diabetes relied only in the presence of glycosuria and cardinal symptoms. Blood glucose determinations were not regularly available, requiring large volumes for sampling. Micromethods for glycemia were developed just in the last years of the investigated period. Hypoglycemia remains undiscovered. Isolation and purification of PE were difficult tasks due to the unknown chemical structure of the antidiabetic hormone. DATA SOURCES: (1) Berliner Medizinhistoriches Museum der Charité (Humboldt University). (2) GeDenKort Charité-Wissenschaft in Verantwortung. (3) Geheim Staatsarchiv Preußischer Kulturbesitz. (4) Archival Collections, University of Toronto: Thomas Fisher Rare Book Library. Academy of Medicine Collection, F. G. Banting Papers, C. H. Best Papers, J. J. R. Macleod Papers. (5) National Library of Medicine: Pubmed search for the topic of history of insulin. History of Medicine-on syllabus archive. (6) Selected books: The Discovery of Insulin (M. Bliss); Diabetes, Its Medical and Cultural History (D. von Engelhardt); Brown-Séquard (M. J. Aminoff); Diabetes: The Biography (R. Tattersall); The Endocrine Organs (E. Schäfer); The Internal Secretions (E. Gley); Health, race and German politics between national unification and Nazism, 1870-1945 (P. Weindling). THERAPEUTIC ADVANCES: Demonstration that diabetes is a pancreatic disease. The outstanding progress of medical physiology led to the birth of endocrinology and the key concepts of homeostasis. Experimental scientists designed new procedures for complete pancreatectomy and elaboration of PE containing the antidiabetic principle. Organotherapy achieved complete success in the treatment of myxedema and partial success in the treatment of experimental and clinical diabetes. CONCLUSIONS: The organotherapy of diabetes was an obliged step to facilitate the identification of the antidiabetic hormone. Organotherapy of diabetes was a paradigm for the integration of basic and applied knowledge about hormone action and development of endocrine pharmacology.

Maternal Roux-en-Y gastric bypass impairs insulin action and endocrine pancreatic function in male F1 offspring.

PURPOSE: Obesity is predominant in women of reproductive age. Roux-en-Y gastric bypass (RYGB) is the most common bariatric procedure that is performed in obese women for weight loss and metabolic improvement. However, some studies suggest that this procedure negatively affects offspring. Herein, using Western diet (WD)-obese female rats, we investigated the effects of maternal RYGB on postnatal body development, glucose tolerance, insulin secretion and action in their adult male F1 offspring. METHODS: Female Wistar rats consumed a Western diet (WD) for 18 weeks, before being submitted to RYGB (WD-RYGB) or SHAM (WD-SHAM) operations. After 5 weeks, WD-RYGB and WD-SHAM females were mated with control male breeders, and the F1 offspring were identified as: WD-RYGB-F1 and WD-SHAM-F1. RESULTS: The male F1 offspring of WD-RYGB dams exhibited decreased BW, but enhanced total nasoanal length gain. At 120 days of age, WD-RYGB-F1 rats displayed normal fasting glycemia and glucose tolerance but demonstrated reduced insulinemia and higher glucose disappearance after insulin stimulus. In addition, these rodents presented insulin resistance in the gastrocnemius muscle and retroperitoneal fat, as judged by lower Akt phosphorylation after insulin administration, but an increase in this protein in the liver. Finally, the islets from WD-RYGB-F1 rats secreted less insulin in response to glucose and displayed increased ß-cell area and mass. CONCLUSIONS: RYGB in WD dams negatively affected their F1 offspring, leading to catch-up growth, insulin resistance in skeletal muscle and white fat, and ß-cell dysfunction. Therefore, our data are the first to demonstrate that the RYGB in female rats may aggravate the metabolic imprinting induced by maternal WD consumption, in their male F1 descendants. However, since we only used male F1 rats, further studies are necessary to demonstrate if such effect may also occur in female F1 offspring from dams that underwent RYGB operation.

Pancreatic Disorders of Pregnancy.

The pancreas is an organ with both exocrine and endocrine functions that has a vital role in both digestion as well as glucose metabolism. Although pancreatic dysfunction and disorders are rare in pregnancy, they are becoming increasingly more common. Recognition of these disorders and understanding how they can affect pregnancy is imperative to allow for proper management. We provide an overview of the most common pancreatic disorders that are seen in pregnancy.

CRABP2 and FABP5 expression levels in diseased and normal pancreas.

Recently, stromal targeting, by agents such as All trans retinoic acid (ATRA), has been regarded as a promising avenue for the treatment of pancreatic ductal adenocarcinoma (PDAC). The intra-cellular transportation of ATRA to the nuclear receptors is performed by either: fatty acid binding protein 5 (FABP5) or cellular retinoic acid binding protein 2 (CRABP2), dictating the transcription of downstream genes and, thus, eventual cell phenotype. Here, we explored the levels of each protein, in pancreatic tissues of patients presenting with a range of pancreatic diseases (pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP), cholangiocarcinoma (CC)). We demonstrate that there is a significantly lower CRABP2 and FABP5 expression in activated fibroblasts or pancreatic stellate cells (PSC) in PDAC, as well as other diseased pancreas as in CC and CP, versus quiescent fibroblasts. The quiescent fibroblasts consistently show a pattern of high FABP5:CRABP2 ratio, whereas PSC in all non-PDAC tissues showed a low FABP5:CRABP2 ratio. PSC in PDAC patients had a range of FABP5:CRABP2 ratios (high, even and low). There was a lower CRABP2 expression in cancerous epithelial cells (PDAC) versus normal epithelial cells. This is also present in other disease states (CP, CC). Contrasting to the patterns seen for fibroblasts, the FABP5 expression in PDAC epithelial cells matched that of the normal epithelial cells. However, the normal epithelial cells had a high FABP5:CRABP2 ratio, compared to the PDAC epithelial cells. These ratios may have correlation with tumor progression, and overall survival. These findings could be confirmed in in vitro cell lysates. CRABP2 and FABP5 levels and ratios could serve as valuable biomarkers.

[Pancreatic arteriovenous malformations†: from pathophysiology to therapy]. / Malformations artérioveineuses pancréatiques†: de la physiopathologie à la prise en charge.

Pancreatic arteriovenous malformations are rare conditions, mostly asymptomatic and increasingly diagnosed incidentally. Once symptomatic, patients can present with non specific abdominal pain, potentially life-threatening gastrointestinal bleeding, acute pancreatitis or portal hypertension. The aim of this article is to present the pathophysiology underlying this type of vascular malformation, to discuss its diagnostic modalities and the therapeutic options described to date in the literature.

Les malformations artérioveineuses pancréatiques sont rares, asymptomatiques dans la majorité des cas et de plus en plus souvent découvertes de manière fortuite. Elles peuvent toutefois être à l'origine de douleurs abdominales peu spécifiques, de saignements gastro-intestinaux potentiellement sévères, d'une pancréatite ou d'une hypertension portale. L'objectif de cet article est de présenter la physiopathologie sous-tendant ce type de malformation vasculaire, d'en discuter les modalités diagnostiques ainsi que les possibilités thérapeutiques décrites à ce jour dans la littérature.

Rationale for enteroviral vaccination and antiviral therapies in human type 1 diabetes.

In type 1 diabetes, pancreatic beta cells are destroyed by chronic autoimmune responses. The disease develops in genetically susceptible individuals, but a role for environmental factors has been postulated. Viral infections have long been considered as candidates for environmental triggers but, given the lack of evidence for an acute, widespread, cytopathic effect in the pancreas in type 1 diabetes or for a closely related temporal association of diabetes onset with such infections, a role for viruses in type 1 diabetes remains unproven. Moreover, viruses have rarely been isolated from the pancreas of individuals with type 1 diabetes, mainly (but not solely) due to the inaccessibility of the organ. Here, we review past and recent literature to evaluate the proposals that chronic, recurrent and, possibly, persistent enteroviral infections occur in pancreatic beta cells in type 1 diabetes. We also explore whether these infections may be sustained by different virus strains over time and whether multiple viral hits can occur during the natural history of type 1 diabetes. We emphasise that only a minority of beta cells appear to be infected at any given time and that enteroviruses may become replication defective, which could explain why they have been isolated from the pancreas only rarely. We argue that enteroviral infection of beta cells largely depends on the host innate and adaptive immune responses, including innate responses mounted by beta cells. Thus, we propose that viruses could play a role in type 1 diabetes on multiple levels, including in the triggering and chronic stimulation of autoimmunity and in the generation of inflammation and the promotion of beta cell dysfunction and stress, each of which might then contribute to autoimmunity, as part of a vicious circle. We conclude that studies into the effects of vaccinations and/or antiviral drugs (some of which are currently on-going) is the only means by which the role of viruses in type 1 diabetes can be finally proven or disproven.