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Physiological Reviews Oct 2021This review deals with the roles of calcium ions and ATP in the control of the normal functions of the different cell types in the exocrine pancreas as well as the roles... (Review)
Review
This review deals with the roles of calcium ions and ATP in the control of the normal functions of the different cell types in the exocrine pancreas as well as the roles of these molecules in the pathophysiology of acute pancreatitis. Repetitive rises in the local cytosolic calcium ion concentration in the apical part of the acinar cells not only activate exocytosis but also, via an increase in the intramitochondrial calcium ion concentration, stimulate the ATP formation that is needed to fuel the energy-requiring secretion process. However, intracellular calcium overload, resulting in a global sustained elevation of the cytosolic calcium ion concentration, has the opposite effect of decreasing mitochondrial ATP production, and this initiates processes that lead to necrosis. In the last few years it has become possible to image calcium signaling events simultaneously in acinar, stellate, and immune cells in intact lobules of the exocrine pancreas. This has disclosed processes by which these cells interact with each other, particularly in relation to the initiation and development of acute pancreatitis. By unraveling the molecular mechanisms underlying this disease, several promising therapeutic intervention sites have been identified. This provides hope that we may soon be able to effectively treat this often fatal disease.
Topics: Adenosine Triphosphate; Animals; Calcium; Calcium Signaling; Humans; Pancreas, Exocrine; Pancreatic Diseases
PubMed: 33949875
DOI: 10.1152/physrev.00003.2021 -
Clinica Chimica Acta; International... Dec 2020Although the pathophysiological mechanisms and consequences of gross derangements in iron metabolism are well known, little is known about the pathophysiological... (Review)
Review
Although the pathophysiological mechanisms and consequences of gross derangements in iron metabolism are well known, little is known about the pathophysiological mechanisms underlying mild-to-moderate alterations in iron metabolism and their consequences. Growing evidence indicates that the exocrine pancreas has a bidirectional relationship with iron metabolism. Studies have shown alterations in circulating markers of iron metabolism, iron absorption, and intra-pancreatic iron deposition in pancreatitis. At the same time, exocrine pancreatic dysfunction has been shown in iron overload disorders. These observations reveal a compelling connection between the exocrine pancreas and iron metabolism, which are further elucidated by observations of therapeutic benefits of iron chelating agents and pancreatic enzyme replacement therapy. While the pancreas is not a major reservoir of iron in the body, better understanding of its relationship with iron metabolism may yield unexpected insights.
Topics: Humans; Iron; Pancreas; Pancreas, Exocrine; Pancreatitis
PubMed: 33058846
DOI: 10.1016/j.cca.2020.10.013 -
Cell Metabolism Sep 2023Type 1 diabetes (T1D) is widely considered to result from the autoimmune destruction of insulin-producing β cells. This concept has been a central tenet for decades of... (Review)
Review
Type 1 diabetes (T1D) is widely considered to result from the autoimmune destruction of insulin-producing β cells. This concept has been a central tenet for decades of attempts seeking to decipher the disorder's pathogenesis and prevent/reverse the disease. Recently, this and many other disease-related notions have come under increasing question, particularly given knowledge gained from analyses of human T1D pancreas. Perhaps most crucial are findings suggesting that a collective of cellular constituents-immune, endocrine, and exocrine in origin-mechanistically coalesce to facilitate T1D. This review considers these emerging concepts, from basic science to clinical research, and identifies several key remaining knowledge voids.
Topics: Humans; Diabetes Mellitus, Type 1; Pancreas, Exocrine; Pancreas; Insulin-Secreting Cells; Immune System; Islets of Langerhans
PubMed: 37478842
DOI: 10.1016/j.cmet.2023.06.018 -
Reviews in Endocrine & Metabolic... Jun 2019In the last 10 years, several studies have shown that the pancreas of patients with type 1 diabetes (T1D), and even of subjects at risk for T1D, was smaller than the... (Review)
Review
In the last 10 years, several studies have shown that the pancreas of patients with type 1 diabetes (T1D), and even of subjects at risk for T1D, was smaller than the pancreas from healthy subjects. This arose the question of the relationships between the endocrine and exocrine parts of the pancreas in T1D pathogenesis. Our review underlines that histological anomalies of the exocrine pancreas are common in patients with T1D: intralobular and interacinar fibrosis, acinar atrophy, fatty infiltration, leucocytic infiltration, and pancreatic arteriosclerosis are all frequent observations. Moreover, 25% to 75% of adult patients with T1D present with pancreatic exocrine dysfunction. Our review summarizes the putative causal factors for these structural and functional anomalies, including: 1/ alterations of insulin, glucagon, somatostatin and pancreatic polypeptide secretion, 2/ global pancreatic inflammation 3/ autoimmunity targeting the exocrine pancreas, 4/ vascular and neural abnormalities, and 5/ the putative involvement of pancreatic stellate cells. These observations have also given rise to new theories on T1D: the primary event of T1D pathogenesis could be non-specific, e.g bacterial or viral or chemical, resulting in global pancreatic inflammation, which in turn could cause beta-cell predominant destruction by the immune system. Finally, this review emphasizes that it is advisable to evaluate pancreatic exocrine function in patients with T1D presenting with gastro-intestinal complaints, as a clinical trial has shown that pancreatic enzymes replacement therapy can reduce the frequency of hypoglycemia and thus might improve quality of life in subjects with T1D and exocrine failure.
Topics: Diabetes Mellitus, Type 1; Humans; Pancreas, Exocrine; Pancreatic Elastase
PubMed: 31077020
DOI: 10.1007/s11154-019-09501-3 -
Frontiers in Endocrinology 2022
Topics: Islets of Langerhans; Pancreas; Pancreas, Exocrine
PubMed: 35966106
DOI: 10.3389/fendo.2022.967066 -
Autophagy Nov 2020Pancreatitis is a common, sometimes fatal, disease of exocrine pancreas, initiated by damaged acinar cells. Recent studies implicate disordered macroautophagy/autophagy...
Pancreatitis is a common, sometimes fatal, disease of exocrine pancreas, initiated by damaged acinar cells. Recent studies implicate disordered macroautophagy/autophagy in pancreatitis pathogenesis. ATG8/LC3 protein is critical for autophagosome formation and a widely used marker of autophagic vacuoles. Transgenic GFP-LC3 mice are a valuable tool to investigate autophagy ; however, comparison of homeostatic and disease responses between GFP-LC3 and wild-type (WT) mice has not been done. We examined the effects of GFP-LC3 expression on autophagy, acinar cell function, and experimental pancreatitis. Unexpectedly, GFP-LC3 expression markedly increased endogenous LC3-II level in pancreas, caused by downregulation of ATG4B, the protease that deconjugates/delipidates LC3-II. By contrast, GFP-LC3 expression had lesser or no effect on autophagy in liver, lung and spleen. Autophagic flux analysis showed that autophagosome formation in GFP-LC3 acinar cells increased 3-fold but was not fully counterbalanced by increased autophagic degradation. Acinar cell () pancreatitis inhibited autophagic flux in WT and essentially blocked it in GFP-LC3 cells. pancreatitis caused autophagy impairment in WT mice, manifest by upregulation of LC3-II and SQSTM1/p62, increased number and size of autophagic vacuoles, and decreased level of TFEB, all of which were exacerbated in GFP-LC3 mice. GFP-LC3 expression affected key pancreatitis responses; most dramatically, it worsened increases in serum AMY (amylase), a diagnostic marker of acute pancreatitis, in several mouse models. The results emphasize physiological importance of autophagy for acinar cell function, demonstrate organ-specific effects of GFP-LC3 expression, and indicate that application of GFP-LC3 mice in disease models should be done with caution.: AP: acute pancreatitis; Arg-AP: L-arginine-induced acute pancreatitis; ATG: autophagy-related (protein); AVs: autophagic vacuoles; CCK: cholecystokinin-8; CDE: choline-deficient, D,L-ethionine supplemented diet; CER: caerulein (ortholog of CCK); CTSB: cathepsin B; CTSD: cathepsin D; CTSL: cathepsin L; ER: endoplasmic reticulum; LAMP: lysosomal-associated membrane protein; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; TEM: transmission electron microscopy; TFEB: transcription factor EB; ZG: zymogen granule(s).
Topics: Acinar Cells; Animals; Autophagosomes; Autophagy; Disease Models, Animal; Endoplasmic Reticulum; Lysosomes; Mice, Transgenic; Pancreas, Exocrine; Pancreatitis
PubMed: 31942816
DOI: 10.1080/15548627.2020.1715047 -
Advances in Experimental Medicine and... 2010
Review
Topics: Animals; Humans; Islets of Langerhans; Pancreas; Pancreas, Exocrine; Pancreatic Ducts
PubMed: 20700835
DOI: 10.1007/978-90-481-9060-7_2 -
Cellular and Molecular Gastroenterology... 2021Differences in pancreatic anatomy, size, and function exist in men and women. The anatomical differences could contribute to the increase in complications associated... (Review)
Review
Differences in pancreatic anatomy, size, and function exist in men and women. The anatomical differences could contribute to the increase in complications associated with pancreatic surgery in women. Although diagnostic criteria for pancreatitis are the same in men and women, major sex differences in etiology are reported. Alcohol and tobacco predominate in men, whereas idiopathic and obstructive etiologies predominate in women. Circulating levels of estrogens, progesterone, and androgens contribute significantly to overall health outcomes; premenopausal women have lower prevalence of cardiovascular and pancreatic diseases suggesting protective effects of estrogens, whereas androgens promote growth of normal and cancerous cells. Sex chromosomes and gonadal and nongonadal hormones together determine an individual's sex, which is distinct from gender or gender identity. Human pancreatic disease etiology, outcomes, and sex-specific mechanisms are largely unknown. In rodents of both sexes, glucocorticoids and estrogens from the adrenal glands influence pancreatic secretion and acinar cell zymogen granule numbers. Lack of corticotropin-releasing factor receptor 2 function, a G protein-coupled receptor whose expression is regulated by both estrogens and glucocorticoids, causes sex-specific changes in pancreatic histopathology, zymogen granule numbers, and endoplasmic reticulum ultrastructure changes in acute pancreatitis model. Here, we review existing literature on sex differences in the normal exocrine pancreas and mechanisms that operate at homeostasis and diseased states in both sexes. Finally, we review pregnancy-related pancreatic diseases and discuss the effects of sex differences on proposed treatments in pancreatic disease.
Topics: COVID-19; Female; Hormones; Humans; Male; Pancreas, Exocrine; Pancreatic Diseases; Pregnancy; Sex Characteristics
PubMed: 33895424
DOI: 10.1016/j.jcmgh.2021.04.005 -
Seminars in Ultrasound, CT, and MR Dec 2019Numerous other solid primary neoplasms may arise from the pancreas besides primary ductal adenocarcinomas and neuroendocrine tumors. Although diagnosis can be difficult... (Review)
Review
Numerous other solid primary neoplasms may arise from the pancreas besides primary ductal adenocarcinomas and neuroendocrine tumors. Although diagnosis can be difficult because of the very low incidence of these tumors, knowledge of several, typical, epidemiologic, biological, and imaging features can help obtain a correct diagnosis. This pictorial review describes the features of solid rare primary pancreatic neoplasms on computed tomography and magnetic resonance imaging focusing on characteristics that can help radiologists differentiate them from classical forms of ductal pancreatic adenocarcinoma and neuroendocrine tumors. Cystic pancreatic neoplasms are beyond the scope of the current review.
Topics: Contrast Media; Diagnosis, Differential; Humans; Magnetic Resonance Imaging; Pancreas, Exocrine; Pancreatic Neoplasms; Tomography, X-Ray Computed
PubMed: 31806147
DOI: 10.1053/j.sult.2019.04.007 -
Annual Review of Physiology 2015Pancreatitis is caused by inflammatory injury to the exocrine pancreas, from which both humans and animal models appear to recover via regeneration of digestive... (Review)
Review
Pancreatitis is caused by inflammatory injury to the exocrine pancreas, from which both humans and animal models appear to recover via regeneration of digestive enzyme-producing acinar cells. This regenerative process involves transient phases of inflammation, metaplasia, and redifferentiation, driven by cell-cell interactions between acinar cells, leukocytes, and resident fibroblasts. The NFκB signaling pathway is a critical determinant of pancreatic inflammation and metaplasia, whereas a number of developmental signals and transcription factors are devoted to promoting acinar redifferentiation after injury. Imbalances between these proinflammatory and prodifferentiation pathways contribute to chronic pancreatitis, characterized by persistent inflammation, fibrosis, and acinar dedifferentiation. Loss of acinar cell differentiation also drives pancreatic cancer initiation, providing a mechanistic link between pancreatitis and cancer risk. Unraveling the molecular bases of exocrine regeneration may identify new therapeutic targets for treatment and prevention of both of these deadly diseases.
Topics: Acinar Cells; Animals; Cell Differentiation; Disease Models, Animal; Humans; Pancreas, Exocrine; Pancreatic Neoplasms; Pancreatitis; Regeneration; Signal Transduction
PubMed: 25386992
DOI: 10.1146/annurev-physiol-021014-071727