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Nature May 2018The pancreas is made from two distinct components: the exocrine pancreas, a reservoir of digestive enzymes, and the endocrine islets, the source of the vital metabolic... (Review)
Review
The pancreas is made from two distinct components: the exocrine pancreas, a reservoir of digestive enzymes, and the endocrine islets, the source of the vital metabolic hormone insulin. Human islets possess limited regenerative ability; loss of islet β-cells in diseases such as type 1 diabetes requires therapeutic intervention. The leading strategy for restoration of β-cell mass is through the generation and transplantation of new β-cells derived from human pluripotent stem cells. Other approaches include stimulating endogenous β-cell proliferation, reprogramming non-β-cells to β-like cells, and harvesting islets from genetically engineered animals. Together these approaches form a rich pipeline of therapeutic development for pancreatic regeneration.
Topics: Adult Stem Cells; Animals; Cell Proliferation; Cellular Reprogramming; Humans; Islets of Langerhans; Pancreas; Pluripotent Stem Cells; Regeneration; Regenerative Medicine
PubMed: 29769672
DOI: 10.1038/s41586-018-0088-0 -
The Korean Journal of Internal Medicine Jan 2021Diabetes following acute pancreatitis (AP) is becoming increasingly recognized. It is unclear what subtype of diabetes mellitus (DM) occurs; however, type 3c diabetes... (Review)
Review
Diabetes following acute pancreatitis (AP) is becoming increasingly recognized. It is unclear what subtype of diabetes mellitus (DM) occurs; however, type 3c diabetes mellitus (T3cDM) is gaining increasing recognition. T3cDM has differing pathophysiology than other subtypes of DM and therefore differing disease course and treatment. Current studies have examined the incidence and prevalence of DM following AP, and meta-analyses have shown around 15% develop DM at 1 year with an increasing proportion developing DM at 5 years. It has been observed that some patients have transient hyperglycemia following AP episode with a subset developing persistent impaired glucose metabolism; however, the exact timeline is not well defined. The data on risk factors for developing DM after AP is limited and mixed; however, it is likely that severity of AP may impact the propensity to develop DM. Screening guidelines have not been established following AP; however, screening 1-year post-event will likely capture a sizable proportion of newly developed DM. The endocrine and exocrine pancreas are closely linked, and studies have found significant overlap in dysfunction of both after AP. Finally, there are some data to suggest that diabetes predisposes patients to structural changes in the pancreas and increased risk of developing AP.
Topics: Acute Disease; Diabetes Mellitus; Humans; Pancreas; Pancreatitis; Risk Factors
PubMed: 33147904
DOI: 10.3904/kjim.2020.505 -
Diabetologia Oct 2020For 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... (Review)
Review
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.
Topics: Adipose Tissue; Amyloidosis; Autoimmunity; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon-Secreting Cells; Humans; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Islets of Langerhans; Pancreas; Pancreas, Exocrine; Somatostatin-Secreting Cells
PubMed: 32894306
DOI: 10.1007/s00125-020-05203-7 -
Experimental & Molecular Medicine Mar 2016In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated... (Review)
Review
In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated network of various hormones and neuropeptides released mainly from the brain, pancreas, liver, intestine as well as adipose and muscle tissue. Within this network, the pancreas represents a key player by secreting the blood sugar-lowering hormone insulin and its opponent glucagon. However, disturbances in the interplay of the hormones and peptides involved may lead to metabolic disorders such as type 2 diabetes mellitus (T2DM) whose prevalence, comorbidities and medical costs take on a dramatic scale. Therefore, it is of utmost importance to uncover and understand the mechanisms underlying the various interactions to improve existing anti-diabetic therapies and drugs on the one hand and to develop new therapeutic approaches on the other. This review summarizes the interplay of the pancreas with various other organs and tissues that maintain glucose homeostasis. Furthermore, anti-diabetic drugs and their impact on signaling pathways underlying the network will be discussed.
Topics: Animals; Cell Communication; Diabetes Mellitus, Type 2; Glucose; Homeostasis; Humans; Insulin; Islets of Langerhans; Pancreas; Pancreas, Exocrine; Signal Transduction
PubMed: 26964835
DOI: 10.1038/emm.2016.6 -
Lancet (London, England) May 2016Chronic pancreatitis describes a wide spectrum of fibro-inflammatory disorders of the exocrine pancreas that includes calcifying, obstructive, and steroid-responsive... (Review)
Review
Chronic pancreatitis describes a wide spectrum of fibro-inflammatory disorders of the exocrine pancreas that includes calcifying, obstructive, and steroid-responsive forms. Use of the term chronic pancreatitis without qualification generally refers to calcifying chronic pancreatitis. Epidemiology is poorly defined, but incidence worldwide seems to be on the rise. Smoking, drinking alcohol, and genetic predisposition are the major risk factors for chronic calcifying pancreatitis. In this Seminar, we discuss the clinical features, diagnosis, and management of chronic calcifying pancreatitis, focusing on pain management, the role of endoscopic and surgical intervention, and the use of pancreatic enzyme-replacement therapy. Management of patients is often challenging and necessitates a multidisciplinary approach.
Topics: Alcohol Drinking; Analgesics; Calcinosis; Endoscopy, Digestive System; Exocrine Pancreatic Insufficiency; Genetic Predisposition to Disease; Humans; Magnetic Resonance Imaging; Pain; Pancreatitis, Chronic; Risk Factors; Smoking; Tomography, X-Ray Computed
PubMed: 26948434
DOI: 10.1016/S0140-6736(16)00097-0 -
The Lancet. Gastroenterology &... Nov 2016Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin... (Review)
Review
Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. It is important to note that type 3c diabetes is not a single entity; it occurs because of a variety of exocrine pancreatic diseases with varying mechanisms of hyperglycaemia. The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. In this Review, we discuss the epidemiology, pathogenesis, and clinical relevance of type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma, and highlight several important knowledge gaps.
Topics: Carcinoma, Pancreatic Ductal; Diabetes Mellitus; Humans; Pancreatic Neoplasms; Pancreatitis, Chronic
PubMed: 28404095
DOI: 10.1016/S2468-1253(16)30106-6 -
Islets 2015Mice remain the most studied animal model in pancreas research. Since the findings of this research are typically extrapolated to humans, it is important to understand... (Review)
Review
Mice remain the most studied animal model in pancreas research. Since the findings of this research are typically extrapolated to humans, it is important to understand both similarities and differences between the 2 species. Beside the apparent difference in size and macroscopic organization of the organ in the 2 species, there are a number of less evident and only recently described differences in organization of the acinar and ductal exocrine tissue, as well as in the distribution, composition, and architecture of the endocrine islets of Langerhans. Furthermore, the differences in arterial, venous, and lymphatic vessels, as well as innervation are potentially important. In this article, the structure of the human and the mouse pancreas, together with the similarities and differences between them are reviewed in detail in the light of conceivable repercussions for basic research and clinical application.
Topics: Animals; Disease Models, Animal; Humans; Insulin-Secreting Cells; Islets of Langerhans; Mice; Pancreas
PubMed: 26030186
DOI: 10.1080/19382014.2015.1024405 -
Nature Jun 2021Genetic risk variants that have been identified in genome-wide association studies of complex diseases are primarily non-coding. Translating these risk variants into...
Genetic risk variants that have been identified in genome-wide association studies of complex diseases are primarily non-coding. Translating these risk variants into mechanistic insights requires detailed maps of gene regulation in disease-relevant cell types. Here we combined two approaches: a genome-wide association study of type 1 diabetes (T1D) using 520,580 samples, and the identification of candidate cis-regulatory elements (cCREs) in pancreas and peripheral blood mononuclear cells using single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) of 131,554 nuclei. Risk variants for T1D were enriched in cCREs that were active in T cells and other cell types, including acinar and ductal cells of the exocrine pancreas. Risk variants at multiple T1D signals overlapped with exocrine-specific cCREs that were linked to genes with exocrine-specific expression. At the CFTR locus, the T1D risk variant rs7795896 mapped to a ductal-specific cCRE that regulated CFTR; the risk allele reduced transcription factor binding, enhancer activity and CFTR expression in ductal cells. These findings support a role for the exocrine pancreas in the pathogenesis of T1D and highlight the power of large-scale genome-wide association studies and single-cell epigenomics for understanding the cellular origins of complex disease.
Topics: Chromatin; Cystic Fibrosis Transmembrane Conductance Regulator; Diabetes Mellitus, Type 1; Epigenomics; Female; Gene Expression Regulation; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Immunity; Male; Pancreatic Ducts; Single-Cell Analysis
PubMed: 34012112
DOI: 10.1038/s41586-021-03552-w -
Cell Metabolism Jan 2023Current differentiation protocols have not been successful in reproducibly generating fully functional human beta cells in vitro, partly due to incomplete understanding...
Current differentiation protocols have not been successful in reproducibly generating fully functional human beta cells in vitro, partly due to incomplete understanding of human pancreas development. Here, we present detailed transcriptomic analysis of the various cell types of the developing human pancreas, including their spatial gene patterns. We integrated single-cell RNA sequencing with spatial transcriptomics at multiple developmental time points and revealed distinct temporal-spatial gene cascades. Cell trajectory inference identified endocrine progenitor populations and branch-specific genes as the progenitors differentiate toward alpha or beta cells. Spatial differentiation trajectories indicated that Schwann cells are spatially co-located with endocrine progenitors, and cell-cell connectivity analysis predicted that they may interact via L1CAM-EPHB2 signaling. Our integrated approach enabled us to identify heterogeneity and multiple lineage dynamics within the mesenchyme, showing that it contributed to the exocrine acinar cell state. Finally, we have generated an interactive web resource for investigating human pancreas development for the research community.
Topics: Humans; Transcriptome; Pancreas; Gene Expression Profiling; Cell Differentiation; Pancreas, Exocrine; Single-Cell Analysis; Gene Expression Regulation, Developmental
PubMed: 36513063
DOI: 10.1016/j.cmet.2022.11.009 -
Gastroenterology May 2019Acute pancreatitis is an inflammatory disorder of the exocrine pancreas associated with tissue injury and necrosis. The disease can be mild, involving only the pancreas,... (Review)
Review
Acute pancreatitis is an inflammatory disorder of the exocrine pancreas associated with tissue injury and necrosis. The disease can be mild, involving only the pancreas, and resolve spontaneously within days or severe, with systemic inflammatory response syndrome-associated extrapancreatic organ failure and even death. Importantly, there are no therapeutic agents currently in use that can alter the course of the disease. This article emphasizes emerging findings that stressors (environmental and genetic) that cause acute pancreatitis initially cause injury to organelles of the acinar cell (endoplasmic reticulum, mitochondria, and endolysosomal-autophagy system), and that disorders in the functions of the organelles lead to inappropriate intracellular activation of trypsinogen and inflammatory pathways. We also review emerging work on the role of damage-associated molecular patterns in mediating the local and systemic inflammatory response in addition to known cytokines and chemokine pathways. In the review, we provide considerations for correction of organelle functions in acute pancreatitis to create a discussion for clinical trial treatment and design options.
Topics: Acute Disease; Alarmins; Animals; Cytokines; Humans; Inflammation Mediators; Organelles; Pancreas; Pancreatitis; Prognosis; Signal Transduction
PubMed: 30660726
DOI: 10.1053/j.gastro.2018.11.082