Chapter Twenty
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Mahvash Disease
a ular nd G ec en l e o t i M c f M o l e Journal of Molecular and Genetic d a i Lucas et al., J Mol Genet Med 2013, 7:4 n c r i n u e o DOI: 10.4172/1747-0862.1000084 J Medicine ISSN: 1747-0862 ReviewResearch Article Article OpenOpen Access Access Mahvash Disease: Pancreatic Neuroendocrine Tumor Syndrome Caused by Inactivating Glucagon Receptor Mutation Matthew B Lucas1, Victoria E Yu1 and Run Yu2* 1Harvard-Westlake School, Los Angeles, California, USA 2Division of Endocrinology, Cedars-Sinai Medical Center, Los Angeles, California, USA Abstract Mahvash disease is a novel pancreatic neuroendocrine tumor syndrome caused by inactivating glucagon receptor mutations. Its discovery was triggered by comparison of a patient with pancreatic neuroendocrine tumors, pancreatic α cell hyperplasia, extreme hyperglucagonemia but without glucagonoma syndrome, and occasional hypoglycemia, with the glucagon receptor knockout mice which exhibit similar phenotype and ultimately prove to be a model of Mahvash disease. So far 6 cases have been reported. The inheritance, prevalence, pathogenesis, natural history, diagnosis, treatment, and long-term follow-up of Mahvash disease are discussed in this article. Although rare, Mahvash disease provides important insights into the pathogenesis of pancreatic neuroendocrine tumors, pancreatic α cell fate regulation by glucagon signaling, and safety of glucagon signaling inhibition for diabetes treatment. Keywords: Mahvash disease; Pancreatic neuroendocrine tumor; tumor. She was tentatively diagnosed with probable glucagonoma and Pancreatic α cell hyperplasia; Hyperglucagonemia; Glucagon receptor; underwent pylorus-sparing pancreaticoduodenectomy to remove this Mutation tumor. Glucagon levels, however, remained elevated postoperatively [6]. Introduction The histological examination of the resected surgical specimen Human tumor syndromes are usually caused by inherited or de revealed unexpected results. -
Alpha Cell Dysfunction in Type 1 Diabetes T Gina L.C
Peptides 100 (2018) 54–60 Contents lists available at ScienceDirect Peptides journal homepage: www.elsevier.com/locate/peptides Review Alpha cell dysfunction in type 1 diabetes T Gina L.C. Yosten Department of Pharmacology and Physiology, Saint Louis University School of Medicine, 1402 S. Grand Blvd, Saint Louis, MO 63104, United States ARTICLE INFO ABSTRACT Keywords: Type 1 diabetes is characterized by selective loss of beta cells and insulin secretion, which significantly impact Type 1 diabetes glucose homeostasis. However, this progressive disease is also associated with dysfunction of the alpha cell Alpha cell component of the islet, which can exacerbate hyperglycemia due to paradoxical hyperglucagonemia or lead to Glucagon severe hypoglycemia as a result of failed counterregulation. In this review, the physiology of alpha cell secretion Hypoglycemia and the potential mechanisms underlying alpha cell dysfunction in type 1 diabetes will be explored. Because type Hyperglycemia 1 diabetes is a progressive disease, a synthesized timeline of aberrant alpha cell function will be presented as an attempt to delineate the natural history of type 1 diabetes with respect to the alpha cell. 1. Introduction species-specificdifferences in islet architecture and cell signaling. For example, although most studies of alpha cell function utilize mouse or Type 1 diabetes (T1D) is an autoimmune disease characterized by rat models, rodent islets are characterized by the localization of beta selective destruction of the pancreatic beta cells [2,50]. Beta cell loss cells predominantly in the center of the islet, surrounded by alpha, can occur over extended periods of time (months to years), but due to delta, and other cell types, which comprise the outer layer of the islets the remarkable compensatory capacity of the beta cells, overt diabetes [40,53]. -
AVP-Induced Counter-Regulatory Glucagon Is Diminished in Type 1 Diabetes
bioRxiv preprint doi: https://doi.org/10.1101/2020.01.30.927426; this version posted January 31, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. AVP-induced counter-regulatory glucagon is diminished in type 1 diabetes Angela Kim1,2, Jakob G. Knudsen3,4, Joseph C. Madara1, Anna Benrick5, Thomas Hill3, Lina Abdul Kadir3, Joely A. Kellard3, Lisa Mellander5, Caroline Miranda5, Haopeng Lin6, Timothy James7, Kinga Suba8, Aliya F. Spigelman6, Yanling Wu5, Patrick E. MacDonald6, Ingrid Wernstedt Asterholm5, Tore Magnussen9, Mikkel Christensen9,10,11, Tina Vilsboll9,10,12, Victoria Salem8, Filip K. Knop9,10,12,13, Patrik Rorsman3,5, Bradford B. Lowell1,2, Linford J.B. Briant3,14,* Affiliations 1Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. 2Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA. 3Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX4 7LE, UK. 4Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen. 5Institute of Neuroscience and Physiology, Metabolic Research Unit, University of Göteborg, 405 30, Göteborg, Sweden. 6Alberta Diabetes Institute, 6-126 Li Ka Shing Centre for Health Research Innovation, Edmonton, Alberta, T6G 2E1, Canada. 7Department of Clinical Biochemistry, John Radcliffe, Oxford NHS Trust, OX3 9DU, Oxford, UK. 8Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, W12 0NN, UK. -
Aging of Human Endocrine Pancreatic Cell Types Is Heterogeneous and Sex-Specific
bioRxiv preprint doi: https://doi.org/10.1101/729541; this version posted August 8, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Aging of human endocrine pancreatic cell types is heterogeneous and sex-specific Rafael Arrojo e Drigo1*#, Galina Erikson2*, Swati Tyagi1, Juliana Capitanio1, James Lyon3, Aliya F Spigelman3, Austin Bautista3, Jocelyn E Manning Fox3, Max Shokhirev2, Patrick E. MacDonald3, Martin W. Hetzer1#,a. 1 – Molecular and Cell Biology Laboratory, Salk Institute of Biological Studies, La Jolla, CA, USA 92037 2 – Integrative Genomics and Bioinformatics Core, Salk Institute of Biological Studies, La Jolla, CA, USA 92037 3 – Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Canada, T6G2E1 * Equally contributing authors # Co-corresponding authors a Lead contact Keywords: Aging, long-lived cells, diabetes, islet of Langerhans 1 bioRxiv preprint doi: https://doi.org/10.1101/729541; this version posted August 8, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Summary The human endocrine pancreas must regulate glucose homeostasis throughout the human lifespan, which is generally decades. We performed meta-analysis of single-cell, RNA- sequencing datasets derived from 36 individuals, as well as functional analyses, to characterize age-associated changes to the major endocrine pancreatic cell types. -
Alpha- and Beta-Cell Proliferation and Extracellular Signaling – a Hypothesis Cyril J Craven*
Craven. Int J Diabetes Clin Res 2015, 2:2 ISSN: 2377-3634 International Journal of Diabetes and Clinical Research Review Article: Open Access Alpha- and Beta-Cell Proliferation and Extracellular Signaling – A Hypothesis Cyril J Craven* Queensland University of Technology, Brisbane, Australia *Corresponding author: Cyril J Craven, Retired Lecturer, Queensland University of Technology, Brisbane, Australia, E-mail: [email protected] is not yet complete with glycemic instability a serious problem Abstract in patients [5] with only a vague understanding of the pathogenic A model is offered towards an understanding of the cellular pathway of Type 2 diabetes [6] and the enigma of the alpha-cells communications of two major cell types of the pancreas. The beta still remaining [7]. The model proposed here goes towards an and alpha cells of the pancreas are considered to be coupled by the insulin and glucagon hormones that they produce, respectively. In understanding of the harmonisation of insulin and glucagon levels this model, insulin stimulates the alpha cells to release glucagon and which occurs by the effect of these hormones on the adjacent cells of grow, especially by cell division, while glucagon similarly stimulates the pancreas. the beta cells to release insulin and grow. Of equal importance to the system is the concentration of the insulin:glucagon complex to A more generic model has already been proposed as a basis which the beta and alpha cells are directly exposed in the pancreatic towards an understanding of multicellular organisation and cellular environment. Its measurement by the cells allows each coupled cell interactions within tissue cells [8]. -
Histogenesis of Medullary Carcinoma of the Thyroid
J. clin. Path., (1966), 19, 114 Histogenesis of medullary carcinoma of the thyroid E. D. WILLIAMS1 From the Institute ofPathology, The London Hospital SYNOPSIS Thirty-one dog thyroid tumours and 28 spontaneous rat thyroid tumours were studied histologically and the findings compared with those of a study of 67 cases of medullary carcinoma of the human thyroid. Five of the dog tumours and 24 of the rat tumours were considered to belong to the same group of tumours as medullary carcinoma, a group characterized by solid sheets or lobules of uniform cells with granular cytoplasm and without papillary or follicular differentiation. In the rat tumours it was shown that the cell of origin was the parafollicular cell and not the thyroid follicle epithelial cell. It is suggested that medullary carcinoma is also derived from a parafollicular cell and that this origin would resolve the discrepancy between the relatively good prognosis and the apparently undifferentiated structure of this tumour. It is also concluded that the whole spectrum of clinical and pathological features of medullary carcinoma makes more sense if it is considered as a parafollicular cell tumour. Medullary carcinoma of the thyroid is a distinct the other 19 tumours, two were classified as papillary and clearly defined entity, and the histological carcinomas, nine as follicular carcinomas, two as features of 67 examples are discussed in the previous anaplastic carcinomas, while one tumour showed a paper (Williams, Brown, and Doniach, 1966). The mixture of follicular carcinoma with osteochondro- survival of patients with this tumour is often pro- sarcoma. The remaining five tumours were similar longed although paradoxically the vast majority of and were made up of nests ofuniform cells, separated cases show no evidence of differentiation towards a into groups by a connective tissue stroma which was thyroid epithelial pattern. -
Endocrine Glands
Endocrine glands David Kachlík Endocrine system • one out if two regulator systems • phylogenetically older than the nervous system • regulates activity of other systems so that they could react to changing requirements of outer and inner environment (maintains homeostasis) • does not originate from anatomically similar structures • secretion into blood – possesses no ducts • nearly all organs and tissues of the human body produce a hormone Hormone • horman in Greek = to arise • chemical messanger produced by endocrine gland and transported into blood to target organs • proteins (polypeptides) – insuline • amines – adrenaline • steroids – estrogenes Clinical consequence • hormonal excess – primary gland overproduction – secondary to excess production of trophic (releasing, stimulating) substance (hormone) • hormonal deficiency – primary gland failure – secondary to lack of stimulation by trophic (releasing, stimulating) substance (hormone) – target organ resistance Endocrine glands History Thomas Wharton • 1614-1673 • Adenographia • first detailed description of glands Ernest Henry Starling • 1866-1927 • general schemes of „endocrine secretion“ • used the already exsiting word „hormones“ Endocrine system arrangement • glands • disseminated cells • neuroendocrine cells Endocrine glands – list • hypothalamus (hypothalamus) • pituitary gland (hypophysis; gl. pituitaria) • thyroid gland (glandula thyroidea) • parathyroid bodies (gll. parathyroideae) • suprarenal glands, adrenals (gll. suprarenales) • pancreatic (Langerhans‘) island (insulae -
Endocrine System
Chapter 17 *Lecture PowerPoint The Endocrine System *See separate FlexArt PowerPoint slides for all figures and tables preinserted into PowerPoint without notes. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Introduction • In humans, two systems—the nervous and endocrine—communicate with neurotransmitters and hormones • This chapter is about the endocrine system – Chemical identity – How they are made and transported – How they produce effects on their target cells • The endocrine system is involved in adaptation to stress • There are many pathologies that result from endocrine dysfunctions 17-2 Overview of the Endocrine System • Expected Learning Outcomes – Define hormone and endocrine system. – Name several organs of the endocrine system. – Contrast endocrine with exocrine glands. – Recognize the standard abbreviations for many hormones. – Compare and contrast the nervous and endocrine systems. 17-3 Overview of the Endocrine System • The body has four principal mechanisms of communication between cells – Gap junctions • Pores in cell membrane allow signaling molecules, nutrients, and electrolytes to move from cell to cell – Neurotransmitters • Released from neurons to travel across synaptic cleft to second cell – Paracrine (local) hormones • Secreted into tissue fluids to affect nearby cells – Hormones • Chemical messengers that travel in the bloodstream to other tissues and organs 17-4 Overview of the Endocrine System • Endocrine system—glands, tissues, and cells that secrete hormones -
P43, a Truncated Form of Thyroid Hormone Receptor , Regulates
International Journal of Molecular Sciences Article p43, a Truncated Form of Thyroid Hormone Receptor α, Regulates Maturation of Pancreatic β Cells Emilie Blanchet , Laurence Pessemesse, Christine Feillet-Coudray, Charles Coudray , Chantal Cabello, Christelle Bertrand-Gaday and François Casas * DMEM (Dynamique du Muscle et Métabolisme), INRAE, University Montpellier, 34060 Montpellier, France; [email protected] (E.B.); [email protected] (L.P.); [email protected] (C.F.-C.); [email protected] (C.C.); [email protected] (C.C.); [email protected] (C.B.-G.) * Correspondence: [email protected] Abstract: P43 is a truncated form of thyroid hormone receptor α localized in mitochondria, which stimulates mitochondrial respiratory chain activity. Previously, we showed that deletion of p43 led to reduction of pancreatic islet density and a loss of glucose-stimulated insulin secretion in adult mice. The present study was designed to determine whether p43 was involved in the processes of β cell development and maturation. We used neonatal, juvenile, and adult p43-/- mice, and we analyzed the development of β cells in the pancreas. Here, we show that p43 deletion affected only slightly β cell proliferation during the postnatal period. However, we found a dramatic fall in p43-/- mice of MafA expression (V-Maf Avian Musculoaponeurotic Fibrosarcoma Oncogene Homolog A), a key transcription factor of beta-cell maturation. Analysis of the expression of antioxidant enzymes in pancreatic islet and 4-hydroxynonenal (4-HNE) (a specific marker of lipid peroxidation) staining Citation: Blanchet, E.; Pessemesse, revealed that oxidative stress occurred in mice lacking p43. Lastly, administration of antioxidants L.; Feillet-Coudray, C.; Coudray, C.; cocktail to p43-/- pregnant mice restored a normal islet density but failed to ensure an insulin Cabello, C.; Bertrand-Gaday, C.; secretion in response to glucose. -
A Case of Calcitonin Producing Adenoma of the Thyroid
Endocrinol. Japon. 1984, 31 (1), 63-70 A Case of Calcitonin Producing Adenoma of the Thyroid TAKAYA KODAMA, MASAKO TAMURA, YOSHIHARU KANAJI, YUKIO ITO, TAKAO OBARA, YOSHIHIDE FUJIMOTO AND AKIRA HIRAYAMA* Department of Endocrine Surgery and Department of Surgical Pathology*, Tokyo Women's Medical College. Ichigaya-Kawadacho, Shinjuku-ku, Tokyo 162 Abstract A thyroid tumor about 4 cm in diameter was removed from a 53-year-old female. The clinical features were those of common thyroid adenomas, such as soft, smooth-surfaced and round contour of the tumor, no calcification and no lymph node metastasis. However, microscopically, the tumor was composed of compact cell nests rather similar to paraganglioma without any follicle formation. Histochemical examination revealed its C-cell nature, such as argyrophilia and calcitonin activity, although no amyloid deposit was demonstrated. Extremely high levels of calcitonin were found in the stored serum taken pre-operatively, but serum carcinoembryonic antigen levels were within normal limits. The calcitonin level dropped to the normal range soon after the operation, indicating the absence of residual tumorous tissues. Thus, the tumor behaves as an adenoma with a C-cell nature. Interestingly enough, the benign counterpart of medullary carcinoma of the thyroid seems to be quite rare in humans, and no similar tumors have ever been reported. Variations of C-cell tumors will be discussed in relation to their production and secretion of carcinoembryonic antigen. Medullary carcinoma of the thyroid hormones, confirming the C-cell as the origin (MCT) was first regarded as a clinical entity of MCT. by Hazard et al. (1959), recognizing a group A wide variation of morphological futures of solid non-follicular tumors with com- and prognosis of MCT had already been paratively good prognosis among apparently pointed out by Williams et al. -
The Endocrine System
PowerPoint® Lecture Slides The Endocrine System: An Overview prepared by Leslie Hendon University of Alabama, Birmingham • A system of ductless glands • Secrete messenger molecules called hormones C H A P T E R 17 • Interacts closely with the nervous system Part 1 • Endocrinology The Endocrine • Study of hormones and endocrine glands System Copyright © 2011 Pearson Education, Inc. Copyright © 2011 Pearson Education, Inc. Endocrine Organs Location of the Major Endocrine Glands Pineal gland • Scattered throughout the body Hypothalamus Pituitary gland • Pure endocrine organs are the … Thyroid gland • Pituitary, pineal, thyroid, parathyroid, and adrenal Parathyroid glands glands (on dorsal aspect of thyroid gland) • Organs containing endocrine cells include: Thymus • Pancreas, thymus, gonads, and the hypothalamus Adrenal glands • Plus other organs secrete hormones (eg., kidney, stomach, intestine) Pancreas • Hypothalamus is a neuroendocrine organ • Produces hormones and has nervous functions Ovary (female) Endocrine cells are of epithelial origin • Testis (male) Copyright © 2011 Pearson Education, Inc. Copyright © 2011 Pearson Education, Inc. Figure 17.1 Hormones Control of Hormones Secretion • Classes of hormones • Amino acid–based hormones • Secretion triggered by three major types of • Steroids—derived from cholesterol stimuli: • Basic hormone action • Humoral—simplest of endocrine control mechanisms • Circulate throughout the body in blood vessels • Secretion in direct response to changing • Influences only specific tissues— those with ion or nutrient levels in the blood target cells that have receptor molecules for that hormone • Example: Parathyroid monitors calcium • A hormone can have different effects on • Responds to decline by secreting different target cells (depends on the hormone to reverse decline receptor) Copyright © 2011 Pearson Education, Inc. Copyright © 2011 Pearson Education, Inc. -
Anatomy of Endocrine System
Anatomy of Endocrine system Introduction, Pituitary gland and Thyroid gland Prepared by Dr. Payal Jain Endocrine System I. Introduction A. Considered to be part of animals communication system 1. Nervous system uses physical structures for communication 2. Endocrine system uses body fluids to transport messages (hormones) II. Hormones A. Classically, hormones are defined as chemical substances produced by ductless glands and secreted into the blood supply to affect a tissue distant from the gland, but now it is understood that hormones can be produced by single cells as well. 1. epicrine a. hormones pass through gap junctions of adjacent cells without entering extracellular fluid 2. paracrine a. hormones diffuse through interstitial fluid (e.g. prostaglandins) 3. endocrine a. hormones are delivered via the bloodstream (e.g. growth hormone Different endocrine glands with cell Organ Division arrangement Cell arrangement/morphology Hormone Hypophysis Adenohypophysis Pars distalis Cells in cords around large-bore capillaries: Acidophils Growth hormone, prolactin Basophils ACTH, TSH, FSH, LH Pars intermedia Mostly basophilic cells around ACTH, POMC cystic cavities Pars tuberalis Narrow sleeve of basophilc cells LH around infundibulum Neurohypophysis Pars nervosa Nerve fibers and supporting cells Oxytocin and (pituicytes) vasopressin (produced in hypothalamus) Infundibulum Nerve fibers (traveling from hypothalamus to pars nervosa) Pancreas Islet of Langerhans Irregularly arranged cells with Insulin, glucagon many capillaries Follicles: Simple