BS31019 The Pancreas Lecture 7.2 PDF

Taken from https://www.newcastle-hospitals.nhs.uk/services/endocrine-and-thyroid-surgery/ BS31019 – The pancreas Dr Claire Y Hepburn  Learning outcomes Explain the functional and structural relationship between insulin and proinsulin Identify the major stimuli and in...

Taken from https://www.newcastle-hospitals.nhs.uk/services/endocrine-and-thyroid-surgery/ BS31019 – The pancreas Dr Claire Y Hepburn  Learning outcomes Explain the functional and structural relationship between insulin and proinsulin Identify the major stimuli and inhibitors of insulin secretion Describe the process of insulin synthesis and stimulus-secretion coupling. Describe how glucagon is synthesised and identify the major stimuli and inhibitors of glucagon secretion Explain how insulin and glucagon regulate glucose homeostasis Describe diseases associated with dysfunction of the endocrine pancreas Describe the closed-loop system for the management of type 1 diabetes Note: the exocrine pancreas was introduced in the ‘Regulation of the GI tract’ lecture Presentation name, Your name, Date Recommended reading Medical Physiology. 3rd Edition. Elsevier. Chapter 51 – The Endocrine Pancreas Amiel, S.A. (2021). The consequences of hypoglycaemia. Diabetologia, 64, 963-970 Hegele, R.A., and Maltman, G.M. (2020). Insulin’s centenary: The birth of an idea. Diabetes and Endocrinology, 8, 971-977. Fuchs, J., and Hovorka, R. (2020). Closed-loop control in insulin pumps for type-1 diabetes mellitus: safety and efficacy. Expert Rev Med Devices, 17, 707-720. What is the pancreas? An accessory organ of digestion with both endocrine and exocrine functions Exocrine – bicarbonate and pancreatic lipases and proteases Endocrine – glucagon and insulin This organ is found in retroperitoneally at about vertebral level L1/L2 Adapted from Moore’s Clinically Oriented Anatomy. 9th Edition, 2023 and Gray’s Anatomy. 42nd Edition, 2021. Histology of the pancreas - exocrine Remember, the pancreas consists of both endocrine and exocrine tissue (majority). Exocrine pancreas looks like this… Adapted from Gray’s Anatomy. 42nd Edition, 2021. Histology of the pancreas - exocrine Remember, the pancreas consists of both endocrine and exocrine tissue (majority). Exocrine pancreas looks like this… Adapted from Netter’s Collection of Medical Illustrations: Endocrine System. 2nd Edition, 2011. Histology of the pancreas - endocrine Remember, the pancreas consists of both endocrine and exocrine tissue (majority). Endocrine pancreas looks like this… Adapted from Gray’s Anatomy. 42nd Edition, 2021. Histology of the pancreas - endocrine Remember, the pancreas consists of both endocrine and exocrine tissue (majority). Endocrine pancreas looks like this… Adapted from Netter’s Collection of Medical Illustrations: Endocrine System. 2nd Edition, 2011. Endocrine pancreas - Islets of Langerhans E= Acinar cells i.e., exocrine pancreas I = Islet of Langerhans i.e., endocrine cells Adapted from Endocrine and Reproductive Physiology. 5th Edition, 2019. Endocrine pancreas – Islets of Langerhans Adapted from Medical Physiology, 3rd Edition, 2017. Brief history of the discovery of insulin and it’s application clinically 1889 – Oskar Minkowski and Joseph von Mering induce ‘diabetes’ in dogs 1901 – Eugene Opie links dysfunction of Islets of Langerhans with diabetes 1921 – Charles Best and Frederick Banting with the support of John MacLeod demonstrate that the blood glucose of a diabetic dog could be lowered by extract of a ductally-ligated pancreas 1922 – Purified insulin produced by James Collip as part of the Banting and Best lab 1923 – 1923 Nobel Prize in Physiology or Medicine awarded to MacLeod and John James Rickard Macleod (left), Charles Herbert Best and Banting Frederick Grant Banting (centre), and James Bertram Collip (right) Photograph of J J R Macleod (ca 1928), University of Toronto Archives, B1995-0034. Photograph of C H Best and F G Banting (ca 1924), MS COLL 76 (Banting) scrapbook 1, box 3, page 171, Thomas Fisher Rare Book Library, University of Toronto. Photograph of J B Collip in a laboratory (ca 1927), MS COLL, 269 (Collip), item 9, Thomas Fisher Rare Book Library, University of Toronto. Adapted from Li, (2021). Insulin’s centenary: complexity and collaboration. The Lancet, 398, 1796-1797  β cells – insulin synthesis Primarily to secrete insulin Insulin gene expression and the development of Islets of Langerhans cells relies on transcription factors - functional cells are present at 6 months of gestation in utero Insulin gene encodes preproinsulin which is cleaved to the bioactive peptide, insulin, in secretory granules The final cleavage of insulin produces equimolar amounts of C peptide β cells – insulin synthesis Adapted from Medical Physiology. 3rd Edition, 2017. β cells – insulin release Fasting blood glucose = 4-5 mmol l-1 Postprandial blood glucose = up to 10 mmol l-1 NOTE: blood glucose concentrations are measured in millimoles per litre by convention. However, in the USA, the same measurement is in milligrams per deciliter. Adapted from AD Instruments. 2020. β cells – insulin release Adapted from Berne and Levy Physiology. 7th Edition, 2018. β cells – insulin release Adapted from Berne and Levy Physiology. 7th Edition, 2018. β cells – regulation of insulin release Stimulation Inhibition Blood glucose concentration Norepinephrine and epinephrine Somatostatin Amino acids Leucine, isoleucine, alanine and arginine Incretins GIP and GLP-1 Glucagon Hyperkalaemia Vagal nerve stimulation β cells – regulation of insulin release No insulin is produced when plasma glucose below 2.8 mmol l-1 Half-maximal insulin response occurs at 8.3 mmol l-1 A maximum insulin response occurs at 16.7 mmol l-1 Ingested glucose has a more substantial effect on insulin secretion than does injected insulin NOTE: This concept was covered in the ‘Regulation of the GI tract’ lecture α cells – glucagon synthesis To secrete glucagon Glucagon gene encodes preproglucagon which is cleaved to the bioactive peptide, glucagon, in secretory granules α cells – glucagon release Euglycaemia/hyperglycaemia Hypoglycaemia Glucose Glucose K+ K+ K+ GLUT1 K+ GLUT1 K+ATP K+ATP Glucose Glucose K+ G-6-P K+ G-6-P ATP Ca2+ ATP 2+ Ca2+ Ca Ca2+ Ca2+ Voltage- Voltage- Glucagon gated Ca2+ Glucagon gated Ca2+ channels channels α cells – regulation of glucagon release Stimulation Inhibition Rising concentrations of amino acids Amylin, insulin and somatostatin Arginine and alanine Insulin GIP GLP-1 Hypoglycaemia Hyperglycaemia Epinephrine Glucose homeostasis Adapted from Berne and Levy Physiology. 6th Edition, 2010 and AD Instruments. 2020.. Glucose homeostasis – roles of insulin and glucagon Both insulin and glucagon are water soluble hormones They are released from the beta and alpha cells in the Islets of Langerhans, respectively, into the plasma No specific carriers or transporters in the plasma Half life in circulation is short Metabolism in liver Interact with cell surface receptors at the target organs/tissues Effects of hypo- and hyperglycaemia Hypoglycaemia Hyperglycaemia Blood glucose < 4 mmol l-1 Blood glucose > 7 mmol l-1 before Low blood glucose deprives eating neurones of source of fuel Chronic state can lead to altered Neuroglycopenia nutrient metabolism Counter-regulatory responses (CNS Glycated proteins and various hormones) Osmotic diuresis Can be side effect of management of Diabetes Mellitus Whipple triad Diabetes Mellitus Serious, long-term condition that occurs when raised plasma glucose concentrations occur because the body cannot produce any or enough insulin OR cannot use insulin effectively when it is produced Group of heterogeneous chronic metabolic disorders clinically characterised by hyperglycaemia Diabetes Mellitus - Classification Type 1 diabetes mellitus (T1DM; 5- Gestational diabetes mellitus (GDM) 10%) Diabetes diagnosed in 2nd and 3rd Autoimmune pancreatic β cell trimester of pregnancy destruction No clear over diabetes prior to Absolute insulin deficiency gestation Type 2 diabetes mellitus (T2DM; Specific types of diabetes due to other causes ~90%) Monogenic diabetes syndromes (for Progressive loss of β cell insulin example, maturity onset diabetes of the secretion young (MODY)) Diseases of the exocrine pancreas (for Insulin resistance example, cystic fibrosis and pancreatitis) Drug-/ chemical-induced diabetes (for example, with glucocorticoids) T1DM – Aetiology and common features Genetic predisposition (polygenic) Environmental tigger (viral infection) Autoimmune response – destruction of pancreatic β cells Most common form of diabetes in childhood and adolescence People living with T1DM are more prone to other auto-immune diseases for example, Addison’s, vitiligo T2DM – Aetiology and common features Genetic and epigenetic factors Environmental factors (sedentary lifestyle, obesity) Insulin resistance and dysfunction of pancreatic β cells Most common form of diabetes globally Prevalence is increasing Closed-loop insulin systems for management of T1DM Low-glucose suspend system Suspends insulin infusion when blood glucose falls below low-threshold Predictive glucose management system Suspends insulin infusion when algorithm predicts blood glucose will fall below low- threshold Hybrid closed-loop systems Continuous glucose monitor Algorithm Insulin pump Adapted from Boughton and Hovorka, 2021.. Emerging methods for quantification of pancreatic dysfunction in T1DM Pancreatic beta cell dysfunction long precedes the diagnosis of T1DM and moreover, this pancreatic beta cell dysfunction is often worse than the beta cell loss observed in T1DM (Gepts, 1965; Kloppel, et al., 1984; Roep, et al., 2021; Joshi et al., 2022) As beta cell function declines over time and current methods of beta cell function are not perfect, a better means of measuring progression of T1DM is needed (plus, the added bonus is that if there are novel therapies which help to preserve beta cell function these can be evaluated more effectively; Joshi et al., 2022) Manganese enhanced magnetic resonance imaging (MRI) Manganese (in the form of manganese chelated with dipyridoxyl diphosphate) can be used as a contrast agent in MRI. It shortens T1 relaxation times It enter cells via the voltage- gated calcium channel and therefore enters cells like the functional cardiomyocytes and pancreatic beta cells Adapted from Joshi et al., 2022 Summary The pancreas is an accessory organ of digestion with both endocrine and exocrine functions The endocrine pancreas consists of four different cell types which release peptides which are responsible for facilitating metabolism The β cells of the Islets of Langerhans are responsible for releasing insulin Insulin gene encodes preproinsulin which is cleaved to the bioactive peptide, insulin, in secretory granule Thank you. Questions?