Glucose Homeostasis and Pathophysiology of Diabetes - Student Copy(1).pptx

Glucose Homeostasis and Diabetic Pathophysiology BSMS203: Theme 1, Lecture 16 Oliver G. Steele [email protected] Join at slido.com #3739905 Lecture in Context This lecture will build on … • Receptor Tyrosine Kinases • Introduction to the pancreas … by introducing and covering … Introduction...

Glucose Homeostasis and Diabetic Pathophysiology BSMS203: Theme 1, Lecture 16 Oliver G. Steele [email protected] Join at slido.com #3739905 Lecture in Context This lecture will build on … • Receptor Tyrosine Kinases • Introduction to the pancreas … by introducing and covering … Introduction to Endocrinolog y • Structure and Series of function of the Endocrin pancreas e • Glucose Physiolo homeostasis in a gy healthy Lectures individual You are • Diabetic here! pathophysiology 2 Intended Learning Outcomes To understand how glucose is metabolised in a healthy person; to understand how disorders of glucose metabolism can manifest as DM, to understand changes in glucose metabolism in pregnancy and how this relates to gestational diabetes. 3 Outline 1. Anatomy of the Pancreas • Structure, blood supply and cell types 2. Glucose Homeostasis • Contrasting actions of glucagon and insulin in glucose homeostasis • Insulin synthesis, mechanism and feedback 3. Type 1 & Type 2 Diabetes Mellitus • Pathophysiology of Type 1 & 2 Diabetes Mellitus • Treatment & Management of T1- & T2-DM 4. Diabetic Pathophysiology and pregnancy • Glucose homeostasis during pregnancy and gestational diabetes 4 Anatomy of the Pancreas Section 1 of 4 5 Pancreas Behind and below the stomach Stoma ch Above and in front of the duodenum Major roles in both the digestion of food, absorption and utilisation of nutrients Hea d Pancreas Tail Nec Bod y k Uncinate Duodenu process m Generally broken into five sections: • Head and Uncinate process • Neck • Body and Tail 6 Blood Supply Coeliac Artery The neck of the pancreas sits over the major blood vessels, with a groove at the posterior The gastroduodenal and splenic arteries branch from the coeliac artery Gastroduod enal Artery Splenic Artery Superior Pancreaticoduo denal Artery The body and tail are supplied by branches of the splenic artery The head and uncinate process are supplied by the superior and inferior pancreaticoduodenal arteries respectively Superior Mesenteric Arte 7 Inferior Pancreaticoduodenal Veinous Drainage The neck of the pancreas sits over the major blood vessels, with a groove at the posterior Hepatic Portal Vein Splenic Vein The head and uncinate process drain into the pancreaticoduodenal veins, which drains into the superior mesenteric vein The body and tail drain into splenic vein The splenic and mesenteric Superior Mesenteric Vein Pancreaticoduodenal Veins 8 Endocrine & Exocrine Pancreas Pancreas has both an endocrine and an exocrine role Exocrine - Secretion of digestive enzymes along the pancreatic duct, along with bile from the gallbladder, into the duodenum - Aid in digestion of foodstuff for later absorption Endocrine - Production of hormones vital for absorption and utilization of nutrients from digested food Liv er Pancreatic Duct Gallblad der Bile duct 9 Duodenu m Islets of Langerhans Islets of Langerhans Stoma ch Hormones are produced by specialised cells, clustered in Islets of (25%) Langerhans (55%) Pancreas (10%) (3%) (5%) Duodenu m Pancreatic Duct 10 • • • • • α cell – Glucagon β cell – Insulin δ cell – Somatostatin ε cell – Grehlin PP cell – Pancreatic polypeptide (Approximate percentage volume of the cell types in adult islets of Langerhans) The pancreas can be subdivided into five distinct sections. Which artery provides blood to the body and tail of the pancreas? A. B. C. D. Gastroduodenal Mesenteric Splenic Pancreatoduodenal Correct Answer: C -reveal Splenic Move to answer 11 Answer Slide Coeliac Artery The neck of the pancreas sits over the major blood vessels, with a groove at the posterior The gastroduodenal and splenic arteries branch from the coeliac artery Gastroduod enal Artery Splenic Artery Superior Pancreaticoduo denal Artery The body and tail are supplied by branches of the splenic artery The head and uncinate process are supplied by the superior and inferior pancreaticoduodenal arteries respectively Superior Mesenteric Arte 12 Inferior Pancreaticoduodenal Glucose Homeostasis Section 2 of 4 13 Glucose Homeostasis Glucagon Sensitive Gluconeogenesis - Glucose synthesis in liver and kidneys from non-carbohydrates (amino acids etc) Glycogenolysis - Glucose release from glycogen stores in the liver Insulin Sensitive Glycolysis (promoted) - Glucose oxidation in tissue Blood Glucose 3.9-5.6 mmol/L (fasting) Diet 14 Glycogen & fat synthesis (promoted) - Conversion of glucose into either glycogen or fat Lipolysis (inhibited) - Breakdown of fat into availably energy Circulating Amount Insulin secretion and blood glucose Blood glucose levels spike after mealtimes Blood Glucose Insuli n Mea l Increased blood glucose drives a pulse of insulin proportionate to the amount of glucose in the blood Mea l Mea l Pancreatic β cells directly sense glucose, and synthesize insulin in response to blood glucose Time 15 Insulin Synthesis Glucose enters down concentration gradient through glucose transporters Products of glucose metabolism drive insulin synthesis and storage as granules Produced ATP also inhibits KATP channels, which depolarizes the membrane Influx of calcium through voltage gated Ca channels drive calciuminduced insulin release Pancreatic β Cell 16 Insulin mechanism of action Insulin binds to insulin receptors, members of the receptor tyrosine kinase family Insulin acts in two stages: Immediate effects (minutes) at lower concentrations - Rapid translocation of glucose transporters (GLUT) into the membrane to aid glucose uptake Delayed effects (hours) at higher concentrations - Expression of glycogen synthesising 17 enzymes Glucose uptake and GLUTs Glucose enters cells by facilitated diffusion - carrier-mediated process transporting glucose down its concentration gradient. High Glucose Concentrati on GLUT2 Liver, pancreatic β cell Glucose entry is facilitated by glucose transporters (GLUTs) There are 5 major types of GLUT encoded by different genes and expressed in different tissue GLUT1 Widespread expression (erythrocytes, muscle, brain, kidney, colon, placenta, foetal tissue) GLUT3 Brain Tissue GLUT4 Skeletal muscle, adipose (INSULIN SENSITIVE) Low Glucose Concentrati on 18 GLUT5 Small intestine Glucagon Blood Glucose Secreted by α cell in the islets of Langerhans in response to low blood glucose Hepatic portal vein connects the pancreas to the liver, delivering glucagon primarily to the liver Gluconeoge nesis Pancrea ticα cell Glycogenoly sis Glucag on Aids in the delivery of energy to other tissues between meal times, i.e. when blood glucose is lower Liver Glucagon, acts via GPCR signaling, to promote breakdown of stored glycogen & gluconeogenesis 19 Net effect: Increased glucose levels in between meals Glucose homeostasis summary 20 Activation of which channels directly facilitates the release of insulin from intracellular granules out of the pancreatic β cell? A. B. C. D. K-ATP Channels Voltage gated calcium channels Glucose transporters Insulin receptors Move to reveal answer Correct Answer: B - Voltage gated calcium channels 21 Answer slide Glucose enters down concentration gradient through glucose transporters Products of glucose metabolism drive insulin synthesis and storage as granules Produced ATP also inhibits KATP channels, which depolarizes the membrane Influx of calcium through voltage gated Ca channels drive calcium-induced insulin release Pancreatic B Cell 22 Pathophysiology of Type 1 and Type 2 Diabetes Mellitus Section 3 of 4 23 Type 1 & Type 2 Diabetes Mellitus Diabetes mellitus – latin for ‘honeyed siphon’ (or ‘to pass through’), or honeyed urine Type 1 Diabetes Mellitus (T1DM) or Type 2 Diabetes Mellitus (T2DM) Maturity onset diabetes of the young (MODY) is a distinct set of disorders relating to genetic disruption of glucose metabolism or insulin synthesis 24 Type 1 Diabetes Mellitus (T1DM) Type 1 Diabetes Mellitus (T1DM) is characterised by autoimmune destruction of β cells. GAD & Insulin antibodies arise first, driving insulitis Fewer functioning β cells results in less insulin produced Historically termed ‘insulin-dependent diabetes’ H&E – Haematoxylin and eosin stain INS – Insulin (β cells) GCG – Glucagon (α cells) CD3 – T-cells (autoimmunity) Health 25 T1DM Type 1 Diabetes Mellitus (T1DM) Environmental Trigger If left untreated hyperglycaemia will develop Not entirely clear Coxsackie viral infection Environmental trigger Blood Glucose Genetic predisposition Insulitis Pre diabetes Diabetes Time 26 Type 1 Diabetes Mellitus (T1DM) Insulin normally acts to increase glucose uptake from cells Less insulin causes less glucose uptake, so cells become ‘starved’ despite high extracellular glucose (hyperglycaemia) Body searches for alternate sources of energy Increased protein degradation and muscle wastage Increased lipolysis and fat loss Treatment Strategy: Replace Insulin 27 Type 2 Diabetes Mellitus (T2DM) More typically characterised by insulin resistance Pancrea ticβ cell Onset of insulin resistance is linked to family history of T2DM, high visceral fat and a sedentary lifestyle. Insulin Exact cause is unclear, however visceral fat is suggested to secrete proteins which directly prevent insulin acting at insulin receptors Beta cells attempt to compensate by increasing insulin production causing hyperinsulinemia Muscle Cell 28 Normal Physiology Glucos e Type 2 Diabetes Mellitus (T2DM) More typically characterised by insulin resistance Pancrea ticβ cell Onset of insulin resistance is linked to family history of T2DM, high visceral fat and a sedentary lifestyle. Insulin Exact cause is unclear, however visceral fat is suggested to secrete proteins which directly prevent insulin acting at insulin receptors Beta cells attempt to compensate by increasing insulin production causing hyperinsulinemia Treatment Strategy: Reduce Glucose Muscle Cell T2DM 29 Glucos e Type 2 Diabetes Mellitus (T2DM) Concurrent release of amyloid by overactive beta cells leads to amyloid scarring and a drop in beta cell function As scarring progresses patients can become Type 1 diabetic as beta cell function continues to drop Treatment Strategy: Replace Insulin & Reduce Glucose H&E – Haematoxylin and eosin stain INS – Insulin (β cells) GCG – Glucagon (α cells) CD3 – T-cells (autoimmunity) 30 T2DM (bottom) Healthy (top) Hyperinsulinemia is characteristic of which form of diabetes? A. B. C. D. Type 1 Type 2 MODY Insulitis Move to Correct Answer: B –reveal Type 2answer 31 Answer Slide More typically characterised by insulin resistance Pancrea ticβ cell Onset of insulin resistance is linked to family history of T2DM, high visceral fat and a sedentary lifestyle. Insulin Exact cause is unclear, however visceral fat is suggested to secrete proteins which directly prevent insulin acting at insulin receptors Beta cells attempt to compensate by increasing insulin production causing hyperinsulinemia Treatment Strategy: Reduce Glucose Muscle Cell T2DM 32 Glucos e Diabetic Pathophysiology during pregnancy Section 4 of 4 33 Hormone and fuel balance during pregnancy Rapidly growing fetus places demands on the maternal metabolic system Early Pregnancy (facilitated anabolism) - Fat deposition is elevated due to enhanced lipogenesis - Maternal prolactin and placental lactogen drive enhanced Beta cell mass - Alpha cell mass is unchanged - Mostly driven by maternal estrogen β cell mass 17βestradiol 34 Lipogene Hormone and fuel balance during pregnancy Rapidly growing fetus places demands on the maternal metabolic system Pancrea ticβ cell Mid-late stage pregnancy (facilitated catabolism) - Fetal glucose demands become higher and placental lactogen promotes lipolysis in mother, to provide glucose preferentially to the child - Progesterone promotes increased maternal insulin resistance Insulin Progesterone Muscle Cell 35 Glucos e Insulin Resistance during Pregnancy Gestational Diabetes Definition High blood sugar (hyperglycemia) that develops during pregnancy, and usually disappears after giving birth Blood sugar over 10.6 mmol/L 36 Glycated heamoglobin Blood glucose is a measure at a single point in time haemoglobin Glycated haemoglobin, or HbA1c, provides a longer term measure of blood glucose Excessive glucose causes glycation of haemoglobin Average blood glucose over the previous 8-10 weeks haemoglobin Prolonged Hyperglyca emia Reference range is < 5.7% < 6.5% is the target for diabetic patients 37 glycated haemoglobin Congenital malformations in diabetes High fetal glucose can perturb organogenesis during the 1st trimester 30 Congenital Malformations (%) 25 Neural tube defects such as hydrocephalus or organ defects such as congenital heart disease 20 15 Severely increased risk of perinatal mortality and life-long disruption to the fetus 10 5 0 Women without diabetes 6.1-7.7 7.8-10.0 >10.0 Hydrocepha ly 38 Central Cyanosis in Congenital Hyperglycemia in late pregnancy High maternal glucose can lead to high fetal glucose levels if not maintained properly and promote a larger gestational age baby (macrosomia) Larger babies have a higher risk of being born prematurely Breathing problems and difficult births are also common with macrosomia Further problems can occur later in life including hypertension, obesity and type 2 diabetes ~7lb healthy baby (left), ~12lb baby with macrosomia (right) 39 During pregnancy which hormone promotes insulin resistance? A. B. C. D. Prolactin Placental Lactogen Progesterone Estrogen Correct Answer: C -reveal Progesterone Move to answer 40 Hormone and fuel balance during pregnancy Rapidly growing fetus places demands on the maternal metabolic system Pancrea ticβ cell Mid-late stage pregnancy (facilitated catabolism) - Fetal glucose demands become higher and placental lactogen promotes lipolysis in mother, to provide glucose preferentially to the child - Progesterone promotes increased maternal insulin resistance Insulin Progesterone Muscle Cell 41 Glucos e Insulin Resistance during Pregnancy What you need to know • Know the broad anatomy of the pancreas and cell types within the islets of Langerhans • Appreciate the role of the pancreas as both an endocrine and exocrine gland • Understand the role of insulin in glucose homeostasis, including its synthesis and mechanism of action • Understand the differing pathophysiology underlying T1DM and T2DM • Understand the changes to glucose homeostasis during pregnancy • 42 Suggested Additional Reading Greenspan’s Basic and Clinical Endocrinology. “Chapter 17 is a great place to start for the pancreas, glucose homeostasis and T1/T2DM, a little further in is the gestational diabetes content.” Tenth Edition. Gardner & Shoback. McGraw-Hill Medical; 2018. ISBN: 978-0071622431. “Chapter 14 and 15 in this book are where you want to go if the above is in too much detail.” Integrated Endocrinology First Edition. Laycock & Meeran. Wiley-Blackwell; 2013. ISBN: 978-0470688120. 43 Feedback Opportunity If you have any feedback for me on this lecture, please either scan the QR code or follow the link below Questionnaire is short (~2 mins) and anonymous All feedback helps me to improve, and as a result improve the quality of your teaching. https://universityofsussex.eu.qualtrics.com/jfe/form/SV_3wVeRAhOFt bXjee 44