Endocrinology (Part A) 2024 Past Paper PDF

BIOM2012 - Systems Physiology Endocrinology Stephen Anderson School of Biomedical Sciences  Endocrinology (Part A) Glucose homeostasis – insulin & glucagon Diabetes Mellitus  Glucose Homeostasis How does the body maintain blood glucose c...

BIOM2012 - Systems Physiology Endocrinology Stephen Anderson School of Biomedical Sciences  Endocrinology (Part A) Glucose homeostasis – insulin & glucagon Diabetes Mellitus  Glucose Homeostasis How does the body maintain blood glucose concentrations within a narrow range? What mechanisms are responsible? What are the pathophysiological consequences of dysregulation of glucose homeostasis?  Nutrients MACRO MICRO Carbohydrates Glucose (mainly) ANABOLIC Proteins Amino acids CATABOLIC Lipids Fatty acids  Glucose Homeostasis ANABOLIC CATABOLIC GLUCOSE GLYCOGEN Utility Storage  Glucose Homeostasis Ketone Glucose bodies is the primary energy substrate backup fuel for all cells when glucose Glycogen is limited not stored in neurons constant supply is critical  Blood glucose homeostasis prevent hypoglycemia prevent hyperglycemia approx. blood glucose < 4mM approx. blood glucose > 10mM osmotic diuresis, increased thirst possible brain dysfunction, seizures diabetes mellitus loss of consciousness, coma vascular and neural damage these are observed in these are observed with acute hypoglycemia (< 3mM) persistent hyperglycemia (> 20mM)  The Pancreas is an exocrine & endocrine gland B&B Fig 51-1 endocrine = Islets of Langerhans The pancreas is a small, leaf-like gland located in the retroperitoneum, posterior to the stomach. It has both exocrine and endocrine functions. Exocrine: acinar cells arranged in lobules that secrete a range of digestive enzymes, sodium bicarbonate and other electrolytes into the duodenum of the small intestines. Endocrine: islets of Langerhans are only 1-2% of pancreatic mass, and secrete hormones (insulin & glucagon) into systemic blood. Within the Islet of Langerhans, there are three major types of endocrine cells: ß Cells that produce insulin → anabolic hormone that promotes storage of glucose, fatty acids and amino acids in cells. α Cells that produce glucagon → catabolic hormone that mobilises glucose, fatty acids and amino acids for energy production. δ Cells that produce somatostatin → acts locally (paracrine role) within pancreas to inhibit both insulin and glucagon secretion. In the context of glucose homeostasis, insulin and glucagon are often stated to be ”functional antagonist” or “counter regulatory” That is, they act opposite to each other and are reciprocally secreted in most circumstances. For example, insulin lowers blood glucose, whereas glucagon increases blood glucose concentrations. Note they are no true antagonists in a pharmacology sense, as they act on different receptors. The idea of counter-regulation is not strict. Because control not solely blood glucose.  Glucose Homeostasis Owens et al. 2001 The Lancet 358:739-746 blood glucose increases following a meal (absorptive state) insulin is secreted and lowers blood glucose ie. regulates hyperglycemia  Glucose Glucose Homeostasis 180 min cycling Lactate Glycerol FFA Blood glucose decreases during prolonged exercise ie. regulation of hypoglycemia by glucagon & other hormones Grego et al. 2004 Neurosci Lett 364:76-80  Pathophysiology Impaired insulin secretion or insulin action results in the metabolic disease called diabetes mellitus. Insulin is the only blood glucose lowering hormone in the body, which explains why diabetes mellitus is such a significant and common disease. In contrast, a lack of glucagon secretion and/or action can be compensated for by other hormones, and no disease state exists for glucagon insufficiency. However, excess glucagon production occurs “glucagonoma”, where a tumour of the pancreatic alpha cells that hyper- secretes glucagon. Is rare condition. Insulin  Linear pre-proinsulin in nucleus Signal peptide removed folded “proinsulin” in ER C peptide cleaved in Golgi mature insulin is 51 amino acids Stored in secretary granules for secretion (exocytosis) Plasma half-life is only 5-10 min B&B Fig 51-2  Hormone Signaling Receptors & Signal Transduction G-protein coupled receptors (GPCRs) eg. oxytocin, GHRH, somatostatin, dopamine Tyrosine kinase receptors (RTKs) eg. Insulin, IGF1 Cytokine receptors, tyrosine kinase associated receptors e.g. EPO, leptin, prolactin and GH Steroid receptors e.g. oestrogen-receptor These topics were covered in BIOL2200 and BIOM2011  Ins Insulin binds Activates receptor Autophosphorylation Activates tyrosine kinase Phosphorylates proteins inactive ATP active P B & B Fig 51-5 Glucose homeostasis Other metabolic functions Liver, skeletal muscle, adipose all cells tissue The complexity of cell signalling downstream of the insulin receptor is shown here. You are NOT expected to know all the detailed signalling molecules. Just an overview - focus on major pathways and their outcomes B&B Fig 51-6 IRS = insulin receptor substrate is a key intracellular signaling molecule various isoforms IRS1 IRS2 IRS3 IRS4 B&B Fig 51-6  Ins B&B Fig 51-6 Activated IRS Activated MAP kinase pathway Activate/deactivate Induce/suppress gene enzymes expression Insulin affects a multitude of physiological processes including glucose homeostasis, wider energy metabolism (fat and protein), and cell growth/mitogenesis. Summary of the major signaling pathways and outcomes: MAPK pathway → promotes cell growth. PI3K/PKB pathway → activated through IRS; promotes glucose transporters (GLUT4) translocation to cell surface. Also glucose storage and oxidation. PI3K/mTOR pathway → activated through IRS; promotes protein synthesis, inhibits proteolysis, cell growth. multiple (other) pathways → activated through IRS; promotes triglyceride synthesis, inhibits lipolysis.  Glucose Transport Glucose Glycogen During digestion carbohydrates are broken down to simple sugars Glucose is the most important sugar in the body Can be oxidized by cells for energy or stored as glycogen So how does Glucose enter cells?  GLUTs B&B Fig 5-7 12 transmembrane domains, approx 500 amino acid residues transport G via facilitated diffusion  Many cells basal G uptake GLUT 1 impt blood brain barrier & insulin-independent erythrocytes Liver hepatocytes G uptake GLUT 2 Pancreatic beta cells insulin-independent Most cells basal G uptake GLUT 3 impt central nervous system insulin-independent (neurons) Muscle myocytes G uptake GLUT 4 Fat adipocytes insulin-dependent Intestinal epithelial cells Fructose transport GLUT 5 (luminal side) insulin-independent There are 14 GLUTS encoded by human genome.  B&B Fig 51-6 PI3K/PKB pathway activated through IRS, promotes GLUT4 translocation to cell surface. PI3kinase = phosphatidylinositol 3-kinase PDK = PIP3 dependent protein kinase PKB = protein kinase B (also known as Akt)  Insulin and GLUT4 Myocytes & Adipocytes Insulin stimulated: vesicles undergo exocytosis, inserting GLUT4 into the cell membrane Unstimulated: GLUT 4 in cytoplasmic vesicles Voet & Voet Biochemistry Fig 18.16 Insulin, GLUT4 and adipocytes Expression and translocation of GFP-GLUT4 in 3T3L1 adipocytes (a cell line often used in insulin research) Oatey et al. (1997) Biochemical Journal 327: 637-642  Insulin, GLUT4 and adipocytes Glucose uptake in isolated adipocytes from control (wild type) mice versus GLUT4 knockout mice. expected increase G uptake with insulin in controls but why small increase in GLUT4 KOs? Dale Abel et al. 2001 Nature 409, 729-733  Insulin actions Insulin is a key metabolic hormone. It affects carbohydrate, proteins & fat metabolism. It is an anabolic hormone, promoting storage. Insulin influences many cells – ubiquitous expression of insulin receptors. However the receptor expression is high in metabolic tissues: liver, muscle and adipose tissue. Insulin actions on hepatocytes Recall that nutrient rich blood from the gastrointestinal tract travels in the hepatic portal vein via the pancreas to the liver. This anatomical arrangement ensures insulin is secreted in response to digested nutrients and has immediate and effective action at the liver.  Insulin actions on hepatocytes The main GLUT in hepatocytes is GLUT2, which is not insulin sensitive, GLUT4 has only very minor expression in hepatocytes. Nevertheless a key action of insulin is G uptake into hepatocytes. Insulin stimulates expression and activation of enzymes that promote storage and utilisation of glucose. Therefore insulin maintains a concentration gradient in hepatocytes that favours glucose intake via GLUT2 (and via other GLUTs1 and GLUT3, low expression). Glucose movement is down the concentration gradient. Important when blood G is high, in the absorptive state. Remember High ECF [glucose] versus ICF [glucose] results in G uptake.  G uptake in the liver Insulin stimulates: B&B Fig 51-8 Glucokinase expression (1) Glycogen synthase activity (2) These maintain concentration Insulin inhibits: gradient to promote further entry of Glucose-6-phosphatase (4) glucose into hepatocytes via GLUT2 Glycogen phosphorylase (3)  Liver (more detail) Insulin promotes: Glycogen synthesis Glucokinase expression (1) Glycogen synthase activity (2) Glycolysis and oxidation Phosphofructokinase activity (5) Pyruvate kinase (6) Pyruvate dehydrogenase (8) Lipid & protein storage Insulin inhibits: Gluconeogenesis enzymes PEPCK (9), FBPase (10) & G6Pase(4) B&B Fig 51-8  Summary Insulin acts on hepatocytes to ….. Stimulate G uptake Promote glycogen synthesis and inhibits its breakdown Promote glycolysis Inhibit gluconeogenesis (glucose output) Promote synthesis and storage of fats and inhibit breakdown Promote protein synthesis and inhibit breakdown  Muscle Insulin promotes: Glucose uptake (GLUT4) Glycogen synthesis Hexokinase expression (1) Glycogen synthase activity (2) Glycolysis and oxidation Phosphofructokinase activity (3) Pyruvate dehydrogenase activity (4) Protein synthesis Note G uptake due to GLUT4 and enzymes B&B Fig 51-9  Summary Insulin acts on myocytes to ….. Promote G uptake, storage and utilisation - similar to hepatocytes with some exceptions: Insulin stimulates movement of GLUT4 to the cell membrane, as the main GLUT expressed in muscle Hexokinase expression : muscle express hexokinase not glucokinase, but the phosphorylation reaction is the same that they facilitate is the same (Glucose → Glucose-6-P) Insulin also has an important protein anabolic effect in muscle by promoting amino acid uptake.  Adipocytes Insulin promotes: Glucose uptake Glycolysis to give precursors for lipogenesis (glycerol phosphate, acetyl CoA) Inhibits hormone-sensitive triglyceride lipase (3) Also synthesis of lipoprotein lipase (LPL) on endothelial cells – generate FFAs B&B Fig 51-10  Summary Insulin acts on adipocytes to ….. promote G uptake via GLUT4 stimulate Hexokinase expression (G to G-6-P), which maintains downhill glucose concentration gradient for G entry promote glycolysis to provide precursors for lipogenesis inhibit hormone sensitive lipase, an important enzyme required for the breakdown of fat (triacyglycerides). Biochemistry – need to know  Summary of insulin actions CHOs. Insulin decreases blood G by promoting uptake by cells (utilization & storage), whilst blocking two mechanisms by which liver increases G into blood (gluconeogenesis and glycogenolysis). Fats. Insulin lowers blood G & FAs, promoting storage as triglycerides. It prevents lipolysis. Proteins. Insulin has a protein anabolic, lowering blood AAs & enhancing protein synthesis. It prevents protein breakdown. Insulin is the major hormone in the absorptive (fed) state.  Insulin Secretion High blood glucose (hyperglycaemia) stimulates insulin secretion from the pancreatic b cells Guyton Textbook  GLUT 2 Secretory Granules of Insulin Glucokinase -6-phosphate Pancreatic ß Cell Glycolysis & Oxidation K K K KK K K K K K K K K K K ATP-sensitive Voltage-dependent K+ Channel Ca2+ Channel Ca Ca Ca Ca Ca  Insulin Regulation STIMULATES INHIBITS Insulin Secretion Insulin Secretion Nutrients ↑ Glucose PRIMARY ↑ Amino acids AUGMENTS ↑ Fatty Acids AUGMENTS Autonomic Nervous System PSNS stimulation (Acetylcholine) SNS stimulation (Noradrenaline) Endocrine Signals “INCRETINS” Glucagon-like-peptide 1 (GLP-1) Gastric inhibitory polypeptide (GIP) Gastrin, secretin, & CCK MINOR Paracrine (local) Signals Glucagon Somatostatin Incretin mimetics (eg. GLP1 agonists) are used in diabetes. Glucagon  Glucagon Maintains adequate blood glucose levels i.e. prevents blood glucose from falling too low Important in post-absorptive (& fasting) state Opposite effects to insulin – counter regulatory Major site of action is liver Promotes catabolism and an increase blood glucose  Glucagon synthesis B&B Fig 51-11 Note differential processing/cleavage by cells Glucagon is a 29 residue polypeptide secreted by pancreatic a cells Glucagon-like peptide 1 (GLP-1) is secreted by intestinal L cells “an incretin”  Glucagon regulation Glucagon is secreted in response to hyperglycemia, not in euglycemia or hypoglycemia. Rix et al. (2019) Glucagon Physiology, Endotext.  Glucagon regulation STIMULATES Glucagon Secretion INHIBITION. Nutrients ↓ Glucose PSNS surprisingly slightly stimulates ↑ Amino acids ↓ Fatty Acids rather than inhibits Autonomic Nervous System Somatostatin inhibits glucagon SNS stimulation (NA and A) (paracrine role) Endocrine Signals Cortisol Insulin shown to inhibit glucagon, Other Signals but some complexity in diabetes – unclear mechanisms Infection Exercise  Glucagon regulation - complexity Why does high AA stimulate both insulin & glucagon? Consider if you ate only a large steak (no vegies) What happens to blood glucose? It has been suggested that the function of protein- induced hyperglucagonemia is to prevent hypoglycemia from aminogenic insulin secretion (Unger et al., 1969). According to this proposal… glucagon, increases hepatic glucose production just enough to replace the glucose lost to peripheral tissues as a result of the increased insulin; in other words, glucose concentration remains unchanged.  Glucagon regulation - complexity Plasma glucagon response of normal subjects to a large protein meal In contrast to the reciprocal bihormonal response of the alpha and beta cells to a carbohydrate meal, a protein meal elicits an increase in both insulin and glucagon secretion (Floyd et al., 1966). So when you consider a mixed nutrient meal is glucagon important in fed state? Answer is possibly yes.  Summary of glucagon actions Major target is liver (and kidney). Increases hepatic glucose production & release via glycogenolysis and gluconeogenesis, increasing blood G. Overall glucagon effect on lipolysis is controversial. Acts on liver, more than adipose tissue. Glucagon does not influence blood AA levels. Limited protein metabolic effect. Glucagon is the key hormone in the post-absorptive state. But not the only hormone involved in starvation responses. See later. Pathophysiology diabetes Diabetes a global health challenge openaccessgovernment.org  Diabetes mellitus Disease of impaired carbohydrate, fat and protein metabolism Characterised by hyperglycaemia “Sweet syphon” - urine is sweet due to glucosuria, causing an osmotic diuresis Polyuria, polydipsia and polyphagia Important to contrast with diabetes insipidus – where observe water diuresis related to issues with ADH Diabetes classification  Type II DM dysfunction Relative early stages Relative later stages Insulin insensitivity Hyperinsulinema & Hyperglycemia + hyperglycemia increased FFA pathophysiology here relatively unknown increased signal to pancreatic beta cells Beta cell failure & increased pancreatic mass hypo-insulinema & hyperinsulinema some type II patients require insulin aka like type I DM patients  Insulin insensitivity Adipocytes Dale Abel et al. 2001 Nature 409, 729-733 B&B Fig 51-7 insensitivity is from a lack of insulin signal transduction  Diabetes classification There is also gestational diabetes mellitus (GDM) Hyperglycemia first detected in pregnancy, routine testing Most common in the third trimester GDM is similar to T2DM, with insulin resistance The hyperglycaemia usually stabilises after birth. However, there are long-term consequences for both mother and child. eg. women with GDM are more susceptible to future T2DM