Lecture 5.1 - Introduction to the Endocrine System and Endocrine Pancreas PDF

Key features of homeostasis: ◦Control centre determines reference set point ‣ Brain, the hypothalamus (controls endocrine system) ◦Receptor: ‣ Sensors required to detect changes (stimuli) in the environment ◦Effector: ‣ Agents that cause change ‣ Con...

Key features of homeostasis: ◦Control centre determines reference set point ‣ Brain, the hypothalamus (controls endocrine system) ◦Receptor: ‣ Sensors required to detect changes (stimuli) in the environment ◦Effector: ‣ Agents that cause change ‣ Control centre produces an output, communicated via efferent pathways to effectors ◦Feedback: ‣ Output (effect) has an effect on the control centre Endocrine hormones: ◦Endocrine hormones = chemical signals produced in endocrine glands or tissues that travel in the bloodstream to cause an effect on other tissues ◦Hormones released from endocrine glands ‣ Travel in blood stream ‣ About 30 seconds to reach all parts of the body - slower than nervous system but gives a more coordinated response ‣ Only interact where there are receptors ‣ Can have different effects in different places ‣ Coordinated multiple responses Glands of the endocrine system: Components of the endocrine system: ◦Endocrine tissue ◦Biologically active chemical ◦Transport in blood ◦Target cells - receptors and response ◦Inactivation of chemical - process of metabolism of hormone causes inactivation  Control of hormone secretion: ◦Rate of secretion usually controlled by negative feedback: ‣ Change in parameter regulated by the hormone ‣ Concentration of hormone itself or another hormone Hormone concentrations in the blood: ◦Hormones circulate in VERY low concentrations ‣ E.g. throxine 10-30 pmol/L ‣ cf Na+ 140 mmol/L in plasma Hormone transport in the blood: ◦Some peptide and amine hormones are water soluble. steroid and thyroid hormones are not ◦Few hormones soluble enough to travel in simple solutions: ‣ Peptides ‣ Adrenaline ◦Most must bind to (usually) proteins ◦Often specific: ‣ Steroids ‣ Thyroid hormones (thyroxine-binding globulin, TBG) ◦Dynamic equilibrium between bound and free forms of hormone in plasma: ‣ Free + binding Bound protein ◦ONLY FREE FORM IS BIOLOGICALLY ACTIVE ◦Role of carrier proteins: ‣ Increase the solubility of the hormone in plasma ‣ Increase half-life ‣ Readily accessible reserve in the blood Classes of hormones: ◦Polypeptide hormones - around 20 ◦Glycoprotein hormones - 4 ◦Amino acid derivatives - 3 major classes ◦Steroid hormones - around 10 Polypeptide hormones: ◦Largest group as there is greater variety ◦Nearly all single chain peptides vary in chain length ‣ Growth hormone - 191 amino acids ‣ Insulin - 51 amino acids in two chains ‣ Thyrotropin-releasing hormone (TRH) - 3 amino acids - stimulates anterior pituitary gland ◦Some organised in closely related families ‣ Gut hormones  Glycoprotein hormones: ◦All have two polypeptide chains with carbohydrate side chains ‣ Alpha and Beta chains ◦Related families: ‣ Thyroid stimulating hormone (TSH) - control og thyroid gland ‣ Follicle stimulating hormone (FSH) - released by anterior pituitary gland ‣ Luteinising hormone (LH) ‣ Human chorionic gonadotrophin (hCG) Amino acid derivatives: ◦Some from tyrosine ◦Thyroid hormones ‣ Tetra-iodothyronine (T4) -> known as thyroxine ‣ Tri-iodothyronine (T3) ◦Adrenaline ◦Histamine from histidine (local hormone, not endocrine) ◦5-hydoxytryptamine (5-HT) from tryptophan (local hormone, not endocrine) Steroid hormones: Classes of steroid hormones: ◦C refers to the number of carbon atoms ◦C27: ‣ Calciferols - e.g. vitamin D ◦C21: ‣ Corticosteroids - adrenal cortex Glucocorticoids (cortisol) Mineralocorticoids (e.g. aldosterone) ‣ Progestins - e.g. progesterone from ovaries ◦C19: ‣ Androgens - e.g. testosterone from testes ◦C18: ‣ Oestrogens - e.g. oestradiol from ovaries  Hormone action: ◦Hormones act by binding to receptors on or in target cells ◦Magnitude of response depends on: ‣ The concentration of active hormone at target tissue ‣ Receptor number (can be varied) ‣ Affinity of hormone for receptor ‣ Degree of signal amplification (enzymes involved) ◦If hormone cannot cross membrane: ‣ Binds to receptor on cell surface ‣ Activates second messenger pathway ‣ Second internal messenger exerts metabolic effects Often modifying action of enzymes (increase or decrease activation of enzyme) Mechanism of action of steroid hormones: Control of energy balance: ◦Energy intake = expenditure -> body weight stable ◦Energy intake exceeds expenditure -> energy stores (fat) will increase ◦Energy expenditure exceeds intake -> energy stores deplete An overview of energy balance: Control of appetite: ◦Appetite control centre (satiety centre) located in the hypothalamus ◦Hypothalamus contains clusters of neurones referred to as nuclei ◦The arcuate nucleus plays a central role in controlling appetite - found in the hypothalamus ◦Other brain areas are also involved  ‣ Complex and emerging area Arcuate nucleus contains two types of neurones: ◦Primary neurones: sense glucose, fatty acids in blood respond to hormones, can sense chemicals in the blood ◦'Glucosensing' neurones involved in meal initiation and termination ◦Synthesise input co-ordinate a response Neurones of the arcuate nucleus: ◦Two types of primary neurone: ‣ Stimulatory (excitatory) - contain Neuropeptide Y (NPY) and agouti-related peptide (AgRP) -> promotes hunger ‣ Inhibitory - contains pro-opiomelanocortin (POMC) which yields neurotransmitters including alpha-MSH and Beta-endorphin (-> reward system) and CART -> promotes satiety (suppresses appetite) ◦Primary neurones synapse with secondary neurones, the signals are integrated for feeding behaviour Feeding, satiation, satiety -> a sequence of signals: Signals from the gut: Feedback from the gut to the hypothalamus: ◦Ghrelin: ‣ Peptide hormone released from stomach wall when stomach is empty  ‣ Stimulates the excitatory primary neurones in arcuate nucleus to stimulate appetite ‣ Filling of stomach (distension) inhibits ghrelin release ◦PYY (Peptide tyrosine tyrosine): ‣ Short (36 aa) peptide hormone released by cells in the ileum and colon in response to feeding ‣ Inhibits the ARC excitatory primary neurones and stimulates the inhibitory neurones. Effect is to suppress appetite. Hormonal signals from body to the hypothalamus: ◦Leptin: ‣ Peptide hormone released into blood by fat cells (adipocytes) ‣ Has two effects in ARC: Stimulatory inhibitory (POMC) neurones in arcuate nucleus Inhibits excitatory (AgRP/NPY) neurones ‣ Overall effect is therefore to suppress appetite ‣ Leptin induces expression of UCP (uncoupling proteins) in mitochondria, energy dissipated as heat ◦Insulin: ‣ Suppresses appetite by similar mechanism as leptin ‣ Seems to be less important than leptin in this respect ◦Amylin: ‣ Peptide hormone secreted by beta cells in pancreas ‣ Roles not fully understood but known to suppress appetite, decrease glucagon secretion and slow gastric emptying ‣ Pramlintide is an amylin analogue approved for treatment of Type 2 diabetes Other players, promising therapeutics: ◦Large intestine: ‣ Oxyntomodulin ‣ GLP-1 ◦Small intestine: ‣ Cholecystokinin ‣ GIP ◦Adipose: ‣ Adiponectin ‣ Resistin ‣ Visfatin ◦Pancreas: ‣ PP (Pancreatic polypeptide) ◦Appetite control is complex ◦Additional hormonal signals also feedback to brain to influence appetite Overview of control of appetite:  Leptin: ◦Discovered in an inbred strain of obese mice (ob/ob) ◦Used positional cloning to show ob/ob mice have loss of function mutation in leptin gene ◦Similar loss of function leptin gene mutations have also been discovered in humans (although incredibly rare) ‣ These patients respond remarkably to leptin injection ‣ Little effect of leptin if administered to "common obesity" patients ("leptin resistance") Integration of energy balance: a Anatomy of the pancreas: Mt ◦Retro-peritoneal gland that sits in the abdomen ◦Majority of the organ is exocrine ◦Highly vascular and innervated organ for communication with the rest of the body The pancreas: ◦Develops embryologically as an outgrowth of the foregut ‣ Same embryological origin as the brain ◦Exocrine ~98-99% secretion of enzymes involved in the digestion of lipids, carbohydrates and proteins ‣ Digestive enzyme-secreting cells are clustered acini with acinar-draining ducts, which drain into the GI tract ◦Endocrine ~1-2% overall pancreatic mass. Secretion of hormones involved in glucose homeostasis and control of upper gastrointestinal motility and function. ‣ Endocrine cells - islets of Langerhans ‣ Very rapid in the secretion of hormones to respond to target tissues and travel through capillaries Cross-section of the pancreas: sedethode learneddesaddeeded  The Islet of Langerhans: ◦Islets sit very close to blood vessels so they can drain hormones into the blood for fast release ◦Delta cells are involved in the release of somatostatin Pancreatic hormones: ◦Insulin - regulation of blood glucose ◦Glucagon - regulation of blood glucose ◦Somatostatin - islet cell secretion regulation after party ◦Pancreatic polypeptide - GI, through CCK ◦Ghrelin - appetite Nutrient homeostasis: Why is plasma glucose so important?: ◦Brain utilises glucose at the fastest rate in body ‣ Kidney next reliant ‣ Relies on glucose in the blood, sensitive to increases or falls ‣ Non-insulin sensitive ◦Circulating levels (fasting) normally 3.3-6 mmol/l (reference range) ◦After a meal, blood glucose rises to approx 7-8 mmol/l ‣ Renal threshold 10.8 mmol/l Glucosuria, glucose appears in the urine ◦Pregnancy renal threshold decreases - pregnancy is sensitive ◦Elderly renal threshold increases (and excretion of glucose) Hormonal controllers of glucose: Properties of insulin and glucagon: ◦Water soluble hormones: ‣ Carried in plasma - no special carrier/transport proteins  ‣ Short T 1/2 life - 5 mins in order to quickly respond to changes in blood glucose levels ‣ Interact with cell surface receptors on target cells - immediate response ‣ Receptor with hormone bound can be internalised - 'results in inactivation' - receptor is then recycled and returned back to cell membrane to be used again Insulin action: ◦Stimulated by feeding ‣ Affects metabolism of carbohydrate, lipid and protein ◦Target tissues - skeletal muscle, liver and adipose (sensitive tissues) ‣ Glycogenic ‣ Anti-gluconeogenic ‣ Anti-lipolytic and anti-ketogenic ‣ Promotes uptake and favours storage (anabolic) Synthesis and secretion of insulin: ◦Insulin consists of 2 un-branched peptide chains connected by 3 disulphide bridges - this ensures stability (alpha chain is shorter than beta chain) ‣ 51 amino acids ‣ 2 polypeptide chains ‣ (A = 21, B = 30) ‣ 3 disulphide bridges = rigid structure Preproinsulin -> proinsulin -> insulin: Insulin secretion: Margination (movement of storage vesicles to the cell surface): ◦Exocytosis - fusion of vesicle membrane with plasma membrane with release of vesicle contents ◦Requires intracellular calcium signal ◦Daily secretion of insulin is 15% of total stored in the pancreas  ◦1/2 life of insulin is 5 minutes - rapid response Control of insulin secretion: ◦Increased blood glucose stimulates insulin secretion: ‣ Normal fasting level of blood glucose, the rate of insulin secretion is minimal. Blood glucose concentration suddenly increases 2-3 times normal and remains high, insulin secretion increases in two phases ◦1st phase - plasma insulin concentration increases almost 10-fold within 3-5 minutes after acute elevation of the blood glucose -> immediate exocytosis preformed insulin ◦2nd phase - beginning at about 15 minutes, insulin secretion rises a second time and reaches a new plateau in 2-3 hours -> new synthesis of insulin Insulin secretion from beta cells - energy sensing: ◦Increased blood glucose levels stimulate insulin release ◦Glucose transported into Beta cell by facilitated diffusion (GLUT2) ◦Increased plasma [glucose] = increased [glucose] within beta cell -> Glucose is metabolised in the cell, and there is an increase in ATP levels ◦Membrane depolarisation (Katp channels), an influx of extracellular Ca2+ through voltage-dependent Ca2+ channels-> rise in cAMP ◦Increased intracellular Ca2+ triggers exocytosis of insulin-containing secretory granules ◦Insulin secretagogues such as sulphonylureas (SUR) have been targeted as therapeutics based on this mode of action -> act on ATP-sensitive K+ channels, preventing this mechanism (Ca2+ from entering the cell) Metabolic effects of insulin: ◦Reduces blood glucose by: ‣ Stimulating glucose uptake into target cells (GLUT 4) Liver: ◦Increases glycogen synthesis, inhibits its breakdown ◦Inhibits breakdown of amino acids Muscle: ◦Increases amino acid uptake after a meal ◦Promotes protein synthesis Adipose: ◦Increases the storage of triglycerides ◦Inhibits fatty acid breakdown Insulin receptor: ◦Insulin exerts its action: ‣ Insulin receptor (tyrosine kinase receptor), transmembrane dimer: Two identical subunits spanning the cell membrane Two subunits: one alpha, one beta-chain, connected by a single disulphide bond  Alpha chain on exterior of cell membrane - binds the hormone Beta-chain spans cell membrane in a single segment - active component so requires energy, and activates the tyrosine kinase pathway ◦When insulin binds: ‣ Conformational change occurs in receptor: Alpha chains move together and fold around the insulin, beta-chains move together Beta chains become an active tyrosine kinase Initiates a phosphorylation cascade ‣ Increased GLUT 4 expression/translocation and glucose uptake Effect of insulin on cells: Glucagon from alpha cells: ◦Synthesised as pre-proglucagon until signal peptides are cleaved ◦29 amino acids in a single polypeptide chain ◦No disulphide bridges, a flexible structure as it is not stabilised Glucagon action: ◦Stimulated by fasting ◦Affects metabolism of carbohydrate and lipid - catabolic ◦Target tissues - liver and adipose ‣ Raises blood glucose levels (glucose remains constant) ‣ Glycogenolytic (breaks down glycogen) ‣ Gluconeogenic (from amino acids) ‣ Lipolytic (increases fatty acid levels) ‣ Ketogenic ◦Glucagon mobilises energy stores (catabolic) Glucagon secretion: ◦Secreted due to low glucose levels in alpha cells ‣ Synthesised in rER transported to Golgi and packaged into secretory granules ◦Target organ is mainly the liver ‣ Like insulin, glucagon granules move to cell surface in alpha cells by margination and release contents into blood by exocytosis Clinical signs when insulin or glucagon levels are abnormal: ◦Insulin:  ‣ High levels result in hypoglycaemia ‣ Low levels result in hyperglycaemia (diabetes mellitus) ‣ Insulin resistance results in hyperglycaemia and hyperinsulinaemia ◦Glucagon: ‣ High levels worsen diabetes ‣ Low levels may contribute to hypoglycaemia Disorders of blood glucose regulation: ◦Diabetes mellitus or insulin resistance ◦Feature of the metabolic syndrome ◦Affects > 3% of population in the UK ◦Prevalence of 8.3% worldwide ◦Characterised by: ‣ Chronic hyperglycaemia ‣ Long-term clinical complications ‣ Elevated glucose levels in urine ‣ Patients are thirsty Resistance or deficiency - what is our target?: ◦Type 1: ‣ Insulin dependent, insulin deficiency ‣ Abnormal secretory response beta-cell (defective beta cell/beta-cell loss) ◦Type 2: ‣ Non-insulin dependent, associated with insulin resistance ‣ Insulin secretion is increased Beta-cells exhausted, insulin levels appear normal for short period ◦Type 3: ‣ Occurs in type 1 diabetes, insulin resistant, type 2 diabetic through diet and obesity ◦Gestational diabetes: ‣ Third trimester, where mother becomes insulin-resistant ◦MODY (Maturity ONSET diabetes) neonatal diabetes, Wolfram and Alstrom syndrome Insulin resistance 'Ominous Octet': ◦Sites of glucose utilisation (adipose, liver, and skeletal muscle) show decreased response to circulating insulin ◦Affects: ‣ ~25% of general population ‣ ~92% of patients with type 2 diabetes ◦Results from combination of: ‣ Genetic factors ‣ Environmental factors: Obesity Sedentary lifestyle Developmental  Insulin resistance and beta-cell failure: History of diabetes drug discovery: ◦Biguanides (typically metformin) -> derived from goat's rue, used since the middle ages as a herbal treatment ◦Sulphonylureas -> discovered to lower glucose during search for sulphur-based antibiotics for typhoid ◦GLP-1 agonists -> venom in gila monster saliva Site of action of available drugs: What are our goals?: ◦Alleviate symptoms, improve patient well-being ◦Normalise glucose levels long-term ◦Reduce risk of long-term vascular complications Revision slides: edddeee eM ddd____ dd__odTddes___ed