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

Summary

This lecture introduces the endocrine system, explaining key features of homeostasis, endocrine hormones, glands, and hormone actions. It covers hormone classifications and mechanisms of hormone action. It is a good resource for undergraduate-level biology students.

Full Transcript

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

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