Endocrinology Flashcards
What is a gland?
Invagination of epihelial cells formed during embryonic development which has endocrine or exocrine function.
What is the difference between exocrine and endocrine glands? Give an example.
Exocrine glands have a duct that leads towards the surface through which substances are secreted e.g.: Sweat gland.
Endocrine glands are vascularised and secrete substances into blood e.g.: Thyroid gland.
What are the similarities between the endocrine and nervous systems?
Both secrete substances into blood.
Cells of both can be depolarised.
Share molecules - Some neurotransmitters can be hormones.
Mechanism of action requires interaction with receptors.
What are the differences between the endocrine and nervous systems?
Nervous signals are rapid and controls fast responses such as reflexes.
Hormonal signals are much slower and control long-term processes such as sexual development.
What is autocrine signalling?
Secretion of hormones to act on self and adjacent cells of the same type.
What is paracrine signalling?
Secretion of hormones into the interstitial fluid to act on nearby cells.
What is endocrine signalling?
Secretion of hormones into the bloodstream to act on distant tissues.
What is neurocrine signalling?
Neuronal secretion of hormones into the bloodstream.
How are hormones classified?
According to their solubility type.
Water/Lipid.
What are the properties of water soluble hormones?
Cannot diffuse through the plasma membrane.
Depend on cell-surface receptors.
Activate 2nd messenger systems or activate ion channels.
Which 2nd messenger pathways are commonly activated by hormones?
cAMP
cGMP
Phosphoinositide (PIP2 etc.)
Calcium ions
Give examples of water soluble hormones.
Catecholamines.
Peptide hormones.
What are the properties of lipid soluble hormones?
Able to diffuse through the plasma membrane.
Act on intracellular receptors (nuclear).
Receptors translocate hormone into nucleus where it modulates gene expression.
Longer response than water-soluble pathways.
Give examples of lipid soluble hormones.
Steroid hormones
Thyroid hormones
Vitamin D
What are the classes of hormones? Give an example
Amines - Catecholamines.
Peptide hormones - Insulin.
Steroid hormones - Cholesterol.
How is hormone distribution regulated?
Regulation of production rate - synthesis/secretion.
Regulation of delivery - organ vascularisation.
Regulation of degradation - metabolism.
What is Negative hormonal feedback?
Response which counteracts the change.
What is positive hormonal feedback?
Response which enhances the change.
Give an example of positive hormonal feedback.
Uterine contractions triggered by prostaglandins.
Cause release of oxytocin.
Oxytocin triggers further prostaglandin production hence increases uterine contractions.
Provide the grammature of calcium distribution around the body.
Skeleton/teeth - 1000g
Soft tissues - 10g
Extracellular fluid - 1g
Provide the grammature of phosphate distribution around the body.
Skeleton/teeth - 600g
Soft tissues - 100g
Extracellular fluid - 0.5g
In what form is phosphate distributed in the body?
Hydrogen phosphate 80% - (HPO4)2-
Dihydrogen phosphate 20% - (H2PO6)-
What are the cellular roles of calcium?
Neuromuscular excitability Coagulation Synaptic transmission Second messenger action for hormones/growth factors Regulation of gene transcription Coordination of metabolism Bone formation
What are the cellular roles of phosphate?
Structure of membrane phospholipids Energy metabolism in the form of nucleic phosphates Protein phosphorylation DNA/RNA Bone formation
Other than body support, what is another function of bones?
Storage of calcium which can be accessed at any time.
How is body calcium regulated?
Regulated by the parathyroid hormone which increases plasma calcium levels on demand.
Where is parathyroid hormone synthesised?
Chief cells of the parathyroid gland.
What is the role of parathyroid hormone?
Increase of calcium levels in blood.
Decrease of phosphate levels in blood.
What are the target organs of parathyroid hormone (PTH)?
Bones
Kidneys
GI tract
What is the function of PTH in bones?
Increase in activity of osteoclasts to break down bone matrix and release calcium and phosphate into the blood.
What is the function of PTH in the kidneys?
Slow rate of calcium excretion
Increase rate of phosphate excretion to compensate the inevitable co-release from bones
What is the function of PTH in the GI tract
Promotes formation of calcitrol which increases the rate of calcium and phosphate absorption from food into the blood.
What is calcitrol?
Active form of Vitamin D - a hormone.
How is remodelling of the bone performed?
Osteoclasts demineralise bone by releasing acids that dissolve calcium/phosphate and enzymes that break down the organic matrix.
Osteoblasts lay down new bone and when retired, are trapped in the bone and form part of it as osteoctytes.
Outline the structure of bone.
Calcium and phosphate embedded in an organic matrix that is organised in osteons.
Describe the fast calcium exchange pathway between blood and bone.
Calcium moved from labile pool in bone fluid into plasma by PTH-activated calcium pumps located in the osteocytic-osteoblastic bone membrane.
Describe the slow calcium exchange pathway between blood and bone.
PTH-induced dissolution of the bone. Calcium moved from stable pool in mineralised bone into plasma.
What is the role of vitamin D in the body?
Control of calcium balance.
What is calcitocin and where is it synthesised?
Peptide hormone synthesised in parafollicular cells of the thyroid gland.
What is the function of calcitocin?
Decrease of plasma calcium and phosphate levels.
What causes secretion of calcitocin?
Secreted as a response to high plasma calcium levels and in response to the GI Gastrin hormone.
Describe the process of calcium regulation when plasma calcium levels are high.
High levels of calcium in blood are detected by the PT gland’s parafollicular cells which respond by secreting calcitocin (CT)
CT promotes movement of calcium into the bone matrix which decreases the plasma calcium level.
Describe the process of calcium regulation when plasma calcium levels are low.
Low levels of calcium in blood plasma are detected by the PT gland’s chief/principal cells which secrete PTH.
PTH promotes release of calcium from bone into blood and slows loss of calcium in urine, increasing levels of calcium in blood plasma.
PTH stimulates kidneys to release calcitrol which increases absorption of calcium from food, further increasing blood calcium.
What is the effect of calcitocin in the kidney?
Decreases reabsorption of calcium and phosphate.
What is the effect of calcitocin in bone?
Decreases breaking down of bone tissue to release calcium.
What is the effect of calcitocin in the GI tract
No effect.
What is the effect of calcitocin on blood calcium?
Decreases levels
What is the effect of calcitocin on blood phosphate?
Decreases levels
What is the effect of calcitrol on blood calcium?
Increases levels
What is the effect of calcitrol on blood phosphate?
Increases levels
What is the effect of calcitriol in the kidney?
Increases reabsorption of calcium and phosphate.
What is the effect of calcitriol in bone?
Promotes activity of PTH - Increases break down of bone tissue.
What is the effect of calcitriol in the GI tract?
Increases absorption of calcium and phosphate.
Where is the pituitsry gland located?
Beneath the hypothalamus in a socket of bone (Sella turcica)
How are the pituitary gland and hypothalamus connected?
Hypothalamus drops down through the infundibulum to the posterior pituitary.
What is Neurohypophsis?
Posterior pituirary gland.
What is Adenohypophsis?
Anterior pituitary gland.
What is the function of the posterior pituitary gland?
Release of oxytocin and antidiuretic hormone.
What type of endocrine function is observed in the posterior pituitary gland?
Neurocrine function?
How is oxytocin/diuretic hormone released from the PPG?
Produced by hypothalamic neurones which transport it down the axon to the PPG. They are then stored and released into the circulation.
What is the function of oxytocin?
Milk let down
Uterus contraction during birth
What is the form of the antidiuretic hormone (ADH)?
Regulation of body water volume.
Which hormones are synthesised and secreted by the PPG?
Thyrotrophin releasing hormone (TRH)
Prolactin releasing hormone (PRH)
Prolactin release-inhibiting hormone (PIH) - Dopamine
Corticotropin releasing hormone (CRH)
Gonadotropin releasing hormone (GnRH)
Growth hormone releasing hormone (GHRH)
Growth hormone release-inhibiting hormone (GIRH) - Somatostatin
What type of hormones are released from PPG?
Trophic hormones.
What is the function of trophic hormones?
Release of other hormones.
What is the function of the anterior pituitary gland?
Endocrine function of hormones which act on distant targets.
Autocrine/paracrine function of hormones which affect self/nearby cells.
What re the hormones released from APG?
Thyroid Stimulating Hormone (TSH) Adrenocorticotrophic Hormone (ACTH) Luteinizing Hormone (LH) Follicle Stimulating Hormone (FSH) Prolactin (PRL) Growth Hormone (GH)
What are the trophic hormones released from APG? State their function.
TSH - Secretion of thyroid hormone from thyroid gland
ACTH - Secretion of hormones from the adrenal cortex
LH - Secretion of sex hormones during ovulation
FSH - Secretion of hormones responsible for development of gametes
GH - Causes release of growth factors which regulate growth and energy metabolism
What is the function of prolactin?
Mammary gland development and lactation.
How is hormone production in the piituitary gland regulated?
Negative feedback loops.
Hormones that are released from PG act target tissue which also releases hormones. Increased concentration of the latter causes inhibition of secretion of the former.
What influences growth?
Genetics
Nutrition
Hormones
Environment
How does the growth hormone regulate growth? Outline the processes performed.
Necrosis - Cell death by damage Apoptosis - Programmed cell death Atrophy - Decrease in cell size/number Hypertrophy - Increase in cell size Hyperplasia - Increase in cell number
Where is the growth hormone produced?
APG
What stimulates GH secretion?
GHRH
What inhibits GH secretion?
GIRH (Somatostatin)
How are the growth hormone effects expressed?
Indirectly via growth factors (IGFs) - Somatomedins, secreted by liver cells and skeletal muscle.
How does GH induce growth.
Stimulates bone and cartilage growth via IGFs.
Maintains muscle and bone mass.
Promotes healing/tissue repair.
Modulates metabolism and body composition.
How is GH secretion regulated metabolically?
Decrease in glucose/fatty acids promotes GH secretion.
Increase in glucose/fatty acids inhibits GH secretion
How is GH secretion regulated via the CNS?
Inputs into the hypothalamus affect GHRH/GIRH levels. Secretion increased during deep sleep Secretion decreased during REM sleep Stress increases GH secretion Exercise increases GH secretion
Describe the long-loop negative feedback control of GH secretion.
Mediated by IGFs - Stomatomedins
Inhibit release of GHRH and the action of GHRH on AP
Stimulate release of GIRH (SS)
Describe the short-loop negative feedback regulation of GH secretion.
Mediated by GH itself.
Stimulates release of SS.
What are the effects of GH defficiency during childhood?
Pituitary dwarfism,
Can be partial or complete.
Treated with GH therapy.
What are the effects of excess GH during childhood?
Pituitary adenoma which leads to gigantism.
What are the effects of excess GH during adulthood?
Acromegaly - Large extremities.
Describe the mechanism of effect of GH on cells.
GH stimulates GH receptors.
GH receptors activate JAKs (Janus Kinases) via cross-phosphorylation.
Phosphorylation of GH receptor causes activation of signalling pathways that lead to transcription factor activation and IGF production.
What are IGFs?
Insulin-like Growth Factors.
What are the IGFs present in mammals?
IGF-1
IGF-2
What are the functions of IGFs?
Regulation of cell growth via hypertrophy,
Regulation of cell number via hyperplasia.
Increase protein synthesis
Increase rate of lipolysis in fat (adipose tissue)
Decrease glucose uptake.
What are the types of action exserted by IGFs?
Paracrine
Autocrine
Endocrine
What is the function of insulin in growth regulation?
Enhancement of somatic growth.
Interaction with IGF receptors.
What is the function of thyroid hormones in growth regulation?
Promote CNS development
Enhance GH secretion
What is the function of androgens?
Accelerate pubertal growth
Increase muscle mass
Promote closure of epiphyseal cells
What is the function of Oestrogens in growth regulation?
Decrease somatic growth
Promote closure of epiphyseal cells.
What is the function of glucocorticoids in growth regulation?
Inhibit somatic growth.
What is the function of parathyroid cells?
Production of PTH.
What is the function of thyroid follicular cells?
Production of thyroid hormone.
What is the structure of thyroid hormone?
2 linked tyrosines.
What are the two forms of thyroid hormone present in the body?
T3 - Triiodothyronine
T4 - Tetraiodothyronine
What are the differences in structure of T3 and T4?
T3: 3 iodines Monoiodothyronine + Diiodothyronine T4: 4 iodines 2 Diiodothyronines combined
What are the functional differences between T3 and T4 and how is one converted to the other?
T3 has quadruple biological activity of T4.
Most of T4 is converted to T3 in liver/kidneys
80% of circulating T3 is derived from T4.
90% of TH is secreted as T4
What is the function of Thyroxine binding globulin?
Transport of T3 and T4.
How is TH secretion regulated?
Via negative feedback loops.
What is the function of thyroid parafollicular cells?
Production of calcitocin.
How are follicular cells arranged and why?
Arranged in spheres. Form the sphere walls. Inside is filled with colloid which is a deposit of thyroglobulin that forms a scaffold for thyroid hormone formation.
What is thyroid peroxidase and what is its function?
Membrane bound enzyme which regulates reactions in formation of TH.
What are the reactions regulated by thyroid peroxidase?
Oxidation of iodide to iodine in presence of H2O2
Addition of iodine to tyrosine acceptor residues on thyroglobulin
Coupling of MITs and DITs to form T3 and T4 within the thyroglobulin molecule.
Is colloid intra or extracellular? How?
Extracellular. Its inside the follicle but not the follicular cells.
What is the fate of dietary iodine?
Reduction to iodide before absorption in the small intestine
Used to produce thyroid hormones/precursors.
How is iodide absorbed in the small intestine?
Via iodine/sodium symporter of thyroid epithelial cells.
Describe how thyroid hormones are synthesised.
Amino acids enter the follicle cell to form thyroglobulin.
Tyrosine also enters and binds to thyroglobulin.
Iodination of tyrosine on thyroglobulin.
Coupling of modified tyrosines on thyroglobulin.
Pinocytosis by villi of the follicle cell.
Fusion of thyroglobulin vesicle with lysosome forming a phagolysosome.
Lysosome cleaves thyroglobulin.
T3 and T4 released into plasma by fusion with the cell membrane.
Leftover MIT/DIT deiodinised.
Describe the structure of TSH.
glycoprotein hormone made on one universal (alpha) and one unique (beta) subunit.
How is the alpha subunit of TSH universal?
Also present in LH and FSH.
How does TSH perform its function?
Induces second messenger pathways (cAMP/PLC)
What are the functions of TSH?
Iodide uptake Iodide oxidation Thyroglobulin synthesis Thyroglobulin iodination Colloid pinocytosis into cell Proteolysis of thyroglobulin Cell metabolism/growth
What are the biological effects of TSH?
Increase in number of mitochondria and synthesis of respiratory enzymes leading to increased basal metabolic rate.
Stimulation of mainly catabolic pathways.
Sympathomimetic effects.
Tissue specific effects.
How is the type of metabolism (ana/cata) induced by TSH regulated?
Depends on level of thyroid hormone.
Low - Glucose to glycogen (anabolic)
High - Glycogen to glucose (catabolic)
What are the sympathomimetic effects of TSH?
Increase in receptor number on target cells leading to increased target cell response to catecholamines.
What are the tissue specific effects of TSH?
Cardiovascular - Increased heart responsiveness to catecholamines.
Nervous - Increase in nerve myelination. Increase in neurone development.
How does TSH increase heart’s responsiveness to catecholamines?
Increases heart rate and force of contraction leading to increased cardiac output.
Increases peripheral vasodilation causing excess heat to be lost via body surface.
What are TSH receptors?
Hormone-modulated transcription factors.
Nuclear receptors.
What is the function of TSH receptors?
Modulation of gene expression.
How does activation of TSH receptors modulate gene expression?
Receptors bind to DNA in absence of hormone to repress transcription.
Hormone binding induces a conformational change leading to transcriptional activation.
Describe the differences in structure of TH receptor variants.
Coded for by 2 genes - Alpha and Beta - both can be alternatively spliced giving 2 variants of each hence 4 combinations are availalbe: Alpha-1 Beta-1 Alpha-1 Beta-2 Alpha-2 Beta-1 Alpha-2 Beta-2
Describe the structure of TH receptors.
2 subunits - alpha and beta.
Transactivation domain
DNA binding domain
Ligand binding dimerisation domain
What is the function of the transactivation domain of TH receptors.
Interacts with other transcription factors to activate/repress transcription.
Where is the ligand binding and dimerisation domain located?
carboxy terminus (COOH)
Which variants of TH receptors have the highest affinity for binding DNA? Why?
Heterodimers. Contain a retinoid X receptor (RXR)
How does occupation of the TH receptor modulate it’s transcriptional properties?
When occupied by T3 it can’t bind to co-repressor complex. Binds to co-activator proteins instead.
When unoccupied - represses transcription by binding to the co-repressor complex.
What is the co-repressor complex and what is it’s function?
Histone deacetylase (HDA). Forms compact chromatin hence represses transcription.
What is the co-activator complex and what is its function?
Protein wth Histone Transacetylase activity (HAT).
Induces an open chromatin configuration.
Give examples of genes that are up-regulated by thyroid hormones.
Oxytocin Nerve growth factor Myosin heavy chain alpha Phosphoenolpyruvate carboxykinase Calcium ATPase Sodium/Potassium ATP ase Cytochrome oxidase 6-phosphogluconate dehydrogenase
Give examples of genes that are down-regulated by the thyroid hormone.
Human growth hormone
EGF receptor
Myosin heavy chain beta
Name 5 diseases associated with thyroid dysfunction
Goitre Hypothyroidism Hyperthyroidism Hashimoto's disease Beef-burger toxicosis
What are the causes and symptoms of Goitre?
Caused by overstimulation of thyroid.
Causes enlarged thyroid gland.
May accompany hypo/hyperthyroidism
What are the causes of hypothyroidism?
Thyroid gland failure
Deficiency of TSH/TRH
Insufficient dietary iodine
What are the symptoms of hypothyroidism in infants?
Cretinism: Dwarfed posture Mental deficiency Poor bone development Slow pulse Muscle weakness GI disturbances
What are the symptoms of hypothyroidism in adults?
Myxedemia: Thick/puffy skin Muscle weakness Slow speech Mental deterioration Intolerance to cold
What is hyperthyroidism?
Autoimmune disease, often Grave’s disease cuased by production of Thyroid stimulating immunoglobin (TSI)
What are the symptoms of hyperthyroidism?
Increased basal metabolic rate Excessive sweating Weight loss Muscle weakness Heart palpitations Fluid retention behind eyes
What is Hashimoto’s disease?
Autoimmune disorder causing destruction of thyroid follicles and TSH receptor-blocking antibodies.
How is Hashimoto’s disease treated?
Oral thyroid hormone
What is beef-burger toxicosis caused by?
Consumption of thyroid tissue which was often present in beef burgers.
What are the symptoms of beef-burger toxicosis?
Sleepiness Nervousness Headache Fatigue Weight loss Excessive sweating
What is the function of the exocrine tissue of the pancreas?
Secretion of digestive enzymes for digestion of protein and carbohydrates.
Secretion of bicarbonate ions for neutralisation of duodenal stomach acid.
Describe the structure of the exocrine tissue of the pancreas.
Cells arranged into grape-like clusters.
What cel types are present in the exocrine tissue of the pancreas?
Duct cells
Acinar cells
What is the function of the duct cells of the pancreas?
Secretion of bicarbonate ions.
What is the primary signal of bicarbonate secretion?
Secretin.
What is the function of acinar cells of the pancreas?
Secrete digestive enzymes.
What is the primary signal of digestive enzyme secretion?
Cholecystokinin.
Name the digestive enzymes secreted by acinar cells.
Proteases Pancreatic lipase Phospholipase A2 Lysophospholipase Cholesterol esterase Pancreatic amylase
Name 2 proteases.
Trypsinogen
Chymotrypsinogen
Why are pancreases secreted as inactive zymogens?
Prevent auto-digestion of pancreatic cells which would lead to pancreatitis
What is the function of enteropeptidases?
Cleave proteases to form trypsin.
Trypsin can cleave proteases into more trypsin.
How is exocrine secretion of the pancreas regulated?
Hormones from cells in the stomach/duodenum.
Describe the structure of the endocrine tissue of the pancreas.
Cells arranged into clusters - Islets of Langherans
What are the cells found in the islets of Langherans and what is their function?
Beta cells - Secrete insulin Alpha cells - secrete glycogen Delta cells - Secrete somatostatin PP cells - secrete pancreatic polypeptide hormone Epsilon cells Secrete ghrelin
When is insulin secreted?
After feeding.
What is meant by the anabolic function of insulin?
Leads to formation of larger molecules from smaller ones
Describe the process of insulin synthesis.
Preproinsulin mRNA translated into preproinsulin. Signal peptide in preproinsuin causes movement to ER with the ribosome still attached.
Preproinsulin converted to proinsulin.
Proinsulin processed proteolytically.
Prohormone convertase 1 cleaves aa31/32
Prohormone convertase 2 cleaves aa64/65
Carboxypeptidase trims ends.
In the end, 51aa molecule of insulin is made and a C-peptide.
How is insulin stored in beta cells?
Stored in vesicles of the trans-golgi network.
Stored in Immature Secretory Granules (ISGs).
Once insulin concentration is high enough, insulin crystalises forming Mature Secretory Granules (MSGs).
Describe the structure of insulin crystals.
Hexamers around 2 zinc ions.
Describe the phases of insulin release.
Phase 1 - Exocytosis of vesicles closest to the plasma membrane. 15 min
Phase 2 - Release of vesicles moving from the middle of the cell. 120 min.
Describe the pathway of glucose stimulated insulin secretion.
Sense: Glucose enters the beta cell via the high Km glucose transporter - Glut 2.
Glucose converted into G6P by a high Km glucokinase.
Signal: Glucose metabolism causes rise in ATP and closure of potassium ATPase channels which causes depolarisation
Response: Depolarisation of the beta cell opens calcium VGCs which causes an influx of calcium.
Calcium induces exocytosis of insulin MSGs.
Gice examples of molecules which stimulate insulin secretion.
Glucose
Leucine
Arginine
Free fatty acids
Give examples of molecules which potentiate insulin secretion.
Glucagon-like peptide-1
ACh
Give examples of molecules which inhibit insulin secretion.
Somatostatin
Adrenaline
Noradrenaline
Describe the structure of the insulin receptor.
2 alpha and 2 beta subunits linked by disulphide bonds.
Recruits and activates signalling molecules.
Describe the hypoglycaemic actions of insulin receptor activation in liver.
Glycogenesis - Inhibits glycogenolysis/gluconeogenesis
Lipogenesis - Inhibits lipolysis
Describe the hypoglycaemic action of insulin receptor activation in muscle tissue.
Glucose transport
Glycogenesis - Inhibits gluconeogenesis and glycogenolysis
Lipogenesis - inhibits lipolysis
Protein synthesis/amino acid transport - inhibits protein catabolism.
Describe the hypoglycaemic effects of insulin receptor activation in adipose tissue,
Glucose transport
Lipogenesis - Inhibits lipolysis
When is glucagon secreted?
During fasting
How is the action of glucagon catabolic?
Breaks down large molecules to form smaller ones.
What sort of receptor is the glucagon receptor?
GaPCR
What is the action of glucagon in liver, muscle and adipose?
Liver - Glycogenolysis/gluconeogenesis
Muscle - No receptors - no ffect
Adipose - Lipolysis.
What is diabetes mellitus?
Chronically raised blood glucose due to lack of insulin or deficiency in insulin action
What are the most common types of diabetes mellitus?
Type 1
Type 2
Give 3 rare examples of diabetes mellitus.
Gestational diabetes
Genetic defects
Endocrinopathies of beta cells
What is the onset of type 1 diabetes?
Onset is sudden and during childhood.
What is the onset of type 2 diabetes?
Onset gradual and during middle-age
Which type of diabetes is more common? Give percentages.
Type 2 is more common with 85-90% of the cases being type 2.
10-15% of diabetes cases are type 1.
What is type 1 diabetes?
An autoimmune disease caused by insulitis and expression of auto-antibodies.
How does insulitis cause type 1 diabetes?
Inflammation of islet cells by chronic inflammatory mononuclear infiltrate.
What are the constituents of chronic inflammatory mononuclear infiltrate?
T-lymphocytes
Macrophages
Which auto-antibodies are associated with type-1 diabetes?
ICAs - Islet Cell Auto-Antibodies
IAAs - Insulin Auto-Antibodies
IA2 - Islet secretory protein
GAD - Glutamic Acid Decarboxylase
Why can only type 1 diabetes be detected before onset?
Type 1 diabetes shows severe symptoms whereas type 2 may not show any.
What can elicit type 1 diabetes?
Family history
Viruses (environmental)
Diet
Toxins
How is diabetes a polygenetic disease?
Many genes contribute to onset e.g.: HLA genes which are involved in antigen presentation.
Which viruses may cause type 1 diabetes?
Coxsackie-B virus
Rubella
Mumps
What are the dietary causes of type 1 diabetes?
Cow’s milk excess
Nitrosamines of smoked fish
Which toxins may cause type 1 diabetes?
Streptozotocin
Alloxin
What are the stages of deveopment of type 1 diabetes?
Genetic predisposition
Environmental trigger
Autoimmune destruction of beta cells
Diabetes mellitus
What are the causes of type 2 diabetes?
Insulin resistance
Beta cell dysfunction/death
Family history
Environmental conditions
How does insulin resistance occur in type 2 diabetes?
Reduction of sensitivity of target cells to insulin.
What are the environmental conditions associated with development of type 2 diabetes?
Excess food consumption
Lack of exercise
Economics
Describe the stages of development of type 2 diabetes.
Obesity causes insulin resistance, increasing the demand for insulin.
Demand not met by beta cells causing hyperglycaemia.
Hyperglycaemia leads to dysfunction/death of beta cells.
Death of beta cells causes diabetes mellitus.
What is a quicker route of development of type 2 diabetes associated with obesity?
Beta cell death can be caused directly by hyperlipidemia.
How is diabetes mellitus diagnosed using the oral glucose tolerance test?
Measuring blood sugar after an overnight fast:
Diabetes if plasma glucose >7mmol/L; Impaired fasting glycaemia if plasma glucose 6.1-7mmol/L
75g of glucose consumed, plasma glucose measured after 2h:
Diabetes confirmed if >11.1mmol/L
Impaired Glucose Tolerance if 7.8-11.1mmol/L.
How is diabetes diagnosed using a HbA1c test?
Measurement of glycated haemoglobin over a period of weeks.
Accurate diagnosis of glycaemic control.
Norm at 48mmol/L
How is type 1 diabetes managed?
Insulin injections or islet transplant.
How is type 2 diabetes managed?
Exercise
Diet
Oral hypoglycaemics
Insulin injections
What are the functions of different types of hypoglycaemics? Give examples.
Increase insulin secretion.
e.g.: Sulphonylureas, Meglitinides, Incretins.
Increase insulin sensitivity.
e.g.: Thiazolidinediones (giltiazones), Biguanides.
Decrease glucose absorption.
e.g.: Alpha-glucosidase inhibitors.
How do sulphonylureas increase insulin secretion? Give examples.
Decrease probability of opening of potassium ATPase channels
Bind to sulphonylurea receptors
Stimulate insulin secretion.
e.g.: Tolbutamide, Glibenclamide, Gliclazide.
How do Meglitinides increase insulin secretion? Give examples.
Target sulphonylurea receptors but a different site. Shorter action.
How do incretins increase inslin secretion?
GLP-1 (glucagon-like peptide-1), Gastric Inhibitory Peptide (GIP). Supress glucagon release Stimulate insulin release Only work in presence of glucose
What inhibits GLP-1 and GIP?
Dipeptidyl peptidase-4.
Give examples of drugs that exploit the DLP-1 pathway of insulin secretion. How do they do it?
Exenatide - GLP-1 agonist resistant to degradation by DPP-4
Liraglutide - GLP-1 analogue
Vildagliptin - DPP-4 inhibitor
Sitagliptin - DPP-4 inhibitor
How do giltiazones/TZDs increase insulin sensitivity? Give ezamples.
Bind to peroxisome proliferator-activated receptor-gamma (PPAR-gamma) expressed in adipocytes.
Increase expression of insulin-sensitive genes
e.g.: Troglizatone - hepatotoxic effects
Rosiglitazone - cardiotoxic effects.
Give examples of insulin-sensitive genes that are expressed by TZDs and their effects.
Glut 4 - Increases glucose uptake
Lipoprotein lipase - increases lipogenesis
Fatty acyl CoA synthetase - Decrease circulating free fatty acids
How do biguanides increase insulin sensitivity? Give an example.
Increase hepatic acod oxidation and glucose uptake
Decrease hepatic glucose production
Reduce LDL cholesterol/triglyceride levels.
Target AMP-activated protein kinases
e.g.: Metformin
How do alpha-glucosidase inhibitors? decrease glucose absorption? Give examples.
Delay carbohydrate absorption Lower postprandial blood glucose concentration. Inhibit disaccharide enzymes e.g.: Acarbose Miglitol
What are gonads?
Reproductive organs.
What is the function of gonads?
Production of reproductive cells via gametogenesis.
Production of sex hormones.
What are the sex hormones produced by gonads and what is their function?
Androgens - Masculinising agents.
Oestrogens - Feminising agents.
Give ezamples of androgens and their site of production.
Testosterone - testes.
Dehydroepiandosterone (DHEA) - Adrenal cortex.
Give examples of oestrogens and their site of production.
Oestradiol - ovaries.
Progesterone - ovaries.
What are the male gonads and what is their specific function?
Testes - Spermatogenesis and testosterone secretion.
What are the female gonads and what is their specific function?
Ovaries - Oogenesis. Secretion of Progesterone and Oestradiol. Maturation of oocyte. Ovulation.
What is spermatogenesis?
Production of spermatozoa.
What is Oogenesis?
Production of ova.
What types of hormones regulate reproductive function? Give examples.
Hypophysiotrophic hormones - GnRH
Pituitary gonadotropins - LH, FSH.
What is the function of pituitary gonadotropins?
Regulation of reproductive function:
Maturation of gametes.
Stimulation of sex hormone secretion.
Describe the events of Stage 1 of gametogenesis.
Mitosis:
Proliferation of germ cells (Oogonia/Spermatogonia) - genetically identical daughter cells (diploid).
How is stage 1 of gametogenesis different in males and females?
Males - occurs from puberty onwards.
Females - occurs in foetal development.
Describe the events of stage 2 of gametogenesis.
Meiosis:
Generation of genetically distinct haploid cells.
Occurs from puberty onwards in both sexes.
Describe the events specific to spermatogenesis.
Spermatogonia undergo mitosis and differentiation to form primary spermatocytes.
Primary spermatocytes undergo meiosis to form secondary spermatocytes (haploid)
Secondary spermatocytes undergo meiosis to form spermatids (haploid).
Spermatids undergo differentiation to form spermatozoa.
How long does spermatogenesis take and how many spermatozoa does 1 spermatogonium yield?
Process takes 64 days.
1 spermatogonium yields 8 spermatozoa.
Where are sertoli cells and what is their function?
Testes. Form the blood-testes barrier. Provide nutrients for developing germ cells Produce seminal fluid Produce androgen-binding protein (ABP).
How do sertoli cells respond to FSH?
Produce chemical signals for proliferation and differentiation of germ cells.
Secrete inhibin which regulates FSH production (-ve feedback).
Describe the structure of a spermatozoan.
Head: Nucleus which holds DNA
Acrosome containing digestive enzymes.
Midpiece: Contains mitochondria for generation of energy for propulsion.
Tail: Flagellum which contracts to promote propulsion.
What is the function of Leydig cells?
Secretion of testosterone.
What is the function of testosterone?
Inhibits secretion of LH by APG and GnRH by HT.
Stimulates sertoli cells.
Misc action on reproductive tract/other organs.
Describe the specific events that occur during oogenesis.
Oogonia undergo mitosis/differentiation to form a primary oocyte.
Primary oocyte undergoes meiosis to form a secondary oocyte (haploid)
Secondary oocyte undergoes meiosis to form an ovum. (haploid).
What is the yield of oogenesis?
6mln oogonia form 1 ovum.
Describe the events that occur during follicle growth.
Primordial follicle comprised of an oocyte and granulosa cells forms a primary follicle as the oocyte cytoplasm expands.
Granulosa cells multiply and form early theca in, now, a preantral follicle. As the preantral follicle forms an early antral follicle, a fluid filled antrum starts to form and the theca layer is distinct.
The follicle matures and becomes the Graafian follicle.
What are the tissue laters resent in a mature follicle?
Oocyte surrounded by zona pellucida that connects it to the granulosa cells. The oocyte is almost surrounded by antral fluid however connects to the inner layer of the follicle - granulosa - by a thin cumulus oophorous, also made from granulosa cells. The granulosa cells are surrounded by a thicker layer of theca cells.
Describe the fate of the follicle during ovulation.
Follicle is released. Remaining graunosa/theca forms a corpus luteum which degrades and becomes corpus albicans.
Describe the hormonal changes that occur during the 1st week of the menstrual cycle (follicular phase).
Decrease in progesterone, inhibin and oestradiol relieves inhibition of gonadotropins (GnRH/FSH/LH).
Increase in LH increases androgen production in theca cells.
Increase in FSH causes converstion of androgens to oestradiol in granulosa cells and enlargement of 25 preantral/early antral follicles.
Increase in oestradiol acts on follicles to increase proliferation of granulosa cells.
Further increase in oestradiol increases inhibin B secretion which causes decrease in FSH due to -ve feedback.
Descrive the events that occur during the 2nd week of the menstrual cycle (follicular phase).
Increase in oestradiol detected in plasma. Acts on APG to inhibit FSH/LH secretion. (FSH also inhibited by inhibin B from granulosa cells).
Decrease in FSH causes death of all but 1 follicles. The one follicle increases FSH receptor number to counter the decrease of FSH.
Describe the events that occur during the 2nd week of the menstrual cycle (ovulatory phase).
Oestradiol levels sustained - Enhances Lh/GnRH secretion,
GnRH pulses + action of oestradiol on APG stimulates an LH surge.
LH acts on granulosa cells to stimulate ovulation.
Describe the events that occur during the 3rd and 4th week of the menstrual cycle (luteal phase).
LH surge stimulates transformation of granulosa/theca into corpus luteum.
Increase in progesterone/oestradiol and inhibin a from corpus luteum causes a decrease in LH/FSH.
Decrease in LH/FSH causes degeneration of corpus luteum.
Progesterone/oestradiol concentration in plasma decreases in absence of corpus luteum which relieves inhibition on APG.
Unless pregnant - a new cycle begins.
What hormones control the menstrual cycle?
Hypophysiotropic hormone (GnRH) Gonadotropins (FSH/LH) Gonadol hormones: Sterioids (Oestradiol, Progesterone) Peptide hormone (Inhibin)
How does Oestradiol control the menstrual cycle?
Low concentration - inhibits FSH/GnRH secretion
High concentration - Promotes FSH/GnRH secretion.
How does Progesterone control the menstrual cycle?
Inhibits FSH.
How does inhibin control the menstrual cycle?
Inhibits FSH secretion.
What are the stages of fertilisation?
Binding of spermatozoan to zona pellucida. Acrosomal reaction. Penetration through zona pellucida. Fusion of plasma membranes. Sperm nucleus enters egg cytoplasm.
Define Conceptus.
Anything derived from the zygote
Define Totipotent.
Having the capacity to reproduce an individual.
Define Monozygotic twins.
Identical twins that arise from cleavage/separation of conceptus cells.
Define Dizygotic twins.
Fraternal twins. Arise from fertilisation of 2 eggs.
Define Blastocyst.
Stage of embryo development where cells begin to differentiate and lose totipotency.
Describe the process of early development.
Zygote divides mitotically to form a 16-32 cell totipotent conceptus.
Conceptus reaches uterus in 3-4 days.
Conceptus differentiates into a blastocyst - loses totipotency.
Progesterone prepared the lining of the uterus for implantation - Blastocyst embeds into the wall.
Describe the hormone level trends during pregnancy.
During the first weeks, tiny progesterone spike observed when uterus wall is prepared. Progesterone steadily increases until delivery.
Oestrogen level increases until delivery, lower than progesterone.
Human chorionic gonadotropin levels boom at 1-3 months. Plateau from 3+ months.
All levels floor during delivery.
