Endocrinology Flashcards
What is endocrinology?
Study of hormones (and their gland of origin), their receptors, the intracellular signalling pathways and associated diseases.
What is the difference between endocrine and exocrine?
Endocrine: glands ‘pour’ secretions into the blood stream
Exocrine: glands ‘pour’ secretions into ducts that lead to the target tissue
What are some of the major chemical messengers present in the body?
Endocrine hormones - can be local or distant
Neurotransmitters - local to the synapse e.g. ACh, GABA
Neuroendocrine - secretion from nerves into blood e.g. ADH, Oxytocin
What do paracrine and autocine mean?
Autocrine: a cell-produced substance that has an effect on the cell by which it is secreted
Paracrine: a cell-produced substance that has an effect on the cell by which it is secreted (near neighbours)
What are the two major types of hormones?
Water-soluble: Unbound, bind to a surface receptor, short half-life, fast clearance e.g. peptides, monoamines
Fat-soluble: protein-bound, diffuse into cell, long half-life, slow clearance e.g. thyroid hormone, steroids
What are the major types of endocrine hormone?
Steroids - adrenal cortex, ovaries, testes
Proteins and polypeptides - growth hormone, insulin
Tyrosine derivatives - adrenaline, thyroxine, 5HT
What does negative feedback do?
Negative feedback involves close regulation of hormone action to prevent over-activity.
It occurs post-stimulus at all levels: transcription, translation, post-translational processing, storage.
The conditions or products from hormone action suppress its further release.
What does positive feedback do?
The end products of the action cause more of that action to occur in a feedback loop. This amplifies the original action.
Time-dependent.
e.g. Oestrogen-induced LH surge in menstrual cycle
What are cyclical variations of hormone release?
Periodic variations in hormone release influenced by Seasonal changes, Developmental stages, Circadian rhythms, Diurnal (daily) cycle, Sleep.
e.g. Growth Hormone
What are the different timelines of hormone action?
Hormone action can be:
- Rapid: msec / sec (nerve impulse; haemostasis)
- Delayed: mins/hours/days (growth, cell division)
Can be induced by very small quantities (picogram to nanogram).
Allows for multiple layers of medical intervention.
What are the major receptors involved in signal transduction?
Ion channels - Ca, Na, Cl, K
Membrane-bound steroid receptors - indirect effect on gene expression
Neurotransmission - AChR, GABA, 5-HT
Growth factor receptors - EGFR, VEGF. IGFs, GH
Nuclear steroid receptors - direct effect on gene expression
GPCRs
What are GPCRs?
G-protein coupled receptors
Ubiquitous (>800 sequences)
>50% of all drugs mimic or inhibit various GPCRs
GPCR is made up of 5 parts:
Receptor – gives primary specificity
Three G-proteins – a, B, Y (Ga further specificity)
Enzyme to modulate second messenger (e.g. cAMP)
What are the different a subunits in GPCRs and their effects?
G as: POSITIVE, makes cAMP,
e.g. b2 agonists, PGE2 via EP2 receptor (uterine relaxation)
G ai: NEGATIVE, prevents cAMP
a adrenergic agonists - ergometrine
PGE2 via EP1 and EP3 receptors (uterine contraction; Misoprostol)
G aq: POSITIVE, makes IP3 and DAG
Oxytocin receptor, PGF2 via FP2a receptor
(uterine contraction; severe PPH; Carboprost)
What are the different parts of the pituitary gland?
- Anterior pituitary (Adenohypophysis): embryonic invagination of pharyngeal epithelium, epithelioid nature of cells, contains Rathke’s pouch
- Posterior pituitary (Neurohypophysis): neural tissue outgrowth of hypothalamus, large numbers of glial cells
- Pars intermedia (part of anterior): secretes Melanocyte-stimulating hormone
Why is it important that the pituitary gland is highly vascularised?
Carries hypothalamic releasing and inhibitory hormones to anterior pituitary through the Hypothalamic hypophysial portal system.
Which hormones come from which part of the pituitary gland?
Anterior pituitary: Thyrotropes (Thyroid stimulating hormone), Somatotropes (Growth hormone), Pro-opiomelancortin (POMC) which gives rise to Corticotropes like Adrenocorticotrophic Hormone
(ACTH) and Melanocyte Stimulating Hormone (MSH), Gonadotropes (LH and FSH), Lactotropes like prolactin.
Posterior pituitary: Anti-diuretic hormone (ADH) and Oxytocin
What regulates pituitary hormone secretion?
Mostly the hypothalamus
Anterior pituitary uses hypothalamic releasing and hypothalamic inhibitory hormones through the hypothalamic-hypophysial portal system.
Posterior pituitary use Magnocellular neurones.
Supra-optic (ADH) and Paraventricular nuclei (Oxytocin)
whose signals terminate in posterior pituitary.
What are the major effects of growth hormone?
PROTEIN DEPOSITION INCREASED: increased cellular amino acid uptake, transcription, translation, decreased protein catabolism.
FAT METABOLISM INCREASED: increased fatty acid mobilisation, Acetyl-CoA formation, lead body mass, may see ketosis.
REDUCED CARBOHYDRATE UTILISATION: promotes insulin resistance, increased hepatic glucose synthesis, insulin secretion, decreased glucose uptake by tissues.
How does Growth Hormone secretion vary over time?
Growth hormone is a protein hormone (191 amino acids)
Released in 8-9 bursts/24 hrs – irregular
Usually in slow-wave sleep phase
Max. secretion in adolescence
Decreases ~14%/decade
Replacement therapy given in the evening
What are the two types of bone growth?
Appositional growth - growth in diameter (bone lamellae)
Interstitial growth - growth in length (Epiphyseal plate)
How does growth hormone promote bone growth?
Growth hormone promotes chondrocyte expansion through hyperplasia and hypertrophy which maintains epiphyseal cartilage matrix.
- Degrade; osteoblast invasion
- New bone added to diaphysis
Balance between chondrocyte growth/degradation important
When is growth hormone release stimulated and inhibited?
Growth hormone secretion
Stimulates: trauma/stress, Ghrelin, increase in AA in blood, deep sleep, GHRH, Fasting, Exercise, decrease in blood glucose/fatty acids, testosterone and oestrogen.
Inhibits: growth hormone inhibitory hormone, somatomedins (IGF-I and IGF-II), increase blood glucose/fatty acids, aging, exogenous growth hormone, obesity.
What are the causes of Child Growth Hormone Deficiency?
50% of cases idiopathic
Pituitary gland atrophy (Pan hypo-pituitarism and Isolated – only GH affected)
Reduced Growth Hormone Releasing Hormone Secretion
Craniopharyngiom: Benign tumour – residue from Rathke’s pouch (mouth epithelium)
What are some of the causes of short stature?
Normal genetic shortness Growth delay Chromosomal disorders Intra-uterine mal-development Endocrine gland disorders Cartilage and bone disorders Disorders of food absorption Heart, lung and kidney problems Steroids and radiation Psychological distress
What is the phenotype of Child Growth Hormone Deficiency?
Ateliosis – proportional short stature but normal features/intelligence
(achondroplasia – non-proportional)
Mismatch between chronological age and skeletal (bone) age.
Reduced lean body mass
Delayed onset of puberty – augmentation with hCG/testosterone
How do you diagnose Growth Hormone Deficiency?
Insulin tolerance test (ITT) tests hypothalamic:pituitary:adrenal axis
Bolus of IV insulin
Hypoglyceamia
Physiological stress
GH and cortisol released to buffer this
GH measured every 15-30 mins for 2 hrs
GH levels < 5ng/ml GHD OR < 3ng/ml severe GHD
What is the treatment for Growth Hormone Deficiency?
Must be done BEFORE epiphyseal plates close
Aim for “acceptable” final adult height
Recombinant growth hormone used – Somatropin
Daily injections of Somatropin
More consistent plasma level using Sub-cutaneous rather than intra-muscular
What are the symptoms and signs of Adult Growth Hormone Deficiency?
Symptoms: Decreased energy level, Social isolation, Lack of positive well-being, Depressed mood, Increased anxiety.
Signs:
Increased body fat, LDL cholesterol, plasma fibrinogen
Decreased insulin sensitivity, muscle mass, bone density, HDL cholesterol, extra-cellular fluid.
What are thyroid hormones?
Incorporate iodine
Thyroxine (T4): 93% metabolically active hormone
Triiodothyronine (T3): 7% metabolically active hormone
T3 has greater potency and shorter half life
Calcitonin involved in plasma Ca regulation
What are the major actions of thyroid hormones?
Significantly increase metabolic rate
Increase activity of mitochondria and Na/K ATPase
Increase growth rate and brain growth in children
Reduced sexual function and libido
Cardiovascular increase
Respiration increase
Pscychoneurotic tendencies and muscle tremor
Increase in gut motility
Increase vitamin requirements
Stimulation of carbohydrate and fat metabolism
What is the action of TSH?
TSH increases all the known secretory activities of the thyroid glandular cells.
TSH causes…
Increased proteolysis of stored thyroglobulin
Increased activity of the iodide pump
Increases “iodide trapping” rate
Increased iodination of tyrosine
Forms thyroid hormones.
Increased size and secretory activity of thyroid cells
Increased number of thyroid cells and infolding of follicle thyroid epithelium
Releases thyroid hormones
What is hyperthyroidism?
Thyroid increase 2-3X normal size due to follicle hyperplasia.
Symptoms include: High state of excitability, Heat intolerance, Increased sweating, Weight loss, Diarrhoea, Anxiety, Muscle weakness, Tremor of hands, Extreme fatigue, Inability to sleep, Exopthalmos.
What is Graves’ Disease?
Most common form of hyperthyroidism
Autoimmune disease
Antibodies raised against thyroid TSH receptor
Thyroid-stimulating immunoglobulins (TSIs) bind TSH receptor and induce continual cell stimulation (~12 hours)
Persistent high level of TSI-induced thyroid hormone secretion suppresses anterior pituitary TSH formation.
TSH concentrations < normal (zero)
What is hypothyroidism?
Not enough thyroid hormone
Symptoms: Fatigue and extreme somnolence, Prolonged sleep periods (2 to 14 hrs/day), Extreme muscular sluggishness, Reduced heart rate, cardiac output, blood volume, Increased body weight, Constipation, Mental sluggishness, Failed growth functions- depressed hair growth of hair and scaliness of the skin, Myxoedema (oedematous body appearance).
What are the main hypothyroidism diseases?
Hashimoto’s disease: Autoimmune thyroiditis (inflammation), Gradual decline in thyroid hormone secretion, Gland destroyed.
Myxoedema: Total lack of thyroid hormone, Non-pitting oedema
Endemic Goitre: Enlarged thyroid gland, Insufficient dietary iodine
Cretinism: Fetal extreme hypothyroidism, Poor growth, Impaired brain development
What is Hyperparathyroidism?
Excess PTH synthesis/secretion
Can be primary or secondary
What is primary Hyperparathyroidism?
Frequent cause of hypercalcaemia
Third most common endocrine disorder
Defect in parathyroid glands – benign tumour
(rarely malignant)
Increased PTH, calcitriol, Ca2+; decreased PO43-
Normal calcitriol/phosphate changes signals seen which indicate normal kidney function but increased cell numbers mean PTH levels increased overall.
What is secondary Hyperparathyroidism?
Arises through defective feedback control - compensation for hypocalcaemia.
Usually associated with chronic kidney disease
Concept of Renal Bone Disease: No renal response to PTH causing poor renal Ca2+ reabsorption, no vit. D activation, poor intestinal Ca2+ reabsorption
(hypocalcaemia), High bone demineralisation as Ca2+ released - Renal osteodystrophy.
Negative feedback mechanisms fail; PTH levels remain elevated.
What are the adrenal hormones?
Two major groups of adrenocortical hormones
Mineralocorticoids
Glucocorticoids
Both have genomic effects, inducing changes in gene expression.
Where are the different adrenal hormones present?
- Mineralocorticoids like Aldosterone: Zona glomerulosa
ECF mineral balance (Na+, K+) - Glucocorticoids like Cortisol, Androgens, and some oestrogen: Zona fasciculata
Increasing blood sugar - DHEA and Androstenedione: Zona Reticularis
- Adrenaline and Noradrenaline: Adrenal medulla
What does Aldosterone do?
Principal mineralocorticoid (90%) but Cortisol, (glucocorticoid) also gives some mineralocorticoid activity.
Main actions:
- Na+/water reabsorption
- K+ homeostasis (generally secretion)
What is primary aldosteronism?
Primary aldosteronism, also known as primary hyperaldosteronism or Conn’s syndrome, refers to the excess production of the hormone aldosterone from the adrenal glands, resulting in low renin levels. This abnormality is caused by hyperplasia or tumors. Many suffer from fatigue, potassium deficiency and high blood pressure which may cause poor vision, confusion or headaches. Symptoms may also include: muscular aches and weakness, muscle spasms, low back and flank pain from the kidneys, trembling, tingling sensations, numbness and excessive urination.
What happens when there is Mineralocorticoid Deficiency?
Severe renal NaCl wasting:
Significant increased renal Na+Cl- loss, reduced [Na+]ECF, reduced plasma volume (Dehydration, Reduced blood pressure, Circulatory shock)
Hyperkalaemia:
Reduced renal K+ excretion, Increased [K+]ECF leading to Hyperkalaemia > 5 mmol/l and Cardiotoxicity.
Mild acidosis becuase H+/K+ exchange less efficient
Death within two weeks. Basis of Addison’s disease.
Where in the body is Aldosterone’s action particularly important?
Sweat glands - conservation of NaCl in hot environment
Salivary glands - conservation of NaCl to prevent excessive loss in saliva
Colon - Enhanced Na+ absorption, reduces faecal Na+ loss
Without it: Poor absorption of Na+, Cl-, other anions, Poor water absorption gives Diarrhoea.
What is cortisol?
Principal glucocorticoid, accounts for ~95% activity.
Corticosterone provides further activity.
Follows a Circadian rhythm of secretion:
- Highest early morning (~20mg/dl)
- Low in evening/night (~5mg/dl)
Involved in metabolic regulation, stress response (physical/mental) and defence against inflammation.
What are the physiological effects of cortisol?
CARBOHYDRATE METABOLISM: Increased gluconeo- genesis: Hepatic gluconeogenic enzymes activated
Amino acid mobilisation from extra-hepatic tissues
Antagonism of insulin-induced hepatic gluconeo-genesis inhibition.
FAT METABOLISM: Increased Fatty acid mobilisation, Oxidation of fatty acids, Metabolism favours fat burning not glucose.
PROTEIN METABOLISM: Reduction in extra-hepatic cellular protein through decreased protein synthesis and amino acid transport, increased protein catabolism.
What kinds of stress might initiate the release of cortisol?
Trauma, infection, surgery, intense hot or cold, debilitating diseases, physical restraint, noradrenaline/sympathomimetic drugs, subcutaneous injection of necrotizing substances.
How does stress initiate the release of cortisol?
Stress on the body
Hypothalamic release of CRH and hypophysial circulation in the pituitary
In the anterior pituitary, corticotrophs release ACTH
ACTH acts on zona fasciculata which causes the secretion of cortisol
Cortisol has direct negative feedback on the anterior pituitary and the hypothalamus
Cortisol acts to cause Gluconeogenesis, Protein Metabolism, Fat mobilisation and Lysosome stabilisation to relieve the stress.
What processes occur in inflammation?
Tissue damage causes release of pro-inflammatory mediators: Histamine, Bradykinin, Proteases, Prostaglandins, Leukotrienes which increase blood flow to area - Erythema.
Increased capillary permeability causes exudation of virtually pure plasma and tissue fluid clots. Causes non-pitting oedema.
Infiltration of leukocytes after several days or weeks leads to ingrowth of fibrous tissue facilitates healing.
How does Cortisol impact the inflammation process?
- Stabilizes lysosomal membranes, reducing cell/ lysosome rupture
- Decreases capillary permeability, preventing plasma exudation into tissues
- Suppresses immune system, reducing Lymphocyte reproduction, T-lymphocyte numbers, Antibodies
- Attenuates fever by reducing IL-1 release from white blood cells (key stimulus for hypothalamic temp control)
- Decreases Extravasation of white blood cells into inflamed area and Phagocytosis of damaged cells
- Inhibits synthesis of Prostaglandins and Leukotrienes
What are the different abnormalities in Adrenocortical Secretion?
Primary Aldosteronism – Conn’s Syndrome
Hypoadrenalism - Addison’s Disease
Hyperadrenalism - Cushing’s syndrome
What is Addison’s disease?
Hypoadrenalism
Reduced adrenocortical hormone synthesis by adrenal cortices.
Commonly caused by primary atrophy or injury of the adrenal cortices due to autoimmunity, TB or a tumour.
Impaired pituitary function
Reduced ACTH secretion means there is decreased cortisol and aldosterone production. Adrenal glands may atrophy because of a lack of ACTH stimulation.
Glucocorticoid deficiency due to lack of cortisol production - failure to stimular gluconeogenesis, mobilise protein or fat.
May lead to a Addisonian Crisis.
Treatment: mineralocorticoids and/or glucocorticoids
What are the possible causes of Cushing’s syndrome?
Many abnormalities of Cushing’s syndrome ascribed to hyper-cortisolism.
- Adrenal cortex adenomas
- Abdominal carcinoma: “Ectopic” ACTH secretion”
- Abnormal hypothalamic function: Increased CRH
increased ACTH release
- Anterior pituitary ACTH-secreting adenomas:
Causes adrenal hyperplasia and excess cortisol secretion (Cushing’s disease)
What’s the difference between Cushing’s syndrome and Cushing’s disease?
Cushing’s disease: Excess anterior pituitary secretion of ACTH is primary problem (70%)
Increased [ACTH]plasma and [cortisol]plasma
Cushing’s syndrome: Primary overproduction of cortisol by adrenal glands (~20-25%). Cortisol feedback inhibition reduces anterior pituitary ACTH secretion
Fat mobilization to thoracic and upper abdominal regions. Excess steroids causes oedematous face.
Androgenic potency may causes acne and hirsutism.
What is the pancreas’ exocrine and endocrine functions?
Exocrine function: Digestive enzymes through the pancreatic acini into Duodenum Endocrine function: Hormones into blood Insulin: b-cells Glucagon: a-cells Somatostatin: d-cells
What are the effects of insulin on metabolism?
INCREASED CARBOHYDRATE METABOLISM - increased hepatic glucose uptake, hepatic glycogen formation, decreases hepatic gluconeogenesis
INCREASED FAT METABOLISM - increased fat storage, increased hepatic fatty acid synthesis, prevents fatty acid release in adipose tissue, promotes Glc uptake
INCREASED PROTEIN METABOLISM - increased cellular amino acid uptake, increased transcription and translation, decreased protein catabolism, decreased gluconeogenesis
What are the effects of decreased blood glucose?
Decreased blood glucose reduces pancreatic insulin secretion.
Decreased insulin secretion promotes hepatic Glycogen breakdown into glucose-6-phosphate (via glycogen phosphatase) and then into hepatic glucose (via glucose phosphatase).
How does the absence of the pancreas affect growth?
Insulin and growth hormone act synergistically to each promote the uptake of different amino acids.
No insulin OR growth hormone - minimal effect
No insulin AND growth hormone - no growth
What happens in a state of insulin deficiency?
Hormone-sensitive lipases activity increases, causing triglycerides to be hydrolysed and an increased concentration of fatty acids in the plasma.
Excess Acetyl-CoA formed so excess Acetoacetate synthesised, which is converted to ketone bodies causing Ketosis – metabolic acidosis.
Protein catabolism increases, increased conc of protein in plasma (significant protein wasting).
How are amino acids involved in insulin secretion?
Amino acids Arginine and Lysine
If administered in absence of increased blood glucose, there are small increases in insulin secretion.
If administered when blood glucose elevated, there is doubled glucose-induced insulin secretion.
Amino acids potentiate glucose stimulus for insulin secretion.
Links insulin to insulin-induced amino acid transport and protein synthesis
How are gastrointestinal hormones involved in insulin secretion?
A number of hormones knowns as incretins:
- Gastrin, Secretin, CCK
- Glucagon-like peptide-1 (GLP-1)
- Glucose-dependent insulinotropic peptide (GIP)
Enhance insulin secretion when blood glucose elevated
Inhibit a-cell glucagon secretion
These GI hormones induce “anticipatory” increase in blood insulin.
Significant augmentation of glucose-induced insulin secretion.
Incretins used as drug targets (metformin, tolbutamide, gliclazide)
What’s the timeline of insulin’s response?
Fasting [Glucose]blood ~5mmol/l
Sudden prolonged Glc increase (2-3X) initiates a biphasic insulin response.
- Initial spike ~10x [insulin]plasma (secretion of preformed insulin, increase not maintained)
- Slower increase ~20 mins later
Higher [insulin]plasma reached
How does insulin control whether fat or glucose are used?
High insulin levels means that glucose utilised principally, fat utilisation depressed and excess blood glucose stored as liver glycogen, fat, and muscle glycogen.
Low insulin levels means increased fat utilisation and nhibition of glucose use (except brain).
Blood glucose levels determines the level of insulin (acts as a switch). Growth hormone, cortisol, adrenaline glucagon also involved.
What is diabetes mellitus?
Impaired carbohydrate, fat, and protein metabolism
Type 1 diabetes (insulin-dependent) - lack of insulin secretion
Type 2 diabetes (non-insulin-dependent) - decreased tissue sensitivity to insulin (resistance)
Baseline [glucose]blood higher and peaks higher for longer. Normally returns to baseline within 2 hours.
Signs: polyphagia, polydypsia, polyurea
What is glucagon?
Secreted by a-cells as response to decreased [glucose]blood.
Functions diametrically opposed to insulin
Principal effect to increase [glucose]blood
Increased [glucose]blood –ve feedback on glucagon secretion
What are the main effects of glucagon?
GLUCOSE METABOLISM: promotes Glycogenolysis and increases Gluconeogenesis, increasing blood glucose
FAT METABOLISM: Activates adipose cell lipase and inhibits hepatic triglyceride storage, increasing availability of fatty acids
Also acts to enhance heart strength, increases blood flow to kidneys, enhance bile secretion and inhibit gastric acid secretion.
What is Thyrotropin-releasing hormone?
Hypothalamus hormone
Peptide structure
Stimulates secretion of thyroid-stimulating hormone and prolactin by thyrotropes
What is Corticotropin-releasing hormone?
Hypothalamus hormone
Peptide structure
Causes release of adrenocorticotropic hormone by corticotropes
What is Growth hormone–releasing hormone?
Hypothalamus hormone
Peptide structure
Causes release of growth hormone by somatotropes
What is Growth hormone inhibitory hormone (somatostatin)?
Hypothalamus hormone
Peptide structure
Inhibits release of growth hormone by somatotropes
What is Gonadotropin-releasing hormone?
Hypothalamus hormone
Causes release of luteinizing hormone and follicle-stimulating hormone by gonadotropes
What is Dopamine or prolactin-inhibiting factor?
Hypothalamus hormone
Amine structure
Inhibits release of prolactin by lactotropes
What is Growth hormone?
Anterior pituitary hormone
Peptide structure
Stimulates protein synthesis and overall growth of most cells and tissues
What is Thyroid-stimulating hormone?
Anterior pituitary hormone
Peptide structure
Stimulates synthesis and secretion of thyroid hormones (thyroxine and triiodothyronine)
What is Adrenocorticotropic hormone?
Anterior pituitary hormone
Peptide structure
Stimulates synthesis and secretion of adrenocortical hormones (cortisol, androgens, and aldosterone)
What is Prolactin?
Anterior pituitary hormone
Peptide structure
Promotes development of the female breasts and secretion of milk
What is Follicle-stimulating hormone?
Anterior pituitary hormone
Peptide structure
Causes growth of follicles in the ovaries and sperm maturation in Sertoli cells of testes
What is Luteinizing hormone?
Anterior pituitary hormone
Peptide structure
Stimulates testosterone synthesis in Leydig cells of testes; stimulates ovulation, formation of corpus luteum, and oestrogen and progesterone synthesis in ovaries
What is Antidiuretic hormone (Vasopressin)?
Posterior pituitary hormone
Peptide structure
Increases water reabsorption by the kidneys and causes vasoconstriction and increased blood pressure
What is Oxytocin?
Posterior pituitary hormone
Peptide structure
Stimulates milk ejection from breasts and uterine contractions
What are Thyroxine (T4) and triiodothyronine (T3)?
Thyroid hormones
Amine structure
Increases the rates of chemical reactions in most cells, thus increasing body metabolic rate
What is Calcitonin?
Thyroid hormones
Peptide structure
Promotes deposition of calcium in the bones and decreases extracellular fluid calcium ion concentration
What is Parathyroid hormone?
Parathyroid hormone
Peptide structure
Controls serum calcium ion concentration by increasing calcium absorption by the gut and kidneys and releasing calcium from bones
What is Cortisol?
Adrenal Cortex hormone
Steroid structure
Has multiple metabolic functions for controlling metabolism of proteins, carbohydrates, and fats; also has anti-inflammatory effects
What is Aldosterone?
Adrenal Cortex hormone
Steroid structure
Increases renal sodium reabsorption, potassium secretion, and hydrogen ion secretion
What are Norepinephrine and epinephrine?
Adrenal medulla hormones
Amine structure
Same effects as sympathetic stimulation
What is Oestrogen?
Ovaries hormone
Steroid structure
Promotes growth and development of female reproductive system, female breasts, and female secondary sexual characteristics
What is Progesterone?
Ovaries hormone
Steroid structure
Stimulates secretion of “uterine milk” by the uterine endometrial glands and promotes development of secretory apparatus of breasts
What is Human chorionic gonadotropin hormone?
Placenta hormone
Peptide structure
Promotes growth of corpus luteum and secretion of oestrogens and progesterone by corpus luteum
What is Human somatomammotropin?
Placenta hormone
Peptide structure
Probably helps promote development of some fetal tissues, as well as the mother’s breasts
What are the major classes of endocrine hormone?
Peptides: linear or ring structures, may bind to carbohydrates, stored in secretory granules, released in pulses or bursts, cleared by circulating enzymes
Amines: use a-adrenoreceptors (PIP2 to IP3 which increases Ca and DAG which activates protein kinase C) OR b-adrenoreceptors (ATP to cAMP via adenylyl cyclase, activates cAMP-dependent protein kinase)
Iodothyronines: 99% protein bound, incorportation of iodine on tyrosine molecules, conjugation to give T£ and T4.
Cholesterol-derivates and steroids: VitD enters cells directly to nucleus, adrenocortical and gonal steroids enter cell and pass to nucleus to induce response, altered to active metabolite and bind to cytoplasmic receptor
How are T3 and T4 made?
- Thyroglobulin is synthesised and discharged into the follicle lumen
- Iodide is actively transported into the cell from the blood
- Iodide is oxidised to iodine
- Iodine is attached to thyrosine in collois, forming DIT and MIT
- Iodinated tyrosines are linked together to form T3 and T4
- Thyroglobulin colloid is endocytosed and combined by lysosome
- Lysosomal enzymes cleave T3 and T4 from thytoglobulin
What is the process of steroid hormone action?
Steroid hormone diffuses through plasma membrane and binds to receptor
Receptor-hormone complex enters nucleus and binds to GRE
Binding initiates transcription of gene to mRNA
mRNA directs protein synthesis
How is hormone secretion controlled?
Basal secretion - continuously or pulsatile
Superadded rhythms - day-night cycle
Release inhibiting factors
Releasing factors
How is hormone action controlled?
Hormone metabolism - increased metabolism to reduce function
Hormone receptor induction - induction of LH receptors by FSH in follicle
Hormone receptor down regulation
Synergism - combined effects of two hormones amplified
Antagonism - one hormone opposes the other hormone
How does the posterior pituitary store Oxytocin and ADH?
Hypothalamic neurons synthesise oxytoxin or ADH.
Oxytoxin and ADH are transported down the axons of the hypothalamic-hypophyseal tract to the posterior pituitary.
Oxytocin and ADH are stored in axon terminals in posterior pituitary.
When hypothalamic neurons activated, hormones released.
What might be the reasons for pituitary dysfunction?
Tumour mass effects
Hormone excess
Hormone deficiency
Hormone tests are important for investigation. If hormone tests are abnormal, perform MRI pituitary.
What does growth hormone do?
GH binds to the liver and other tissues
Produces insulin-like growth factor
Skeletal - increased cartilage formation and skeletal growth
Extraskeletal - increased protein synthesis, cell growth and proliferation
Fat metabolism - increased fat breakdown and release
Carbohydrate metabolism - increased blood glucose, anti-insulin effects
What does thyroid hormone do?
Accelerate food metabolism Increases protein synthesis Stimulation of carbohydrate metabolism Enhances fat metabolism Increase in ventilation rate Increase in CO and HR Brain development in foetal and postnatal life Growth rate accelerated
What does appetite, hunger, and satiety mean?
Appetite: the desire to eat
Hunger: the need to eat
Satiety: feeling of fullness (disappearance of appetite)
What are the BMI values?
<18.5 Underweight 18.5-24.9 Normal 25.0-29.9 Overweight 30.0-39.9 Obese >40 Morbidly obese
What are the risks of obesity?
Type 2 diabetes Hypertension Coronary heart disease Stroke Osteoarthritis Obstructive sleep apnea Carcinoma (breast, endometrium, prostate, colon)
Why do we eat?
Internal physiological drive to eat
Feeling that prompts the thought of food and motivates food consumption
External psychological drive to eat
In the absence of hunger
How do the hypothalamus and other factors regulate eating?
Lateral hypothalamus (hunger centre)
Ventromedial hypothalamic nucleus (satiety centre)
NPY, MCH, AgRP, Orexin, Endocannabinoid increase desire to eat.
a-MSH, CART, GLP-1, Serotonin decrease desire to eat.
Peripheral factors like leptin (white fat) and insulin (pancreas) also have an impact.
Gut peptides like Ghrelin, PYY, GLP1 and CKK.
Central areas - NPY in arcuate nucleus
Hypothalamus - POMC, MSH, Agouti-related peptide, MC3 and MC4 receptors
What is the action of Leptin?
Increase in Leptin decreases appetite
Expressed in white fat
Binds to Leptin receptor (cytokine receptor family in hypothalamus), switches off appetite and is immunostimulatory.
Blood levels increase after meal and decrease after fasting.
What does Peptide YY do?
Structurally similar to NPY, binds NPY receptors.
Secreted by neuroendocrine cells in ileum, pancreas and colon in response to food.
Inhibits gastric motility and reduces appetite.
What does Cholecystokinin do?
Receptors present in pyloric sphincter - delays gastric emptying, gall bladder contraction and insulin release.
What does Ghrelin do?
Expressed in stomach.
Action stimulates growth hormone release, stimulates appetite,
Blood levels high when fasting, fall on re-feeding.
Levels lower after gastric bypass surgery.
What does POMC do?
Proopiomelanocortin (POMC) is the pituitary precursor of circulating melanocyte stimulating hormone (α-MSH), adrenocorticotropin hormone (ACTH), and β-endorphin.
If POMC is not present, ACTH deficiency.
What increases satiety as you eat?
Stretch receptors in stomach increase satiety
Release of CCK, GLP, insulin, PYY increase sateity
More long-term, leptin, nutrients and temp regulate satiety and hence energy balance
How do Ca levels affect PTH?
When serum Ca decreases, this is detected by the parathyroid and parathyroid hormone increases.
This results in increased Ca reabsorption, increased bone modelling and increased Ca absorption.
Small change in Ca, big change in PTH.
Why might the levels of PTH change?
Appropriately - to maintain calcium balance
Inappropriately - to cause calcium imbalance
What are the consequences of hypocalcaemia?
Parasthesia Muscle spasm: Hands and feet, Larynx, Premature labour Seizures Basal ganglia calcification Cataracts ECG abnormalities - long QT interval – Long QT interval
Why do we need to calculate a corrected calcium value?
Low serum albumin means there is a low total serum calcium but not a low ionised calcium
corrected calcium =
total serum calcium + 0.02 * (40 – serum albumin)
What are some of the causes of hypocalcaemia?
Undermineralised bone - pseudofractures
Vitamin D deficiency - lack of sunshine, dietary input
Cannot absorb calcium (or phosphate)
What are the signs for Hypocalcaemia?
Chvostek’s sign: tap over facial nerve, look for spasm of facial muscles
Trousseau’s sign: inflate blood pressure cuff to 20mmHg above systolic for 5 mins - pointed hand
What are some of the consequences of Hypoparathyroidism?
Thymic aplasia Immunodeficiency Cardiac defects Cleft palate Abnormal facies
What are some of the causes of Hypoparathyroidism?
Can be caused by surgical damage (removing the thyroid or neck cancer surgery)
Radiation treatment
Autoimmune effect - isolated or polyglandular type 1
Infiltration - haemochromatosis and wilson’s disease
What happens in Hypoparathyroidism?
Low Calcium
Low PTH
High Phosphate
Inappropriate response
What is pseudohypoparathyroidism?
Rare resistance to parathyroid hormone
Sometimes seen in genetic disorders - Mutation with deficient Ga subunit.
Signs: short stature, obesity, round facies, mild learning difficulties, subcutaneous ossification, short fourth metacarpals and other hormone resistance.
Low Ca, High PTH, High Phosphate
Appropriate behaviour
What is pseudopseudohypoparathyroidism?
Pseudo phenotype
Ca metabolism is normal
PTH, Ca, Phosphate is normal
What are the consequences of hypercalcaemia?
Thirst Polyuria Nausea Constipation Confusion - coma Renal stones ECG abnormalities - Short QT
What are the causes of hypercalcaemia?
Malignancy – bone mets, myeloma, PTHrP, lymphoma
(80% due to a single benign adenoma on parathyroid)
Primary hyperparathyroidism
Thiazides
Thyrotoxocosis
Sarcoidosis
Familial hypocalciuric / benign hypercalcaemia
Immobilisation
Milk-alkali
Adrenal insufficiency
Phaeochromocytoma
What is tertiary hyperparathyroidism?
Renal failure (can't activate vitamin D) Can't absorb calcium from gut or kidnet Can borrow Ca from bone but only for a bit Increased Ca, PTH, PO4 Inappropriate response
What’s occurring in the fasting state of a non-diabetic human?
All glucose comes from liver (and a bit from kidney)
Breakdown of glycogen and gluconeogenesis
Glucose is delivered to insulin independent tissues, brain and red blood cells
Insulin levels are low
Muscle uses FFA for fuel
Some processes are very sensitive to insulin, even low insulin levels prevent unrestrained breakdown of fat
What’s occurring in the fasting state of a non-diabetic human?
After feeding (post prandial) - physiological need to dispose of a nutrient load
Rising glucose (5-10 min after eating) stimulates insulin secretion and suppresses glucagon
40% of ingested glucose goes to liver and 60% to periphery, mostly muscle
Ingested glucose helps to replenish glycogen stores both in liver and muscle
High insulin and glucose levels suppress lipolysis and levels of non-esterified fatty acids (NEFA or FFA) fall
Where does insulin and glucagon secretion occur?
Islets of Langerhans in the endocrine pancreas
a cells - secrete glucagon
B cells - secrete insulin
Paracrine ‘crosstalk’ between a and B cells is physiological
How does glucose initiate the release of insulin?
Glucose enters B cell by GLUT2 glucose transporter with help from glucokinase.
Glucose undergoes metabolism.
K channel closes and depolarises cell membrane
Ca channel opens, Ca enters cell
Insulin secretory granules secrete insulin
How does insulin allow glucose into the cell?
Insuliin binds to insulin receptor causing an intracellular signalling cascade.
Intracellular GLUT4 vesicles mobilized to plasma membrane, glucose entry into the cell via GLUT4.
What is the action of insulin?
Supresses hepatic glucose output
Glycogenolysis
Gluconeogenesis
Increases glucose uptake into insulin sensitive tissues (muscle, fat)
Suppresses Lipolysis and Breakdown of muscle
What is the action of glucagon?
Increases hepatic glucose output Glycogenolysis Gluconeogenesis Reduce peripheral glucose uptake Stimulate peripheral release of gluconeogenic precursors (glycerol, AAs) through lipolysis and muscle glycogenolysis and breakdown
How does diabetes mellitus cause morbidity and mortality?
Acute hyperglycaemia which if untreated leads to acute metabolic emergencies diabetic ketoacidosis (DKA) and hyperosmolar coma (Hyperosmolar Hyperglycaemic State )
Chronic hyperglycaemia leading to tissue complications (macrovascular and microvascular)
Side effects of treatment- hypoglycaemia
What are some of the major complications of diabetes mellitus?
Diabetic retinopathy Diabetic nephropathy Stroke Cardiovascular disease Diabetic neuropathy
What are the different types of diabetes?
Type 1
Type 2
Includes gestational and medication induced diabetes
Maturity onset diabetes of youth (MODY), also called monozygotic diabetes
Pancreatic diabetes
“Endocrine Diabetes” (acromegaly/Cushings)
Malnutrition related diabetes
How is diabetes diagnostically defined?
Symptoms and random plasma glucose > 11 mmol/l
Fasting plasma glucose > 7 mmol/l
No symptoms - GTT (75g glucose) fasting > 7 or 2h value > 11 mmol/l (repeated on 2 occasions)
HbA1c of 48mmol/mol (6.5%)
What is the pathogenesis of Type 1 diabetes?
An insulin deficiency disease characterised by loss of beta cells due to autoimmune destruction
Beta cells express antigens of HLA histocompatability system perhaps in response to an environmental event(?virus)
Activates a chronic cell mediated immune process leading to chronic ‘insulitis’
What happens to glucose metabolism in Type 1 diabetes?
Failure of insulin secretion leads to continued breakdown of liver glycogen and u nrestrained lipolysis and skeletal muscle breakdown providing gluconeogenic precursors and inappropriate increase in hepatic glucose output and suppression of peripheral glucose uptake
Rising glucose concentration results in increased urinary glucose losses as renal threshold (10mM) is exceeded
Failure to treat with insulin leads to increase in circulating glucagon (loss of local increases in insulin within the islets leads to removal of inhibition of glucagon release), further increasing glucose.
Perceived ‘stress’ leads to increased cortisol and adrenaline. Progressive catabolic state and increasing levels of ketones.
What happens to glucose metabolism in Type 2 diabetes?
A consequence of insulin resistance and progressive failure of insulin secretion (but insulin levels are always detectable)
Impaired insulin action leads to
- Reduced muscle and fat uptake after eating
- Failure to suppress lipolysis and high circulating FFAs
- Abnormally high glucose output after a meal
- Even low levels of insulin prevent muscle catabolism and ketogenesis so profound muscle breakdown and gluconeogenesis are restrained and ketone production is rarely excessive
How does the pathophysiology between type 1 and type 2 diabetes differ?
Type 1 diabetes
Severe insulin deficiency due to autoimmune destruction of the B cell (initiated by genetic susceptibility and environmental triggers)
Type 2 diabetes
Insulin resistance and impaired insulin secretion due to a combination of genetic predisposition and environmental factors (obesity and lack of physical activity)
What are the principles for treatment of Type 2 diabetes?
Control of symptoms
Prevention of acute emergencies, ketoacidosis, hyperglycaemic hyperosmolar states
Identification and prevention of long-term microvascular complications
Limited evidence yet that glucose control per se reduces cardiovascular events (confirmed by recent clinical trials, ACCORD, ADVANCE) in the short-term
But long-term follow-up indicates a modest reduction in IHD from tight glucose control if started at diagnosis
HbA1c 50mmol/mol (6.5%) (as low as possible in those not on insulin or sulphonylureas)
What are the two major types of insulin you can take for diabetes?
Basal insulin: long-acting
Prandial/meal-time insulin: fast-acting (imitating normal insulin release after meals
What is modern insulin therapy like for T1 diabetics?
Separation of basal from bolus insulin to mimic physiology
Pre-meal rapid acting boluses adjusted according to pre-meal glucose and carbohydrate content of food to cover meals
Basal insulin should control blood glucose in between meals and particularly during the night
Basal insulin is adjusted to maintain fasting blood glucose between 5–7 mmol/L
Why does T1 and T2 diabetes require different insulin approaches?
T1:
Autoimmune condition (β-cell damage) with genetic component
Profound insulin deficiency
T2:
Insulin resistance
Impaired insulin secretion and progressive β-cell damage but initially continued insulin secretion
Excessive hepatic glucose output
Increased counter-regulatory hormones including glucagon
What is modern insulin therapy like for T2 diabetics?
Many people with T2DM require insulin – particularly later in the disease course or in individuals with poor glycaemic control on other medications
In general, basal insulin is initiated followed by addition of a prandial insulin where necessary
Long-acting basal insulin analogues are associated with lower risk of symptomatic, overall and nocturnal hypoglycaemia1
Prandial insulins mimic meal-time insulin secretion2 and their faster action allows for greater flexibility at mealtimes3
Premix insulins are also available
What are the different insulin options?
Human basal insulin: intermediate-acting, 90mins onset, peak action 2-4 hrs, duration 24 hrs e.g. NPH
Basal analogues: steady state after 1-2 days, duration 24hrs, e.g. Detemir, Glargine U100
Rapid-onset analogues: 10-20mins onset, peak action 30-90mins, duration 2-5hrs e.g. insulin aspart, insulin lispo, insulin glulisine
Human premixed 70/30: 30mins onset, peak action 2-8 hrs, duration 24hrs e.g. Mixtarol, Humulin M3
What are the advantages and disadvantages of basal insulin in Type 2
Advantages: Simple for the patient, adjusts insulin themselves, based on fasting glucose measurements
Carries on with oral therapy
Less risk of hypoglycaemia at night
Disadvantages: Doesn’t cover meals
Best used with long-acting insulin analogues which are considered expensive.
What are the advantages and disadvantages for pre-mixed insulin?
Advantages: Both basal and prandial components in a single insulin preparation
Can cover insulin requirements through most of the day
Disadvantages: Not physiological, Requires consistent meal and exercise pattern, Cannot separately titrate individual insulin compononents, increased risk for nocturnal hypoglycaemia and fasting hyperglycaemia if basal component does not last long enough
Often requires accepting higher HbA1c goal of <7.5% or ≤8% (<58 or ≤64 mmol/mol)
How is hypoglycaemia defined?
Low plasma glucose causing impaired brain function neuroglycopenia 3mmol/l Clinical definition of hypoglycaemia:
Mild: self-treated (but many episodes are asymptomatic)
Severe: requiring help for recovery (Except in children)
3.9 mmol/L used clinically
How is hypoglycaemia classified into levels?
Level 1 (Alert value): Plasma glucose <3.9 mmol/l (70 mg/dl) and no symptoms Level 2 (Serious biochemical): Plasma glucose <3.0 mmol/l (55 mg/dl) Non-severe: Patient has symptoms but can self-treat and cognitive function is mildly impaired Severe: Patient has impaired cognitive function sufficient to require external help to recover (Level 3)
What are the common hypoglycaemia symptoms?
Autonomic: trembling, palpitations, sweating, anxiety, hunger
Neuroglycepenic: difficulty concentrating and speaking, confusion, weakness, drowsiness, dizziness, visual impairment
Non-specific: nausea, headache
What are the risk factors of severe hypoglycaemia in T1D?
History of severe episodes HbA1c <6.5% (48 mmol/mol) Long duration of diabetes Renal impairment Impaired awareness of hypoglycaemia Extremes of age
What are risk factors of severe hypoglycaemia in T2D?
Advancing age Cognitive impairment Depression Aggressive treatment of glycaemia Impaired awareness of hypoglycaemia Duration of MDI insulin therapy Renal impairment and other comorbidities
What is the impact of non-severe hypoglycaemia on a patient?
Reduced quality of life in both T1DM and T2DM
May cause fear of hypoglycaemia
May cause psychological morbidity
What are the consequences of hypoglycaemia?
Seizures, comas, cognitive dysfunction, accidents, fear, poor quality of life, CVD risk
What are the established risk factors to initiate diabetes screening?
Low HbA1c; high pre-treatment HbA1c in T2DM Long duration of diabetes A history of previous hypoglycaemia Impaired awareness of hypoglycaemia (IAH)* Recent episodes of severe hypoglycaemia Daily insulin dosage >0.85 U/kg/day Physically active (e.g. athlete) Impaired renal function
What are the glucose targets for a T1 diabetic?
Aim for lowest HbA1c not associated with frequent hypoglycaemia
It may sometimes be appropriate to relax targets in patients with advanced disease, complications or limited life expectancy
In such patients, aim for glucose levels low enough to minimize symptoms of hyperglycaemia
What are the glucose targets for a T2 diabetic?
Aim for lowest HbA1c not associated with frequent hypoglycaemia
HbA1c <7.0% (53 mmol/mol) is usually appropriate for recent-onset disease
It may sometimes be appropriate to relax targets (e.g. severe complications, advanced co-morbidities, cognitive impairment, limited life expectancy, unacceptable hypoglycaemia from stringent control)
How can patient education help prevent hypoglycaemia?
Discuss hypoglycaemia risk factors and treatment with patients on insulin or sulphonylureas
Educate patients and caregivers on how to recognize and treat hypoglycaemia
Instruct patients to report hypoepisodes to their doctor/educator
Consider enrolling patients with frequent hypoglycaemiain a blood glucose awareness training programme
How should insulin medication be adjusted for hypoglycaemia?
If on an SU (for T2DM), revise dose or consider changing to another drug class
If on basal-bolus insulin, check BG before each meal every day
Ensure medication is dosed correctly
Consider insulin adjustments:
Regular/soluble insulin → rapid-acting insulin
NPH/isophane → insulin analogues
Adjusting insulin in relation to exercise
How should a hypoglycaemic attack be treated?
Recognise the symptoms so that they can be treated
Confirm the need for treatment
Treat with 15g of fast-acting carbohydrate
Retest in 15mins to ensure blood glucose is greater tjam 4.0mmol/l
Eat a long-acting carbohydrate to prevent recurrence of symptoms
What are the metabolic changes that occur in pregnancy?
Increased erythropoetin, cortisol, noradrenaline High cardiac output Plasma volume expansion High cholesterol and triglycerides Pro thrombotic and inflammatory state Insulin resistance
What are some of the potential gestational syndromes that could occur in pregnancy?
Pre-Eclampsia Gestational Diabetes Obstetric cholestasis Gestational Thyrotoxicosis Transient Diabetes Insipidus Lipid disorders Postnatal depression Postpartum thyroiditis Postnatal autoimmune disease Paternal Disease
