Met physiology Flashcards
Toxic sources of acid
Methanol poisoning –> formic acid
Ethylene glycol poisoning –> glycol acid, oxalic acid
Death zones of acidity/alkalinity
> 8
<6.8
Normal anion gap
with K+ = 8-12mEq/L
without K+ = 12-16mEq/L
Causes of normal gap acidosis
Diarrhoea Laxative abuse Fistulas NG tube Carbonic anhydrase inhibitors Renal tubular acidosis Ureteric diversion Excessive HCl intake
Causes of low anion gap acidosis
Ketoacidosis Lactic acidosis Ethylene glycol poisoning Methanol poisoning Uraemia Isoniazid Iron overload Salicyclates Aspirin Paraldehyde
Causes of low gap acidosis
Hypoalbuminaemia Haemorrhage Nephrotic syndrome Intestinal obstruction Liver cirrhosis
Where is bicarbonate reabsorbed?
PCT
70-90%
Via carbonic anhydrase
Types of carbonic anhydrase
CA IV = through membrane
CA II = within cell
Which cells function more in acidosis?
Alpha intercalated cells
Which cells function more in alkalosis?
Beta intercalated cells
How do potassium levels change with acid base balance?
Acidosis = hyperkalaemia Alkalosis = hypokalaemia
Features of acromegaly
Acral enlargement Sweating Menstrual upset Headache Arthritis Carpal tunnel Diabetes Impotency Hypertension Visual changes Sleep apnoea Coronary artery disease
Which cells release GH?
Somatotrophs
What inhibits GH release?
Somatostatin
IGF-1
How do the adrenal glands develop?
From the gonadal ridges
Become invaded by primordial germ cells but gonads split off
Then becomes invaded by neural crest cells (become the medulla)
Becomes surrounded by a layer of mesenchymal cells (becomes the capsule)
Blood supply within the adrenal gland
Sub scapular plexus in ZG
Venous sinusoids in ZF
Medullary plexus in ZR and medulla
Steroidogenic pathway
Cholesterol –> pregnenolone –> steroids
What enzyme inactivates cortisol in the kidney? Why does it do this?
11bHSD-2
Converts it to cortisone
Prevents excessive activation of the mineralocorticoid receptor
Causes of primary hyperaldosteronism?
Conn’s syndrome
Adrenal adenoma
Bilateral adrenal hyperplasia
Glucocorticoid remediable aldosteronism
Promotor regions for CYP11B2 and CYP11B1 get switched around
Causes ACTH release to stimulate aldosterone release
Treatment with glucocorticoid drugs to suppress ACTH
Symptom of apparent mineralocorticoid excess
Inhibition of 11b-HSD2
Allows cortisol to activate the mineralocorticoid receptor
E.g. liquorice consumption
Features of Liddle syndrome
Low renin Low aldosterone Hypertension Metabolic alkalosis Hypokalaemia
HPA axis
CRH –> ACTH –> cortisol
Cortisol inhibits CRH and ACTH
ACTH inhibits CRH
ACTH inhibits itself
What else stimulates the HPA axis?
CRH stimulated by stress, catecholamines, AgII and ghrelin
ACTH stimulated by AgII, IL-1, IL-2, IL-6
What else inhibits the HPA axis?
CRH inhibits by ANP, opioids and oxytocin
ACTH inhibited by CRIF
Causes of Cushing’s syndrome
Iatrogenic (too much drug) Pituitary adenoma Ectopic ACTH tumour (commonly lung) Adrenal adenoma Bilateral adrenal hyperplasia
Features of Cushing’s syndrome
Hypertension Hyperglycaemia Moon face Thin skin Proximal myopathy Osteoporosis Ulcers
Features of Addison’s disease
Fatigue Myalgia Anorexia Weight loss Hyper pigmentation
Features of Addisonian crisis
Low BP
Low glucose
Low Na
High K
Addison’s disease replacement steroids
Hydrocortisone = cortisol Fludrocortisone = aldosterone
Congenital adrenal hyperplasia
Due to 21-hydroxylase deficiency
Cannot produce GCs or MCs from pregenonlone
Instead produces large amounts of androgens
–> salt loss, virilisation, adrenal hyperplasia
Noradrenaline synthesis pathway
L-tyrosine –> L-dopa –> dopamine –> noradrenaline –> adrenaline
Noradrenaline vs adrenaline effects
Noradrenaline more with BP control
Adrenaline more with glucose control
Where are chromaffin cells found/
Adrenal medulla
Sympathetic chain
Organ of Zuckerkandl
Bladder wall
Symptoms of catecholamine excess
Hypertension Hyperglycaemia Tachycardia Dyspnoea Diaphoresis Weight loss
How are catecholamines inactivated?
By COMT = catechol-O-methyltransferase
What is a phaeochromocytoma?
Tumour of the chromatin cells of the adrenal medulla
Treatment for phaeochromocytoma
Alpha blockers Beta blockers MUST HAVE BOTH Avoid opiates Surgical resection
How much calcium is protein bound?
Around 50%
What happens to calcium levels in acid-base changes?
Acidosis = more ionised Alkalosis = less ionised
Where do the parathyroid glands originate from?
3rd and 4th pharyngeal pouches
Cell types in parathyroid gland
Chief cells
Oxyphil cells
How is PTH made?
PreproPTH
–> proPTH by RER
–> PTH by Golgi
Releases in vesicles
How does the CASR work?
GPCR Calcium binding activates PLC Inhibits cAMP signalling Reduces PTH secretion and transcription Increases breakdown of stored PTH
Other regulators of PTH release?
Supressed by activated vitamin D
Stimulated by phosphate
Inhibited by cinacalcet
Actions of PTH
Decreases kidney calcium excretion
Increases kidney phosphate excretion
Increases bone calcium and phosphate resorption
Increases intestinal calcium and phosphate absorption
Vitamin D activation
PCT gluconeogenesis
How is calcium absorbed in the kidney?
65% in PCT by voltage gradient
20% in LoH by voltage gradient
10% in DTC by PTH control
PTH action on the bone
Stimulate RANKL production
Dow regulate OPG (inhibits osteoclasts)
What stimulates vitamin D activation?
PTH
What inhibits vitamin D activation?
High calcium
High phosphate
FGF23
High 1,25(OH)2 D
Vitamin D2 vs D3
D2 = ergocalciferol from vegetables D3 = cholecalciferol from meat
Inactive forms of vitamin D
1, 24, 25
24, 25
Effects on vitamin D receptor activation
Increased gut reabsorption of calcium and phosphate
Reduced PTH transcription
Increased bone resorption - increases RANKL
Increased FGF23 release to promote renal phosphate loss
Increased amino acid uptake
FGF23 function
Increases renal phosphate excretion
Symptoms of hypercalcaemia
Polyuria and polydipsia
Kidney stones
Osteoporosis
Mood disorder
Primary vs secondary vs tertiary
Primary = absence of hypocalcaemia Secondary = compensation for hypercalcaemia Tertiary = autonomous PTH following chronic secondary
Symptoms of hypocalcaemia
Convulsions
Arrhythmias
Tetany
Parasthesia
Treatment of hypoparathyroidism
PTH infusion
Calcium supplmenets
Alfacalcidiol
What is mutated in familial hypocalciuric hypocalcaemia?
CASR receptor
Causes of respiratory acidosis
CNS depression
Chest wall abnormalities
NM disease
Lung disease –> COPD, severe asthma
Causes of metabolic alkalosis
Diuretics (Cl- loss) Vomiting Hyperaldosteronism Liquorice Barter's/Liddle/Gitelman's Milk alkali syndrome Bicarbonate therapy Dialysis
Causes of metabolic alkalosis
Anxiety, pain CVA Fever and sepsis Pregnancy Altitude Asthma, PE, pneumonia Salicyclates, progesterone
Levels of cortisol in the day
Morning = 150-500 Evening = 25-125 Stress = 650-2500
Genomic effects of GCs
Trans-activation
Binds to GC response elements
Stimulates/inhibits transcription
Transrepression
Blocks actions of cytokines/prostinoids/mitogens
Blocks transcription of target genes
Where does the pituitary develop from?
Oral ectoderm
What does somatostatin inhibit?
GH and TSH
What inhibits and stimulates PRL?
Stimulates = dopamine Inhibits = TRH
What stimulates ACTH?
CRH, AVP
What stimulated GnRH?
Kisspeptin
GHRH receptor mutation
Mosaic = McCune-Albright syndrome Germline = death
ACTH independant Cushing’s syndrome
= low ACTH
Steroid therapy
Adrenal tumour
Adrenal hyperplasia
ACTH dependant Cushing’s syndrome
Pituitary tumour
ACTH secreting lung tumour
Congenital hyperbilirubinaemia
= Gilbert’s disease
Types of viral hepatitis
A and E = acute
B and C = chronic
D only occurs with B
Nodule size in cirrhosis
Macro = autoimmune Micro = alcohol
Alcohol metabolic pathway
Ethanol to acetaldehyde --> alcohol dehydrogenase in the cytoplasm --> MEOS in microsomes --> catalase in peroxisomes Acetaldehyde --> acetate --> aldehyde dehydorgnase --> NAD --> NADH Large amounts of NADH promote fatty acid synthesis --> steatosis
Hepatitis C treatment
PegInterverfon + ribacvarin
+ protease inhibitors
Transplant
Hepatits B treatment
Entecavir
Drugs causing cirrhosis
Amiodarone
Methotrexate
What cytokine is involved in cirrhosis?
TGFb
Contraindications for liver transplant
Active sepsis
Malignancy outside the liver
Non-Ccompliance with drugs
Severe CR problems
Bladder afferent nerves
Pelvic nerves
–> pontine micrurition centre
Parasympathetic nerves –> bladder
S2-4 pelvic splanchnic nerves
Sympathetic nerves –> bladder
Hypogastric plexus
Somatic nerves –> bladder and sphincter
S2-4 pudendal nerve
M receptors on bladder
M3
Beta receptors on bladder
Beta 3
Alpha receptors on sphincter
Alpha 1
Storage symptoms
Increased frequency
Nocturne
Urgency
Incontinence
Voiding symptoms
Hesitancy Straining Poor flow Intermittent flow Incomplete emptying Terminal dribbling Dysuria Haematuria
Outflow problems
Bladder neck obstruction
Stricture
Meatus problem
Foreskin problem
Pump problems
Bladder failure
OAB
Cardiac failure
Medications
Control problems
Stroke Spinal cord injury Parkinson's MS Tumour
Constituent problems
UTI
Cancer
Inflammation
Stones
BPH drugs
Alpha blockers (tamsulosin, doxazosin) 5 alpha reductase inhibitors (finasteride)
OAB drugs
Anticholinergics (oxybutynin, solifenacin) –> reduce bladder contractility
B3 agonist (mirabegron) –> increases bladder capacity
Botox –> prevents contraction
Neurogenic bladder
Above pons = safe
Below T12 = safe –> flaccid bladder
Lesions between are unsafe –> loss of sympathetic relaxation –> spastic bladder
Acute renal failure causes
Sepsis Hypo perfusion Toxicity Obstruction Primary renal disease
Consequences of acute renal failure
Increased retention of salt, water, electrolytes
Acidosis
Toxins
Presentation of acute renal failure
Acutely unwell Hypertensive Oliguric Acute urine on dipstick Normal sized kidneys
Systemic manifestations of acute kidney failure
Pulmonary oedema Hyperkalaemia --> arrhythmia Acidosis Uraemia Encephalopathy Pericarditis Effusions
Common causes of chronic renal failure
Hypertension
Diabetes
Polycystic kidneys
GN
CKD staging
1 = GFR >90 2 = GFR 60-90 3 = GRR 30-60 4 = GFR 15-30 5 = GFR <15
When is haemodialysis performed?
3x per week
For 4 hours
Complications of haemodialysis
Thrombosis
Infection at access site
Lack of access
Hypotension
Advantages of haemodialysis
Hospital or home based
Less time than CAPD
Disadvantages of haemodialysis
Requires access to circulation
Limited by staff and space
When is CAPD performed?
Four daily exchanges
0.5h for each exchange
Principles of CAPD
Fluid pumped into abdominal cavity Peritoneum acts as exchange membrane Contains high amounts of glucose Can also contain buffers and amino acids Fluid equalises in concentrations Can then be drained and replaced
Advantages of CAPD
Can be done at home
Less CV demanding
Disadvantages of CAPD
Patient competence
Risk of membrane failure
Abnormal glycosylation
Creatinine vs GFR
In early kidney disease, large GFR drops will have a low impact on creatinine levels
In late kidney disease small drops in GFR can cause large increases in creatinine
Caveats of using creatinine
Product from muscle so depends on persons muscularity
Drugs such as trimethoprim inhibit tubular secretion
Glucose absorption threshold
10mmol/L
NIS function
Sodium and iodine into follicular cell
Pendrin function
Iodine from cell –> colloid
TPO function
Iodine oxidation
DUOX1 and 2 function
Oxidising agents
IYD function
Recycles iodine
How does TSH lead to thyroid hormone synthesis?
Binds to TSHR
Acts via cAMP cascade
Upregulation of all the components in thyroid hormone synthesis
D1 enzyme
Found peripherally
Upregulated by hyperthyroidism
D2 enzyme
Found in brain and pituitary
Down regulated in hyperthyroidism
Up regulated in hypothyroidism
D3 enzyme
Deactivation of thyroid hormones
T4 –> rT3
T3 –> T2
How is T4 excreted?
Glucoronidation by the liver
Gut excretion
How does T3 alter gene transcription?
Binds to thyroid hormone receptor in nucleus
Releases homodimer
Binds retinoic acid and co-activation molecule
Binds to thyroid response elements
Stimulates or inhibits gene transcription
Features of hyperthyroid
Tachycardia Increased risk of AF Increased BMR Increased appetite Heat intolerance Weight loss Myopathy Hyperglycaemia Seizures Proptosis Pretibila myxoedema Osteoporosis Hypercalcaemia Amenorrhoea Gynaecomastia
Causes of hyperthyroidism
Grave's disease Toxic multi nodular goitre Toxic adenoma Excess iodine Amiodarine HCG Stroma ovarii TSHoma Hamburger thyrotoxicosis
Treatment of hyperthyroidism
Thionamide drugs –> carbomaxole, propylthiouracil
Radioactive iodine
Thyroidectomy
Features of hypothyroidism
Pale and dry skin Hair and eyebrows loss Hypercarotenaemia Bradycardia Hypothermic J waves Sensitivity to cold Reduced appetite Weight gain Constipation Slowed relaxing reflexes Growth retardation Delayed puberty Decreased GLUT4 stimulation
Causes of hypothyroidism
Hashimoto's disease Iodine deficeincy Lithium Cabbage Infiltrative disease Pendred's disease Hypopituitarism
Hypothyroidism treatment
Levothyroxine
When does hyper acute rejection occur?
Immediately after the transplant
When there are pre-existing antibodies present in the blood
May be ABO incompatibility
Type II hypersensitivity
When does acute rejection occur?
One week - 6 months after transplant Due to helper T cell activation May be due to MHC incompatibility May be cellular or antibody mediated Type IV hypersensitivity
When does chronic infection occur?
Months to years after transplant
Due to immunological and non-immunological factors
Characteristics of hyperacute rejection
Neutrophil invasion
Intravascular coagulation
Intra-tissue haemorrhage
Characteristics of acute rejection
Cell mediated
Infiltration of lymphocytes
Macrophage activation
Antibodies mediated
–> endarteritis
C4d production
Important complement protein in rejection
C4d
Reasons for chronic rejection
Damaged graft Surgical complications Recurrence of original disease Infection Inadequate immunosuppression
Immunosuppression drugs
Block TCR = alemtuzumab
Blocks transcription factor production = calcineurin inhibitors (tacrolimus, cyclosporin)
Inhibits gene transcription = corticosteroids
Anti-IL2 receptor antibodies = basiliximab
Prevents B/T cell activation = rapamycin (sirolimus), everolimus
Prevent T cell proliferation = azathiprone, MMF
Most important HLAs to match
A, B, DR
Preventing transplant rejection
Hyper acute –> ABO matching and direct cross match
Acute –> HLA matching and minimising ischaemia
Chronic –> best quality organ, minimising surgical damage, minimise drug toxicity
Complications of transplant
Viral infection --> CMV, warts Bacterial infection --> UTI, RTI Protozoa --> pneumocystis Cardiovascular disease Diabetes Osteoporosis Cushing's syndrome Tumours --> skin, solid organ, PTLD
Option for non-compatible transplants
Plasma exchange
IV immunoglobulins
Organ exchange scheme
Advantages of live donation
Donor can be screened for organ function
Shorter cold ischaemia time
Elective procedure
Order of kidney connection
Vein
Artery
Ureter
How do the 3 germ layer contribute to the gut?
Endoderm = mucosa, mucosal glands, submucosal glands Mesoderm = lamina propria, muscularis, submucosa, blood vessels, adventita/serosa Ectoderm = neurones and enteric nervous system
Foregut
–> upper duodenum
Supplied by coeliac trunk
Midgut
Upper duodenum –> proximal 2/3 of transverse colon
Supplied by SMA
Hindgut
Distal 1/3 of traverse colon –> anal aperture
Supplied by IMA
Imperforate anus
Failure of endodermal and ectodermal portions o the anal canal to communicate
Rectoanal atresia
Failure of recanalisation or defective blood supply
Persistent cloaca
Urethra, vagina and anus all open out into one cavity
Hirschsprung’s disease
Absence of parasympatehctsi ganglia in the bowel walls
Derived from neural crest cells
Signs = failure to pass meconium, swollen belly, vomiting bile
Puborectalis
Forms a sling around the and-rectal junction to form the anorectal angle
Internal anal sphincter innervation
Sympathetic = excitatory = hypogastric nerve L1-2 Parasympathetic = inhibitory = pelvic nerves (S2-4)
External anal sphincter innervation
Inferior rectal brach of the pudendal nerve
How if faecal continence maintained?
Tonic contraction of both anal sphincters
Puborectalis (and EAS) muscle creating anorectal angle
How does the puborectalis create a flap valve?
Pushes the anterior rectal wall downwards onto the anal canal
What structures on the sigmoid colon and rectal walls also help with continence?
Valves of Houston
Lateral angulations
Valsalva manoeuvre
Holding breath and forcibly exhaling against a closed glottis to create a pushing down effect
What stimulates the closure reflex?
Receptor adaption removed from rectus so inhibitory drive on IAS releases –> IAS contracts
Voluntary contraction of EAS
Smooth muscle in sigmoid colono realces –> reservoir function returns
What drugs commonly cause constipation?
Opiates, anticholinergics, anticonvulsants, antidepressants
What endocrine conditions can cause constipation?
Diabetes, hypothyroidism
Passive vs urge incontinence
Passive = internal sphincter problem Urge = external sphincter problem
Causes of anal structural damage
Obstetric tear
Iatrogenic tear
Radiation damage
Congenital defects
Hypersensitive rectal sensation
Urge incontinence
Hyposensitive rectal sensation
Evacuation difficulties, functional disorders, constipation
Orexigenic signals
SPY
AgRP
MHC
Where are oriexigenic centres found?
Medially
Anorexigenic signals
POMC
CART
Where are anorexigenic signals found?
Laterally
How does AgRP act?
As a melanocortin receptor antagonist
What is POMC converted to?
Alpha-MSH
How does serotonin act to control appetite?
Increases POMC signalling via HTr2c
Decreases AgRP signalling via HTr1b
Action of ghrelin on appetite
Stimulates NPY neurones
Where are PYY GLP1 released from?
Intestinal L cells
What is the action of GLP-1 and PYY?
Inhibit NPY signalling
Increased POMC signalling
Where is CCK produced?
Duodenal I cells
What is the action of CCK?
Increases POMC signalling
Inhibits NPY signalling
Also causes bile release from the gallbladder
Where is leptin produced?
Adipose tissue
How does leptin affect appetite?
Increases POMC signalling
Decreases NPY and AgRP signalling
Effect of insulin of AgRP levels
Decreases them
Leptin mutations
Defective leptin = ob
Defective receptor = db
When is malonyl CoA produced?
Produced when high levels of ATP are present
High levels suggest adequate energy supply
Effect of high malonyl CoA
Inhibits carnitine shuttle to inhibit fatty acid oxidation
Suppresses food intake by inhibiting NPY and stimulating POMC
Therapies to reduce appetite
GLP-1 agonists Leptin Cannabinoid antagonists SSRI derivatives Amphetamine derivatvies
PYY receptor
Y2R
Melanocortin receptor
MCR4
Metabolic syndrome
Insulin resistance
Hypertension
Dyslipidaemia
Abdominal obesity
What is arachidonic acid produced from?
Omega 6
What does arachidonic acid produce?
Inflammatory mediators
Prostaglandins, leukotrienes
What is omega 3 metabolised to?
Anti-inflammatory molecules such as resolvins and protectins
Action of aspirin
Enhances the production of anti-inflammatory mediators from omega 3
Where are flavonoids found?
Fruit and veg, tea, chocolate, wine, olive oil
Action of flavonoids
Inhibits NADPH oxidase that produces ROS
Decreases risk of MI and stroke
Where are sulforaphanes found?
In Brassica vegetables
Consequences of low B12 and folate
Low methionine and high homocysteine
Effects of high homocysteine
–> thiolactate
Damages endothelial cells
Fat soluble vitamins
A, D, E, K
Which vitamins can be stored?
Fat soluble
Not water soluble
Which vitamins can be toxic in excess?
Fat soluble
Not water soluble
Selenium deficiency
–> cardiomyopathy
Zinc deficiency
Growth retardation
Alopecia
Dermatitis
Copper deficiency
Defective keratinisation of hair
Vitamin A deficiency
Xerophthalmia
Vitamin D deficiency
Rickets
Osteomalacia
Vitamin E deficiency
Peripheral neuropathy
Vitamin K deficiency
Coagulopathy
Vitamin C deficiency
Scurvy
Vitamin B1 thiamine deficiency
Beri Beri
Wernicke’s encephalopathy
Korsakoff syndrome
Vitamin B2 riboflavin deficiency
Angular stomatitis
Vitamin B3 niacin deficiency
Pellagra
Vitamin B6 pyridoxine deficiency
Neuropathy
Anaemia
Causes of vitamin D deficiency
Reduced sunlight exposure Obesity, smoking, alcohol Malabsorption Hyperparathyroidism Breast feeding Drugs
Role of vitamin B1
TTP cofactor for pyruvate –> acetyl CoA
Features of Beri Beri
Dry –> peripheral neuropathy
Shoshin –> cardiac failure and lactic acidosis
Wet –> cardiomegaly, tachycardia, peripheral oedema
Features of Wernicke’s encephalopathy
Horizontal nystagmus
Ophthalmoplegia
Cerebellar ataxia
Features of Korsakoff’s syndrome
Amnesia
Psychosis
Features of pellagra
Loss of appetite Weakness Abdominal pain Glossitis Casals neck Vaginitis Dermatitis Diarrhoea Dementia
Causes of B12 deficiency
Veganism
Terminal ileum disorder
Inadequate IF
Consequences of haemochromatotiss
Bronzed skin
Cirrhosis
Diabetes
Cardiomyopathy
MUST assessment
BMI
Recent weight loss
Acute disease effects
Surrogate height measures
Knee height
Ulna length
Demispan
Surrogate weight measure
Mid upper arm circumference
Ascites weight estimation
14kg
6kg
2kg
Peripheral oedema weight estimation
Sacrum = 10kg Knee = 5kg Ankle = 1kg
Normal albumin level
35-50g/L
Consequences of feeding syndrome
Seizures Rhabdomyolysis Osteomalacia Cardiac failure Arrhythmias Tetany Paraesthesia
Indications for parenteral nutrition
Short bowel Ileus Motility disorder Ischaemia Perforation Pancreatitis Obstruction Fistulae Severe IBD
Problems with PN
Risk with placement Catheter related sepsis Disordered liver function Gut atrophy Psychological Cost
Indications for tube feeding
Unsafe swallow
Head and neck cancer
Cystic fibrosis
Obesogenic drugs
Corticosteroids Mood stabilsiers Diabetes medications Beta blockers Allergy relievers Anti-epileptics
Which diabetes drugs cause weight change?
Gain = insulin, sulfonylureas, TZDs Stable = metformin, DPP4 inhibitors Loss = SGLT-2 inhibitors, acarbose
What does the thrift gene hypothesis state?
Genes that predispose to obesity have a selective advantage in populations frequently experiencing starvation
Autosomal dominant syndormes –> obesity
Prader Willi
Fragile X
Autosomal recessive syndormes –> obesity
Bardet-Biedl
Alstom
= ciliopathies
X linked syndromes –> obesity
Wilson-Turner
Borjeson-Forssman-Lehmann
Orlistat
Gastric and pancreatic lipase inhibitor
Lorcaserin
5HT antagonist
Liraglutide
GLP-1 agonist
Phentermine
Noradrenaline transporter inhibitor
Topiramate
GABA agonist
Naltrexone
Opioid receptor antagonist
Bupropion
Noradrenaline transporter inhibitor
Restrictive procedures
Gastric banding
Sleeve gastroplasty
Malabsorptive procedures
Biliopancreatic diversion
Gastric bypass
Normal fasting glucose levels
3.5-5.5mmol/L
Normal glucose levels 2 hours after a meal
<8mmol/L
Why is the brain dependant on glucose?
Cannot synthesis glucose
Cannot store it in large amounts
Cannot use other substrates except for ketones
Cannot extract glucose from the ECF at low concentrations
Cells in the pancreatic islets
Alpha cells --> glucagon Beta cells --> insulin Delta cells --> somatostatin PP (F) cells --> pancreatic polypeptide Epsilon cells --> ghrelin
Insulin synthesis
Preproinsulin
- -> proinsulin by ER
- -> insulin by Golgi
Insulin amino acid lengths
Preproinsulin = 110
Proinsulin = 86
Insulin = 21+30
C peptide = 35
How is insulin released from vesicles?
Enters through GLUT1 channels
Glucokinase converts glucose –> acetyl CoA –> ATP
Rise in ATP:ADP ratio closes K+ channels
–> membrane depolasrisaion
–> calcium influx
Triggers vesicles to bind to membrane and release insulin
Occurs when glucose >5mmol/L
Other signals causing insulin release
Arginine and leucine GLP-1 and GIP Fatty acids CCK Phospholipase C Acetylcholine
How does GLP1 act?
Through GLP-1R receptors
GCPR
How do leucine and arginine increase insulin secretion?
Act through glutamate dehydrogenase (GDH)
Can directly depolarise the membrane
How does phospholipase C lead to insulin secretion?
Cleaves PIP3 –> IP3
IP3 binds to SER and causes calcium release
Insulin receptor type
Tyrosine kinase receptor
Action of insulin binding to its receptor
Insulin binds to alpha portion
Tyrosine kinase domain in beta subunit phsophaorlyaes tyrosine residues on the C-terminus of the receptor for auto regulation
Also phosphorylates tyrosine resides on IRS
Leads to the activation of Akt
Actions of Akt
GLUT4 translocation in muscle and adipose tissue
Stimulation of muscle glycogen synthesis
Inhibit of lipolysis
How does Akt stimulate glycogen synthesis?
Akt phosphorylates and inactviates glycogen synthase kinase that usually inactviates glycogen synthase
How does insulin inhibit lipolysis?
Inhibits hormone sensitive lipase
Inhibits TAG hydrolysis and release of FAs into the circulation
Inhibits CPT-1
Action of insulin on the liver
Enhances glucose uptake and glucokinase activity
Increases glycogen synthesis
Increases lipogenesis
Inhibits gluconeogenesis
Action of insulin on proteins
Stimulates amino acid uptake into cells
Increases translate of mRNAs
Inhibits catabolism of proteins
Inhibits gluconeogenesis (uses proteins)
Post-prandial metabolism
Insulin levels rise
Increased uptake and TAG and glycogen synthesis
Increased liver uptake and storage of glucose
Inhibition of gluconeogenesis, glycogenolysis and lipolysis
Metabolism during fasting
Low insulin levels Less tissue glucose uptake Glycogen breakdown Lipolysis releases FFAs Gluconeogenesis proceeds in the liver Lactate used in Cori cycle
Insulin resistance
Serine and threonine residues phosphorylated on IRS instead of tyrosine
Act cannot be activated
Reduced insulin action
–> hyperglycaemia and dyslipidaemia
How is insulin switched off?
Serine/threonine kinases
Endocytosis and degradation of receptor
Dephosphorylation of tyrosine residues
How many amino acids in glucagon?
29
Synthetic pathway of glucagon
Preproglucagon
- -> proglucagon
- -> glucagon, GLP-1, GLP-2
Regulation of glucagon secretion
Low blood glucose levels
Increased blood amino acids (alanine and arginine)
Exercise
Inhibited by insulin and somatostatin
Mechanism of action of glucagon
Binds to GPCR
Alpha subunit detaches and activates adenylyl cyclase
ATP –> cAMP
Activates PKA
What does PKA activate?
PEPCK
G-6-P
Glycogen phosphorylase
How does glucagon inhibit glycolysis?
Inhibits PFK-1 by modulation of F-2,6-P2 levels
Inhibits pyruvate kinase
How does glucagon increase lipolysis?
Activates hormone sensitive lipase
Activates CPT-1
When are catecholamines releases?
In response to stress and hypoglycaemia
What amino acid is used in catecholamine synthesis?
Tyrosine and phenylalanine
Metabolic actions of adrenaline
Inhibits insulin secretion
Stimulates glucagon secretion
Stimulates glycogen breakdown
Stimulates lipolysis
Metabolic actions of cortisol
Inhibits glucose uptake
Stimulates lipolysis
Stimulates muscle proteolysis
Stimulates gluconeogenesis
When is cortisol released?
Trauma Infection Intense heat or cold Surgery Any debilitating disease
Metabolic actions of growth hormone
Reduced glucose uptake
Increases lipolysis
Increases glycogen breakdown
Increases gluconeogenesis
Metabolic actions of thyroid hormones
Increase the number of mitochondria Increase insulin secretion Increase glucose uptake Increase glycolysis and gluconeogenesis Increase lipolysis --> increase BMR
Metabolic actions of incretins
Increase insulin secretion
Inhibit gluconeogenesis
Promote satiety
Mechanisms of insulin resistance
Diacylglycerol induced activation of protein kinase C
Pro-Inflammatory cytokines releases
Normal mechanisms of islet compensation
Increase in size and number of beta cells
Increased beta cell function
Beta cell adaption to insulin resistance
Increased GK activity
Increased malonyl CoA levels –> inhibition of CPT-1
Fatty acids binding to gRP40
GLP-1 binding to its receptor
Release of acetyl choline from parasympathetic nerve terminals
Diagnosis of diabetes
Random blood glucose >11
Fasting blood glucose >7
Symptoms of hyperglycaemia
HbA1c level for diabetes diagnosis
48mmol/mol
6.5%
Biguanides
Metformin Inhibit hepatic gluconeogensis Reduce FA synthesis Increase GLP-1 levels Increase GLUT4 translocation
Sulfonylureas
Glicazide
Increase insulin secretion
Inhibit K+ channels –> depolarisation
Metglitinides
Repaglinine
Increase insulin secretion
Inhibit K+ channels –> depolarisation
TZDs
Pioglitozone
Increase insulin sensitivity
Increase adipose storage of FFAs
GLP-1 agonists
Exanatide
Increase insulin secretion
inhibit gluconeogenesis
DPP-4 inhibitors
Sitagliptin
Increase insulin secretion
inhibit gluconeogenesis
SGLT2 inhibitors
Decrease kidney reabsorption of glucose
Alpha-glucosidase inhibitors
Acarbose
Decrease gut absorption of glucose
How does ketoacidosis arise?
Continual use of fatty acids for energy production leads to ketone body formation
Ketone bodes
Acetoacetate
b-hydroxybutarate
Treatment of ketoacidosis
Fluids
Electrolytes
Insulin
Hypoglycaemia Whipple triad
Low blood glucose
Symptoms and signs associated with low blood glucose
Resolution of signs and symptoms with carbohydrate ingestion
Causes of hypoglycaemia
Alcohol excess Insulinoma Excessive exercise Reactive hypoglycaemia High dose insulin in T1DM
Responses to hypoglycaemia
Decreased insulin secretion
Increased glucagon and adrenaline release
Carbohydrate ingestion
Prolonged hypoglycaemia
GH and cortisol are released
Symptoms of hypoglycaemia
Trembling Palpitations Sweating Anxiety Tingling Difficulty concentrating Confusion Weakness Drowsiness Vision changes Difficulty speaking Dizziness Fitting Loss of consciousness
How does hyperglycaemia cause damage?
Activates protein kinase C Increases inflammation Increases ROS production Increases endothelial permeability and occlusion Causes mitochondrial dysfunction
Non-proliferative diabetic retinopathy
Dilation of retinal veins
Micro aneurysms
Internal haemorrhaging and oedema
Proliferative diabetic retinopathy
New blood vessels from near optic disk and in the vitreous humour
These can rupture and bleed
Can lead to detachment of the retina
Diabetic nephropathy features
Proteinuria
Glomerular hypertrophy
Decreased GFR
Renal fibrosis
Sites of diabetic neuropathy
Peripheral nerves –> hands, feet, legs, arms
Autonomic nerves –> digestion, bladder control, erectile dysfunction, heart
Proximal –> thighs and hips
Focal –> any nerve in the body
How does diabetes lead to atherosclerosis?
AGE formation
Oxidised LDL receptor to increase LDL uptake
Pro-Inflammatory cytokine production
Impaired cholesterol efflux from plaques
