Endocrine Flashcards
Define diabetes mellitus
A persistent state of hyperglycaemia due to the body’s inability to properly utilise glucose
Compare the two different types of diabetes mellitus
T1DM - pancreas does not produce any insulin due to beta-cells in islets of Langerhans being destroyed
T2DM - relative insulin deficiency and/or resistance
What is T2DM commonly associated with?
Obesity, physical inactivity, HTN, dyslipidaemia, tendency to develop thrombosis
Explain the signs and symptoms of DM
Polyuria, nocturia, polydipsia - osmotic diuresis
Lethargy - inability to utilise glucose to provide energy
Weight loss - breakdown of body protein and fat as alternative energy sources as glucose is unavailable
Describe the different types of insulin available
Short acting
Intermediate
Long acting
Ultra long acting
When is short acting insulin used and why?
Mimics usual increases of insulin around meal times.
Soluble insulins are injected 15-30mins before meals, onset is 30-60m, peak action is 1-4h and duration is <9h.
Human insulin analogues are injected just before, with or just after a meal, onset is faster, peak action is 0-3h and duration is 2-5h.
What is the onset, peak action and duration of intermediate and long acting insulins?
Onset 1-2h, peak 3-12h, duration 11-24h.
Provide baseline
What ADRs are associated with insulin?
Local reactions at injection site
Hypoglycaemia
Hypersensitivity
What are the risk factors for gestational diabetes?
Obesity
Family history of DM
Unexplained stillbirth or death of a neonate in a previous pregnancy
Very large infant in a previous pregnancy
Previous history of gestational diabetes
Family origin south Asian, black Caribbean or middle eastern
What are the glucose targets?
Pre-prandial 4-7mmol/L
Post-prandial <9mmol/L
What are the symptoms of hypoglycaemia?
Feeling shaky Sweating Hunger Tiredness Pallor Blurred vision Headaches Irritability
What are the causes of hypoglycaemia?
Too much insulin Delayed/missed meal or snack Not eating sufficient carbohydrates Excess physical activity Drinking large amounts of alcohol
What is the treatment for hypoglycaemia in a conscious patient?
15-20g fast acting carbohydrate
15-20g slower acting carbohydrate to prevent levels dropping low again
Blood glucose retested after 15-20mins and treatment repeated if levels <4mmol/L
What is the treatment for hypoglycaemia in an unconscious patient?
Recovery position
Glucagon injection
Ambulance
Define hyperglycaemia
Pre-prandial >7.5mmol/L
2h post-prandial >8.5mmol/L
What are the symptoms of hyperglycaemia?
Excessive thirst
Passing more urine than usual
Headaches
Tiredness/lethargy
What are the causes of hyperglycaemia?
Missing doses of medication Eating more carbohydrates than the body or medication can cope with Stress Concurrent infections Over treating a hypoglycaemic episode
What is the main purpose of energy homeostasis in the fed state?
Store calories
What changes does insulin induce?
Glucose stored as glycogen in muscle and liver
Glucose used as fuel in muscle
Glucose carbons and calories sorted in fatty acids
Switched off glycogen degradation and gluconeogenesis
What effect does insulin have on lipid metabolism?
Glucose-> fatty acids
Fatty acid storage in adipose
Describe protein metabolism by the liver
Fed state - excess amino acids deaminated
Fasting - amino acids a major source of glucose (gluconeogenesis)
Glucagon => increased uptake, deamination and urea cycle activity
How is liver glycogen metabolism controlled?
Glycogen - stimulates PKA when blood glucose is scarce. FBPase2 is activated. Glycolysis is inhibited, and gluconeogenesis is stimulated.
High levels of fructose-6-phosphate stimulate phosphoprotein phosphatase. PFK2 is activated. Glycolysis is stimulated and gluconeogenesis is inhibited.
What occurs during the well-fed state?
Glucose and amino acids from food enter the blood stream and reach the liver via the portal vein.
Triacylglycerol from food is packed into chylomicrons and absorbed via the lymphatic system.
Insulin is secreted to stimulate the storage of fuels:
Glycogen synthesis occurs in the liver and muscles
Glycolysis occurs in the liver which generates acetyl-CoA for FA synthesis
Triglycerides are stored in adipose tissue
What effect does insulin have during the well-fed state?
Liver
- switch off glycogenolysis and gluconeogenesis to reduce glucose output
- switch on glycolysis - increased acetyl CoA to increase FA synthesis
Adipose
- switch off hormone sensitive lipase to reduce FA production and increase fat storage
Muscle
- increase GLUT4 expression - increased glucose uptake to increase use of glucose as fuel and decrease use of FAs
Brain
- decreased appetite
What changes occur between meals?
Blood glucose levels drop
Glucagon secreted
- glycogenolysis stimulated to release glucose - glucose taken up primarily by the brain
- FA released from adipose tissue increased, muscle uses FAs as primary fuel source
- gluconeogenesis stimulated
What changes occur during the fasting state?
Glucose no longer taken up by muscles - muscles use FAs and ketone bodies
Proteins broken down => atrophy - amino acids, lactate and glycerol all used to maintain a supply of glucose for the brain
Brain begins to rely more upon ketone bodies
Long-term starvation leads to brain malfunction
How does encephalopathy occur?
Reduced gluconeogenesis, glycogen storage - inadequate hepatic glucose production
Reduced fatty acid oxidation - inadequate ketone body production, inadequate energy for gluconeogenesis
Brain runs out of energy - toxic metabolites accumulate in brain cells => brain swelling and coma
How does T2DM occur?
Resistance to insulin, cannot raise insulin sufficiently to promote glucose uptake in muscle or control glucose production by the liver
Consequence of obesity
Normal increase in fructose 2,6-bisphosphate and down-regulation of phosphoenolpyruvate carboxylase does not occur
Translocation of GLUT4 to plasma membrane is decreased
Ketoacidosis rarely develops, observed increase in VLDL
How does T1DM occur?
Complete absence of insulin production by pancreas
Stuck in starved state
- liver is always gluconeogenic and glycogenolytic -> hyperglycaemia
- uncontrolled proteolysis-> muscle wasting and provides substrates for gluconeogenesis
- uncontrolled adipose tissue lipolysis increased plasma [FA] - liver ketone body production, uncontrolled by insulin leading to ketoacidosis
Describe normoglycaemia in endothelial cells
Glucose in via GLUT1 -> acetyl CoA -> ATP
What changes occur in endothelial cells during hyperglycaemia?
Glucose in via GLUT1 -> acetyl CoA -> ATP, no more ATP or acetyl CoA can be made, glucose takes other pathways:
Glucose -> sorbitol (reduced NADPH leads to oxidative stress, increased sorbitol leads to reduced vasoelasticity)
Glucose -> glycation (AGE) (increased protein stability, altered cellular interactions, altered extracellular matrix)
Glucose -> acetyl CoA -> FAs -> diacyl glycerol (DAG activates protein phosphorylation, altered cellular signalling, multiple effects on vascular cells)
Outline the major complications of T1DM
Chronic effects of hyperglycaemia
Hypoglycaemia
Diabetic ketoacidosis
How does diabetic ketoacidosis occur?
Uncontrolled lipolysis and beta-oxidation -> over-production of ketone bodies (strong acids) -> overwhelms the buffering capacity of the body -> acidosis -> coma and death
What causes insulin resistance?
Genetics Environment Ectopic lipid accumulation Cellular stress-response Inflammation
What are the long-term complications of diabetes?
Microvascular damage => retinopathy, nephropahty, and neuropathy
How does diabetes cause peripheral neuropathies?
Endothelial damage -> wall thickening -> ischaemia and neural death
Compare the different types of diabetic peripheral neuropathies
Somatic - parasethesias; impaired pain, temperature, light touch, two-point discrimination and vibratory sensation
Autonomic - vasomotor function (postural hypotension), gastrointestinal function (postprandial and nocturnal diarrhoea), genitourinary function (impotence), cranial nerve (impaired pupillary responses)
What are the risk factors for diabetic nephropathy?
Genetic and familial predisposition Elevated BP Poor glycaemic control Smoking Hyperlipidaemia Microalbuminuria
What are the risk factors for diabetic retinopathy?
Poor glycaemic control
Elevated BP
Hyperlipidaemia
Describe the pathogenesis for diabetic retinopathy
Endothelial change of vascular wall
- microaneurysms -> burst -> scarring, damage to cellular environment, macular oedema
- ischaemia -> fragile new blood vessels, more prone to aneurysms and bursting
What class of drug is metformin?
A biguanide
Describe the mechanism of action of metformin
Becomes concentrated in hepatocytes Inhibit mitochondrial respiratory chain complex I Alters ATP:AMP Activates AMPK Decreased glucose output
What ADRs are associated with metformin?
Lactic acidosis
Hypoglycaemia
What cautions surround the use of metformin?
Patients receiving radiological contrast agent may suffer temporary renal impairment - withdraw metform for 48h
What are the contraindications for the use of metformin?
Renal insufficiency - risk of lactic acidosis
What interactions are associated with metformin?
Drugs which impair renal function e.g. NSAIDs (risk of lactic acidosis)
Give examples of sulfonylureas
Gliclazide, glibenclamide, glipizide, glimepiride, tolbutamide
Describe the mechanism of action of sulfonylureas
Bind SUR1 ATP-sensitive potassium channel closes Membrane depolarises Voltage-gated calcium channel opens Insulin secretion and synthesis triggered
What ADRs are associated with sulfonylureas?
Hypoglycaemia Weight gain Nausea Vomiting Diarrhoea Constipation
What cautions surround the use of sulfonylureas?
Elderly, debilitated and malnourished patients are at greater risk of hypoglycaemia
Hepatic impairment - increased risk of hypoglycaemia
What are the contraindications for the use of sulfonylureas?
Acute porphyria
Ketoacidosis
What interactions are associated with sulfonylureas?
Corticosteroids (increase expression of enzymes involved in gluconeogenesis)
Thiazides (hypokalaemia causes beta-cell hyperpolarisation so less insulin secretion)
Meglitinides
Give examples of meglitinides
Nateglinide and repaglinide
Describe the mechanism of action of meglitindes
Close potassium channels
Membrane depolarises
Calcium channels open
Insulin synthesis and secretion triggered
What ADRs are associated with meglitinides?
Hypoglycaemia Weight gain Nausea Vomiting Diarrhoea Constipation
What cautions surround the use of meglitinides?
Elderly, debilitated and malnourished at greater risk of hypoglycaemia
Hepatic impairment - increased risk of hypoglycaemia
What interactions are associated with meglitinides?
Corticosteroids - increase expression of enzymes involved in gluconeogenesis
Thiazides - hypokalaemia causes beta-cell hyperpolarisation so less insulin secretion
Sulfonylureas
What effect does GLP-1 have on insulin secretion?
Potentiates glucose-stimulated insulin secretion
- increases secretory machinery
- increases insulin biosynthesis
- increases calcium channel activity
What is the mechanism of action of DPP-4 inhibitors?
Increases GLP-1 concentration
- increases secretory machinery
- increases insulin biosynthesis
- increases calcium channel activity
Give examples of GLP-1 agonists
Liraglutide Lixisenatide Exenatide Albiglutide Dulaglutide
Give examples of DPP-4 inhibitors
Alogliptin Linagliptin Saxaglitpin Sitagliptin Vildaglitpin
What ADRs are associated with GLP-1 agonists?
Nausea and vomiting
Significant weight loss
Pancreatitis and kidney failure
What ADRs are associated with DPP-4 inhibitors?
Pancreatitis and kidney failure
Some GI ADRs
What class of drug is pioglitazone?
Thiazolidinedione
Describe the mechanism of action of pioglitazone
Ligand for transcription factor PPAR-gamma
Decrease ectopic fat storage
Improving insulin resistance
What cautions surround the use of pioglitazone?
HF
Increased risk of bladder cancer
What are the contraindications for the use of pioglitazone?
Hepatic insufficiency
History of HF
Active bladder cancer
History of bladder cancer or uninvestigated haematuria
What interactions are associated with pioglitazone?
Clopidogrel
Oral contraceptives
Give examples of SGLT-2 inhibitors
Dapagliflozin
Canagliflozin
Empagliflozin
Describe the mechanism of action of SGLT-2 inhibitors
Inhibit SGLT-2 leading to reduced reabsorption and increased loss of glucose in urine
What ADRs are associated with SGLT-2 inhibitors?
Increased risk of UTIs
Increased risk of breast and bladder cancer
Minor risk of euglycaemia diabetic ketoacidosis
What cautions surround the use of SGLT-2 inhibitors?
Increased urination -> increased risk of hypovolaemia or hypotension
Reduced efficacy in patients with impaired renal function
What are the contraindications for the use of SGLT-2 inhibitors?
Hepatic insufficiency
Impaired left ventricular function
What interactions are associated with SGLT-2 inhibitors?
Diuretics
Describe the action of oestrogen
Oestrogen act as signalling molecules by interacting with specific target cells
- include tissues of the breast, uterus, brain, heart, liver and bone
- ER modulation used in contraception
ER undergoes dimerisation in order for it to have increased affinity for EREs and regulate gene expression
What are the targets and uses of progestins?
Physiological target - reproductive tract
- decreases oestrogen-driven endometrial proliferation
- establishment and maintenance of pregnancy
Uses
- oral contraceptives
- HRT
- Uterine bleeding disorders
- premature labour
Name a progesterone antagonist
Mifepristone
What is mifepristone used for?
Termination of pregnancy
Induction of labour after foetal death
Describe the pituitary hormone effects that occur in the early follicular phase
FSH stimulates several follicles to grow, and stimulates estradiol secretion
Describe the ovarian hormone effects that occur during the early follicular phase
Follicles produce low levels of estradiol which:
- causes endometrial arteries to constrict, resulting in menstruation
- inhibits LH secretion
- stimulates FSH secretion
Describe the pituitary hormone effects that occur during the late follicular phase/ovulation
FSH stimulates one follicle to further develop
LH surge stimulates ovulation from that follicle
Describe the ovarian hormone effects that occur during the late follicular phase/ovulation
Follicles produce increasing levels of estradiol which:
- stimulates GnRH secretion by hypothalamus
- with GnRH drives LH levels to spike, causing ovulation
- causes the endometrium to further develop
Describe the pituitary hormone effects of the luteal phase
LH stimulates development of a corpus lute up left behind after ovulation
Describe the ovarian hormone effects that occur during the luteal phase
The corpus luteum secretes progesterone and estradiol which:
- blocks GnRH secretion by the hypothalamus and LH and FSH secretion by the pituitary
- causes the endometrium to further develop
Describe the pituitary hormone effects that occur during menstruation
Low GnRH, LH, FSH
Describe the ovarian hormone effects that occur during menstruation
Progesterone and estradiol levels fall:
- causes endometrial arteries to constrict, resulting in menstruation
What changes occur to the menstrual cycle during pregnancy?
Implantation - blastocyst produces hCG which supports continued secretion of progesterone by corpus luteum until placenta takes over
Progesterone:
- maintains decidua (lining of uterus)
- promotes blood vessel growth
What changes occur to the menstrual cycle during the menopause?
All follicles depleted
Decreased oestrogen and inhibin -> LH, FSH
What are the two types of method of contraception?
Mechanical
- condoms, diaphragms, intrauterine devices
- some can be combined with chemical spermicide - essential with a diaphragm, nonoxynol 9 (surfactant)
Hormonal
- p.o, depot formulation for i.m. Injection, transdermal patch, vaginal ring, intrauterine devices
What oestrogens are used in hormonal contraception?
Ethinyl estradiol or mestranol
What progestins are used in hormonal contraception?
Norethisterone (1st gen)
Norgestrel/levonorgestrel (2nd gen) - agonists at AR
Desogestrel/gestodene/norgestimate (3rd gen) - less androgen activity
Drospirenone (4th gen) - anti-androgenic and anti-mineralocorticoid
What is the mechanism of action of COCs?
Suppress GnRH, LH, and FSH release at hypothalamic and pituitary level
Progestin inhibits oestrogen-induced LH “surge” and inhibits ovulation
- oestrogen up-regulates PGR, increasing negative feedback by the progestogen
What effects do oestrogen only contraceptives have?
Promote endometrial growth => Endometrial cancer
Outline the PK of COCs
Phase 1 - extensive first pass by CYP3A4
Phase 2 - sulfation and glucuronidation followed by biliary secretion
Compare monophasic and multiphasic COCs
Monophasic - dose of oestrogen and progestin doesn’t vary
Multiphasic
- biphasic - progestin dose varies
- triphasic - 3 different dose combinations
What ADRs are associated with oestrogens?
Fluid retention
HTN
Increased risk of endometrial cancer
What ADRs are associated with progestogen?
Headache
Nausea
Vomiting
Lower back pain
What ADRs are associated with COCs?
HTN
Thromboembolism
Cancer
What are the contraindications for the use of COCs?
Risk of CV, thromboembolic or malignant disease
Pregnancy
What interactions are associated with COCs?
CYP3A4 inducers => contraceptive failure
- rifampicin
- phenytoin
- phenobarbital
- st john’ wort
What is the mechanism of action of POPs?
Inhibit GnRH release
No menstruation
What ADRs are associated with POPs?
Breakthrough bleeding
What progestogen only depot injections are available?
Medroxyprogesterone
- t1/2~30h
- aqueous depot formulation for i.m injection every ~12weeks
Norethisterone
- oil depot formulation used for short term contraception
- also used to treat heavy periods
What progestogen only subdermal implants are available?
Levonorgestrel
- fertility restored on removal
- irregular and prolong bleeding can occur
What progestogen only intrauterine devices are available?
Levonorgestrel
- prevents endometrial thickening
- fertility restored on removal
- irregular and prolonged bleeding can occur
- dysmenorrhoea less than with copper IUD
How do copper IUDs work?
Release copper to prevent fertilisation
What EHCs are available?
Levonorgestrel
- high single dose
- blocks LH surge
- useful for up to 72h after intercourse
Ulipristal
- useful for up to 120h after intercourse
How does tamoxifen work?
ER antagonist in breast tissue (inhibits oestrogen-dependent growth of breast cancer)
Partial ER agonist in endometrium and bone
How do SERMs work?
Tissue-specific patterns of oestrogen receptors
Tissue-specific pattern of co-regulator expression
- pattern of genes activated by ER activation regulated by the expression of co-regulator proteins
- co-regulator repertoire varies from tissue to tissue
- co-regulator recruitment may be ligand-dependent, thus a ligand may recruit co-activators specific to one tissue but co-repressors specific to another
Effects on ER stability and degradation
Outline the properties of an ideal SERM
Strengthen bones Lower LDL Raise HDL Relieve hot flushes Reduce breast cancer risk Reduce uterine cancer risk
Outline the good effects of real oxide effects
Strengthens bones Lowers LDL Reduces risk for invasive breast cancer Fewer uterine cancers than tamoxifen Fewer blood clots than tamoxifen
Outline the bad effects of raloxfiene
Hot flushes
Blood clots
Leg cramps
Teratogenic
What are the effects of raloxifene?
Antagonist in breast and endometrium
Agonist in bone