Endocrinology Flashcards
what are endocrine glands?
ductless glands of the endocrine system that secrete their products directly into the blood
what are exocrine glands?
- glands that secrete substances onto an epithelial surface by way of a duct
- e.g. sweat, salivary, mammary, ceruminous, lacrimal, sebaceous, mucous, pancreas
what are types of hormone action?
- endocrine (cell targets distant cell through bloodstream)
- paracrine (cell targets adjacent/nearby cell)
- autocrine (cell targets itself)
- holocrine (rupture of plasma membrane, destroying cell and secretion of product into lumen)
- merocrine (secretions excreted via exocytosis into duct)
- apocrine (apical portion of cell pinches off and becomes extracellular vesicle)
what are characteristics of water-soluble hormones?
- unbound transport
- bind to surface receptor
- short half-life
- fast clearance
- e.g. peptides, monoamines
what are characteristics of fat-soluble hormones?
- protein bound
- diffuse into cell
- long half-life
- slow clearance
- e.g. thyroid hormone, steroids
what are are characteristics of peptide hormones? what is the structure, storage, release, clearance like?
- vary in length
- linear or ring structures
- two chains and may bind to carbohydrates
- stored in secretory granules
- hydrophilic
- released in pulses or bursts
- cleared by tissue or circulating enzymes
what catalyses the formation of L-tyrosine from L-phenylalanine?
phenylalanine hydroxylase
- 6-BH4 affects this
what catalyses the formation of L-dopa from L-tyrosine?
tyrosine hydroxylase
- 6-BH4 affects this
what catalyses the formation of dopamine from L-dopa?
L-aromatic amino acid decarboxylase
- pyridoxal phosphate affects this
what catalyses the formation of norepinephrine from dopamine?
dopamine-beta-hydroxylase
- ascorbate affects this
what catalyses the formation of epinephrine from norepinephrine?
phenylethanolamine-N-methyltransferase
- S-adenosyl methionine affects this
- site of cortisol potentiation
what can be produced from norepinephrine? what catalyses this?
norepinephrine -> normetanephrines
- catalysed by catechol-O-methyltransferase
what can be produced from epinephrine? what catalyses this?
epinephrine -> metanephrines
- catalysed by catechol-O-methyltransferase
what can be produced from normetanephrines and metanephrines? what catalyses this?
vanillylmandelic acid
- catalysed by monoamine oxidase A
what is the pathway of cortisol synthesis?
cholesterol -> pregnenolone -> progesterone -> 17-hydroprogesterone -> 11-deoxycortisol -> cortisol
what is the pathway of estriol production?
cholesterol -> pregnenolone -> 17-hydroxypregnenolone -> DHEA -> androstenedione -> testosterone/estrone -> estradiol/16alpha-hydroxysterone -> estriol
what enzyme catalyses the formation of 17-hydroxypregnenolone from pregnenolone?
17 alpha-hydroxylase
what enzyme catalyses the formation of 17-hydroxyprogesterone from progesterone?
17alpha-hydroxylase
what enzyme catalyses the formation of 11-deoxycortisol from 17-hydroxyprogesterone?
21-hydroxylase
what enzyme catalyses the formation of cortisol from 11-deoxycortisol?
11beta-hydroxylase
what enzyme catalyses the formation of estradiol from testosterone?
aromatase
what enzyme catalyses the formation of estrone from androstenedione?
aromatase
what enzyme catalyses the formation of testosterone from androstenedione?
17beta-hydroxysteroid dehydrogenase
what enzyme catalyses the formation of dihydrotestosterone from testosterone?
5alpha-reductase
what is humoral-stimulated hormone release?
hormone release caused by altered levels of certain critical ions or nutrients
what is hormone receptor downregulation?
hormone secreted in large quantities causes down regulation of its target receptors
what is synergism?
combined effects of two hormones amplified
what is hormone antagonism?
one hormone opposes other hormone
what is negative feedback?
a product feeds back to decrease its own production
what is positive feedback?
a product feeds back to increase its own production
what produces vasopressin/ADH?
supraoptic nucleus in the hypothalamus
what controls vasopressin release?
- caffeine and alcohol inhibit its release
- nausea, vomiting, stress, exercise stimulate its release
- increased osmolality and decreased blood volume stimulate its release
what is oxytocin? what produces it?
- stimulates myoepithelial cells (mammary glands), leading to suckling and milk ejection
- stimulates the uterus and cervical dilation, leading to labour and uterine contractions
- produced by paraventricular nucleus in the hypothalamus
what hormones are released by the anterior pituitary?
- thyroid stimulating hormone
- growth hormone
- adrenocorticotropic hormone
- luteinising hormone
- melanocyte stimulating hormone
- prolactin
- follicle stimulating horone
what are the direct actions of growth hormones?
- metabolic, anti-insulin
- fat metabolism -> increased fat breakdown and release
- carbohydrate metabolism -> increased blood glucose and other anti-insulin effects
what are the indirect actions of growth hormone?
- growth promoting
- production of insulin-like growth factors
- increased cartilage formation and skeletal growth
- increased protein synthesis and cell growth and proliferation
what is the function/action of thyroid hormone?
- accelerates food metabolism
- increases protein synthesis
- stimulation of carbohydrate metabolism
- enhances fat metabolism
- increase in ventilation rate
- increase in cardiac output and heart rate
- brain development during foetal life and postnatal development
- growth rate accelerated
what is the short-term stress response?
- increased HR
- increased BP
- bronchioles dilate
- liver converts glycogen to glucose and releases glucose to blood
- blood flow changes, reducing digestive system activity and urine output
- metabolic rate increases
what is the long term stress response?
- kidneys retain sodium and water
- blood volume and blood pressure rise
- proteins and fats converted to glucose or broken down for energy
- blood glucose increases
- immune system suppressesd
what are some other hormones?
- atrial natriuretic peptide
- insulin-like growth factor I
- erythropoietin
- gastrin, secretin
- prostanoids, nitric oxide, endothelin
what is BMI?
body mass index = weight/(height)^2
what are the different ranges of BMI?
underweight: <18.5
normal: 18.5-24.9
overweight: 25.0-29.9
obese: 30.0-39.9
morbidly obese: >40
what are some complications of obesity? what fat is this usually caused by?
usually abdominal (visceral) rather than subcutaneous fat
- type 2 diabetes
- hypertension
- coronary artery disease
- stroke
- osteoarthritis
- obstructive sleep apnoea
- carcinoma of the breast, endometrium, prostate and colon
what is the role of the hypothalamus in appetite regulation?
- lateral hypothalamus (hunger centre)
- ventromedial hypothalamic nucleus (satiety centre)
what are central controllers of appetite?
increase
- NPY
- MCH
- AgRP
- orexin
- endocannabinoid
decrease
- alpha-MSH
- CART
- GLP-1
- serotonin
what are central controllers of appetite?
- psychological factors
- neural afferents (vagal)
- gut peptides: CCK, ghrelin, PYY
- metabolites: glucose and ketones
- hormones: leptin, insulin, cortisol
- cultural factors
what are peripheral factors affecting appetite regulation?
leptin and insulin
what are gut factors affecting appetite regulation?
- ghrelin
- PYY3-36
- glucagon like peptide 1
- CCK
what are factors from central areas of the hypothalamus affecting appetite regulation?
NPY (arcuate nucleus) POMC - alpha MSH (acuate nucleus) agouti related peptide (arcuate nucleus) MC3 and MC4 receptors (paraventricular nucleus) serotonin
how does leptin affect the brain?
- leptin inhibits NPY/agouti related peptide (in arcuate nucleus) which affects PVN and LHA/PFA
- leptin stimulates pro-opiomelanocortin/cocaine and amphetamine regulated transcript which affects LHA/PFA and PVN
- decreased fat cell mass -> decreased leptin/insulin expression -> decreased leptin/insulin action in hypothalamus
what are the responses to satiety signals (from the adipose tissue)?
- catabolic pathways activate nucleus tractus solitarius (NTS)
- anabolic pathways inhibit nucleus tractus solitarius (NTS)
what are characteristics of leptin?
- Greek ‘leptos’ - thin
- binds to leptin receptor
- switches off appetite and is immunostimulatory
- blood levels increase after meal and decrease after fasting
what is decreased leptin/insulin action in hypothalamus on the arcuate nucleus?
- activates NPY/AgRP neuron and increases NPY/AgRP expression, which blocks binding of alpha-MSH to melanocortin receptors leading to decreased activity of pathways, leading to increased food intake (obesity)
- inhibits POMC neuron and decreases alpha-MSH expression and release
what is peptide YY? what is its action and effects?
- 36 amino acids
- structurally similar to NPY
- binds NPY receptors
- secreted by neuroendocrine cells in ileum, pancreas and colon in response to food
- inhibits gastric motility
- reduces appetite
what is cholecystokinin? what are its actions and effects?
- receptors in pyloric sphincter
- delays gastric emptying, gall bladder contraction, insulin release
- increases satiety
what is ghrelin? what are its actions and effects?
- 28 aa
- expressed in stomach
- stimulates growth hormone release and appetite
- blood levels high when fasting, fall on re-feeding
- levels lower after gastric bypass surgery
- used in anorexia/cachexia
what are some melanocortin receptors?
MCR1 - melanocytes; skin pigmentation
MCR2 - adrenal; adrenal cortex, steroid production
MCR3/4 - brain, signalling of satiety
MCR5 - skin
what are the consequences of POMC deficiency?
no MCR1 - pale skin
no MCR2 - adrenal insufficiency
no MCR3/4 - hyperphagia and obesity
what are the actions of leptin and insulin? what is their net effect?
- stimulate POMC/CART neurons -> increased CART and alpha-MSH levels
- inhibits NPY/AgRP neurons -> decreased NPY and AgRP
net effect: increased satiety and decreased appetite
what are the actions of ghrelin? what is its net effect?
stimulates NPY/AgRP -> increased NPY/AgRP secretion
net effect: increased appetite
what is the action of PYY3-36? what is its net effect?
- homolog of NPY
- binds to an inhibitory receptor on NPY/AgRP -> decreased secretion of NPY and AgRP
net effect: decreased appetite
what is AMPK?
5’ AMP activated protein kinase
- plays a role in cellular energy homeostasis, to activate glucose and fatty acid uptake and oxidation when cellular energy is low
what activates AMPK in the fasted state?
- decreased glucose (GLUT3)
- decreased insulin (IR)
- increased ghrelin (GR)
- decreased leptin (LR)
- decreased alpha-MSH (MCR)
- increased AgRP (MCR)
what deactivates AMPK in the fed state?
- increased glucose (GLUT3)
- increased insulin (IR)
- decreased ghrelin (GR)
- increased leptin (LR)
- increased alpha-MSH (MCR)
- decreased AgRP (MCR)
what is the central metabolic signal that mediates energy metabolism in fed and fasted states? what are its levels like?
malonyl CoA
- fasted state: decreased levels
- fed state: increased levels
what is the epidemiology of hypercalcaemia and hypocalcaemia?
- hypercalcaemia is much more common than hypocalcaemia
- mild asymptomatic hypercalcaemia occurs in 1 in 1000 of the population
- incidence of 25-30 per 100000 population
- occurs mainly in elderly females
- usually due to primary hyperparathyroidism
what is the structure of parathyroid hormone (PTH)?
- 84 amino acids
- derived from a 115 residue preprohormone
- secreted from the chief cells of the parathyroid glands
how does PTH levels change with calcium? how is this detected?
- PTH levels rise as serum ionised calcium falls
- this is detected by specific G protein coupled calcium-sensing receptors on the plasma membrane of the parathyroid cells
what are the actions of PTH?
all serve to increase plasma calcium by:
- increasing osteoclastic resorption of bone (occurring rapidly)
- increasing intestinal absorption of calcium (slow response)
- increasing synthesis of 1,25-dihydroxy-cholecalciferol
- increasing renal tubular reabsorption of calcium
- increasing excretion of phosphate
what are the major causes of hypercalcaemia?
- excessive PTH secretion
- malignant disease; low PTH levels (myeloma, bone deposits, osteoclastic tumour factors, PTH secretion)
- excess action of vitamin D
- excessive calcium intake (milk-alkali syndrome)
- other endocrine disease (thyrotoxicosis, Addison’s)
- drugs (thiazide diuretics, vitamin D analogues, lithium administration, vitamin A)
- micellaneous (long-term immobility, familial hypocalciuric hypercalcaemia)
what can cause excessive PTH secretion?
- primary hyperparathyroidism, adenoma, hyperplasia or carcinoma
- tertiary hyperparathyroidism
- ectopic PTH secretion (very rare)
what can cause excess vitamin D?
- iatrogenic or self-administered excess
- granulomatous diseases, e.g. sarcoidosis, TB
- lymphoma
what are some causes of primary hyperparathyroidism?
- unknown causes
- monoclonal adenoma
- multiple adenomas/hyperplasia
- MENtype1 or familial hypocalciuric hypercalcaemia
- inactivation of some tumour suppressor genes
- cancer
what are some causes of secondary hyperparathyroidism? what is it?
occurs when the parathyroid glands become enlarged and release too much PTH
- severe calcium deficiency
- severe vitamin D deficiency
- chronic kidney failure
what is tertiary hyperparathyroidism? what is it caused by?
- development of apparently autonomous parathyroid hyperplasia after long-standing secondary hyperparathyroidism, most often in renal failure
- plasma calcium and phosphate are both raised
- parathyroidectomy is necessary
what are some symptoms and signs of hypercalcaemia?
- tiredness, malaise, dehydration and depression
- renal colic from stones
- polyuria or nocturia, haematuria and hypertension
- polyuria due to the effect of hypercalcaemia on renal tubules, reducing their concentration ability
- bone pain (affects mainly cortical bone)
- bones cysts and locally destructive brown tumours
- pain
- chrondocalcinosis and ectopic calcification
- corneal calcification
what defines mild and severe hypercalcaemia?
mild: adjusted calcium <3mmol/L
severe: >3mmol/L
what are the common tumours associated with hypercalcaemia?
bronchus, breast, myeloma, oesophagus, thyroid, prostate, lymphoma, renal cell carcinoma
what investigations are done to detect PTH levels?
several fasting serum calcium and phosphate samples should be done
- serum PTH
- hyperchloraemic acidosis
- renal function (usually normal, measured as baseline)
- 24-hour urinary calcium or single calcium creatinine
- elevated serum alkaline phosphatase
- protein electrophoresis/immunofixation (to exclude myeloma)
- serum TSH (to exclude hyperthyroidism)
- 0900 hours cortisol and/or ACTH test (to exclude Addisons disease)
- serum ACE (diagnosis of sarcoidosis)
- hydrocortisone suppression test
what are the actions of parathyroid hormone?
kidney
- increased Ca2+ reabsorption
- decreased phosphate reabsorption
- increased 1alpha-hydroxylation of 25-OH vitamin D
bone
- increased bone remodelling
- bone resporption -> bone formation
GI tract
- no direct effect
- increased Ca2+ absorption because of increased 1,25-dihydroxy-cholecalciferol
what is the relationship between serum calcium and PTH?
normal: equal
low Ca2+: low Ca2+ and raised PTH
high Ca2+: high Ca2+ and low PTH
how is corrected calcium calculated?
corrected calcium = total serum calcium + 0.02*(40 - serum albumin)
what are consequences of hypocalcaemia?
- parasthesia
- muscule spasm: hands and feet, larynx, premature labour
- seizures
- basal ganglia calcification
- cataracts
- ECG abnormalitites: long QT interval
- Chvostek’s sign
- Trousseau’s sign
how do you test for the Chvostek’s sign?
- tap over the facial nerve
- look for spasm of facial muscles
- sign of neuromuscular irritability
how do you test for Trousseau’s sign?
- inflate the blood pressure cuff to 20mmHg above systolic for 5 minutes
- in hypocalcaemia, there is flexion of the wrist and metacarpophalangeal joints, extension of DIP and PIP joints and adduction of fingers
what are the causes of hypocalcaemia?
- vitamin D deficiency (no gut absorption of Ca2+ and Pi)
- undermineralised bone
- hypoparathyroidism
- renal disease
- cancer
- hungry bone syndrome
- Fanconi syndrome
- radiation exposure
- metabolic disorder
what are some syndromes associated with hypoparathyroidism?
- Di George
- HDR
- Kenney-Caffey
- Sanjad-Sakati
- Kearns-Sayre
- blomstrand chondrodysplasia
what does Di George syndrome lead to? what is it associated with?
developmental abnormality of third and fourth branchial pouches
- hypoparathyroidism
- thymic aplasia
- immunodeficiency
- cardiac defects
- cleft palate
- abnormal facies
what are some causes of hypoparathyroidism?
- neck surgery
- autoimmune disease
- hereditary hypoparathyroidism
- low magnesium
- radiation to face/neck
- haemochromatosis
- Wilson’s disease
what are effects of decreased PTH? what does this lead to?
- decreased renal calcium reabsorption -> increased relative calcium excretion -> decreased serum calcium
- increased renal phosphate reabsorption -> increased serum phosphate -> decreased formation of 1,25(OH)2D
- decreased bone resorption -> decreased serum calcium
- decreased formation of 1,25(OH)2D -> decreased intestinal calcium absorption -> decreased serum calcium
what is associated with pseudohypoparathyroidism?
- short stature
- obesity
- round facies
- mild learning difficulties
- subcutaneous ossification
- short fourth metacarpals
- other hormone resistance
- resistance to PTH
what is associated with pseudopseudohypoparathyroidism?
- short stature
- obesity
- round facies
- mild learning difficulties
- subcutaneous ossification
- short fourth metacarpals
- other hormone resistance
normal calcium metabolism
what is the regulation of carbohydrate metabolism in non-diabetic humans in the fasting state?
- all glucose comes from the liver (and some from the kidney)
- glucose delivered to insulin independent tissues, brain and erythrocytes
- 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 is the regulation of carbohydrate metabolism in non-diabetic humans in the fed state?
after feeding (post prandial) - physiological need to dispose of a nutrient load
- rising glucose (5-10 mins 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 NEFA or FFA fall
what is the site of insulin and glucagon secretion?
- endocrine pancreas
- Islets of Langerhans
what is the microstructure of the islets of Langerhans? what do they secrete?
- duct and pancreatic acini on the periphery
- red blood cells
- islets of Langerhans: alpha cells, beta cells, delta cells, epsilon cells, PP cells
- alpha cells: glucagon
- beta cells: insulin and amylin
- delta cells: somatostatin
- epsilon cells: ghrelin
- PP cells: pancreatic polypeptide
what is insulin’s action in muscle and fat cells?
- insulin binds to the insulin receptor on muscle and fat cells
- intrasignalling cascade
- intracellular GLUT4 vesicle mobilisation to plasma membrane
- GLUT4 vesicle integration into plasma membrane
- glucose entry into cell via GLUT4
what are the effects of insulin?
- decreased glycogenolysis
- decreased gluconeogenesis
- increases glucose uptake into insulin sensitive tissues (muscle, fat)
- supresses lipolysis and breakdown of muscle
what are the effects of glucagon?
- increased glycogenolysis
- increased gluconeogenesis
- reduces peripheral glucose uptake
- stimulates peripheral release of gluconeogenic precursors (glycerol, AAs) by lipolysis and muscle glycogenolysis and breakdown
what are some types of diabetes?
- type 1
- type 2: includes gestational and medication induced diabetes
- maturity onset diabetes of youth (MODY), aka monozygotic diabetes
- pancreatic diabetes
- endocrine diabetes (acromegaly/Cushings)
- malnutrition related diabetes
what is the definition of diabetes?
- symptoms and random plasma glucose > 11mmol/l
- fasting plasma glucose > 7mmol/l
- no symptoms - GTT (75g glucose) fasting >7 or 2h value > 11mmol/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 perhaps in response to an environmental event
- activates a chronic cell mediated immune response leading to chronic ‘insulitis’
what does failure of insulin secretion lead to?
- continued breakdown of liver glycogen
- unrestrained lipolysis and skeletal muscle breakdown
- inappropriate increase in hepatic glucose output and suppression of peripheral glucose uptake
- rising glucose concentration leads to increased urinary glucose losses as renal threshold (10mM) is exceeded
- reduced insulin leads to fat breakdown and formation of glycerol (a gluconeogenic precursor) and FFA
- ketogenesis is exquistely sensitive to insulin
what does failure to treat with insulin lead 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 increased levels of ketones
what is the activity of FFA in diabetes mellitus?
- impair glucose uptake
- are transported to the liver, providing energy for gluconeogenesis
- are oxidised to form ketone bodies (beta hydroxy butyrate, acetoacetate and acetone)
what are features of ketoacidosis in diabetes mellitus?
- absence of insulin and rising counterregulatory hormones leads to increasing hyperglycaemia and rising ketones
- glucose and ketones escape in the urine but lead to an osmotic diuresis and falling circulating blood volume
- ketones cause anorexia and vomiting
- vicious circle of increasing dehydration, hyperglycaemia and increasing acidosis eventually lead to circulatory collapse and death
what is the pathophysiology of type 2 diabetes?
genes and environment -> impaired insulin secretion and insulin resistance -> impaired glucose tolerance -> type 2 diabetes -> progressive hyperglycaemia and high FFA
progressive hyperglycaemia and high FFA -> insulin resistance and impaired insulin secretion
what does impaired insulin action in type 2 diabetes lead to?
- reduced muscle and fat uptake after eating
- failure to suppress lipolysis and high circulating FFAs
- abnormally high glucose output after a meal
what can even low levels of insulin do in type 2 diabetes?
- even low levels of insulin prevent catabolism and ketogenesis
- profound muscle breakdown and gluconeogenesis are restrained
- ketone production is rarely excessive
what is the pathogenesis of type 1 diabetes?
one defect: absent insulin secretion
- > no hepatic insulin effect
- > no muscle/fat insulin effect
- unrestrained glucose + ketone production, more glucose enters the blood
- impaired glucose clearance + muscle/fat breakdown, less glucose enters peripheral tissues
hyperglycaemia + raised plasma ketones -> glycosuria/ketonuria
what is the pathogenesis of type 2 diabetes?
two defects
impaired insulin secretion
-> hepatic insulin resistance
-> muscle/fat insulin resistance
- excessive glucose production, more glucose enters bloodstream
- impaired glucose clearance, less glucose enters peripheral tissues
hyperglycaemia -> glucosuria
what is the pathophysiology of type 2 diabetes, in summary?
insulin resistance and impaired insulin secretion due to a combination of genetic predisposition and environmental factors (obesity and lack of physical activity)
why doesn’t diabetic ketoacidosis occur in type 2 diabetes?
- it is rare because the low insulin levels are sufficient to suppress catabolism and prevent ketogenesis
- can occur if hormones e.g. adrenaline rise to high levels (e.g. during an MI)
why does insulin secretion become impaired in type 2 diabetes?
- genetic predisposition (i.e. abnormalities of insulin secretion in first degree relatives)
- deposition of peptides within the beta cell (amilyn)
- glucotoxicity hyperglycaemia inhibits insulin secretion
- main factor is probably lipid deposition in the pancreatic islets which prevents normal function
what are basal insulins available for T1DM and T2DM?
- NPH insulin
- insulin glargine (100 and 300 U/ml)
- insulin detemir
- insulin degludec
- lente insulin series
- pumped insulin
what are prandial/meal-time insulins available for T1DM and T2DM?
- insulin lispro
- insulin glulisine
- EDTA/citrate human insulin
- faster acting insulin aspart
what are characteristics of modern insulin therapy in T1D?
- 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 inbetween meals and during night
- basal insulin is adjusted to maintain fasting blood glucose between 5-7 mmol/L
what are the differences between T1DM and T2DM?
T1DM
- autoimmune condition (beta-cell damage) with genetic component
- profound insulin deficiency
T2DM
- insulin resistance
- impaired insulin secretion and progressive beta-cell damage but initially continued insulin secretion
- excessive hepatic glucose output
- increased counter-regulatory hormones including glucagon
what are characteristics of insulin use in T2DM?
- many people with T2DM need insulin; esp. later or in individuals with poor glycaemic control on other medications
- basal insulin is initiated followed by addition of a prandial insulin where necessary
- premix insulins also available
- long-acting basal insulin analogues associated with lower risk of symptomatic, overall and nocturnal hypoglycaemia
- prandial insulins mimic meal-time insulin secretion and their faster action allows for greater flexibility at mealtimes
what are the pharmacokinetics of human basal insulin (NPH)?
- human basal (intermediate-acting)
- 90 minutes onset
- 2-4 hours peak action
- up to 24 hours duration
what are the pharmacokinetics of basal analogues (Detemir/Glargine U100)
- basal analogue
- steady state onset after 1-2 days
- N/A peak action
- up to 24 hours duration
what are the pharmacokinetics of rapid acting analogues (insulin aspart, insulin lispro, insulin glulisine)?
- human short acting
- 10-20 minutes onset
- 30-90 minutes peak action
- up to 2-5 hours duration
what are the pharmacokinetics of human premixed 70/30 insulin (mixtard, humulin M3)?
- human premixed 70/30
- 30 minutes onset
- 2-8 hours peak action
- up to 24 hours duration
what is an example of human basal insulin?
NPH (neutral protamine hagedorn)
what are examples of basal analogues of insulin?
Detemir/Glargine U100
what are examples of rapid-acting analogues of insulin?
insulin aspart, insulin lispro, insulin glulisine
what are examples of human premixed 70/30 insulin?
mixtard, humulin M3
what are the different insulin approaches in type 2 diabetes?
- once daily basal insulin
- twice daily mix-insulin
- basal-bolus therapy
what are advantages of basal insulin in type 2 diabetes?
- simple for the patient, adjusts insulin themselves, based on fasting glucose measurements
- carries on with oral therapy
- less risk of hypoglycaemia at night
what are disadvantages of basal insulin in type 2 diabetes?
- doesn’t cover meals
- best used with long acting insulin analogues which are considered expensive
what are advantages of premixed insulin?
- both basal and prandial components in a single insulin preparation
- can cover insulin requirements through most of the day
what are disadvantages of premixed insulin?
- not physiological
- requires consistent meal and exercise pattern
- cannot separately titrate individual insulin components
- risk for nocturnal hypoglycaemia
- risk for fasting hyperglycaemia if basal component does not last long enough
- often requires accepting higher HbA1c goal of <7.5% or <8%
when do many T2DMs begin insulin therapy?
with HbA1c levels of >9%
- earlier
what are the definitions of hypoglycaemia and recent limitations?
low plasma glucose causing impaired brain function (neuroglycopenia) 3mmol/l
- mild: self treated
- severe: requiring help for recovery
hypoglycaemia: 3.9mmol/L
what is level 1 in the new classification of hypoglycaemia?
alert value
- plasma glucose <3.9mmol/l (70mg/dl) and no symptoms
what is level 2 in the new classification of hypoglycaemia?
serious biochemical
- plasma glucose <3.0mmol/l (55mg/dl)
what is non severe vs severe symptomatic hypoglycaemia?
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 of new classification)
what are symptoms that develop in hypoglycaemia?
- trembling
- palpitations
- sweating
- anxiety
- hunger
- difficulty concentrating
- confusion
- weakness
- drowsiness, dizziness
- vision changes
- difficulty speaking
- nausea
- headache
what are some protective mechanisms against severe hypoglycaemia?
- inhibition of endogenous insulin secretion (4.6 mmol/l)
- counter-regulatory hormones: glucagon and adrenaline
- symptom onset (autonomic-neuroglycopenic) (3.2-3 mmol/L)
what are some consequences of hypoglycaemia?
- widespread EEG changes (3.0 mmol/L)
- neurophysiological dysfunction (2.6 mmol/L)
- cognitive dysfunction; inability to perform complex tasks (3.0-2.4 mmol/L)
- severe neuroglycopenia; reduced consciousness, convulsions, coma (<1.5mmol/L)
- seizures, coma
- cognitive dysfunction
- accidents in employment
- prevents desirable glucose targets
- fear
- quality of life
what are risk factors for severe hypoglycaemia in T1DM?
- 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 for severe hypoglycaemia in T2DM? (on insulin or sulphonylureas)
- advancing age
- cognitive impairment
- depression
- aggressive treatment of glycaemia
- impaired awareness of hypoglycaemia
- duration of multiple daily injection insulin therapy
- renal impairment and other comorbidities
what are established risk factors for severe hypoglycaemia?
- low HbA1c; high pre-treatment HbA1c in T2DM
- long duration of diabetes
- a history of previous hypoglyaemia
- impaired awareness of hypoglycaemia
- recent episodes of severe hypoglycaemia
- daily insulin dosage >0.85 U/kg/day
- physically active
- impaired renal function
what are hypoglycaemia and glucose targets in T2DM?
- aim for lowest HbA1c not associated with frequent hypoglycaemia
- HbA1c <7.0% (53 mmol/mol) is usually appropriate for recent-onset disease
- may be appropriate to relax targets (severe complications, advanced co-morbidities, cognitive impairment, limited life expectancy, unacceptable hypoglycaemia from stringent control)
what are the less stringent targets in the frail elderly?
HbA1c <7.5%, <8% and <8.5%
how is medication adjusted to prevent 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
what is the treatment of hypoglycaemia?
- recognise symptoms so they can be treated as soon as they occur
- confirm the need for treatment if possible (BG <3.9 mmol/l is the alert value)
- treat with 15g fast acting carbohydrate to relieve symptoms
- retest in 15 minutes to ensure BG >4.0 mmol/l and retreat if needed
- eat a long-acting carbohydrate to prevent recurrence of symptoms
how is imaging used in investigations of disorders of calcium metabolism?
- abdominal x-rays may show renal calculi or nephrocalcinosis
- high definition hand x-rays can show subperiosteal erosions in the middle or terminal phalanges
- DXA bone density scan is useful in detecting bone effects in asymptomatic people with hyperparathyroidism in whom conservative management is planned
what are methods of imaging used in investigations of disorders of calcium metabolism?
- ultrasound, which, although insensitive for small tumours, is simple and safe
- high resolution CT scan or MRI (more sensitive)
- radioisotope scanning using 99Tc-sestamibi, which is 90% sensitive in detecting adenomas
what is the medical management of primary hyperparathyroidism?
- no effective medical therapies atm
- high fluid intake should be maintained, a high calcium or vitamin D intake avoided and exercise encouraged
- new therapeutic agents targeting calcium-sensing receptors (e.g. cinacalcet) are of proven value in parathyroid carcinoma and in dialysis patients and used in primary hyperparathyroidism where surgical intervention is contraindicated
when is surgery indicated in primary hyperparathyroidism?
- people with renal stones or impaired renal function
- bone involvement or marked reduction in cortical bone density
- unequivocal marked hyerglycaemia
- uncommon younger patient, below 50 years
- previous episode of severe acute hypercalcaemia
what does acute severe hypercalcaemia present as? when is immediate treatment mandatory?
- dehydration
- nausea and vomiting
- nocturia and polyuria
- drowsiness and altered consciousness
- serum Ca2+ is over 3 mmol/L and sometimes as high as 5 mmol/L
- immediate treatment is mandatory if the patient is seriously ill or if the Ca2+ is above 3.5 mmol/L
what is the treatment of acute severe hypercalcaemia?
- rehydrate
- IV bisphosphonates
- prednisolone (30-60mg daily may be effective)
- calcitonin (200 units IV 6hourly has short lived action and is little used)
- oral phosphate (sodium cellulose phosphate 5g TDS; produces diarrhoea)
how is rehydration used in treatment of acute severe hypercalcaemia?
- at least 4-6L of 0.9% saline on day 1, and 3-4L for several days thereafter
- central venous pressure (CVP) may need to be monitored to control the hydration rate
how are IV bisphosphonates used in treatment of acute severe hypercalcaemia?
- used for hypercalcaemia of malignancy or of undiagnosed cause
- pamidronate is preferred (60-90mg as an IV infusion in 0.9% saline or glucose over 2-4 hours, or if less urgent, over 2-4 days)
- levels fall after 24-72 hours, lasting for about 2 weeks
- zoledronate is an alternative
what are complications of parathyroid surgery?
- postop hypocalcaemia
- bleeding and recurrent laryngeal nerve palsies (<1%)
- vocal cord function
what is involved in postoperative care for parathyroid surgery?
treatment for hypocalcaemia (more common in patients who have significant bone disease and/or vitamin D deficiency)
- pre-treating with alfacalcidol 2 um daily from 2 days postop for 10-14 days
- routine vitamin D replacement (preferably without calcium) is indicated if deficiency is diagnosed
- Chvostek and Trousseau signs monitored
- biochemistry monitored
- plasma calcium measurements are performed daily until stable
- oral or IV calcium given temporarily
what is familial hypocalciuric hypercalcaemia? what are levels like?
- uncommon
- autosomal dominant
- usually asymptomatic
- demonstrates increased renal reabsorption of calcium despite hypercalcaemia
- PTH levels are normal or slightly raised and urinary calcium is low
- loss of function mutations in the gene on the long arm of chromosome 3 encoding for calcium-ion-sensing GPCR in the kidney and parathyroid gland
how is familial hypocalciuric hypercalcaemia treated? how is the diagnosis differentiated from hyperparathyroidism?
- detected by genetic analysis
- parathyroid surgery is not indicated as course appears benign
- diagnosis can be differentiated from hyperparathyroidism in an isolated case by the calcium creatinine ratio in blood and urine
what are causes of hypoparathyroidism?
- increased phosphate levels (CKD, phosphate therapy)
- hypoparathyroidism (surgery, DiGeorge’s, idiopathic, severe hypomagnesaemia)
- vitamin D deficiency (osteomalacia/rickets, vitamin D resistance)
- resistance to PTH (pseudohypoparathyroidism)
- drugs (calcitonin and bisphosphonates)
- miscellaneous (acute pancreatitis, citrated blood transfusion, low albumin, malabsorption)
what often accompanies idiopathic hypoparathyroidism?
- rare autoimmune disorder
- vitiligo, cutaneous candidiasis, other autoimmune disease
what is DiGeorge’s syndrome?
familial condition in which the hypoparathyroidism is associated with intellectual impairment, cataracts and calcified basal ganglia, and occasionally with specific autoimmune disease
what is pseudohypoparathyroidism? what is it associated with?
- syndrome of end-organ resistance to PTH owing to a mutation in the Gsalpha-protein (GNAS1) which is coupled to the PTH receptor
- variable degrees of resistance involving other G-protein linked hormone receptors may also be seen (TSH, LH, FSH)
what is pseudo-pseudohypoparathyroidism?
- phenotypic defects of pseudohypoparathyroidism
- without any abnormalities of calcium metabolism
- may share same gene defect as individuals with pseudohypoparathyroidism and be in the same families
what are clinical features/presentations of hypoparathyroidism?
- neuromuscular irritability and neuropsychiatric manifestations
- paraesthesiae, circumoral numbness, cramps, anxiety and tetany are followed by convulsions, laryngeal stridor, dystonia and psychosis
- Chvostek’s sign: gentle tapping over the facial nerve causes twitching of the ipsilateral facial muscles
- Trousseau’s sign: inflation of the sphygmomanometer cuff above systolic pressure for 3 min induces tetanic spasm of the fingers and wrist
- severe hypocalcaemia may cause papilloedema and frequently a prolonged QT interval on the ECG
what are investigations used to detect hypocalcaemia?
- low serum calcium (after correction for any albumin abnormality)
- clinical history and picture
- serum and urine creatinine (for renal disease)
- PTH levels in serum (absent or inappropriately low in hypoparathyroidism, high in other causes of hypocalcaemia)
- parathyroid antibodies (present in idiopathic hypoparathyroidism)
- 25-hydroxy vitamin D serum level (low in vitamin D deficiency)
- magnesium level (severe hypomagnasaemia results in functional hypoparathyroidism which is reversed by magnesium replacement)
- x-rays of metacarpals showing short 4th metacarpals occurring in pseudohypoparathyroidism
what is the treatment of hypocalcaemia?
- cholecalciferol in vitamin D deficiency
- alpha-hydroxylated derivatives of vitamin D may be preferred for their shorter half life, especially in renal disease as the others require renal hydroxylation
- daily maintenance doses are 0.25-2ug for allfacalcidol
- plasma calcium must be monitored for hypercalcaemia
- oral calcium supplements may be used in early stages of treatment
- severe hypocalcaemia presenting as an emergency may require replacement with IV calcium gluconate
what are causes of tetany in alkalosis?
- hyperventilation
- excess antacid therapy
- persistent vomiting
- hypochloraemic alkalosis e.g. primary hyperaldosteronism
what is diabetes mellitus?
a syndrome of chronic hyperglycaemia due to relative insulin deficiency, resistance or both
- affects more than 220 million worldwide
- will affect 440 million by the year
- complications result in reduced life expectancy and major health costs (including coronary artery disease, peripheral vascular disease and stroke and microvascular damage causing diabetic retinopathy and nephropathy, and neuropathy)
what are features of insulin structure and secretion? what is it coded by? what is it metabolised by?
- involved in storage and controlled release within the body of the chemical energy available from food
- coded for on chromosome 11
- synthesised in beta cells of pancreatic iselts
- enters portal circulation and is carried to the liver
- about 50% is extracted and degraded in the liver and kidneys
- C peptide is only partially extracted by the liver and is mainly degraded by the kidneys
what are usual blood glucose levels?
- blood glucose levels are closely regulated in health
- around 3.5-8.0 mmol/L (63-144 mg/dL)
- stay similar despite food, fasting and exercise
what is the main organ involved in glucose homeostasis?
- liver absorbs and stores glucose (as glycogen) in the post-absorptive state and releases it into circulation between meals to match the rate of glucose utilization by peripheral tissues
- combines 3-carbon molecules derived from breakdown of fat (glycerol), muscle glycogen (lactate) and protein (e.g. alanine) into the 6-carbon glucose molecule by gluconeogenesis
how is glucose produced? what is it derived from?
- about 200g of glucose is produced and utilised each day
- more than 90% is derived from liver glycogen and hepatic gluconeogenesis, and the remainder from renal gluconeogenesis
what is the glucose requirement for the body?
1 mg/kg bodyweight per minute, or 100g daily in a 70kg man
what happens to glucose that’s taken up by the muscle?
stored as glycogen or metabolised to lactate or CO2 and water
what happens to glucose that’s taken up by fat?
- source of energy
- substrate for TG synthesis
- lipolysis releases fatty acids from triglyceride together with glycerol, a substrate for hepatic gluconeogenesis
how is insulin synthesised and secreted?
- ribosomes manufacture pre-proinsulin from insulin mRNA
- hydrophobic pre portion of the pre-proinsulin allows it to transfer to the Golgi apparatus, and is enzymatically cleaved off
- proinsulin is parcelled into secretory granules in the Golgi
- pass towards membrane and are stored before release
- proinsulin molecule folds back onto itself and is stabilised by disulphide bonds
- biochemically inert peptide, connecting (C) peptide splits off from proinsulin, leaving insulin as two linked peptide chains
what are the two different pathways of insulin secretion by the beta cell?
regulated pathway: releases equimolar quantities of insulin and C-peptide
constitutive pathway: small amount of insulin is secreted by the beta cell directly. bypasses the secretory granules
what are local forces regulating insulin secretion from beta cells?
- glucose enters the beta cell via the GLUT-2 transporter protein
- metabolism of glucose within the beta cell generates ATP
- ADP/ATP binds to SUR1 (regulatory subunit)
- ATP closes potassium channels in the cell membrane
- closure of potassium channels predisposes to membrane depolarisation, allowing calcium ions to enter the cell; if a sulfonylurea binds to its receptor this also closes potassium channels
- rise in intracellular calcium triggers activation of calcium-dependent phospholipid protein kinase, which leads to fusion of the granules and exocytosis
- this secretes insulin
what is the role of GLUT-1?
enables basal non-insulin-stimulated glucose uptake into many cells
what is the role of GLUT-2?
transports glucose into beta cell, a prerequisite for glucose sensing, and is also present in renal tubules and hepatocytes
what is the role of GLUT-3?
enables non-insulin-mediated glucose uptake into brain neurones and placenta
what is the role of GLUT-4?
enables much of the peripheral action of insulin. glucose is taken up into muscle and adipose tissue cells following stimulation of the insulin receptor
what is the structure and function of the insulin receptor?
- glycoprotein (400 kDa)
- coded for on the short arm of chromosome 19
- on cell membrane
- dimer with two alpha subunits which include the binding sites for insulin, and two beta subunits, which traverse the cell membrane
- when insulin binds to the alpha subunits it induces a conformational change in the beta subunits, which activates tyrosine kinase and initiation of a cascade response
- leads to migration of GLUT-4 to cell surface and increased transport of glucose into the cell
- insulin receptor complex is internalised, insulin is degraded and the receptor is recycled
- insulin signal pathway leads to effects on protein metabolism, effects on growth, effects on lipid metabolism and translocation of GLUT-4 vesicle to cell membrane
what are diseases of the exocrine pancreas that can cause diabetes?
- pancreatitis
- trauma/pancreatectomy
- neoplasia
- CF
- haematochromatosis
- fibrocalculous pancreatopathy
what are endocrinopathies that can cause diabetes?
- acromegaly
- Cushing’s syndrome
- glucagonoma
- phaeochromocytoma
- hyperthyroidism
- somatostatinoma
- aldosteronoma
what are drugs and chemicals that can cause diabetes?
- vacor (pyrinuron)
- pentamidine
- nicotinic acid
- beta blockers
- thyroid hormone
- diazoxide
- beta adrenergic agonists
- thiazides
- phenytoin
- alpha interferon
- protease inhibitors
what are immunosuppressive agents that can cause diabetes?
- glucocorticoids
- ciclosporin
- tacrolimus
- sirolimus
what are anti psychotic agents that can cause diabetes?
- clozapine
- olanzapine
what are infections that can cause diabetes?
- congenital rubella
- cytomegalovirus
what are uncommon forms of immune-mediated diabetes?
- stiff person syndrome
- anti-insulin receptor antibodies
what are other genetic syndromes sometimes associated with diabetes?
- Down’s
- Friedreich’s ataxia
- Huntington’s chorea
- Klinefelter’s syndrome
- Laurence-Moon-Biedl syndrome
- myotonic dystrophy
- porphyria
- Prader-Willi syndrome
- Turner’s syndrome
- Wolfram’s syndrome
what are characteristics of type 1 diabetes, including hereditary factors, pathogenesis, clinical features, epidemiology?
- younger age (<30)
- lean weight
- symptom duration of weeks
- northern/European people have higher risk
- seasonal onset
- HLA-DR3 or DR4 in >90%
- autoimmune disease
- ketonuria
- clinical: insulin deficiency, ketoacidosis, always need insulin
- C-peptide disappears
what are characteristics of type 2 diabetes, including hereditary factors, pathogenesis, clinical features, epidemiology?
- older (>30)
- overweight
- symptom duration of months/years
- Asian, African, Polynesian and American-Indian have higher risk
- no seasonal onset
- no HLA links
- no immune disturbance
- no ketonuria
- clinical: partial insulin deficiency initially, hyperosmolar state, need insulin when beta cells fail over time
- C-peptide persists
how can the HLA system cause diabetes?
- chromosome 6
- 90% of patients carry HLA-DR3-DQ2, HLA-DR4-DQ8 or both, compared to 35% of the background population
- all DQB1 alleles with an aspartic acid at residue 57 confers neutral to protective effects with the strongest effect from DQB1*0602 (DQ6), while DQB1 alleles with an alanine at the same position (DQ2 and DQ8) confer strong susceptibility
- HLA DR3-DQ2/HLA DR4-DQ8 heterozygotes have an increased risk of disease
- some HLA class I alleles modify the risk conferred by class II susceptibility genes
what are genes or gene regions other than the HLA system that can cause diabetes?
- more than 50 non-HLA genes or gene regions influence risk
- gene encoding insulin (INS) on chromosome 11
- cytotoxic T-lymphocyte-associated protein-4 (CTLA4) gene
- lymphoid-specific protein tyrosine phosphatase (PTPN22) gene
- IL-2R alpha-subunit of the IL-2 receptor complex locus (IL2RA)
what are some islet cell autoantibodies (ICA)?
- GAD65 (glutamic acid decarboxylase)
- IA-2/ICA512 (protein tyrosine phosphatase)
- insulin
- cation transporter ZnT8
what is insulitis?
infiltration of pancreatic islets by mononuclear cells
- resembles that in other autoimmune diseases e.g. thyroiditis
what are environmental factors affecting type 1 diabetes?
- incidence of childhood diabetes is rising across Europe by 2-3% each year
- islet autoantibodies appear in the first few years of life
- exposure to dietary constituents, enteroviruses e.g. Coxsackie B4 and relative deficiency of vitamin D may play a role
- cleaner environment with less early stimulation of the immune system may increase susceptibility
- atopic/allergic conditions and more rapid weight gain leading to insulin resistance may accelerate clinical onset
what is pre-type 1 diabetes and how can type 1 be prevented?
- children who test positive for 2+ autoantibodies have a >80% risk of progression to diabetes, and the risk approaches 100% in those who lose their first phase insulin response to IV glucose and/or develop glucose intolerance
- intervention before clinical onset of diabetes has been unsuccessful
what factors affect onset of type 2 diabetes?
- increasing age
- ethnicity
- family history
- in poor countries, it’s a disease of the rich, and in rich countries, a disease of the poor
- stress of pregnancy, drug treatment or intercurrent illness may accelerate onset
- more prevalent in South Asian, African, Caribbean people
- those of Middle Eastern and Hispanic American origin living western lifestyles have risk
- obesity increases the risk of type 2 80-100 fold
- sedentary/western lifestyle
- insulin resistance
- metabolic syndrome
what is metabolic syndrome? what are the criteria for its diagnosis?
- type 2 diabetes is associated with central obesity, hypertension, hypertriglyceridaemia, decreased HDL-cholesterol, disturbed haemostatic variables and modest increases in pro-inflammatory markers
- insulin resistance and increased cardiovascular risk is associated with these variables
- criteria: increased waist circumference (or BMI >30) plus two of the following: diabetes (or fasting glucose >6.0 mmol/L), hypertension, raised TGs or low HDL cholesterol
what are genetic components of type 2 diabetes?
- transcription factor-7-like (TCF7-L2) most common variant in Europeans; increased risk of 35%; modulates pancreatic islet cell function
- KCNQ1 (potassium voltage gated channel) in Asians; increased risk of 10-20%
what are early and late environmental factors affecting type 2 diabetes?
- low weight at birth and at 12 months is linked to glucose intolerance later in life, esp. in overweight/obese
- poor nutrition early in life impairs beta-cell development and function, predisposing to diabetes
- low birthweight also predisposes to heart disease and hypertension
how does inflammation affect type 2 diabetes?
- subclinical inflammatory changes are characteristic of both type 2 diabetes and obesity
- in diabetes, high sensitivity C-reactive protein levels are modestly elevated in association with raised fibrinogen and increased plasminogen activator inhibitor-1 (PAI-1)
- CRP levels contribute to cardiovascular risk
- circulating levels of pro-inflammatory cytokines TNF-alpha and IL-6 are elevated in diabetes and obesity
how do abnormalities of insulin secretion and action affect type 2 diabetes?
- some degree of beta-cell dysfunction is necessary
- insulin binds normally to its receptor
- insulin resistance is associated with central obesity and accumulation of intracellular TG in muscle and liver, and many have NAFLD
- patients retain up to 50% of their beta cell mass at time of diagnosis
- show islet amyloid deposition at autopsy, derived from amylin or islet amyloid polypeptide, which is cosecreted with insulin
what is the Starling curve of the pancreas in type 2 diabetes?
- circulating insulin levels are higher than healthy people following diagnosis
- tend to rise further
- decline after months or years due to secretory failure
insulin deficiency relative to increased demand leads to hypersecretion of insulin by a depleted beta-cell mass and progression towards absolute insulin deficiency requiring insulin therapy
how can beta cells be affected by excess glucose?
glucotoxicity: hyperglycaemia and lipid excess are toxic to beta cells; this results in further beta-cell loss and further deterioration of glucose homeostasis
what are rare forms of type 2 diabetes?
- insulin receptor mutations (obesity, insulin resistance, hyperandrogenism, acanthosis nigricans)
- maternally inherited diabetes and deafness
- Wolfram’s syndrome
- severe obesity and diabetes (Alstroems, Bardet-Biedl, Prader-Willi, reinitis pigmentosa, mental insufficiency, neurological disorders)
- disorders of intracellular insulin signalling (Leprechaunism, Rabson-Mendenhall, pseudoacromegaly, lipodistrophy)
- genetic defects of beta cell function
what are features of MIDD?
- mutation in mitochondrial DNA
- diabetes onset before age 40
- variable deafness
- neuromuscular and cardiac problems
- pigmented retinopathy
what is Wolfram’s syndrome?
DIDMOAD - diabetes insipidus, diabetes mellitus, optic atrophy and deafness
- recessively inherited
- mutation in the transmembrane gene, WFS1
- insulin-requiring diabetes and optic atrophy in the first decade
- diabetes insipidus and sensorineural deafness in teh second decade progressing to multiple neurological problems
- few live beyond middle age
what are features of HNF-4a as a cause of beta-cell dysfunction?
- 20q
- 5% of all cases
- teens/30s onset
- progressive hyperglycaemia
- frequent microvascular complication
what are features of glucokinase as a cause of beta-cell dysfunction?
- 7p
- 15% of all cases
- present from birth
- little deterioration with age
- rare microvascular complications
- reduced birthweight
what are features of HNF-1a as a cause of beta-cell dysfunction?
- 12q
- 70% of all cases
- teens/20s onset
- progressive hyperglycaemia
- frequent microvascular complications
- sensitivity to sulfonylureas
what are features of IPF-1 as a cause of beta-cell dysfunction?
- 13q
- <1% of all cases
- teens/30s onset
- progression unclear
- pancreatic agenesis in homozygotes
what are features of HNF-1b as a cause of beta-cell dysfunction?
- 17q
- 2% of all cases
- teens/20s onset
- progression unclear
- renal cysts, proteinuria, CKD
what is TNDM?
transient neonatal diabetes mellitus
- occurs soon after birth
- resolves at a median of 12 weeks
- 50% of cases relapse later in life
- most have an abnormal imprinting of the ZAC and HYMAI genes on chromosome 6q
what is the cause of PNDM?
permanent neonatal diabetes mellitus
- mutations in the KCNJ11 gene encoding the Kir6.2 subunit of the beta-cell potassium-ATP channel
what is the acute presentation of diabetes?
young people often present with a 2-6 week history and report:
- polyuria: due to osmotic diuresis that results when blood glucose levels exceed the renal threshold
- thirst: due to loss of fluid and electrolytes
- weight loss: due to fluid depletion and the accelerated breakdown of fat and muscle secondary insulin deficiency
ketonuria is often present in young people and may progress to ketoacidosis
what is the subacute presentation of diabetes?
- clinical onset may be over several months or years, esp. in older patients
- thirst, polyuria and weight loss are present
- lack of energy, visual blurring (glucose-induced changes in refraction) or pruitus vulvae or balanitis due to Candida
what are complications of diabetes as the presenting feature?
- staphylococcal skin infections
- retinopathy noted during a visit to the optician
- polyneuropathy causing tingling and numbness in the feet
- erectile dysfunction
- arterial disease, resulting in MI or peripheral gangrene
how can asymptomatic diabetes be detected?
- glycosuria or raised BP on routine examination
- glycosuria indicates need for further investigations
- 1% of the population have renal glycosuria
what can be results of physical examination in diabetes?
- evidence of weight loss and dehydration
- breath smells of ketones
- older patients may have complications
- retinopathy is diagnostic of diabetes
- physical signs of an illness causing secondary diabetes
- may have acanthosis nigricans
what are the WHO diagnostic criteria for diabetes?
- fasting plasma glucose >7.0 mmol/L (126 mg/dL)
- random plasma glucose >11.1 mmol/L (200 mg/dL)
- one abnormal lab value is diagnostic in symptomatic individuals; two values for asymptomatic people
- HbA1c >6.5 (48 mmol/mol)
what are the WHO criteria for the glucose tolerance test for fasting and 2hrs after glucose conditions?
normal
f: <7.0 mmol/L
2hrs: <7.8 mmol/L
impaired glucose tolerance
f: <7.0 mmol/L
2hrs: 7.8-11.0 mmol/L
diabetes mellitus
f: >7.0 mmol/L
2hrs: >11.1 mmol/L
what is HbA1c?
haemoglobin A1c
- integrated measure of prevailing blood glucose over several weeks
>6.5% (48 mmol/mol) is diagnostic of diabetes
5.7-6.4% (39-46 mmol/mol) is increased risk of diabetes
what is recommended for food for diabetics?
- low in sugar (not sugar free)
- high in starchy carbohydrate (esp. foods with low glycaemic index) i.e. slower absorption
- high in fibre
- low in fat (esp. saturated fat)
what is the action of biguanide (metformin)?
- used in diabetes
- activates AMP-kinase, which is involved in regulation of cellular energy metabolism
- reduces the rate of gluconeogenesis, and hence hepatic glucose output, to increase insulin sensitivity
- doesn’t induce hypoglycaemia, doesn’t affect weight gain and doesn’t affect insulin secretion
what adverse effects of biguanide (metformin)?
- anorexia
- epigastric discomfort
- diarrhoea
- prohibits its use in 5-10% of patients
what is the action of sulfonylureas?
- diabetes
- act on beta cell to promote insulin secretion in response to glucose and other secretagogues
- ineffective in patients without a functional beta-cell mass, and are usually avoided in pregnancy
- bind to sulfonylurea receptor which closes ATP-sensitive potassium channels and leads to depolarisation
what are advantages and disadvantages of sulfonylureas?
- cheap
- more effective than other agents in achieving short term (1-3 years) glucose control
- effect wears off as the beta cell mass declines
- may hasten beta cell apoptosis and promote weight gain
- best avoided in the overweight
- can cause potentially fatal hypoglycaemia
- long half lives
- avoided in liver disease and renal impairment
what are the most commonly used sulfonylureas for diabetes?
- tolbutamide
- glibenclamide
- glipizide and glimepiride
- gliclazide
- chlorpropamide
what are properties of tolbutamide (sulfonylurea used in diabetes)?
- lower maximal efficacy than other sulfonylureas
- short half life; preferable in elderly
- largely metabolised by liver; can use in renal impairment
what are properties of glibenclamide (sulfonylurea used in diabetes)?
- long biological half-life
- severe hypoglycaemia
- do not use in elderly
what are properties of glipizide and glimepiride (sulfonylureas used in diabetes)?
- active metabolites
- renal excretion; avoid in renal impairment
what are properties of chlorpropamide (sulfonylurea used in diabetes)?
- very long biological half-life
- renal excretion - avoid in renal impairment
- 1-2% develop inappropriate ADH-like syndrome
- facial flush with alcohol
- very inexpensive - major issue for developing countries
- can produce fatal hypoglycaemia
- not recommended in the elderly
what is the action of meglitinides (in diabetes)?
- e.g. repaglinide and nateglinide
- insulin secretagogues
- the non-sulfonylurea moiety of glibenclamide
- act via closure of K+-ATP channel in beta cells
- short acting agents that promote insulin secretion in response to meals
what is the action of thiazolidinediones?
- known as the glitazones
- reduce insulin resistance by interaction with peroxisome proliferator-activated receptor-gamma (PPAR-gamma); this regulates large numbers of genes including those in lipid metabolism and insulin action
- potentiate the effect of endogenous or injected insulin
- binds to nuclear receptors mainly found in fat cells
- act indirectly via the glucose-fatty acid cycle, lowering free fatty acid levels and thus promoting glucose consumption by muscle
- reduce hepatic glucose production (synergistic with metformin) and enhance peripheral glucose uptake
what are the uses of thiazolidinediones?
- troglitazone and rosiglitazone have been withdrawn for safety reasons (liver failure and increased CV risk)
- pioglitazone is only remaining agent
unwanted effects of pioglitazone
- weight gain of 5-6kg
- fluid retention and heart failure
- mild anaemia and osteoporosis resulting in peripheral bone fractures
- increased risk of bladder cancer
what is the action of dipeptidyl peptidase-4 (DPP4) inhibitors?
- enhance the incretin effect
- enzyme dipeptidyl peptidase 4 rapidly inactivates GLP-1 as this is released into circulation
- potentiates the effect of endogenous GLP-1 secretion
- lower blood glucose and are weight neutral
what are the currently available dipeptidyl peptidase 4 inhibitors? when are they most effective?
- linagliptin
- saxagliptin
- sitagliptin
- vildagliptin
most effective in early stages of type 2 diabetes when insulin secretion is relatively preserved. currently recommended for second-line use in combination with metformin or a sulfonylurea
what are adverse effects of dipeptidyl peptidase 4 inhibitors?
adverse effects are uncommon
- nausea
- acute pancreatitis
- short term safety record is good
- it’s widely distributed in the body
- long-term consequences of inhibition of this enzyme in other tissues is not known
what is the incretin effect?
the insulin response to oral glucose is greater than the response to IV glucose
what is the incretin effect caused by?
two intestinal peptide hormones, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) have a potentiating effect on pancreatic secretion of insulin
- GIP causes 30% and GLP-1 70% of the incretin effect
- both hormones have short half-lives in the circulation, being degraded by DPP4
- diminished in T2DM
where are glucose-dependent insulinotropic peptide and glucagon-like peptide 1 secreted from?
- GIP is secreted from the K cells in the duodenum
- GLP-1 is secreted from the L cells of the ileum in response to food
what is the action of GLP-1 agonists?
- exenatide and liraglutide are long-acting analogues of GLP-1, which enhance the incretin effect
- promote insulin release, inhibit glucagon release, reduce appetite and delay gastric emptying
- blunt the post-prandial rise in plasma glucose and promote weight loss
what are advantages and disadvantages of GLP-1 agonists?
- main disadvantage is the need for subcutaneous injection (twice daily for exenatide and once daily for liraglutide)
- main advantage is improving glucose control while inducing useful weight reduction
- work well in 70% but have little benefit in 30%
what are side effects of GLP-1 agonists?
nausea, acute pancreatitis and acute kidney injury
how are short-acting insulins used to treat diabetes?
- insulin derived from beef or pig pancreas have been replaced by biosynthetic human insulin
- short-acting insulins are used for pre-meal injection in multiple dose regimens, for continuous IV infusion in labour or in medical emergencies, and in patients using insulin pumps
how is human insulin absorbed?
- slowly, reaching a peak 60-90 min after subcutaneous injection and its action tends to persist after meals, predisposing to hypoglycaemia
- absorption is delayed because soluble insulin is in the form of stable hexamers (six insulin molecules around a zinc core) and needs to dissociate to monomers and dimers before it can enter circulation
why is absorption of human insulin delayed?
- soluble insulin is in the form of stable hexamers (six insulin molecules around a zinc core)
- needs to dissociate to monomers or dimers before it can enter the circulation
what are the actions of insulin analogues?
- short acting insulin analogues have been engineered to dissociate more rapidly following injection without altering the biological effect
- insulin analogues e.g. rapid acting insulins (insulin lispro, insulin aspart and insulin glulisine) enter the circulation more rapidly than human soluble insulin and disappear more rapidly
- short-acting analogues have little effect upon overall glucose control
what are some rapid acting insulins?
insulin lispro, insulin aspart and insulin glulisine
how can the action of human insulin be prolonged?
by addition of zinc or protamine derived from fish sperm
what are examples of intermediate and longer-acting insulins?
- NPH (isophane insulin)
- insulin glargine
- insulin detemir
what is the use of NPH as an intermediate and longer-acting insulin?
- can be premixed with soluble insulin to form stable mixtures (biphasic insulins)
- combination of 30% soluble with 70% NPH is most widely used
what is the action of insulin glargine?
- long acting insulin
soluble in the vial as a slightly acidic (pH 4) solution, but precipitates at subcutaneous pH, thus prolonging its duration of action
what is the action of insulin detemir?
- long acting insulin
has a fatty acid tail, which allows it to bind to serum albumin, and its slow dissociation from the bound state prolongs its duration of action
what is the structure of human insulin?
A chain and B chain connected by disulphide bridges
what is lispro?
a genetically engineered rapidly acting insulin analogue created by reversing the order of the amino acids proline and lysine in positions 28 and 29 of the B chain
what is insulin aspart?
similar analogue to lispro created by replacing proline at position 28 of the B chain with an aspartic acid residue
what is insulin glargine?
a genetically engineered long-acting insulin created by replacing asparagine in position 21 of the A chain with a glycine residue and adding two arginines to the end of the the B chain
what is insulin detemir?
discards threonine in position 30 of the B chain and adds a fatty acyl chain to lysine in position B29
what are stages of T2DM treatment?
stage 1: lifestyle changes and metformin
stage 2: add sulphonylurea, basal insulin, consider adding DPP4 inhibitor or glitazone
stage 3: change from SU to basal insulin or add DPP4 inhibitor, add mealtime short-acting SU or intensity insulin to basal insulin, change to basal insulin from DPP4 inhibitor or glitazone or add remaining DPP4 inhibitor or glitazone
stage 4: further intensify treatment or switch to insulin
progress to further step if HbA1c >53mmol/mol
what are types of insulin regimen in type 2 diabetes?
- an intermediate insulin given at night with metformin during the day
- multidose insulin regimens
- metformin is a useful adjunct
- addition of a morning dose of insulin may be needed to control postprandial hyperglycaemia
- twice daily injections of pre-mixed soluble and isophane insulins
- more aggressive treatment e.g. multiple injections or continuous infusion pumps
why is ideal control in insulin therapy difficult to achieve?
- low first-pass metabolism in subcutaneous injection compared to secreted insulin
- subcutaneous soluble insulin takes 60-90 min to achieve peak plasma levels, so the onset and offset of action are too slow
- absorption of subcutaneous insulin insulin into the circulation is variable
- basal insulin levels are constant in normal people, but injected insulin peaks and declines in diabetics, with swings in metabolic control
when should insulin analogues be used?
- hypoglycaemia between meals and particularly at night is the limiting factor for patients on multiple injection regimens
- more expensive rapid-acting insulin analogues are a substitute for soluble insulin
- analogues reduce frequency of nocturnal hypoglycaemia
- used on convenience, as patients can inject before meals
- analogues can reduce high or erratic morning blood sugar readings
what should be done to adjust insulin dosage according to blood glucose results before breakfast?
persistently too high: increase evening long-acting insulin
persistently too low: reduce evening long-acting insulin
what should be done to adjust insulin dosage according to blood glucose results before lunch?
persistently too high: increase morning short-acting insulin
persistently too low: reduce morning short-acting insulin or increase mid-morning snack
what should be done to adjust insulin dosage according to blood glucose results before evening meal?
persistently too high: increase morning long-acting insulin or lunch short-acting insulin
persistently too low: reduce morning long-acting insulin or lunch short-acting insulin or increase mid-afternoon snack
what should be done to adjust insulin dosage according to blood glucose results before bed?
persistently too high: increase evening short-acting insulin
persistently too low: reduce evening short-acting insulin
what are the times of greatest risk for hypoglycaemia episodes?
- before meals
- during the night
- during exercise
- irregular eating habits, unusual exertion and alcohol excess may precipitate episodes
- other cases are just due to variation in insulin absorption
what are symptoms of hypoglycaemia during insulin treatment?
- develop when blood glucose level falls below 3 mmol/L
- develop over a few minutes
- adrenergic features of sweating, tremor and a pounding heartbeat
- all patients with type 1 have intermittent hypoglycaemia
- one in three go into a coma at some point
- pallor and a cold sweat
- hypoglycaemic unawareness: lose warning symptoms; risk of central nervous dysfunction
- pale, drowsy, detached
- clumsy, inappropriate, irritable or aggressive behaviour
- hypoglycaemic coma
what is nocturnal hypoglycaemia?
- basal insulin requirements fall during the night but increase from 4am, when injected insulin levels are falling
- patients may wake with high glucose levels, but find that injecting more insulin at night increases the risk of hypoglycaemia in the morning
