Diabetes Flashcards
List the insulin dependent vs insulin independent glucose transporters
i. Insulin independent
1. Brain = GLUT1
2. B islet cells, liver, kidney + small intestine (basolateral) = GLUT2
3. Neurons = GLUT3
4. GI tract (apical – fructose transport) + spermatocytes = GLUT5
ii. Insulin dependent
1. Skeletal muscle + adipocytes = GLUT4
What is the pattern of insulin secretion? Loss of this =?
i. Pulsatile (periodicity of 9-14 minutes)
ii. Loss of pulsatility = one of the earliest signs of basal cell dysfunction
Physiology of insulin secretion in pancreatic beta cells
i. Glucose enters B cell of pancreas via GLUT-2 transporter
ii. Glucose is phosphorylated to glucose-6-phosphate by glucokinase
iii. Glucose-6-phosphate can then be metabolised to generate ATP
iv. ↑ ATP leads to closure of ATP-sensitive K channel (K-ATP)
1. K-ATP is made up of two subunits:
a. SUR gene – chromosome 11 p
b. KIR 6.2 gene – chromosome 11 p
v. Closure of channel = intracellular accumulation of potassium = depolarisation of membrane
vi. Calcium channels open
vii. Influx of calcium leads to secretion of insulin
Pathophysiology of neonatal diabetes
Activating mutation = ↑ number of open KATP channels at the plasma cell
Hyperpolarization of the beta cells
Decreased release of insulin
Pathophysiology of hyperinsulinism of infancy
Inactivating mutations in either gene reduce the number of KATP channels
Depolarisation of beta cells
Increased/hypersecretion of insulin
which hormones counteract insulin (4)?
glucagon, GH, adrenaline, cortisol
which is the only organ glucagon clinically acts on?
liver
- sources of blood glucose (hormones, timing, and how we get the glucose)
- what is the order in which these hormones are released?
Glucose Diet 2-4 hours
Glycogenolysis Glucagon 10-12 hours
Gluconeogenesis Cortisol 12-24 hours
Lipolysis GH 17-36 hours
adrenaline > glucagon > cortisol > GH
name the three ketone types
B-hydroxybutyrate, acetoacetic acid, acetone
3 processes we get glucose from
- glycolysis
- glycogenolysis
- gluconeogenesis
physiology of glycolysis (aerobic vs anaerobic)
Anaerobic fermentation
glycogen -> x2pyruvate and 2ATP
pyruvate -> lactic acid -> to liver
usually just muscle
AAerobic respiratory
pyruvate oxidation -> acetyl coA
-> krebs -> ETC -> CO2 + H2O + 38ATP
in mitochondria
What infections can induce diabetes (name 3)
CMV, HUS, rubella
how many % of new T1DM have FHx?
85% have no FHx
what is peak age of t1dm dx?
bimodal peak at 4-6 years of age, and another at 10-14 years of age
what genes are associated with t1dm (most common)?
HLADR3/DR4
DQ2/8
how much of beta cell is destroyed before you get clinical signs in t1dm
90%
dawn phenomenon and t1dm:
- what is it
- what causes it
- when
- how to fix
i. Early morning (2-8am) hyperglycaemia due to overnight GH secretion + ↑ insulin clearance
ii. Occurs in peri-pubertal + pubertal years
iii. Manage with ↑ evening protophane dose
somogyi phenomenon and t1dm
- what
- why
- Rebound hyperglycaemia from late night/ early AM hypoglycaemia,
- Due to exaggerated counter regulatory response-
classic t1dm triad of symptoms
- polydipsia - from inc serum osm
- polyuria - glycosuria + osmotic diuresis
- weight loss - hypovolaemia + inc catabolism, insulin def
diagnostic criteria t1dm
one of:
- Fasting (>8 hours) BSL >7 mmol/L on more than one occasion
- Random BSL >11.1 mmol/L on more than one occasion in a patient with symptoms of hyperglycaemia
- BSL >11.1 two hours after oral glucose load of 1.75 g/kg (max 75g) in OGTT (rarely done)
nb HbA1c >6.5 – not established as diagnostic for diabetes in children
the 5 t1dm autoantibodies - which is best predictor, and which is most present at dx? progression of autoabs?
Insular at first, GAD its mentioned most, but NOMA is the best. Issa Zingga!:
Anti-insulin antibodies (IAA) - first
Anti-glutamic acid decarboxylase (anti-GAD) - second, best
Anti-insulinoma protein 2 (anti-IA2) - third, best
Islet cell cytoplasmic antibodies (ICA) - 70%
Anti-zinc transporter (anti-ZNT8)
which t1dm-associated gene is more associated with AI conditions?
HLA DR3 - note longer dm dormancy period, a/w ICA autoabs.
Note HLADR4 - a/w anti-IAA
what % of t1dm will developed coeliac within first 6 yrs of dx?
7-15% of children with T1DM develop celiac disease within the first 6 years of diagnosis
what % of t1dm will develop hyper vs hypothyroidism?
2-5% develop hypothyroidism
1% develop hyperthyroidism (much rarer, but more common than general population)
name 5 autoimmune conditiions associated with t1dm
- thyroid disorder
- coeliac disease
- AI adrenalitis - 1 %
- Gastric autoimmunity - anti-parietal cells, anti-IF
- vitiligo - 6%
name two autoimmune syndromes associated with t1dm
APS-2
IPEX
recommended diet stuff for t1dm
CHO 50% and low GI, fat 30% with saturated <10%, protein 20%
t1dm: target bsl, hba1c, what bsl to treat for hypo, and what ketones to treat
Target BSL = 4-8
Target HbA1C = <7.5%
Treat:
Hypoglycaemia = <4
Ketosis = >1
6 side effects of insulin Rx
- Hypoglycaemia
- Lipohypertophy at injection sites
- insulin resistance
- Insulin antibodies - nearly all develop antibodies after several moths
- weight gain
- local allergy
BD vs basal-bolus insulin regimens:
- TDD
- distribution
both TDD = 1UKD
basal bolus:
- usually nocte levemir (0.4UKD) + tds novo (each 0.2UKD)
BD: usually levemir and novo BD
- mane 2/3 TDD, evenine 1/3 TDD
2 molecules to assess mid-long term diabetes control
hba1c (2-3 month control)
fructosamine (glycated serum proteins) - 1-2 week control, useful in haemoglobinopathies (HbA1c spuriously ↓/↑)
pathogenesis of most of the macro/microvascular complications of t1dm
- Polyol pathway – metabolisms excess glucose to sorbitol then fructose = tissue damage
- Glycosylation of proteins – glucose binds to proteins irreversibly and alteration leads to loss of function
types of diabetic retinopathy
- background - dilated vessels
- non-proliferative - microinfarcts, cotton wool spots / soft exudate
- proliferative - hard shit: ischaemia, haemorrhage, scarring, RD!
what is the earliest sign of diabetic nephropathy? define it.
albuminuria: albumin excretion between 30-300 mg/day (20-200 mcg/min)
what is necrobiosis lipoidica
inflammatory, granulomatous condition - oval/round plaques on shins. initially red/dusky -> yellow, central atrophy
mauriac syndrome:
pathophys
a/w
signs
rare complication t1dm
glycogen laden liver -> hepatomegaly + cushingoid facies
a/w delayed puberty and DWARFISM
catch up growth if diabetes fixed
what are normal ketone levels
<0.6
glucagon dosing in severe hypoglycaemia
- 0.5ml = children <25 kg
2. 1ml = children >25kg
definition of DKA
hyperglycaemia + metabolic acidosis + ketonaemia
venous gas <7.3 + blood or urinary ketones
hypo and hyperkalaemia on ECG
- Hyperkalaemia = peaked T waves, widened QRS
2. Hypokalaemia = flattened or inverted T waves, ST depression, widened PR interval
outline steps in DKA Mx
- ABC
- fluids
- insulin infusion (0.1MKH if new Dx)
- potassium - total body K deficit but apparent hyperK, risk of hypoK with insulin
when to switch to SC insulin from continuous in DKA? When to stop the infusion?
start SC just before meal.
stop continuous 30 mins after SC (for overlap)
when to give bicarb in DKA?
not recommended - causes paradoxical cerebral acidosis
what to do if still hypoglycaemic with DKA Mx?
inc to 10% dex - dont reduce insulin until 10% dex really not working
what is the rule for Na correcting during DKA?
Na should improve as glucose falls - hypoNa is dilutional effect of glucose
complications of DKA - and which is responsible for highest mortality
- hypoNa
- hypoglycaemia
- cerebral oedema - causes 60% deaths
- hypo/hyperK
- renal failure
- pancreatitis
cerebral oedema:
- 3 at risk groups
- warning signs related to Mx
- how to treat
- first presentation, long history of poor control, young age (< 5 yr)
- No sodium rise as glucose falls, hyponatraemia during therapy, initial adjusted hypernatraemia
- mannitol
which other endocrine condition is a risk factor for DKA
hyPERthyroidism
best T2DM test for Dx?
fasting GTT
clinical signs of insulin resistance in T2DM, and which is the most common?
- cutaneous: acanthosis nigricans (best!), alopecia, skin tags
- reproductive: amenorrhoea, hirsutism, virilisation
- fat
treatment regimen of chocie in T2DM
metformin monotherapy
what is worse than DKA for T2DM?
hyperosmolar non-ketotic acidosis
- insulin deficiency
- extreme hyperglycaemia
- extreme dehydration in cells
- GNG without ketones bc there’s still insulin
- fluid resus +++
MODY inheritance pattern
AD
MODY 2
- pathogenesis + gene
- frequency
- key clinical feature
- risk of microvascular disease
- optimal treatment
- Glucokinase gene GCK (glucose sensor)
- Defective glucokinase -> increased plasma levels of glucose to elicit normal levels of insulin secretion
- 15-30%
- Mild, stable, fasting hyperglycemia, often diagnosed during routine screening. Not progressive.
- generally no risk of microvascular disease
- diet Mx
MODY 3
- pathogenesis + gene
- frequency
- key clinical feature
- risk of microvascular disease
- optimal treatment
- Hepatocyte nuclear factor-1-alpha HNF1alpha
- Mechanism unclear, ?reduced insulin secretory response to glucose, low renal threshold for glucose (decreased renal absorption of glucose)
- glycosuria key feature
- yes to microvascular disease
- sulfonylureas
