T2DM Flashcards
what is the simple definition of type 2?
state of chronic hyperglycaemia sufficient to cause long-term damage to specific tissues
what are the 3 main contributors to T2?
- body weight
- lipids
- blood pressure
does ketosis occur in T2DM?
T2 is not ketosis prone or mild but it can happen
what is the fasting glucose in T2?
> 7 mmol/L (normally 6)
what is the range between 6 and 7 mmol/L fasting glucose called?
what is the 2 hour response to this called?
impaired fasting glucose
impaired glucose tolerance
these people are not diabetic but are on course to be. They are also developing macrovascular complications.
which is the more common form of diabetes?
type 2
who can be affected by T2?
adults mostly
children can be too
what factor varies the incidence of T2 around the world?
ethnicity
in which demographics is type 2 greatest?
ethnic groups who move from rural to urban lifestyles
how many hereditary forms of MODY (uncommon) are there?
inheritance method?
1-8 (each type has a specific treatment)
autosomal dominant
what mutation causes MODY (Maturity Onset Diabetes of the Young)?
glucokinase gene:
transcription factor used by beta cells to recognise glucose concentration leading to ineffective beta cell insulin secretion
- no obesity caused
- there will be a positive family history
what factors influence the pathophysiology of Type 2?
genetics
intrauterine environment (epigenetic changes)
adult environment
what are the two errors with insulin in type 2?
insulin resistance
insulin secretion deficit (deficiency)
fatty acids also involved
what two factors lead to microvascular problems?
1) insulin resistance
(causes dyslipidaemia, increased mitogenic pathway, hypertrophy and increase in BP all whilst blood glucose is normal)
atheroma progression
Beta cell failure and eventual insulin loss
2) dyslipidaemia
what factor leads to microvascular problems?
hyperglycaemia
what factor increases the chances of the foetus developing type2?
IUGR- intrauterine growth restriction effects the foetus modulating gene expression
what is the genetic inheritance pattern in T2?
follows an almost autosomal dominant pattern whilst type 1 has less genetic output
T2DM has a great genetic input
weight at birth and risk of type 2
the lighter the baby, the greater the risk
normal changes to insulin with age
production decreases with age and we become more resistant to it with age
when resistant and low production bisect, insulin supply does not meet the resistance
the bisection occurs at age 110 in caucasians and sooner in others
what is the presentation of type 2 DM?
Heterogeneous – there are many forms/causes of T2DM; there isn’t just one T2DM.
Obesity.
Insulin resistant and secretion deficient.
Hyperglycaemia and dyslipidaemia –> acute and chronic complications.
what is the delayed insulin production response called?
hyperglycaemia clamp
where people developing type 2 will have some insulin production but they lose their first phase response to glucose so make insulin eventually but it takes longer
what is the first phase response to glucose
stored insulin is released when stimulated
what is the second phase response to glucose
insulin which is produced and secreted over time
what causes the increased blood glucose in type 2?
hyperglycaemia due to insulin resistance affecting glucose uptake:
- deficient insulin means glucose can’t move into muscle and metabolising tissue
- HGO continues to produce glucose even after eating thinking there isn’t enough glucose
- glucose remains in the blood and reaches high level
what happens with insulin sensitivity with age?
insulin sensitivity decreases therefore secretions are increased to compensate
diabetics under-compensate
how are VLDLs present?
as fatty acids can not be made into glucose, they are made into atherogenic VLDLs
The role of obesity in T2DM
More than a precipitant.
Fatty acids and Adipocytokines are important.
Central/omental obesity is common - 80% of T2DM.
Weight reduction is a useful treatment.
role of gut microbiota in type 2
They increase free fatty acids
therefore: associated with obesity, insulin resistance, T2DM, inflammation and adipocytokine pathways.
- Possibly via host signalling
role of gut bacteria
Various lipopolysaccharides are fermented by gut bacteria to short chain FFAs which enter the host circulation and modulate bile acids
which is the only drug to reduce weight
metformin
why does weight increase during diabetes treatment
reduction of blood glucose increases appetite
how does late T2DM present
pancreas makes immature insulin that is dysfunctional
what is the clinical presentation of T2DM?
o obesity o glycosuria o polydipsia, polyuria, nocturia o fatigue o blurred vision o Infections , thrush – hyperglycaemia is favourable for bacteria. o Screening tests. o Often found at presentation of complications – acute (hyperosmolar coma) or chronic (IHD, retinopathy).
where can complications presented arise from?
Complications can be:
- microvascular
- macrovascular
- metabolic (much rarer than for T1DM and ketoacidosis)
- from treatment (hypo attack).
what are the management options for T2DM
- education
- diet
- pharmacological treatment
- complication screening.
therefore help symptoms, reduce chance of complications and educate
how must the diet be controlled?
Control total calorie intake/increase exercise.
Reduce fat as proportion of calories and reduce refined carbohydrate (sugar).
Increase complex carbohydrate, unsaturated fat as proportion of fat and soluble fibre.
what 3 things are monitored in treatment?
- weight
- glycaemia
- BP
- dyslipidaemia
what drugs are used to treat type 2?
- orlistat (pancreatic lipase inhibitor) - metformin (biguanide-insulin sensitiser) - sulphonylureas (existing pancreas makes more insulin) - alpha glucosidase inhibitors (delays glucose absorption and boosts first phase) - thiazolidinediones (acts on adipocytes and insulin sensitiser peripherally in fat and muscle) - glifozins (SLGT-2 inhibitor) - GLP-1 agonists + DPP4 inhibitor (increase satiety)
what class of drugs are insulin sensitisers?
biguanide e.g metformin
oral anti-hypertensive drugs
example of biguanide
use?
metformin (1st line)
- insulin sensitiser
- used in the overweight patients where diet alone has not worked out
- reduce insulin resistance therefore reduced HGO and increases peripheral glucose disposal
has GI side effects
side effects of metformin
GI side effects
do not use in severe liver/cardiac failure and mild renal failure
GOOD: no weight gain
example of sulphonylureas
Glibenclamide
what is the action of sulphonylureas
act on remaining beta cells to increase insulin secretions by blocking ATP sensitive potassium channels and cause influx of calcium
cause weight gain
in which patients are sulphonylureas used in ?
in lean patients (as it can cause weight gain)
side effects of sulphonylureas
Hypoglycaemia
weight gain
example of alpha glucosidase inhibitor
acarbose
slow down glucose absorption and aids first phase
action of alpha glucosidase inhibitors
prolongs absorption of oligosaccharides
allows insulin secretion to cope following defective first phase insulin
side effect of alpha glucosidase inhibitor
just as effective as insulin but can cause flatuence
example of thiazolidinediones
pioglitazone
reduce insulin resistance
what is the action of thiazolidinediones?
what are the effects?
why is there peripheral weight gain?
peroxisome proliferator-activated receptor agonist (PPAR-GAMMA):
- sensitises insulin peripherally
- improves glycaemia and dyslipidaemia
- good vascular outcomess
- prevent MI
- adipocytes are rearranged so weight gain is peripheral rather than central
NB gemfibrozil (a lipid lowering fibrate agonises the PPAR-ALPHA receptor)
what are the side effects of thiazolidinediones e.g. proglitazone?
hepatitis
heart failure
examples of GLP-1
exenatide
liraglutide
Where is GLP-1 secreted from normally?
in response to what?
L-cells in response to nutrients in the gut (incretin effect)
what is the action of GLP-1
main: incretin effect
stimulates insulin and suppresses glucagon and increases satiety
what is GLP-1 broken down by?
how is this clinically relevant?
DPP-4 (gliptins)
therefore has a short half life
therefore DPP-4 inhibitors can be used to prolong the action go GLP-1 analogues
GLP-1 drug
injected
long acting GLP-1 agonist
decreases glucagon and glucose
leads to weight loss
what are DPP-4 inhibitors?
Gliptins (anti-glucagon effect)
- increase half life of exogenous GLP-1 so it can have its incretin effect
- neutral effect on weight
what does empagliflozin (gliflozins) do?
inhibits Na-glucose transporter (SLGT-2 inhibitor)
increase glycosuria by affecting PCT of the kidney
reduce mortality
reduce HF due to sodium transport effect in the heart
what are the contributors to major problems of diabetes?
1) high BP- 90% of T2 patients have issues
2) dyslipidaemia- high cholesterol, TG and less HDLs –> macrovasc complications
what is the incretin effect?
oral glucose has a greater metabolic effect
more insulin produced in response to oral load of glucose than IV glucose
what is the most successful intervention in Type 2 diabetics?
lifestyle changes including dietary over metformin
which groups of people need to be identified as high risk of diabetes?
gestational diabetes (temporary pregnant diabetics)
impaired glucose tolerance people
why is Type 2 hard to screen?
doesn’t present until complications have arisen
what effect will statins have?
for ischaemic heart disease to reduce LDLs and increase HDLs
but increases chance of t2Dm development and myositis
what effect does metformin have?
insulin sensitiser:
- decreases HGO
- increased sensitivity to insulin
side effects: diarrhoea, nausea, abdominal pain and lactic acidosis.
no weight gain
what effect does sulphonylurea have compared to metformin?
sulphonylurea increases insulin secretion
metformin is an insulin sensitizer.
how can weight increase during DM treatment be tackled?
give GLP-1 to stimulate incretin effect for increased insulin secretion and increases satiety.
what is the incretin effect? is the incretin effect present in diabetic?
The incretin effect is defined as the increased stimulation of insulin secretion elicited by oral as compared with intravenous administration of glucose under similar plasma glucose levels.
Patients with type 2 diabetes have been demonstrated to exhibit an almost total loss of incretin effect (don’t respond with increased insulin when ingesting glucose)
how can the incretin effect induced by GLP-1 be enhanced?
DPP4-Inhibitors
– reduce breakdown of GLP-1
what do DPP4-Inhibitors do?
inhibit breakdown of GLP-1 so the incretin effect is done on diabetics (which they lack)
