Endo 17: Type 2 diabetes Flashcards
Define DM
Diabetes mellitus can be defined as a state of chronic hyperglycaemia sufficient to cause long-term damage to specific tissues, notably the retina, kidney, nerves, and arteries
T/F T2DM is ketosis prone
F: not prone, but can happen
Oral glucose test
less than 6 when fasing
2 hrs after oral glucose, should be 7.8 or less
random test shouldn’t be above 11.1
Which diabetes have greater genetic basis
T2DM
Greatest diabetes risk
Greatest in ethnic groups that move from rural to urban lifestyle
Pathophysiology of T2DM
- Genes and intrauterine environment and adult environment.
- Insulin resistance and insulin secretion defects
- Fatty acids important in pathogenesis and complications
What is MODY, how is it different from type 1 and type 2
Several hereditary forms (1-8)- i.e. MONOGENIC (so different to T2DM)
Autosomal dominant
Ineffective pancreatic B cell insulin production
+ve FH, no obesity
Due to not enough insulin production/poor insulin sensing by the b cells, NOT autoimmune destruction (like type 1)
Differentiate MODY and T2DM
MODY monogenic, T2DM multiple genes contribute to disease
What kind of mutation in MODY
Mutations of transcription factor genes, glucokinase gene
What is the relationship between intrauterine environment and T2DM
Intrauterine growth restriction…if you’re born light more likely to be diabetic (possible due to epigenetic mechanisms)
Which factors cause macrovascular disease in T2DM
Genes leading to insulin resistance MODULATED (not caused by) adipocytokines. Genes can leading to obesity and FAs can affect the insulin resistance. Genes also leading to IUGR which is a risk factor for T2DM.
Insulin resistance leading to MITOGENIC (due to growth protperties of insulin) and METABOLIC DYSLIPIDAEMIA which lead to macrovascular disease.
Insulin resistance can also lead to inflammation but this doesn’t affect macrovascular disease
How can you differeniate between vascular disease in diabetics vs normal people
Diabetics have microvascular disease, never normal people have this
What lads to microvacular disease
Beta cell falure leads to metabolcic dyslipidaemia (leadingg to macrovasc)
and
HYPERGLYCAEMIA (LADS TO MICROVACULAR)
Rates of concordance in type 1 and type 2 diabetes
T1DM: mono= 35%, di=10%
TD2M: monozygous=70%, dizygous= 40%
DOMINANT FOR T2DM!
What else other than genetics is associated with diabetes
Intrauterine environment and prebirth weight
Change in insulin prodction and resistance wih age normally
Increased resistace
Falling insulin production….
When it gets to a point that the resistance increases above the amount of insulin that can be produced that’s diabetes.
Insulin problems in T2DM
Insulin resistance and insulin secretion deficit
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How does insulin secretion change with impairment of glucose tolerance
Insulin Secretion Deteriorates with Progressive Impairment of Glucose Tolerance
The 1st phase of insulin release in response to increased glucose due to a meal is much reduced in those with impaired glucose tolerance, and not increase at all in those with TD2M.
What is the reason for hyperglycaemia in T2DM
There is inability to stop the HGO (due to insulin resistance and GLP1)
There is reduced glucose clearance (i.e. reduced ability to drive glucose into muscle and liver)
Effect of insulin resistance on adipocyte vs what happens when insulin resistance
Normally switches of lipolysis….
BUT if you have insulin resistance, more TG–> glycerol and NEFA….
NEFA is made into VDLD and glycerol…. glycerol turned into glucose
THIS MOSTLY COMES FROM OMENTAL FAT
See card I wrote for this bit
Effect of insulin on muslce
So there is more glucose produced from liver due to glycogenolysis and increased gluconeogenesis from the glycerol but
glucose cannot be taken up intomuscle
Other than the increased lipolysis, how else can adipocytes affect diabetes
Hormones are produced by adipocytes= adipocytokines.
E.g. TNF-a can cause lipolysis and VLDL secretion
etc.
Why is central fat more important in diabetes
Drains straight to liver… more endocrine function than peripheral
Why is obesity important in diabetes
Fatty acids and adipocytokines important
T/F most obese people develop diabetes
F- but 80% of TD2M people are obese
CENTRAL/OMENTAL obesity is most important
Involvement of gut microbiome in T2DM
problem with most diabetes treatments, and the exception
It can affect intermediary metabolism
Bacterial lipopolysaccharide fermentation short chain FAs, and bacterial modulation of bile acids,
Inflammation, signaling metabolic pathways
most cause weight gain, apart from metformin
Presentation of T2DM
Summarise the complications
Osmotic symptoms (less likely compared to T1DM…. so presents later, high plasma glucose leaks into urine)
Infections
On screening test
at presentation of complication
- Acute; hyperosmolar coma,
- Chronic; ischaemic heart disease, retinopathy
Complications:
-Macrovasc: IHD, cerebrovascular disease, renal artery stenosis, PVD
- Microvasc: retinopathy, neuropathy and nephropathy
- Metabolic: hyperosmolar and lactic acidosis
- Due to treatment: hypoglycaemia
Microvascular complicaions of diabetes
retinopathy
nephropathy
neuropathy
Metabolic complicaions of diabetes
These are less common than in type 1
Lactic acidosis
Hyperosmolar
Macrovascular complications of T2DM
Ishcaemic heart disease
Cerebrovascular
Renal artery stenosis
PVD
Complication of treatment of diabetes
Treatment types
hypoglycaemia
Education, diet, pharmacological, complication screening
How should T2DM be treated in terms of diet
Control total calories/increase exercise (weight)
reduce refined carbohydrate (less sugar)
increase complex carbohydrate (more rice etc)
reduce fat as proportion of calories (less IR)
increase unsaturated fat as proportion of fat (IHD)
increase soluble fibre (longer to absorb CHO)
Address salt (BP risk)
Drugs acting on the liver to reduce sugar output
Metformin and insulin (but this causes weight gain
Drugs acting on the pancrease
Sulphonylurease (increase insulin release)
How does metformin work
insulin sensitiser overweight patient with T2DM where diet alone has not succeeded Reduces insulin resistance Reduced hepatic glucose output Increases peripheral glucose disposal
What is measured in TD2M for monitoring
What drug works to reduce fat absorption
What drugs work on sugar
Weight
Glycaemia
Blood pressure
Dyslidiaemia
ORLISTAT is a GI lipase inhibitor
RIMONABANT is a cabbanoid antagonist (suppress action of GABA on the MCH neurones, and prevent increased orexin production)
Metformin/insulin (but it would cause weigt gain) reduce HGO
Sulphonylureas increase insulin secretion from pancreas (control sugar but cause weight gain)
a-glucosidase inhibitor… increasing time to absorb sugar (gets over the reduced 1st phase insulin release)
GLP1 anlogue + DPP4 inhibitor (to increase amount of insulin from pancreas)
Thiazolidinediones (deal with insulin resistance)
SGLT2 inhibitor= increase glucose excretion
How does metformin work
When is it indicated
How does it work
Side effects and contraindication
Biguanide, insulin sensitiser
overweight patient with T2DM where diet alone has not succeeded
Reduces insulin resistance:
-Reduced hepatic glucose output
-Increases peripheral glucose disposal
GI side effects
Not in severe heart, liver or MILD renal failure
Release of insulin
Glucose comes in, increases ATP, blocks ATP sensitive K+channels,
causes Ca2+ influx and insulin release
When can sulphonylureas be used
When patient still has some beta cell function
How does sulphylureas work and what are they also known as
INSULIN SECRETAGOGUES
Blocks the ATP sensitive K+ chanenel, forcing it to close to increase insulin release
USED IN TYPE II ONLY (not type I there is no pancreatic function)
cause weight gain
What is acarbose
Alpha glucosidase inhibitor
Prolongs absorption of oligosaccharides
Allows insulin secretion to cope, following defective first phase insulin
As effective as metformin
Side effects of acarbose
Flatus
Actio of thiazolidineodione
Peroxisome proliferator-actived receptor agonists PPAR-γ
Insulin sensitizer, mainly peripheral
Adipocyte differentiation modified, weight gain but peripheral not central
Improvement in glycaemia and lipids
Evidence base on vascular outcomes
Older types cause hepatitis
Side effects of thiazolidineodiones
Side effects of older types hepatitis, heart failure
What happens if you inject someone with glucose vs get someone to drink glucose orally
If you inject glucos into one patient, and oral administer glucose in another, then you get MUCH more insulin secretion in oral admin.
What is the incretin effect
Secreted in response to nutrients in gut
Release of hormones from L cells in GI system increase insulin secretion
What is GLP1 made from and what is its effect
How is it broken down
Transcription product of proglucagon gene, mostly from L cell.
Stimulates insulin, suppresses glucagon
Increases satiety
Restores B cell glucose sensitivity
Short half life, rapid degredation from enzyme dipeptidyl peptidase-4
Use therapeutically of GLP1
GLP-1 agonist .. INJECTED
AND
DPPG4 inhibitor = GLIPTINS … ORAL (but not as effective)
Effect of GLP1 on weight
weight loss (due to feeling of satiety)
GLP1 example, PK and action
- Exenatide, liraglutide
- Injected
- Long acting GLP-1 agonist
- Decrease glucagon
- Decrease glucose
- Weight LOSS
DPPG-4 inhibitor, example, PK and action
GLIPTINS Increase half life of exogenous GLP-1 Increase [GLP-1] Decrease [glucagon] Decrease [glucose] Neutral on weight
How do SGLT2 inhibitors work
Reduce uptake of glucose from the PCT (block SGLT2, which is a Na/glucose transporter inhibitor) but leads to osmotic symptoms
REALLY GOOD for heart failure and also lower mortality
Why do lots of patient s eventually need insulin
Because of the beta cell failure that eventually occurs
What else should we control in T2DM
Blood pressure
Diabetic dyslipidaemia (reduce cholesterol, TGs and increase HDL)
Screening for diabetes
Specifics of program unclear
Diagnosis on glucose, fasted or stimulated?
How to prevent progression to diabtetes
Diet and exercise BETTER than metformin
