Type 2 diabetes Flashcards
What is macrovascular disease?
- ischaemic heart disease
- heart disease
- cerebrovascular disease (stroke)
In T2DM does ketosis occur, and are ketone levels abnormal in blood/urine in hyperglycaemia?
ketosis not seen, but ketones in blood and urine abnormal if glucose is high
What is normal fasting blood glucose?
<6mmol/l
What is a normal 2 hr glucose in a glucose tolerance test?
<7.8mmol/l
What does fasting glucose and 2 hr glucose have to be for the person to have DM?
FG = >7mmol/l
2hr G = >11mmol/l
What is the range for impaired fasting glucose/glucose tolerance?
FG = 6-7mmol/l GT = 7.8-11.2 (2 hr)
What do impaired glucose levels tell us?
This tells you that the patient has increased macrovascular risk, and at risk of diabetes. The patient doesn’t yet have microvascular risk (only with diabetes).
Describe the epidemiology of T2DM
- 10% of 60 year olds have it
- T2DM more common
- Seen more with increasing age
- Depends on ethnicity and environment too
- prevalence increasing
- more younger people are being diagnosed
- greatest in ethnic groups that have moved from rural to urban lifestyles
- greatest prevalence will be in south Asia
Which factors are implicated in T2DM?
Genetics (associated with obesity and insulin resistance), intrauterine environment and adult environment.
Epigenetic changes in the intrauterine environment can affect the functioning of developing genes.
The intra-uterine environment may be programming insulin resistance for life
Give an example of a mutation known to be involved in T2DM?
Mutations in transcription factor glucokinase gene produce ineffective beta cell insulin secretion
What are the problems with insulin in T2DM?
T2DM is caused by insulin resistance and insulin secretion deficits.
Which molecule is involved in the complications of T2DM?
fatty acids
What have twin studies found about the influence of genetics on T2DM?
In identical twins, the prevalence of T2DM may be over 70%. In non-identical twins, the prevalence is 40%. T2DM behaves like an autosomal disease.
What have twin studies found about genetic influences on T1DM?
MZ - 35%
DZ - 10%
T1 has genetic influence but not as great as T2.
What is the relationship between birth weight and risk of diabetes in adulthood?
Why is this?
Light birth weight is associated with diabetes in adulthood.
Need to think about genes susceptible to epigenetic manipulation in utero
What happens to insulin resistance and beta cells with age?
As you age, you become progressively more insulin resistant – and our beta cells fail as we age
What is the presentation of T2DM?
- Heterogeneous presentation
- Obesity
- Insulin resistance and insulin secretion deficit
- Patients have hyperglycaemia and dyslipidaemia
- Patients may have acute and chronic complications (far less than T1DM)
How does a person with diabetes go from becoming insulin resistant to insulin deficient?
Patients who are diagnosed with T2DM have had insulin problems for many years before a diagnosis. In these patients, in their earlier years, insulin is less able to drive glucose into muscle, and less able to switch off HGO.
As we become older, we become more insulin resistant, but we are able to make more insulin to overcome this.
An individual who has diabetes cannot do this – they become insulin deficient as the time goes by.
What is the effect of insulin resistance on adipocytes and why does this result in increased waist circumference?
Adipocytes store triglycerides -> glycerol and non-esterified fatty acids. The fatty acids go to the liver; glycerol is used to make glucose.
Fatty acids cannot be made into glucose. But the fatty acids contribute to VLDL production. An insulin resistant person, 30 years before they are diagnosed, still has fatty acid coming to the liver, and contributing to dyslipidaemia, hence increased waist circumference. The circumference can be used to predict risk of ischaemic heart disease.
What % of T2 diabetic patients have central or omental obesity?
nearly all
80% are obese at presentation so weight loss is useful as treatment
What is a common side effect of diabetes treatment and what is the exception?
Weight gain
Metformin is the only drug associated with weight maintenance/loss. Even insulin causes weight gain.
Why do T2 diabetic patients present with osmotic symptoms, infections?
Osmotic symptoms
- High glucose in the blood overruns the ability for full glucose reabsorption
- Glucose leaks out of the urine, taking water with it (polyuria, polydipsia)
Infections – yeast and microorganisms thrive in high glucose environments
What is an acute complication of T2DM?
hyperosmolar coma
What are some microvascular, macrovascular and metabolic complications of T2DM?
Microvascular: retinopathy, nephropathy, neuropathy
Macrovascular: ischaemic heart disease, cerebrovascular disease, renal artery stenosis, PVD (peripheral vascular disease)
Metabolic: lactic acidosis, hyperosmolar complications
What is the management of T2DM?
- Education
- Diet
- Pharmacological treatment
- Complication screening
Why is it important to treat T2DM?
- Alleviate the symptoms with treatment, and stop long term complications
- Reduce the chance of acute metabolic complications (unlikely in T2DM)
What should a T2 diabetic diet be like?
- Control total calories/increase exercise
- Reduce refined carbohydrate (less sugar) – more important in T1DM
- Increase complex carbohydrate (more rice etc.)
- Reduce fat as proportion of calories
- Increase unsaturated fat as proportion of fat
- Increase soluble fibre
- Control salt (risk of hypertension)
Which treatment can be given to control weight in diabetes?
Orlistat (GI lipase inhibitor), but patients should consider surgery (gastric bypass but there are uncertainties regarding its use)
Which treatments are given to control glucose?
- Metformin and insulin
- Sulphonylureas and metaglinides
- Alpha-glucosidase inhibitors
- Thiazolidinediones – act on central adiposity
- Newer agents: GLP-1 and DPP4 inhibitors (prolong GLP-1 action)
- SGLT2 inhibitors – increases glycosuria – patient excretes glucose in urine
Which other treatments are given in T2DM?
medicines to control dyslipidaemia and blood pressure
How does metformin work?
SE?
When to not use?
It is a a biguanide - insulin sensitiser, prevents HGO and reduces glucose absorption in SI (given to all diabetic patients)
- GI side effects but it is very safe and effective
- If severe liver, cardiac or mild renal failure
How do sulphonylureas work?
Glucose enters the cell, it is metabolised with glucokinase acting as a glucose sensor. When ATP is made the K+ channel closes , membrane depolarises, calcium influx and the granules containing insulin are released.
Sulphonylureas can forcefully block the channel, even when there is little glucose, to induce the mechanism of insulin release. Where the patient has functioning beta cells, insulin secretion will result.
Give an example of a sulphonylurea, which patients is it given to and SE?
- Glibenclamide
- Given to lean patients with type 2 diabetes, where diet alone has not succeeded
- Side effects include hypoglycaemia and weight gain
How do alpha glucosidase inhibitors work?
Give an example of one
SE?
- Acts within the gut to prolong glucose absorption
- Allows insulin secretion to cope, following defective first phase insulin
- Side effects: flatus
What is the incretin effect?
Incretin Effect - food stimulates more insulin secretion if given orally rather than intravenously.
- When we eat a meal and there is food in our intestine we start producing insulin.
- In this experiment someone is given a 50g oral glucose load and a matched intravenous infusion of glucose to cause exactly the same glucose profile.
- When given oral glucose, he makes considerably more insulin.
What is GLP-1?
- Secreted in response to nutrients in gut, that stimulates insulin and supresses glucagon
- It is a transcription product of the proglucagon gene, mostly from L cells
- It increases satiety
- It restores B cell glucose sensitivity
- Short half life, rapid degradationby DPPG-4
How can we manipulate the effects of GLP-1?
GLP-1 agonists: Exenatide, liraglutide
- Injectable, long acting GLP-1 agonist, decrease [glucagon] and [glucose], result in weight loss
GLIPTINS: DPPG-4 inhibitors (oral agents)
- Increase half life of GLP-1, increase [GLP-1], decrease [glucagon] and [glucose], neutral on weight
What are other aspects of diabetic control in addition to maintaining BG?
- Around 90% of T2DM patients have an elevated blood pressure so important to control
- Diabetic dyslipidaemia (increased cholesterol and triglyceride)
- There are clear benefits to treating dyslipidaemia, to increase HDL, and reduce cholesterolaemia
Compare:
prevalence, age of onset, time taken for onset, family history, weight of person, geography, weight loss, ketosis prone, serum insulin, HLA association, state of B cells and islet cell antibodies in type 1 and 2 diabetes
1:
- 0.25%, child/adolescent, acute onset, uncommon history, lean, europids, usually, yes, low/absent, DR3/4, destroyed and present
2:
4-7%, middle-aged/older, gradual, common, obese, less europids, uncommon, no, varies, none, functioning and absent
What are SGLT2 inhibitors used for?
Give an example
To reduce glucose reabsorption
- this increases polyuria and polydipsia but control glucose
- Empagliflozin -> inhibits the sodium glucose transporter and causes HBA1c to decrease
- SGLT2 inhibitors reduce mortality and risk of heart failure
What can disturbances in gut microbiota be associated with?
- Obesity and insulin resistant T2DM (maybe via host signalling)
- Bacterial lipopolysaccharides fermentation to short chain FA, bacterial modulation bile acids
- Inflammation, signaling metabolic pathways
What is insulin resistance associated with?
metabolic complications (dyslipidaemia - abnormal handling of cholesterol)
Which types of genes are defective in T2 diabetics?
Those associated with obesity and handling of fatty acids - obesity isn’t just a precipitant but part of the mechanism. Obesity contributes to insulin resistance.
What are the different factors involved in T2DM development?
- Genes contributing to to insulin resistance through an adult’s life (associated genes with insulin secretion/resistance)
- Diabetic insulin resistant mechanisms involve adipocytokines (hormones made by fat cells
- Microbiota from our mother, which may alter and express defects
What are thiazolidinediones?
Give an example
SE?
- Peroxisome proliferator-activated receptor agonists PPAR-γ
- Pioglitazone
- Acts as an insulin sensitizer mainly peripherally
- Modifies adipocyte differentiaiotn
- Improvement in glucose and lipid control
- SE: peripheral weight gain, heart failure
Diabetic screening
- on whom
- why is it difficult?
- treatment?
To try to prevent diabetes, we need to find those high risks.
E.G. gestational diabetics
E.G. Impaired glucose tolerance people
Screening is difficult as T2DM doesn’t present until complications arise.
Intensive lifestyle and a good diet is the best cure/symptom reliever (better than drugs).
