1B type 2 diabetes mellitus Flashcards
Define T2DM
- A condition where the combination of insulin resistance and beta cell failure results in hyperglycaemia
- Associated with obesity but not always
- Resultant chronic hyperglycaemia may initially be managed by changes to diet/weight loss and may even be reversible
- With time, glucose lowering therapy including insulin will be needed
At what ages can T2DM develop and how has our view of this changed?
- Traditionally thought to be a condition of late adulthood
- Now good evidence it can present through every decade of life
- Increasing in all groups but rapidly in early adulthood
What does the graph below show?
If you develop T2DM at an old age, the life expectancy is similar to a normal person
If you develop it at a young age, the life expectancy is a lot lower than a normal person
Describe the development of T2DM
OGTT is Oral Glucose Tolerance Test
Insulin production increases during intermediate state showing the body trying to compensate for the increase in insulin resistance, then starts to fall
How can a random glucose test be used to diagnose T2DM?
If it’s above 11.1 and there are symptoms of T2DM like passing a lot of urine, feeling very thirsty
What are the beta cell function levels at when you’re diagnosed with T2DM?
The function has already decreased to around 50% at time of diagnosis
What is relative insulin deficiency in T2DM?
Insulin is still produced in T2DM by pancreatic beta cells but relative to amount of insulin resistance, it’s not enough
What does relative insulin deficiency explain about diabetic ketoacidosis in T2DM?
Explains why hyperglycaemia doesn’t usually cause ketosis
Ketones typically form when there’s no insulin, but here there’s still some
When can T2DM people present with diabetic ketoacidosis?
Not spontaneously, usually because person is unwell (infected/catabolic/septic)
What happens in long duration T2DM?
Beta cell failure may progress to complete insulin deficiency. Usually patients are on insulin at this point, but it is important not to stop it or they’ll be at risk of ketoacidosis.
What is the pathophysiology of T2DM?
- Unclear, but there’s a perfect storm of internal adiposity, a proinflammatory state and production of adipocytokines
- Genes and intrauterine environment and adult environment interactions cause it
- There are defects in both insulin resistance and insulin secretion
- Fatty acids important in pathogenesis and complications
What does it mean that T2DM is heterogenous?
People develop T2DM at variable BMI, ages and progress differently
What is a hyperglycaemic clamp?
When you keep a patient in a steady state with infusions of glucose and insulin
What is the glucose and insulin response in normal (grey) vs impaired glucose tolerance (blue) vs T2DM (green)?
- When we infuse glucose into them, the T2DM people already have a higher level in their blood from before
- The insulin response in normal people is a nice spike as soon as the glucose enters the blood, for impaired glucose tolerance there is a blunted response and for T2DM person there’s no response at all
This is called loss of first phase insulin release
What is the problem with HGO in T2DM?
- Reduced insulin action causes less uptake of glucose into skeletal muscle
- HGO is also increased due to both a reduction in insulin action and increase in glucagon action
What is HGO production and glucose clearance like in T2DM people?
- Impaired insulin-mediated glucose disposal
- Excessive glucagon-mediated glucose output
What does the relationship between insulin sensitivity (and thus resistance) and insulin secretion look like in normal vs T2DM people?
Normal relationship is the line shown (least sensitive people need a lot of insulin secretion for the desired affect and most sensitive people don’t need much insulin for the desired effect)
T2DM people have ‘fallen off the curve’- for any given level of insulin sensitivity they secrete less insulin
What are the consequences of insulin resistance in the liver?
Increased HGO
What are the consequences of insulin resistance in adipocytes?
Increased fatty acid uptake from gut
Triglycerides form unhealthy types of lipid (usually inhibited by insulin)
Increased fatty acid production
What are the consequences of insulin resistance in the muscle?
Muscle usually takes up glucose in presence of insulin, but in T2DM there is less glucose uptake by muscle
What is monogenic diabetes?
- Single gene mutation that means you’re born with it and are always going to develop diabetes no matter how hard you try
- MODY- mature onset diabetes of the young
How is T2DM polygenic?
- Polymorphisms increase the risk of diabetes
- Not born with it but high risk and may develop later depending on other factors
How does genetic and environmental risk interact in the chance of development of T2DM?
- If you have low genetic risk, you’ll need strong environmental factors to develop T2DM and vice versa- that’s why some ethnic groups need lower BMI to get T2DM
- High genetic + high environmental risk is double whammy and you’re very likely going to get diabetes
- Low genetic and low environmental risk groups are relatively protected against T2DM
What do genome wide association studies of T2DM show?
- GWAS of T2DM are done by taking people with and without T2DM and sequencing their whole genome to see for nucleotide changes present in T2DM group but not control
- They show that each individual SNP has only a mild effect on risk
What about the cumulative effect of all SNPs?
This has a bigger effect- those with more SNPs are more likely to get T2DM
What is the role of obesity in T2DM?
- Major risk factor of T2DM- 80% of T2DM are obese
- Fatty acids and adipocytokines are important in development of T2DM
- Visceral and central obesity are different- because of this, it’s thought that people with lower BMIs that get T2DM have more visceral fat
What treatment is useful in diabetes caused by obesity?
Weight reduction
What role do perturbations in gut microbiota have on T2DM cases?
- Bacterial lipopolysaccharides fermentation to short chain FA, bacterial modulation bile acids
- Inflammation, signalling metabolic pathways
- Most studies are correlative
What role does intrauterine growth retardation have on T2DM people?
- If you haven’t developed well in womb or if mother had diabetes, this affects intrauterine growth environment
- People with intrauterine growth retardation are more likely to develop T2DM
How does T2DM present?
- Hyperglycaemia
- Overweight
- Dyslipidaemia (high plasma cholesterol and triglycerides)
- Fewer osmotic symptoms
- With complications
- Insulin resistance
- Later insulin deficiency
What are risk factors for T2DM?
- Age
- Increased BMI
- PCOS
- Ethnicity
- Family history
- Inactivity
How do we diagnose T2DM?
- Osmotic symptoms
- Infections
- Screening test for tiredness or something and it’s an incidental finding
- At presentation of a complication, e.g. an acute metabolic decompensation
What is an acute metabolic decompensation?
When someone is in a life threatening state because of their high blood sugar.
In T2DM this is a hyperosmolar hyperglycaemic state.
What chronic complications can arise from acute metabolic decompensation?
- Ischaemic heart disease
- Retinopathy
What is the first line test for T2DM diagnosis?
HbA1c:
- 1x HbA1c above or equal 48 mmol/L with symptoms
- 2x HbA1c above or equal 48 mmol/L without symptoms
What is a hyperosmolar hyperglycaemic state?
- A diabetic emergency where patients commonly present with renal failure
- Unchecked gluconeogenesis → hyperglycaemia → osmotic diuresis → dehydration
- There’s often an identifiable precipitating event (infection, MI)
What’s the relation between insulin and hyperosmolar hyperglycaemic state?
There’s insufficient insulin (not absent) for prevention of hyperglycaemia but sufficient insulin for suppression of lipolysis and ketogenesis
Therefore there is an absence of significant acidosis
What’s the difference between DKA and hyperosmolar hyperglycaemic syndrome?
What is the management for T2DM?
Usually GP looks after these patients.
- Diet
- Oral medication
- Structured education (taking tablets)
- May need insulin later
- Remission/reversal
- Prevention of diabetes related complications and their risk factors
What are diabetes related complications and their risk factors?
- Retinopathy
- Neuropathy
- Nephropathy
- Cardiovascular
What are the principles of a T2DM consultation?
- Glycaemia- HbA1c, glucose monitoring if on insulin, medication review
- Blood pressure
- Dyslipidaemia- do a cholesterol profile
- Weight assessment- losing weight is central part of dealing with T2DM
- Screening for complications- foot check, urine check, retinal screening
How do we deal with excess hepatic glucose production?
Reduce hepatic glucose production. Metformin helps.
How do we deal with resistance to action of circulating insulin?
Improve insulin sensitivity via drugs:
- Metformin
- Thiazolidinediones
How do we deal with inadequate insulin production for extent of insulin resistance?
Boost insulin secretion. Drugs that can help:
- Sulphonylureas
- DPP4-inhibitors
- GLP-1 agonists
How do we deal with excess glucose in circulation?
- Inhibit carb gut absorption
- Inhibit renal glucose resorption
Drugs to help us do this:
- Alpha glucosidase inhibitor- inhibit gut absorption
- SGLT-2 inhibitor- reduce renal reabsorption
What does metformin do?
- Biguanide type of drug, insulin sensitiser
- Reduces insulin resistance
- Reduced HGO
- Increases peripheral glucose disposal
- GI side effects
When is metformin the first line of treatment?
When dietary/lifestyle adjustment has made no difference
When is metformin contraindicated?
- Severe liver failure
- Severe cardiac failure
- Moderate renal failure
What do sulphonylureas e.g. gliclazide do?
- Boost insulin production of beta cells
- They bind to ATP-sensitive potassium channel and close it, independent of glucose/ATP, which needs to be done for insulin production
- They therefore bypass normal physiology to produce a lot of insulin
What does pioglitazone do?
- Insulin sensitiser, mainly in peripheral tissues
- Makes action of insulin a bit more efficacious at a tissue level
- Causes improvement in glycaemia and lipids
- Adipocyte differentiation modified
- There’s weight gain but it’s peripheral not central
What are some side effects of older types of pioglitazone?
- Hepatitis
- Heart failure
How does glucagon like peptide-1 (GLP-1) work?
- Gut hormone secreted in response to nutrients in gut
- Transcription product of pro-glucagon gene, mostly from L-cell
- Stimulates insulin, suppresses glucagon
- Increases satiety
- Short half life due to rapid degradation from DPP4 enzyme
What do GLP-1 agonists do and give examples
- Liraglutide, semaglutide
- Injectable- daily or weekly
- Decrease glucagon and glucose
- Cause weight loss
What do gliptins (DPPG-4 inhibitors) do?
- Increase half life of exogenous GLP-1
- Increase GLP-1
- Decrease glucagon and glucose
- Neutral on weight
What do SGLT-2 inhibitors do?
- Inhibits Na-Glu transporter, increases glycosuria
- Cause weight loss
- Lower HbA1c
- Improve CKD (chronic kidney disease)
- Improve microalbuminuria
- Improve risk of heart failure, strokes, MI
Give examples of SGLT-2 inhibitors
- Empaglifozin
- Dapaglifozin
- Canaglifozin
Despite treatment, what happens to beta cell function?
They continue to decline and there’s progressive loss of beta-cell function
How do we push T2DM patients into remission?
- Gastric bypass surgery has potential to induce remission of T2DM
- Very low calorie diet (800 a day) for 3-6 months has potential to induce remission, which appears to be sustained at 2 years
There’s an NHS England remission programme being piloted
How is blood pressure managed in T2DM?
- Hypertension very common in T2DM
- Clear benefits for reduction esp with use of ACE-inhibitors
Describe lipid management in T2DM
- Total cholesterol raised
- Triglycerides raised
- HDL cholesterol reduced
- Clear benefit to lipid-lowering therapy
Give examples of healthy eating
- Total calories control
- Reduce calories as fat
- Reduce calories as refined carbohydrate
- Increase calories as complex carbohydrate
- Increase soluble fibre
- Decrease sodium
