The Aetiology And Treatment Of Type 2 Diabetes Mellitus Flashcards
What tests are performed to diagnose diabetes and what are the defining values?
Fasting Blood Glucose:
Normal < 6
Impaired Fasting Glucose = 6-7
Diabetes > 7
Glucose Tolerance Test (2 hr measurement):
Normal < 7.8
Impaired Glucose Tolerance = 7.8-11.1
Diabetes > 11.1
State three factors that influence the pathophysiology of T2DM.
Genetics
Intrauterine environment
Adult environment (which would accelerate pathogenesis)
How is the intrauterine environment important in the pathogenesis of T2DM?
There will be epigenetic changes that take place in utero, which affect blood glucose control in the future
What is MODY?
Mature onset diabetes of the young (8 types):
- It is autosomal dominant
- Characterised by ineffective pancreatic beta cell insulin production e.g. caused by mutations of transcription factor genes (glucokinase gene)
- Positive family history with NO obesity
How would you describe the pathogenesis of T2DM?
It results from a combination of insulin resistance and a failure of the beta cells to be able to increase insulin secretion sufficiently in order to overcome the resistance.
- Initially as the insulin resistance worsens, the beta cells overcome this and produce more insulin, so that the patient is hyperinsulinaemic and euglycaemic.
- Eventually the pancreas cannot keep up the large insulin production rate and the blood glucose concentration then begins to rise.
- There is, however, enough insulin to prevent ketogenesis, but not enough to prevent the hyperglycaemia.
- There is a gradual and insidious increase in plasma glucose levels over time, and patients present with polyuria and polydipsia without ketoacidosis.
What do adipocytes secrete which may be implicated in insulin resistance?
Adipocytokines (e.g. leptin, Adiponectin etc.)
In terms of weight, what type of babies are more likely to develop T2DM in later life?
Small babies (low birth weight) This is due to intrauterine growth restriction
How does insulin resistance lead to hypertension?
The hyyperinsulinaemia stimulates the mitogenic pathway causing smooth muscle hypertrophy => high blood pressure
Describe how beta cell reserve and insulin resistance change with age normally
Beta cell reserve decreases with age and insulin resistance increases
(The point at which these lines meet comes at an earlier stage in life for patients pre-disposed to T2DM)
Describe the presentation of a typical patient with T2DM.
- Heterogeneous
- Obese (80%)
Insulin resistance and insulin secretion deficit =>
- Hyperglycaemia
- Dyslipidaemia
- Acute complications
- Chronic complications
State (and explain) the acute complications of T2DM
- Patients may develop urinary tract infections because the high level of glucose in the urine encourages organisms to grow there
- Severe hyperglycaemia can sometimes cause a hyperosmolar state (of the blood) that can be life threatening, occasionally causing coma = hyperosmolar non-ketotic coma (HONKC).
- Not only is the blood glucose level high, but also because the glycosuria takes water with it, the plasma sodium concentration can rise, causing hypernatraemia which contributes to the hyperosmolar state.
- The very high osmolality can contribute to confusion and loss of consciousness.
What are the potential long term complications of T2DM?
Stroke Myocardial Infarction Neuropathy Retinopathy Nephropathy Hypoglycaemia
What happens to fatty acids when they go into the liver?
They cannot be used to make glucose so they are converted to very low-density lipoproteins (VLDLs), which are highly atherogenic
Which adipocytes are particularly marked for breakdown of triglycerides?
Omental adipocytes (this is why omental fat correlates with risk of heart disease); have a more direct connection with liver
Describe how gut microbiota is implicated in T2DM.
They may be important in host signalling – they ferment various lipopolysaccharides to produce short chain fatty acids, which enter the circulation and modulate bile acids (so they can also affect host metabolism)
They are also important in inflammatory and adipocytokine pathways
What is a very common side effect of diabetes treatment?
Weight gain
Which diabetes treatment does not cause this problem?
Metformin
What dietary measures are recommended for someone with T2DM?
- Decreased fat (particularly saturated fats)
- Decreased refined carbohydrates
- Increased complex carbohydrates to release glucose more slowly (reduces the effect of the missing first phase insulin release)
- Increased soluble fibre
- Control total calories/increase exercise
What is orlistat and why is it sometimes used in T2DM?
Pancreatic Lipase Inhibitor
It reduces the break down of fats in the intestines thus reducing the absorption of fats
State 5 classes of drugs that are used to treat T2DM and briefly state what they do.
- Metformin – decreases gluconeogenesis, increases insulin sensitivity, enhances peripheral glucose uptake and decreases intestinal absorption of glucose (drug class = biguanides)
- Sulphonylureas – makes the existing pancreas produce more insulin
- Alpha-glucosidase inhibitors – prolongs the absorption of glucose from the intestine
- Thiazolidinediones – addresses peripheral insulin resistance (muscle and fat)
- GLP-1 agonists and DPIV inhibitors – increase insulin secretion
When should you NOT use metformin?
Severe liver failure
Severe cardiac failure
Mild renal failure
Name one sulphonylurea. Who is it given to?
Glibenclamide
Given to lean patients with T2DM
Explain how sulphonylureas work.
They bind to receptors and block the ATP-sensitive K+ channels on the pancreatic beta cell membranes
This ultimately leads to Ca2+ influx, which causes insulin release
Name one alpha-glucosidase inhibitor. Explain how it works and state some side effects.
Acarbose
- They act as competitive inhibitors of enzymes needed to digest carbohydrates (specifically alpha-glucosidase enzymes in the brush border of the small intestines)
- Therefore, they prolong the absorption of oligosaccharides and allow the body to cope with the loss of first phase insulin
Side effect: it means that some sugars get to the colon and are fermented => flatulence
Name one thiazolidinedione. What are they and describe their effects. Side effects?
Pioglitazone
- These are peroxisome proliferator-activated receptor (PPAR-) agonists.
- This activated nuclear receptor increases transcription of a number of specific genes and decreases transcription of others
- These are insulin sensitisers mainly in peripheral tissues
- Increase storage of fatty acids in adipocytes leads to peripheral weight gain, not central
- Main side effect = water retention, leading to oedema
- For older thiazolidinediones, side effects = hepatitis, heart failure
What class of drugs prolong the duration of GLP-1? How?
Gliptins
They inhibit Dipeptidyl peptidase-4 (which breaks it down)
What does GLP-1 do?
- Responsible for the incretin effect
- Stimulates insulin and suppresses glucagon
What effect do long-acting GLP-1 agonists and gliptins have on weight gain?
GLP-1 agonists = weight loss
Gliptins = neutral
What other pharmaceutical interventions must be considered with T2DM patients?
Many T2DM patients also have dyslipidaemia (high cholesterol, high triglyceride, low HDL) and hypertension, which need to be dealt with as well
What can occur during pregnancy to identify women who are at high risk of getting diabetes in the future?
Gestational diabetes
