Week 1/2 - C - Type II diabetes and treatment Flashcards
What percentage of patients with diabetes does type II diabetes account for?
approx 85%
How does obesity lead to type II diabetes? 90% of people with type 2 diabetes are overweight or obese
Leads to a decreased number and decreased sensitivity of insulin receptors causing hyperinsulinaemia and hyperglycaemia
Is being a pear or apple shape a risk factor for diabetes? What two conditions in women can cause type II diabetes? (one can affect getting pregnant, one occurs during pregnancy)
Obesity – central/apple shape
Gestational diabetes and polycystic ovarian syndrome (PCOS)
What are the two main pathophysiological defects associated with type II diabetes? How do they occur?
Insulin resistance and beta cell dysfunction
Insulin resistance can occur due to obesity - insulin resistance causes an initial attempt of compensation by the beta cells leading to the initial hyperinsulinaemia
followed by beta cell exhaustion (beta cell dysfunction) causing hypoinsulinaemia
Apart from obesity, what are other risk factors for type II diabetes?
Smoking
Genetics
Inactivity
Hypertension
What are symptoms of type II diabetes?
Thrush
Fatigue
Infections
Blurred vision
Signs of complication eg retinopathy or neuropathy
Symptoms of hyperglycaemia, appears rapid although takes place over a long time and weight loss What are the symptoms of hyperglycaemia in type II diabetes and how T2DM diagnosed?
Polyuria and polydipsia
Diagnosed by measuring blood glucose levels
What is usually seen on histological appearance of the islet cell in T2DM?
Amyloid deposition within the islet cell
How is the prognosis of T2DM greatly improved?
Greatly improved with weight loss and exercise
What type of diabetes develops in pregnancy and resolves post-natally?
Gestation diabetes - greatly increases risk of T2DM
If weight loss and exercise fail to maintain blood sugar with these methods alone, what can be given as first line for Type 2 diabetes mellitus? Start low and go slow How does this drug work?
Give metformin
Metformin is an insulin sensitizer
Also decreases hepatic gluconeogenesis and decreases carbohydrate absorption in the GI tract
What positive effects does metofrmin have? (name 4)
Reduces HbA1c by 15-20mmol/mol by lowering insulin resistance
Does not cause hypoglycaemia
Prevents micro and macrovascular complications
Reduces BP and weight loss
What are the adverse effect of metofrmin and what patients should be avoided in? Also what type of drug is metformin?
Can cause GI upset - mostly anorexia, diarrhoea and nausea
Avoid in patients with liver, cardiac or renal failure as can cause lactic acidosis
Metformin is a biguanide
What HbA1c level is targeted for a person with T2DM on metformin? What is the recommended HbA1c level before adding a second drug to metformin to manage the diabetes?
In a patient taking maximum dose metformin who has a HbA1c of 58 or greater current guidelines recommend the addition of a second agent.
The average patient who is taking metformin for T2DM, you can titrate up metformin and encourage lifestyle changes to aim for a HbA1c of 48 mmol/mol (6.5%),
but should only add a second drug if the HbA1c rises to 58 mmol/mol (7.5%)
What is the second line treatment of type 2 diabetes? How does this drug work?
Sulphonylureas -
they work by binding to the sulphonylurea subunit receptors (SUR1) on the ATP sensitive potassium channels and therefore closing them increasing the release of endogenous insulin -
* increase endogenous insulin secretion
What are the subunits of the Katp channels?
4 potassium inward rectifier subunits (Kir6.2) and
4 sulphonylurea recpeptor subunits (SUR1)
The Katp channel has an octomeric structure
When the sulphonylurea class of drug binds to the SUR1, how does this cause release of insulin?
This causes the Katp channels to close preventing potassium efflux which causes depolarization of the cell membrane causing opening of the voltage activated calcium channels and the influx of calcium
The influx of calcium causes the fusion of the secretory vesicle with the cell membrane and the release of insulin
The Katp channel is described as an ATP:ADP ratio for opening and closing the channel What do the SU displace when binding to the channel causing it to close?
SU appears to act by displacing the binding of ADP-Mg from the SUR1 subunit
Name two types of sulphonylurea
What are the positive effects of sulphonylureas?
Glibenclamide and gliclazide
They reduce HbA1c levels by 15-20mmol/mol
Prevents microvascular complications but does not prevent macrovascular complication
What are the two main adverse effects of sulphonylureas? When should they be used as a first line treatment for type II diabetes?
Are not insulin sensitive and therefore can cause hypoglycaemic attacks especially in the elderly
Causes weight gain
Only use as first line in underweight patients with T2DM or patients who are metformin intolerant
What T2DM drug, also a potential third line - Works on nuclear receptors causing transcription of insulin sensitive genes? The receptor is PPARy
Thiazolidinediones (TZDs) - glitazones
What is the only glitazone in use and why is it risky to use long term in women? What else can it cause?
Pioglitazone
Causes increased bone resorption therefore
Contraindicated in elderly patients with osteoporosis or bone fractures
Can also cause heart failue
Causes weight gain
Which drug is from the saliva of glia monster?
Incretin analogues -
Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels
How do incretin analogues work?
- They bind to GPCR GLP-1 (Glucagon-like peptide-1 ) receptors that increase intracellular cAMP concentration
This causes an increase in insulin secretion after eating before blood glucose levels become elevated
What are the two main incretin analogues? What is an example of an incretin analogue name?
- The 2 main incretins are GIP and GLP-1.
* (glucose‐dependent insulinotropic polypepide aka gastric inhibitory peptide (GIP)
* and glucagon‐like peptide (GLP)‐1)
Exenatide - GLP1 agonist
What is adverse in administration of incretin?
Injectable not oral
Does incretin cause hypoglycaemia and weight gain?
No does not cause hypoglycaemia
Acts on hypothalamus to reduce appetite causing weight loss
What drug is known as the Gliptins and is weight neutral without hypoglycaemia however may cause pancreatitis?
DPP4 inhibitors
Inhibitors of dipeptidyl peptidase 4 are a class of oral hypoglycemics that block the enzyme dipeptidyl peptidase-4 (DPP-4).
What is DPP4 a direct antagonist of?
DPP4 is a direct antagonist of incretins (GLP-1 and GIP) which will therefore cause decreased insulin production and increased blood sugar
What drug blocks reabsorption of glucose by SGLT2 in the proximal tubule of the kidney? Give example
SGLT2 inhibitor - dapaglifozin
What is a positive and 2 negative effects of SGLT2 inhbitors?
Positive - causes weight loss
Negative - thrush and UTIs due to glucose in urine
Is the main reabsoprtion of glucose in the kidneys take place via the SGLT1 or SGLT2 pathway?
The SGLT2 pathway accounts for 90% of glucose reabsorption
What is the brush border enzyme that breaks down starch and disaccharides to absorbable glucose?
Alpha-glucosidase
Inhibitors of this prevent glucose absorption in the GUT
What are side effects of alpha-glucosidase inhibitors?
GI upset – flatulence, loose stools, diarrhoea, abdominal pain, bloating
What T2DM drug causes a risk of pancreatitis as a side effect?
The gliptins - DPP4 inhibitors
Weight neutral promoting insulin secretion with side effect of pancreatitis
Give an example of an alpha-glucosidase inhibitor?
Acarbose
Bariatric surgery, is used to treat people who are dangerously obese. This type of surgery is only available on the NHS to treat people with potentially life-threatening obesity when other treatments, such as lifestyle changes, haven’t worked. What BMI does a patient need to be to be considered for bariatric surgery?
BMI of 35 with a comorbidity - eg hypertension or T2DM BMI of 40
What are the three types of bariatric surgery? Describe them
- gastric band – a band is used to reduce the stomach size, so a smaller amount of food is required to make you feel full
- gastric bypass – the digestive system is re-routed past most of your stomach, so you digest less food and it takes much less to make you feel full
- sleeve gastrectomy –some of the stomach is removed to reduce the amount of food that’s required to make you feel full
Which gastric bypass surgery is a combination of both restrictive and malabsorptive?
Gastric bypass surgery is a combination of both restriction and malabsorption
