Week 1/2 - C - Type II diabetes and treatment

Question 1

What percentage of patients with diabetes does type II diabetes account for?

Answer 1

approx 85%

Question 2

How does obesity lead to type II diabetes? 90% of people with type 2 diabetes are overweight or obese

Answer 2

Leads to a decreased number and decreased sensitivity of insulin receptors causing hyperinsulinaemia and hyperglycaemia

Question 3

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)

Answer 3

Obesity – central/apple shape

Gestational diabetes and polycystic ovarian syndrome (PCOS)

Question 4

What are the two main pathophysiological defects associated with type II diabetes? How do they occur?

Answer 4

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

Question 5

Apart from obesity, what are other risk factors for type II diabetes?

Answer 5

Smoking

Genetics

Inactivity

Hypertension

Question 6

What are symptoms of type II diabetes?

Answer 6

Thrush

Fatigue

Infections

Blurred vision

Signs of complication eg retinopathy or neuropathy

Question 7

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?

Answer 7

Polyuria and polydipsia

Diagnosed by measuring blood glucose levels

Question 8

What is usually seen on histological appearance of the islet cell in T2DM?

Answer 8

Amyloid deposition within the islet cell

Question 9

How is the prognosis of T2DM greatly improved?

Answer 9

Greatly improved with weight loss and exercise

Question 10

What type of diabetes develops in pregnancy and resolves post-natally?

Answer 10

Gestation diabetes - greatly increases risk of T2DM

Question 11

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?

Answer 11

Give metformin

Metformin is an insulin sensitizer

Also decreases hepatic gluconeogenesis and decreases carbohydrate absorption in the GI tract

Question 12

What positive effects does metofrmin have? (name 4)

Answer 12

Reduces HbA1c by 15-20mmol/mol by lowering insulin resistance

Does not cause hypoglycaemia

Prevents micro and macrovascular complications

Reduces BP and weight loss

Question 13

What are the adverse effect of metofrmin and what patients should be avoided in? Also what type of drug is metformin?

Answer 13

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

Question 14

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?

Answer 14

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%)

Question 15

What is the second line treatment of type 2 diabetes? How does this drug work?

Answer 15

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

Question 16

What are the subunits of the Katp channels?

Answer 16

4 potassium inward rectifier subunits (Kir6.2) and

4 sulphonylurea recpeptor subunits (SUR1)

The Katp channel has an octomeric structure

Question 17

When the sulphonylurea class of drug binds to the SUR1, how does this cause release of insulin?

Answer 17

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

Question 18

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?

Answer 18

SU appears to act by displacing the binding of ADP-Mg from the SUR1 subunit

Question 19

Name two types of sulphonylurea

What are the positive effects of sulphonylureas?

Answer 19

Glibenclamide and gliclazide

They reduce HbA1c levels by 15-20mmol/mol

Prevents microvascular complications but does not prevent macrovascular complication

Question 20

What are the two main adverse effects of sulphonylureas? When should they be used as a first line treatment for type II diabetes?

Answer 20

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

Question 21

What T2DM drug, also a potential third line - Works on nuclear receptors causing transcription of insulin sensitive genes? The receptor is PPARy

Answer 21

Thiazolidinediones (TZDs) - glitazones

Question 22

What is the only glitazone in use and why is it risky to use long term in women? What else can it cause?

Answer 22

Pioglitazone

Causes increased bone resorption therefore

Contraindicated in elderly patients with osteoporosis or bone fractures

Can also cause heart failue

Causes weight gain

Question 23

Which drug is from the saliva of glia monster?

Answer 23

Incretin analogues -

Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels

Question 24

How do incretin analogues work?

Answer 24

• 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

Question 25

What are the two main incretin analogues? What is an example of an incretin analogue name?

Answer 25

• 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

Question 26

What is adverse in administration of incretin?

Answer 26

Injectable not oral

Question 27

Does incretin cause hypoglycaemia and weight gain?

Answer 27

No does not cause hypoglycaemia

Acts on hypothalamus to reduce appetite causing weight loss

Question 28

What drug is known as the Gliptins and is weight neutral without hypoglycaemia however may cause pancreatitis?

Answer 28

DPP4 inhibitors

Inhibitors of dipeptidyl peptidase 4 are a class of oral hypoglycemics that block the enzyme dipeptidyl peptidase-4 (DPP-4).

Question 29

What is DPP4 a direct antagonist of?

Answer 29

DPP4 is a direct antagonist of incretins (GLP-1 and GIP) which will therefore cause decreased insulin production and increased blood sugar

Question 30

What drug blocks reabsorption of glucose by SGLT2 in the proximal tubule of the kidney? Give example

Answer 30

SGLT2 inhibitor - dapaglifozin

Question 31

What is a positive and 2 negative effects of SGLT2 inhbitors?

Answer 31

Positive - causes weight loss

Negative - thrush and UTIs due to glucose in urine

Question 32

Is the main reabsoprtion of glucose in the kidneys take place via the SGLT1 or SGLT2 pathway?

Answer 32

The SGLT2 pathway accounts for 90% of glucose reabsorption

Question 33

What is the brush border enzyme that breaks down starch and disaccharides to absorbable glucose?

Answer 33

Alpha-glucosidase

Inhibitors of this prevent glucose absorption in the GUT

Question 34

What are side effects of alpha-glucosidase inhibitors?

Answer 34

GI upset – flatulence, loose stools, diarrhoea, abdominal pain, bloating

Question 35

What T2DM drug causes a risk of pancreatitis as a side effect?

Answer 35

The gliptins - DPP4 inhibitors

Weight neutral promoting insulin secretion with side effect of pancreatitis

Question 36

Give an example of an alpha-glucosidase inhibitor?

Answer 36

Acarbose

Question 37

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?

Answer 37

BMI of 35 with a comorbidity - eg hypertension or T2DM BMI of 40

Question 38

What are the three types of bariatric surgery? Describe them

Answer 38

• 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

Question 39

Which gastric bypass surgery is a combination of both restrictive and malabsorptive?

Answer 39

Gastric bypass surgery is a combination of both restriction and malabsorption