Type 2 Diabetes Treatments

Question 1

What is the main aim of treatment in type 2 diabetes?

Answer 1

Reduce the risk of microvascular complications

Question 2

The KATP channel involved in insulin secretion is an octomeric complex composed of what?

Answer 2

4 potassium inward rectifier (Kir) 6.2 subunits // 4 sulphonylurea receptor (SUR) 1 subunits

Question 3

In the KATP channel involved in insulin secretion, what forms the potassium selective ion channel?

Answer 3

Tetramer of Kir 6.2 subunits

Question 4

In the KATP channel involved in insulin secretion, what regulates potassium channel activity?

Answer 4

SUR1 subunits

Question 5

Where does ATP bind to the KATP channel involved in insulin secretion?

Answer 5

Each of the Kir 6.2 subunits

Question 6

What happens in the KATP channel involved in insulin secretion, to maintain the resting potential of the beta cell and inhibit insulin secretion until ATP is bound?

Answer 6

ADP-Mg++ binds to the SUR1 subunits to keep the channel open

Question 7

Which type 2 diabetes drugs have their action at the KATP channel which regulates insulin secretion?

Answer 7

Sulphonylureas

Question 8

What type of drug is a biguanide?

Answer 8

Metformin

Question 9

What is the 1st line agent for type 2 diabetes?

Answer 9

Metformin

Question 10

In what dosages is metformin available?

Answer 10

500mg, 850mg, 1g

Question 11

Metformin should usually be started on what dose?

Answer 11

500mg once or twice daily

Question 12

There is little evidence for taking more than how much metformin daily?

Answer 12

1g

Question 13

Where does metformin act? What is its role there?

Answer 13

Liver // Lower glucose production

Question 14

How does metformin lower glucose production at the liver?

Answer 14

Decrease hepatic gluconeogenesis // Increase peripheral glucose uptake

Question 15

What are some other functions that metformin is said to have?

Answer 15

Reduced absorption of glucose from the gut // Enhanced anaerobic glycolysis

Question 16

How effective is metformin at hyperglycaemia management?

Answer 16

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

Question 17

How likely is metformin to cause hypoglycaemia?

Answer 17

Very unlikely (when used as monotherapy)

Question 18

What effect does metformin have on weight?

Answer 18

Weight loss (suppresses appetite)

Question 19

Does metformin prevent microvascular complications?

Answer 19

Yes

Question 20

What is the only drug to prevent macrovascular complications of type 2 diabetes?

Answer 20

Metformin

Question 21

Is metformin safe in pregnancy?

Answer 21

Yes

Question 22

What are some minor effects of metformin which may contribute to its ability to decrease risk of macrovascular complications?

Answer 22

Reduces triglycerides and LDL, minor reduction in BP

Question 23

What other conditions can metformin be used in?

Answer 23

PCOS and NAFLD

Question 24

Where are the main metformin side effects? Give examples.

Answer 24

GI tract: anorexia, nausea, vomiting, diarrhoea, abdominal pain, taste disturbance

Question 25

How common are GI side effects from metformin? How often can people not tolerate them?

Answer 25

25% will have side effects, 5% will be intolerable

Question 26

Metformin can interfere with the absorption of which vitamins?

Answer 26

B12 and folic acid

Question 27

What are some very rare side effects of metformin?

Answer 27

Lactic acidosis, liver failure, rash

Question 28

When may lactic acidosis occur in a patient on metformin?

Answer 28

Co-existing renal failure or acute illness

Question 29

How can adverse effects of metformin be reduced?

Answer 29

Slow release formulations and start low go slow methods

Question 30

Does metformin cause renal toxicity?

Answer 30

Not directly, only if there is underlying renal disease

Question 31

With regards to renal toxicity, when should metformin be stopped?

Answer 31

If eGFR < 30ml/min // Serum creatinine > 150macromol/l

Question 32

If a patient is on metformin and their eGFR is between 30-45ml/min, what should be done?

Answer 32

Halved dose

Question 33

When should metformin be temporarily withheld?

Answer 33

If a patient is getting IV contrast

Question 34

If a patient is on metformin and is acutely unwell or having elective surgery, what should they be put on instead?

Answer 34

Insulin

Question 35

With regards to liver toxicity, when should metformin be stopped?

Answer 35

If there is advanced cirrhosis/liver failure // Risk of lactic acidosis e.g. encephalopathy or alcohol excess

Question 36

When are sulphonylureas used as treatment for type 1 diabetes?

Answer 36

1st line in underweight type 2 diabetics, or those intolerant to metformin // 2nd line as an add on to metformin

Question 37

Chlopropramide and tolbutamide are examples of what?

Answer 37

1st generation sulphonylureas (rarely used now)

Question 38

2nd generation sulphonylureas are used in practice now. Give 2 examples? Why are these better than 1st generation?

Answer 38

Gliclazide, glibenclamide // Shorter acting

Question 39

What is the time taken until peak release of insulin, following a sulphonylurea?

Answer 39

1-2 hours

Question 40

What is the dosage of gliclazide?

Answer 40

40mg od - 160mg bd

Question 41

What is the dosage of glibenclamide?

Answer 41

5mg - 15mg od

Question 42

What must still be functioning in order for sulphonylureas to work?

Answer 42

Beta cells

Question 43

How do sulphonylureas work?

Answer 43

Displace the binding of ADP-Mg++ from the SUR1 subunit thus closing the beta cell KATP channel to depolarise the cell and increase insulin secretion

Question 44

Is there a risk of hypoglycaemia with sulphonylureas?

Answer 44

Yes

Question 45

How effective are sulphonylureas at hyperglycaemia management?

Answer 45

15-20mmol/mol decrease in HbA1c by increasing insulin secretion and rapid reduction in hyperglycaemia

Question 46

Which type(s) of complications do sulphonylureas prevent?

Answer 46

Microvascular only

Question 47

Who should sulphonylureas be given with care in, because of the risk of hypoglycaemia?

Answer 47

Elderly/frail, alcohol excess, liver disease

Question 48

What effect do sulphonylureas have on weight?

Answer 48

Weight gain

Question 49

Apart from hypoglycaemia, what are some side effects of sulphonylureas?

Answer 49

GI upset, headache (rarely hypersensitivity and liver dysfunction)

Question 50

When should sulphonylureas be avoided?

Answer 50

Hepatic or renal failure, pregnancy

Question 51

What other drugs will impede the actions of biguanides and sulphonylureas due to their own effects on insulin action?

Answer 51

Corticosteroids and thiazides

Question 52

What type of drug are thiazolidinediones?

Answer 52

PPAR gamma agonists

Question 53

What is the only available thiazolidinedione agent?

Answer 53

Pioglitazone 15-45mg once daily

Question 54

What is PPAR gamma?

Answer 54

A nuclear receptor which is found predominantly in adipose tissue, but also in skeletal muscle and liver

Question 55

How are thiazolidinediones taken into a cell? What do they bind with?

Answer 55

They are lipophilic and readily enter cells // Bind with PPAR gamma with high affinity

Question 56

Thiazolidinediones acting on PPAR gamma has what effect?

Answer 56

Transcription of genes which encode lipoprotein lipase, fatty acid transport proteins, fatty acid CoA synthase and GLUT4

Question 57

What is the role of lipoprotein lipase?

Answer 57

Hydrolyses the breakdown of lipids in lipoproteins into fatty acids and glycerol

Question 58

Deficiency of lipoprotein lipase leads to what?

Answer 58

Hypertriglyceridaemia

Question 59

What is the overall action of pioglitazone?

Answer 59

Enhance the action of insulin at target tissues

Question 60

What effect do thiazolinediones have on hyperglycaemia management?

Answer 60

Reduces HbA1c by 15-20mmol/mol by increasing insulin sensitivity

Question 61

What effect do thiazolinediones have on fatty acids?

Answer 61

Increase uptake and storage in adipocytes, rather than the skeletal muscle and liver

Question 62

Do thiazolinediones cause hypoglycaemia?

Answer 62

Not unless used in combination with sulphonylureas

Question 63

Do thiozolinediones prevent complications?

Answer 63

No (improvement in microalbuminaemia though)

Question 64

What cardiac effect do thiazolinediones have?

Answer 64

Big risk of worsening heart failure due to fluid retention (in those with PRE-EXISTING heart failure)

Question 65

Are thiazolinediones hepatotoxic?

Answer 65

Yes

Question 66

What effect will thiazolinediones have on weight? Why?

Answer 66

Increase- increased subcutaneous fat and fluid retention

Question 67

Who are thiazolinediones not recommended in and why?

Answer 67

Those over the age of 65 due to increased risk of hip fractures

Question 68

Which two types of diabetes drugs act on the incretin pathway?

Answer 68

DPP-IV inhibitors and GLP-1 agonists

Question 69

What happens to the incretin effect in type 2 diabetes?

Answer 69

It is reduced

Question 70

Drugs involving the incretin effect will only work if there is what?

Answer 70

Some degree of insulin production present

Question 71

GIP is one of the hormones involved in the incretin effect. Where is it secreted from? In response to what?

Answer 71

Secreted from endocrine K cells, in response to absorbable carbohydrates and lipids (hence increased after meals)

Question 72

What action does GIP have in response to meals?

Answer 72

It binds with its receptor on the beta cells to increase cAMP and produce insulin

Question 73

Where is GLP-1 expressed?

Answer 73

Pancreatic alpha cells and L cells of intestinal mucosa

Question 74

The secretion of GLP-1 throughout the day is correlated with what?

Answer 74

Secretion of insulin

Question 75

What is the function of GLP-1?

Answer 75

Binds to GPCRs on the beta cell to increase cAMP and release insulin. Also decreases glucagon so there is decreased glucose production.

Question 76

Delayed gastric emptying is an action of which drugs? What is the advantage of this?

Answer 76

DDP-IV inhibitors and GLP-1 agonists, it means not as much CHO needs broken down at once

Question 77

GLP-1 is metabolised by what?

Answer 77

DDP-IV

Question 78

Do drugs acting on the incretin pathway cause hypos? Why/why not?

Answer 78

No- when glucose is in a normal range, incretin drugs do not bind

Question 79

Give 2 examples of GLP-1 receptor agonist?

Answer 79

Exenatide and liraglutide

Question 80

Which GLP-1 agonist drug has a shorter half life?

Answer 80

Exenatide

Question 81

How often and how are GLP-1 agonists taken?

Answer 81

Exenatide = twice daily SC injection, liraglutide = once daily SC injection

Question 82

What are the actions of GLP-1 agonists?

Answer 82

Increase insulin secretion from pancreas // decrease glucagon secretion // increase insulin sensitivity

Question 83

What effect do GLP-1 agonists have on weight? Why?

Answer 83

Weight loss- acts on the hypothalamus to reduce appetite

Question 84

What are the adverse effects of GLP-1 agonists?

Answer 84

Nausea (usually resolves), injections, potential pancreatic cancer/pancreatitis

Question 85

What do all DDP-IV inhibitor drug names end in?

Answer 85

Gliptin

Question 86

How are DDP-IV inhibitors administered? How often?

Answer 86

Once daily oral

Question 87

DDP-IV inhibitors are usually used in combination with which other drugs? Can they be used as mono therapy?

Answer 87

Metformin and thiazolinediones // They can but not common

Question 88

What is the action of DDP-IV inhibitors?

Answer 88

Increase the action of GLP-1, promote insulin secretion from the pancreas

Question 89

What effect do DDP-IV inhibitors have on weight?

Answer 89

Neural

Question 90

Which drug which acts on the incretin pathway has the biggest decrease in HbA1c?

Answer 90

GLP-1 agonists

Question 91

Give 2 examples of SGLT2 inhibitors?

Answer 91

Canagliflozin, empagliflozin

Question 92

What is the mechanism of action of SGLT2 inhibitors?

Answer 92

Selectively block the reabsorption of glucose by the SGLT2 transporter in the proximal tubule to deliberately cause glycosuria

Question 93

Do SGLT2 inhibitors have a risk of hypoglycaemia?

Answer 93

No

Question 94

What effect do SGLT2 inhibitors have on weight?

Answer 94

Weight loss (because you pee out the sugar i.e. calories)

Question 95

Is the action of SGLT2 inhibitors dependent on insulin?

Answer 95

No

Question 96

Apart from reduction in blood glucose, what are some other positive effects of SGLT2 inhibitors?

Answer 96

Reduces CV risk and hospitalisation for heart failure, beneficial for most renal outcomes

Question 97

What are some adverse effects of SGLT2 inhibitors?

Answer 97

Thrush, and increased risk of UTIs

Question 98

Who do SGLT2 inhibitors not work in?

Answer 98

Those with an eGFR < 60

Question 99

Which type 2 diabetics receive insulin?

Answer 99

Those who fail on non-insulin therapies

Question 100

What type of insulin is used in type 2 diabetes? What treatment is this added onto?

Answer 100

Intermediate acting insulin once daily, with metformin +/- sulphonylurea

Question 101

What type of insulin (i.e. human or analogue) is used in type 2 diabetes?

Answer 101

Human

Question 102

Is there an upper limit to the amount of insulin that can be given to a type 2 diabetic?

Answer 102

No, keep going until sugars are back to normal

Question 103

What are some side effects of insulin treatment?

Answer 103

Hypo/hyperglycaemia, local reaction at injection site, loss of fatty tissue at injection site, insulin resistance

Question 104

What should happen to insulin dose in a patient with renal failure?

Answer 104

Decreased (as it will take longer to be excreted)