The Aetiology and Treatment of Type 2 Diabetes Mellitus

Question 1

What tests are performed to diagnose diabetes and what are the defining values?

Answer 1

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

Question 2

State three factors that influence the pathophysiology of T2DM.

Answer 2

Genetics
Intrauterine environment
Adult environment

Question 3

How is the intrauterine environment important in the pathogenesis of T2DM?

Answer 3

There will be epigenetic changes that take place in utero, which affect blood glucose control in the future

Question 4

What is MODY?

Answer 4

Mature onset diabetes of the young (8 types)
It is autosomal dominant
Ineffective pancreatic beta cell insulin production
Caused by mutations of transcription factor genes (glucokinase gene)
Positive family history with NO obesity

Question 5

What can modulate insulin resistance through adult life beforesomeone develops diabetes?

Answer 5

Adipocytokines

Question 6

What type of babies are more likely to develop T2DM in later life?

Answer 6

Small babies (low birth weight)  
This is due to intrauterine growth restriction

Question 7

How does insulin resistance lead to hypertension?

Answer 7

Insulin resistance leads to a compensatory hyperinsulinaemia
Though the insulin doesn’t affect the glycaemic control pathway, it stimulates the mitogenic pathway causing smooth muscle hypertrophy –> high blood pressure

Question 8

What eventually happens to the beta cells in T2DM?

Answer 8

Insulin resistance damages the beta cells and eventually results in beta cell failure

Question 9

Describe how beta cell reserve and insulin resistance change with age.

Answer 9

Beta cell reserve decreases with age and insulin resistance increases

Question 10

Describe the presentation of a typical patient with T2DM.

Answer 10

Obese (80%)
Insulin resistance and insulin secretion deficit
Hyperglycaemia and dyslipidaemia
Acute and chronic complications

Question 11

What dietary changes can someone with T2DM make to reduce the effect of the missing first phase insulin release?

Answer 11

Complex carbohydrates – release glucose more slowly

Question 12

Describe glucose clearance and hepatic glucose output in T2DM.

Answer 12

Glucose clearance is decreased

Hepatic glucose output is increased

Question 13

What normally happens to insulin secretion as insulin resistance increases?

Answer 13

Insulin secretion increases to compensate for the increased insulin resistance

Question 14

Which adipocytes are particularly marked for breakdown of triglycerides?

Answer 14

Omental adipocytes (this is why omental fat correlates with risk of heart disease)

Question 15

What happens to fatty acids when they go into the liver?

Answer 15

They cannot be used to make glucose so they are converted to very low-density lipoproteins (VLDLs), which are highly atherogenic

Question 16

Describe how gut microbiota is implicated in T2DM.

Answer 16

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 inflammation and adipocytokine pathways

Question 17

What is a very common side effect of diabetes treatment?

Answer 17

Weight gain

Question 18

Which diabetes treatment does not cause this problem?

Answer 18

Metformin

Question 19

What are the potential complications of T2DM?

Answer 19

Stroke 
Myocardial Infarction  
Neuropathy 
Retinopathy 
Nephropathy 
Hypoglycaemia

Question 20

What dietary measures are recommended for someone with T2DM?

Answer 20

Decreased fat (particularly saturated fats) 
Decreased refined carbohydrates  
Increased complex carbohydrates  
Increased soluble fibre  
Control total calories/increase exercise

Question 21

What is orlistat and why is it sometimes used in T2DM?

Answer 21

Pancreatic Lipase Inhibitor

It reduces the break down of fats in the intestines thus reducing the absorption of fats

Question 22

State 5 classes of drugs that are used to treat T2DM and state how they work.

Answer 22

Metformin – insulin sensitiser (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

Question 23

When should you NOT use metformin?

Answer 23

Severe liver failure
Severe cardiac failure
Mild renal failure

Question 24

Name one sulphonylurea.

Answer 24

Glibenclamide

Given to lean patients with T2DM

Question 25

Explain how sulphonylureas work.

Answer 25

They bind to receptors and block the ATP-sensitive K+ channel
This leads to Ca2+ influx, which causes insulin release

Question 26

Name one alpha-glucosidase inhibitor. Explain how it works and state some side effects.

Answer 26

Acarbose
It prolongs the absorption of oligosaccharides and allows 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 –> flatus

Question 27

Name on thiazolidinedione. What are its effects?

Answer 27

Pioglitazone
These are peroxisome proliferator-activated receptor (PPAR-) agonists
These are insulin sensitises mainly in peripheral tissues (leads to peripheral weight gain)

Question 28

What does GLP-1 do?

Answer 28

Responsible for the incretin effect

Stimulates insulin and suppresses glucagon

Question 29

What breaks down GLP-1?

Answer 29

Dipeptidyl peptidase-4 (DP-IV)

Question 30

What class of drugs prolong the duration of GLP-1?

Answer 30

Gliptins

They inhibit DP-IV

Question 31

What effect do long-acting GLP-1 agonists and gliptins have on weight gain?

Answer 31

GLP-1 agonists = weight loss

Gliptins = neutral

Question 32

What other pharmaceutical interventions must be considered with T2DM patients?

Answer 32

Many T2DM patients also have dyslipidaemia and hypertension, which need to be dealt with as well

Question 33

What can occur during pregnancy to identify women who are at high risk of getting diabetes in the future?

Answer 33

Gestational diabetes