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 3 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

Epigenetic changes 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)
Autosomal dominant
Ineffective pancreatic B 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 before someone 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)  
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 causing high BP

Question 8

What eventually happens to the beta cells in T2DM?

Answer 8

Insulin resistance damages the B cells, eventually results in B cell failure

Question 9

Describe how beta cell potential for insulin secretion and insulin resistance change with age.

Answer 9

Potential for insulin secretion decreases with age

Insulin resistance increases with age

Question 10

Describe the metabolism + presentation of a typical patient with T2DM.

Answer 10

Heterogeneous
Obese (80%) 
Insulin resistance + insulin secretion deficit  
Hyperglycaemia + dyslipidaemia 
Acute + 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 (less able to enter muscle + less stored as glycogen)
HGO 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 (thus, omental fat correlates with risk of heart disease)

Question 15

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

Answer 15

Can’t be used to make glucose so are converted to VLDL’s which are highly atherogenic

Question 16

Describe how gut microbiota is implicated in T2DM.

Answer 16

May alter host signalling: they ferment lipopolysaccharides to short chain fatty acids, which enter the circulation + modulate bile acids (so affect host metabolism)
Associated with inflammation + 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 weight gain?

Answer 18

Metformin

Question 19

What are the management strategies for T2DM?

Answer 19

Education
Diet
Pharmacological treatment
Complication screening

Question 20

What dietary measures are recommended for someone with T2DM?

Answer 20

Decreased fat (particularly sat. fats) + refined carbs
Increased complex carbs + soluble fibre
Control total calories + increase exercise
Reduce salt

Question 21

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

Answer 21

Pancreatic Lipase Inhibitor
Reduces break down of fats in the intestines thus reducing absorption of fats
More is excreted

Question 22

State 7 classes of drugs that are used to treat T2DM and state how they work.

Answer 22

Insulin: reduces HGO
Metformin: insulin sensitiser
Sulphonylureas: makes existing pancreas produce more insulin
Alpha-glucosidase inhibitors: prolongs absorption of glucose from the intestine
Thiazolidinediones: act on insulin resistance (central + peripheral)
GLP-1 agonists + DPP4 inhibitors: increase insulin secretion + have anti-glucagon effect
SGLT2 inhibitors: act on PCT to increase glycosuria

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 (as causes weight gain)

Question 25

Explain how sulphonylureas work.

Answer 25

Bind to receptors + block the ATP-sensitive K+ channel | Leads to Ca2+ influx, which causes insulin release

Question 26

Name one alpha-glucosidase inhibitor. Explain how it works and state 1 side effect.

Answer 26

Acarbose Prolongs absorption of oligosaccharides + allows the body to cope with the loss of 1st phase insulin Side effect: flatus

Question 27

Name a thiazolidinedione. What are its effects?

Answer 27

Pioglitazone =PPAR agonist 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 (where oral glucose stimulates more insulin than IV glucose) Stimulates insulin + suppresses glucagon

Question 29

What breaks down GLP-1?

Answer 29

Dipeptidyl peptidase-4 (DPP4)

Question 30

How do gliptins work?

Answer 30

``` Inhibit DPP4 (increase half life of GLP1) Increases [GLP1] Decreases [glucagon] Decreases [glucose] Neutral on weight ```

Question 31

Name a GLP1 agonist. Describe the action of GLP1 agonists

Answer 31

``` Exenatide. Injectable, long acting Decrease [glucagon] Decrease [glucose] Cause weight loss ```

Question 32

Name an SGLT2 inhibitor and describe its mechanism of action

Answer 32

Empaglifozin Inhibits Na-Glu transporter Increases glycosuria

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

Question 34

Define Diabetes Mellitus

Answer 34

State of chronic hyperglycaemia sufficient to cause long-term damage to specific tissues e.g. retina, kidney, nerves + arteries

Question 35

Is T2DM ketosis prone?

Answer 35

No

Question 36

What 3 clinical signs and symptoms indicate T2DM?

Answer 36

Osmotic symptoms Infections Presentation of complication e.g. hyperosmolar coma, ischaemic heart disease, retinopathy

Question 37

List 3 microvascular complications of T2DM

Answer 37

Retinopathy Nephropathy Neuropathy

Question 38

List 2 metabolic complications of T2DM

Answer 38

Lactic acidosis | Hyperosmolar coma

Question 39

List 4 macrovascular complications of T2DM

Answer 39

Ischameic heart disease Cerebrovascular disease Renal artery stenosis Peripheral vascular disease

Question 40

What treatment complications may arise in T2DM?

Answer 40

Hypoglycaemia | Weight gain

Question 41

What 4 elements must be targeted in treatment of T2DM?

Answer 41

Weight Glycaemia Blood pressure Dyslipideamia

Question 42

What weight loss treatment may cause T2DM to go into remission?

Answer 42

Gastric bypass surgery

Question 43

By what mechanisms does metformin reduce insulin resistance?

Answer 43

Reduced HGO | Increases peripheral glucose disposal

Question 44

What intervention is most effective at reducing incidence of T2DM?

Answer 44

Lifestyle changes