Biochemistry of Type 2 Diabetes

Question 1

What is the single highest risk factor for type 2 diabetes?

Answer 1

BMI >25

Question 2

Can diet make a difference to the risk of developing type 2 diabetes?

Answer 2

Yes, independent of BMI

Question 3

Below what blood glucose concentration is it critical hypoglycaemia?

Answer 3

2.2 mM

Question 4

Why does type 2 diabetes develop?

Answer 4

Can’t compensate for loss of insulin sensitivity

Question 5

What is the initial hyperinsulinaemic phase of type 2 diabetes?

Answer 5

Increased insulin production by pancreas compensates for insulin resistance of peripheral tissues
- Beta cell mass can expand

Question 6

What leads to hyperglycaemia in type 2 diabetes?

Answer 6

Loss in beta cell function/mass

Question 7

What is the onset of type 2 diabetes?

Answer 7

Gradual

Question 8

What are the three phases of type 2 diabetes progression?

Answer 8

1) Hyperinsulinaemia
2) Impaired glucose tolerance
3) Hyperglycaemia in fasting state

Question 9

What happens during the hyperinsulinaemia phase in type 2 diabetes?

Answer 9

Peripheral tissues have insulin resistance
To compensate pancreatic insulin secretion increases
Normal glucose
Elevated insulin

Question 10

What happens during the impaired glucose tolerance phase in type 2 diabetes?

Answer 10

Hyperglycaemia despite elevated insulin > pre-diabetic
Elevated glucose
Elevated insulin

Question 11

What happens during the hyperglycaemia in the fasting state phase in type 2 diabetes?

Answer 11

Insulin secretion declines > overt diabetes
Elevated glucose
Decreased insulin

Question 12

What is the earliest detected abnormality in people who are likely to develop type 2 diabetes?

Answer 12

Insulin resistance

Question 13

What is insulin resistance?

Answer 13

When biological effects of insulin subnormal for glucose disposal in skeletal muscle and suppression of endogenous glucose production by liver

Question 14

When is the action of insulin impaired?

Answer 14

After it binds to insulin receptor - signalling affected

Question 15

How can insulin resistance be observed?

Answer 15

Hyperinsulinaemia in response to glucose load

Question 16

What are the key precipitating factors of insulin resistance?

Answer 16

High circulating levels of free fatty acids
- Activation of TLRs
- Intracellular signalling
Enhanced pro-inflammatory cytokines in obesity
- TNF-alpha
- IL-6
Extra altered intracellular activities
- Mitochondrial ROS
- ER stress

Question 17

What is the end signalling result of the key precipitating factors of insulin resistance?

Answer 17

Phosphorylation of serine residues on IRS1 > inhibition of signalling cascade activated by insulin binding
Increased SOCS levels > degrade IRS1 > prevent signalling

Question 18

Why might bariatric surgery decrease the severity of type 2 diabetes?

Answer 18

Weight control
Altered timing and amount of secretion of gut hormones > influence insulin production
Increased production of certain bile acids > make more cells sensitive to insulin
Surgery-induced changes to gut microbiome

Question 19

What is the response of beta pancreatic cells in type 2 diabetes?

Answer 19

Responses blunted

Question 20

What do higher blood glucose levels in type 2 diabetes trigger in beta pancreatic cells?

Answer 20

Lower insulin secretion rates

Question 21

What is the pattern of beta pancreatic cell loss in type 2 diabetes?

Answer 21

Delayed but progressive

Question 22

What does a smaller beta cell population in type 2 diabetes mean for the remaining cells?

Answer 22

Remaining cells must individually produce higher insulin levels to maintain total insulin production > extra strain on remaining cells

Question 23

How might obesity impact beta cell dysfunction?

Answer 23

Exposure to free fatty acids > loss of co-localisation of voltage-gated Ca channels and insulin secretory granules > Ca channels open but influx occurs in “wrong” place > no secretion

Question 24

What are the factors contributing to beta cell decline?

Answer 24

Direct glucotoxicity
Dietary fatty acid
Obesity
Inflammation-induced cytokines
ER stress

Question 25

What is ER stress?

Answer 25

Imbalance between protein folding capacity of ER and protein load Accumulation of misfolded proteins > trigger downstream signalling events = unfolded protein response

Question 26

What are the long term complications of diabetes closely related to?

Answer 26

Severity and duration of hyperglycaemia

Question 27

What is the most common cause of diabetic ketoacidosis in Australia?

Answer 27

Poor adherence to treatment

Question 28

What factors, other than poor adherence, can cause diabetic ketoacidosis?

Answer 28

``` Infection/other illness - Higher levels of hormones countering effect of insulin Drugs affecting carbohydrate metabolism - Corticosteroids - Sympathomimetics - Atypical antipsychotics - SGLT1 inhibitors ```

Question 29

What is SGLT1?

Answer 29

Glucose transporter in kidney's proximal tubule

Question 30

What are the clinical features of diabetic ketoacidosis?

Answer 30

Hyperglycaemia Hyperketonaemia Metabolic acidosis

Question 31

What is the key diagnostic criterion for diabetic ketoacidosis?

Answer 31

Direct measurement of beta-hydroxybutyrate

Question 32

What are the clinical features of hyperglycaemic hyperosmolar state?

Answer 32

``` Slower onset than diabetic ketoacidosis - several days More severe manifestations of - Hyperglycaemia - Dehydration - Plasma hyperosmolality ```

Question 33

What are common causes of hyperglycaemic hyperosmolar state?

Answer 33

Infection | Poor adherence to therapy

Question 34

What is the key diagnostic criterion for hyperglycaemic hyperosmolar state?

Answer 34

Plasma glucose >33.3 mM | Absence of acidosis and ketonaemia

Question 35

What is the most frequent and serious adverse effect of antidiabetic therapy?

Answer 35

Hypoglycaemia