Diabetes Pathogenesis Type 2

Question 1

Describe Type 2 overall

Answer 1

Insulin resistance
Gradual onset
Develops later in life
Obesity

Question 2

Describe how Type 2 develops

Answer 2

Hyperinsulinemia = beta cells try to compensate for peripheral resistance
Beta cells then fail + cannot keep up peripheral demand
Insulin secretion decreases
Diabetes = hyperglycaemia + total failure of insulin secretion

Question 3

Describe how obesity + insulin resistance is linked

Answer 3

FAs oxidised
= DAG activates Ser/Thr kinases
= phosphorylates insulin receptor
= interrupts signalling pathway

Question 4

What is released by adipocytes?
Obesity + insulin resistance

Answer 4

Pro-hyperglycaemic + anti-hyperglycaemic (help insulin) adipokines

Question 5

What is adiponectin?
Obesity + insulin resistance

Answer 5

Anti-hyperglycaemic
= improves insulin sensitivity
= activating AMPK
= reduces liver lipogenesis

Question 6

What is reduced in obesity?
Obesity + insulin resistance

Answer 6

Expression of adiponectin

Question 7

How does inflammation contribute?
Obesity + insulin resistance

Answer 7

Adipocytes produce IL-6 + IL-1
= attract macrophages to fat deposits
= cytokines = activate lymphocytes
= inflammation
(reduction in cytokines improve insulin resistance)

Question 8

What is PPAR-gamma?
Obesity + insulin resistance

Answer 8

Nuclear receptor involved in adipocyte differentiation
= promotes anti-hyperglycaemic adipokines

Question 9

What is 1st line for Type 2?

Answer 9

Diet + exercise can reverse development

Question 10

What is Thiazolidinediones (TZDs)?

Answer 10

Agonist of nuclear receptor of PPAR-gamma

Question 11

What is an example of TZD?

Answer 11

Pioglitazone

Question 12

What does TZDs do?

Answer 12

Promote expression + secretion of anti-hyperglycaemic adipokines
= increases hypoglycaemic action of insulin by sensitising cells
= collectively reduce insulin resistance

Question 13

What is Metformin?

Answer 13

Activate AMPK (adiponectin)

Question 14

How does Metformin work?

Answer 14

Reduces liver lipogenesis = improves insulin sensitivity
= supresses glucose release from liver
= increases GLP-1 secretion = stimulates insulin + inhibits glucagon

Question 15

Who do you NOT give Metformin to?

Answer 15

NOT obese patients

Question 16

What is the anti-obesity effect of Metformin?

Answer 16

Decreases appetite
Reduces liver lipogenesis

Question 17

What are Sulphonylureas?

Answer 17

Bind to sulphonylurea receptors expressed on membrane of beta cells

Question 18

What is an example of a Sulphonylurea?

Answer 18

Gliclazide

Question 19

How does Sulphonylureas work?

Answer 19

Block ATP-sensitive K+ channels in beta cells
K+ accumulates inside cell
Beta cells depolarise
Ca2+ channels open + allow insulin secretion

Question 20

How does alpha-glucosidase inhibitors work?

Answer 20

Delay carbohydrates absorption
= reduce postprandial increase in blood glucose

Question 21

What is an example of an alpha-glucosidase inhibitor?

Answer 21

Acarbose

Question 22

What are alpha-glucosidase inhibitors useful in?

Answer 22

Obese patients

Question 23

What are alpha2-adrenoreceptor antagonists?
NEW DRUG

Answer 23

Increase insulin secretion

Question 24

What are selective beta-3 agonists?
NEW DRUG

Answer 24

Control lipolysis = obese patients
= enhance sensitivity of whole body

Question 25

What is an example of beta-3 agonist?

Answer 25

Mirabegron

Question 26

What are the long term complications of Type 2?

Answer 26

Damage to large blood vessels = coronary artery disease, cerebrovascular disease + peripheral vascular disease
Damage to small blood vessels = retinopathy + neuropathy

Question 27

What is the cause of the longer term complications?

Answer 27

Increased glucose + FAs
= increased ROS
Also = AGEs
= ROS generation, inflammation + metabolic + structure defect

Question 28

Describe how AGE works

Answer 28

Crosslinks with collagen
= endothelium thickens
= traps LDL in artery wall
= oxidation
Also traps IgG
= activation = inflammation
= blood vessel damage