Diabetes Pathogenesis Type 2 Flashcards
Describe Type 2 overall
Insulin resistance
Gradual onset
Develops later in life
Obesity
Describe how Type 2 develops
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
Describe how obesity + insulin resistance is linked
FAs oxidised
= DAG activates Ser/Thr kinases
= phosphorylates insulin receptor
= interrupts signalling pathway
What is released by adipocytes?
Obesity + insulin resistance
Pro-hyperglycaemic + anti-hyperglycaemic (help insulin) adipokines
What is adiponectin?
Obesity + insulin resistance
Anti-hyperglycaemic
= improves insulin sensitivity
= activating AMPK
= reduces liver lipogenesis
What is reduced in obesity?
Obesity + insulin resistance
Expression of adiponectin
How does inflammation contribute?
Obesity + insulin resistance
Adipocytes produce IL-6 + IL-1
= attract macrophages to fat deposits
= cytokines = activate lymphocytes
= inflammation
(reduction in cytokines improve insulin resistance)
What is PPAR-gamma?
Obesity + insulin resistance
Nuclear receptor involved in adipocyte differentiation
= promotes anti-hyperglycaemic adipokines
What is 1st line for Type 2?
Diet + exercise can reverse development
What is Thiazolidinediones (TZDs)?
Agonist of nuclear receptor of PPAR-gamma
What is an example of TZD?
Pioglitazone
What does TZDs do?
Promote expression + secretion of anti-hyperglycaemic adipokines
= increases hypoglycaemic action of insulin by sensitising cells
= collectively reduce insulin resistance
What is Metformin?
Activate AMPK (adiponectin)
How does Metformin work?
Reduces liver lipogenesis = improves insulin sensitivity
= supresses glucose release from liver
= increases GLP-1 secretion = stimulates insulin + inhibits glucagon
Who do you NOT give Metformin to?
NOT obese patients
What is the anti-obesity effect of Metformin?
Decreases appetite
Reduces liver lipogenesis
What are Sulphonylureas?
Bind to sulphonylurea receptors expressed on membrane of beta cells
What is an example of a Sulphonylurea?
Gliclazide
How does Sulphonylureas work?
Block ATP-sensitive K+ channels in beta cells
K+ accumulates inside cell
Beta cells depolarise
Ca2+ channels open + allow insulin secretion
How does alpha-glucosidase inhibitors work?
Delay carbohydrates absorption
= reduce postprandial increase in blood glucose
What is an example of an alpha-glucosidase inhibitor?
Acarbose
What are alpha-glucosidase inhibitors useful in?
Obese patients
What are alpha2-adrenoreceptor antagonists?
NEW DRUG
Increase insulin secretion
What are selective beta-3 agonists?
NEW DRUG
Control lipolysis = obese patients
= enhance sensitivity of whole body
What is an example of beta-3 agonist?
Mirabegron
What are the long term complications of Type 2?
Damage to large blood vessels = coronary artery disease, cerebrovascular disease + peripheral vascular disease
Damage to small blood vessels = retinopathy + neuropathy
What is the cause of the longer term complications?
Increased glucose + FAs
= increased ROS
Also = AGEs
= ROS generation, inflammation + metabolic + structure defect
Describe how AGE works
Crosslinks with collagen
= endothelium thickens
= traps LDL in artery wall
= oxidation
Also traps IgG
= activation = inflammation
= blood vessel damage
