27 - Anti-Diabetic Drugs Flashcards
Causes of insulin resistance
Strong genetic component
- Identical twins >90% concordant
- Indigenous populations
Environment important
- Increased incidence over the last century
What’s changed?
- Lifestyle, exercise, habits etc.
- Most commonly associated with obesity (>80% of cases)
- Diet
Features of insulin resistance
- inability of tissues to respond to normal levels of insulin
- all process malfunctioning in IR
- blocking of GLUT4 translocation and glucose uptake
- block on glujconeogeneis
-activation of certain Ser/Thr kinases
Inability of tissues to respond to normal levels of insulin
Insulin normally:
- Increases muscle and adipocyte glucose uptake (via GLUT4 translocation)
- Increases glycogenesis, lipogenesis and other anabolic processes
- Decreases glycogenolysis, lipolysis, proteolysis, gluconeogenesis
Insulin acts via tetrameric receptor
- Tyrosin phosphorylation
- IRS1, various protein kinases/phosphatases
All process malfunctioning in IR
Receptor phosphorylation, receptor number, GLUT4, IRS1 phosphorylation
What is blocked in insulin resistance?
When the insulin receptor is activated, for example in the muscle, we get Akt causing GLUT4 translocation and glucose uptake
o This is blocked in insulin resistance
In the liver there is a block on gluconeogenesis
What is activated in insulin resistance?
Activation of certain Ser/Thr kinases, particularly members of the PKC family (PKC is activated by diacylglycerol)
o Activation of these conventional and novel PKCs seems to inhibit either phosphorylation of the insulin receptor, or phosphorylation of IRS1
- Phosphorylation of atypical PKCs seem to be involved in blocking Akt, and particular phosphatases are activated to decrease the phosphorylation of Akt
- Driven by accumulation of toxic lipids called ceramides inside the cell
- This leads to hyperglycaemia because there is no longer glucose uptake and gluconeogenesis is no longer blocked
- Secretion of glucose
Ser/Thr kinase activation results
o Classical/atypical PKC & PKA
- Inhibit phosphorylation of the insulin receptor
o Classical, novel PKC, JNK, IKK, S6K1
- Act on IRS1 to alter its phosphorylation and activation
o JNK, GSK3
- In vascular endothelial cells, phosphorylation of IRS2 affected
o Atypical PKC
- inhibit activity of Akt
Causes of Ser/Thr activation
o Lipotoxicity
- Too much fat production
o Inflammation
- Inflammation is linked with obesity, triggering unwanted activation of these kinases
o Hyperglycaemia
- When blood glucose levels are too high
o Mitochondrial dysfunction
- Associated with environmental stress
o ER stress
Complications of type 2 diabetes
The secondary complications of hyperglycaemia:
o Glycosylation: retinopathy, blood vessel disease, nephropathy
- Proteins in the blood stream get sugar residues added to them, like haemoglobin
o Blindness, impotence, kidney disease, amputation, atherosclerosis
o Complication appear before you know you’re diabetic
Treatment for type 2 diabetes
Exercise
- Good, but unpopular
Diet
- Low calorie, low saturated fat, low GI
- Great, but unpopular
Insulin
- To combat the insulin resistance
- Danger of hypoglycaemia
- Anabolic- so increases weight
- Popular option
How do drugs lower glucose levels?
- blocking glucose production in the blood
- increasing insulin resistance
- increasing movement of glucose from the blood into tissue
How do drugs lower blood glucose by blocking glucose production in the blood
Reducing glucose production in the liver
- Thiazolidinediones act on the liver to prevent glucose secretion, so there’s less glucose in the blood
- Biguanidine lowers glucose production by the liver
Block glucose absorption in the intestine
- Inhibit alpha glucosidase which lowers absorption
How do drugs lower blood glucose by increasing insulin resistance?
Enhance insulin secretion in the pancreas
- Sulfonylureas helps glucose stimulate insulin exocytosis from the pancreas, and interact with the signalling pathways that lead to the triggering of insulin
How do drugs lower blood glucose by increasing the movement of glucose from the blood into tissue?
Targeting adipose tissues and muscle
- Insulin sensitisers like the thiazolidinediones or biguanides promote glucose uptake
- Increase the ability of GLUT4 to be expressed at the cell surface
Drug treatments for type 2 diabetes (hypoglycaemic western medicine)
- LIVER (decreased glucose production): Biguanide, Thiazolidinediones
& - INTESTINE (decreased glucose absorption): alpha-glucosidase inhibitor
= less glucose into the blood - PANCREAS (increased secretion): meglitinides, sulfonylureas, phenylalanine derivatives, insulin
= increase insulin secretion - ADIPOSE TISSUE & MUSCLE (peripheral glucose uptake): biguanide, thiazolidinediones
= more glucose leave blood into tissue
