Chemical pathology of diabetes W2 Flashcards
What are the most wildly reported long-term diabetes complications?
- Heart disease
- Diabetic retinopathy
- Neuropathy
- Nephropathy
All of the above associated with accumulation of blood vessel and nerve damage over many years as a consequence of elevated blood glucose levels
Extremely high glucose levels can lead to
Keto acidosis – a process which can be lethal in a very short time scale
What is the common theme amongst the biochemical consequences of elevated glucose?
Oxidative stress – the generation of high levels of toxic oxidising molecules which damage proteins and biological processes causing CV and nerve tissue damage in long-term
What are the main toxic oxidants
Hydrogen peroxide
Superoxide
Hydroxy radicals
These are also called reactive oxygen species (ROS)
What does glutathione do?
Is a cofactor (GSH) which maintains an intracellular reducing environment and helps neutralise reactive oxygen species
Glutathione reductase
Uses NADPH to regenerate GSH from glutathione disulphide
What does increased NADH/FADH2 do
Increases proton gradient across in a mitochondria membrane
This inhibits the electron transfer from complex three endothelial cells
What does superoxide overproduction do?
Inhibits GAPDH which diverts upstream glycolysis metabolites into the four pathways of hyperglycaemic damage
What are the pathways of hyperglycaemic damage?
Polyol, hexosamine, protein kinase C, AGE
One, three and four are significant
Polyol pathway
Can consume lots of NADPH which can lower capacity for regeneration of GSH from GSSG
Protein kinase pathway
Excess DHAP is converted to DAG which activates PKC
PKC activity then affects function of various proteins associated with blood flow abnormalities, capillary and vascular occlusion, pro-inflammatory gene expression, increased NADPH oxidise activity
Methylglyoxal
A toxic by products of glycolysis
A very reactive carbonyl
Formed by the chemical degradation of DHAP and GAP
Irreversible elimination of the phosphate leaving group
What is keto acidosis?
The most severe and life-threatening complication of poorly controlled type one diabetes
Insulin functions
- Stimulate glucose into cells.
- Stimulate conversion of excess glucose into glycogen.
- Promote triacylglycerol(TAG) biosynthesis.
- Inhibit hydrolysis of TAG.
Keto acidosis: what happens?
Increased TAD hydrolysis leads to:
Increased fatty acid levels which are catabolised to give :
Increased acetyl-CoA levels:
Excess acetyl. co A is converted into ketone bodies
How long does the red blood cell last for?
Live for 120 days
How is glycated haemoglobin formed?
Haemoglobin is contained in a red blood cell
Glucose enters the bloodstream and the red blood cell
It will naturally bind to the haemoglobin and the binding creates glycated haemoglobin (HbA1c)
