Pathophysiological effects of hyperglycaemia

Wikis > Diabetes > Diabetes Pathophysiology > Pathophysiological effects of hyperglycaemia

Pathophysiological effects of hyperglycaemia

There is no unifying hypothesis of the mechanism by which the hyperglycaemia results in the acute and chronic complication of diabetes. A number of biochemical and functional mechanisms may act independently or interact

A number factors also complicate the link between hyperglycaemia and the diabetes related compilations (eg hypertension, hyperlipidemia, smoking, obesity, genetic and environmental factors) – there is also possibly some unknown ‘independent accelerating factors’ when it comes to the development and progression of complications.

Biochemical consequences of hyperglycaemia:

Hyperglycaemia results in a number of biochemical changes that may cause tissue damage:

Non-enzymatic glycation (advanced glycation end products):
Glucose can combine with proteins (glycation)
Glycation of intra- and extra-cellular proteins.

Reactive aldehyde of glucose reacts non-enzymatically with the amino groups of proteins to form reversible Schiff base, then form a stable Amadori rearrangement  further degrade into carbonyl compounds  heterogenous group of fluorescent protein bound molecules  advanced glycation end products (AGE’s)  cause adverse cellular events (eg reduction in enzymatic activity, cross linking of proteins, damage to nucleic acids, etc)

The attachment of glucose to proteins occurs at a rate that is proportional to the mean blood glucose concentrations. (HBA1c)

Can be reversed early, but eventually become irreversible  accumulation of AGEs (advanced glycation end products).

Oxidative-reductive stress:

Increased polyol pathway activity:
Glucose is converted to sorbitol in the presence of intracellular hyperglycaemia (pathway is inactive normally). The enzyme, aldose reductase, acts to convert the glucose to sorbitol. Increased activity of this pathway results in accumulation of the osmotically active sorbitol  osmotic stress  cell damage.
Aldose reductase is found in nerve, retinal, kidney cells and walls of blood vessels

Intracellular myo-inositol depletion:

Increased protein kinase C activity:
Protein kinase activity in endothelial cells increases as a result of the accumulation of diacylglycerol from the high intracellular concentration of glucose. This alters vascular permeability and increased basement membrane synthesis.

Hexosamine Pathway:
Increase glucose levels activiates this pathway.

Functional consequences of hyperglycaemia:

Hyperglycaemia results in a number of functional changes that may cause tissue damage:

Haemodynamic disturbances:

Haemorrheological abnormalities:

Enhanced erythrocyte aggregation/adhesion  increased viscosity of blood  may have detrimental rheological effects. This is not correlated to blood glucose control .

Microvascular dysfunction:
Increased vascular permeability
Impaired autoregulation of blood flow

Impaired vascular reactivity is associated with insulin resistance
Non-occlusive microvascular dysfunction

Structural changes – thickening capillary basement membrane (does not lead to narrowing of lumen)

Endothelial dysfunction:

Associated with insulin resistance, hyperinsulinaemia and hyperglycaemia

Impairment of the endothelial dependent vasodilatation – may play an important role in the pathogenesis of atherosclerosis and hypertension

Serum concentration of AGE’s in those with type 2 diabetes is associated with endothelial dysfunction .

Comments are closed.