High Blood Glucose Levels

High blood glucose levels are largely responsible for the development of complications in people with diabetes. There is much research evidence to support this fact, and accordingly it is now well established that improved blood glucose control reduces one's risk of developing complications.

Hyperglycaemia is directly related to the development of the diabetes-specific complications retinopathy (eye disease) nephropathy (kidney disease) and neuropathy (nerve damage). These problems are mainly caused by damage to small blood vessels - hence the term microvascular disease.

Hyperglycaemia is also related to other 'complications' that are not specific to people with diabetes - heart disease, for example. However, other factors also come into play with large blood vessel (macrovascular) disease, including high blood pressure (hypertension) and altered levels of fats in the blood (dyslipidaemia).

Mechanisms of Hyperglycaemic Damage

At the cellular level, considerable research has been carried out into the microvascular (small blood vessel) and macrovascular (large blood vessel) damage that occurs in diabetes. Several different mechanisms have been described - and these are likely interrelated - but the exact contribution from each of the factors remains unclear.




What's covered on this page


Microvascular damage
(leading to diabetic eye, kidney and nerve disease)

Advanced glycation endproducts (AGEs)
Polyol accumulation
Reactive oxygen species
Protein kinase C

Macrovascular damage
(leading to large blood vessel disease and heart disease)

Genetics





Microvascular damage

High blood glucose levels - hyperglycaemia - may cause damage to the smaller blood vessels in the body in a number of ways. The damage is widespread and affects many other organ systems, including the eyes, nerves, kidneys, heart, brain and skin. Several 'biochemical pathways' have been proposed to link high glucose levels with these diabetes-specific microvascular complications.

Advanced glycation endproducts (AGEs)

When blood glucose is high, excess glucose may be channelled into chemical reactions that wouldn’t normally occur. One of the most important of these is the binding of glucose to proteins, forming what are known as ‘AGEs’ (Advanced Glycosylation (or Glycation) End products). This happens over a period of time and depends on (a) the protein involved and (b) how long the prevailing blood glucose level is high. The process starts off without the need for any enzymes (extra chemicals often needed to make a chemical reaction in the body happen) - and this means that the chemical reactions are effectively uncontrolled, and are therefore largely dependent on the amount of glucose present.

This reaction of glucose with protein actually forms the basis of the blood test which gives an indication of how well blood glucose levels have been controlled. Glucose reacts with haemoglobin (the red oxygen-carrying molecules in blood) forming glycated haemoglobin or HbA1c. The level of HbA1c in the blood is related to the overall blood glucose control in the previous few weeks and can be used as a general predictor of risk of developing complications. (For more details, see the section 'The HbA1c Test')

Often, when glucose reacts with protein, the properties of the protein are affected. We have a great number of proteins in our bodies and most of these are potentially at risk of being altered by glycosylation. The problem though, is that it doesn’t stop there. Once altered, these proteins may start a series of damaging reactions.

Many of the complications of diabetes are the consequence of damage to blood vessels. AGEs may contribute to this in a number of ways, including:

  • AGEs are able to cross-link with each other and with other proteins causing cell membranes to become thickened and damaged. This will alter how the cell reacts to other cells and chemical messengers in its environment.
  • AGEs are able to trigger a series of events which would normally only occur if the vessel wall was damaged. This can lead to deposits of fibrous and fatty material.
  • Blood vessels normally relax and contract depending on blood flow and other factors. AGEs can hinder the relaxation which means that vessels may be ‘constricted’ or narrower than they should be.
  • Finally, AGEs may be broken down in the body, but this process in itself can lead to the release of toxic products.

A compound called aminoguanidine has been shown to inhibit AGE formation, and may prevent - or at least reduce - a number of diabetic complications (although clinical trials in humans have shown that it may be associated with anaemia). More research is going on now - watch this space!

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Polyol accumulation

Another chemical reaction which glucose is channeled into when it is present in high concentrations is the 'polyol pathway'; this results in a build up of sorbitol in cells, which in turn is thought to be related to osmotic damage (water moving where it shouldn't) and/or oxidative stress (see 'Reactive Oxygen Species' below).

The polyol pathway is mainly controlled by the level of an enzyme called aldose reductase. Any agent that stops or binds this enzyme (called an 'aldose reductase inhibitor') has the potential to reduce this damaging effect of high glucose levels. Thus the investigation of potential aldose reductase inhibitors (ARIs) remains an ongoing concern in diabetes research.

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Reactive oxygen species

The term 'free radical' is familiar to many; in medical or biological terms it relates to a particularly reactive form of the oxygen molecule, which can trigger numerous chains of damaging events at the cellular level. Reactive oxygen species (ROS) can be formed in a number of different ways, and are thought to be involved in many aging- and disease related processes.

In hyperglycaemic diabetes-related damage, ROS may arise from any of one or more mechanisms that are related to high blood glucose levels:

  • Glucose auto-oxidation
  • Polyol pathway
  • Protein glycation
  • Prostanoid production
>> More details

Some studies have suggested that anti-oxidants, such as Vitamin E, may be helpful in reducing or preventing some diabetes complications. One study of interest implied that high-dose Vitamin E may even promote the reversal of some of the very early changes seen in diabetic retinopathy.

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Protein kinase C

Protein kinase C (PKC) is an enzyme that can be found throughout the body (check!); its activation appears to be related to the small blood vessel damage associated with high blood glucose levels. Reactive oxygen species (ROS) are partly responsible for PKC activation in vascular cells.

Activation of PKC results in numerous effects at a cellular level, and these in turn affect blood vessels characteristics, and blood flow.

Increased matrix proteins (e.g. collagen, fibronectin)
Increased vasoactive mediators (e.g. endothelin)

Thickening of basement membrane
Increased vascular permeability
Alterations in blood flow

>> More details

Since PKC activation is related to microvascular damage, there is potential for drugs that block the activation of PKC ('PKC inhibitors') in the reduction of microvascular complications. However… there are frequently two sides to a research question and in this case, it has been argued that inhibiting PKC may actually do more harm than good. As is often the case, 'the jury is still out' on this one.

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Macrovascular Damage

High blood glucose levels also contribute to macrovascular damage in diabetes, leading to disease of the large blood vessels, and heart disease. More on these topics can be found in the sections, 'Heart Disease' and 'Feet and Legs'.

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Genetics

Studies have suggested that genetics may play a part in rendering people at higher risk of developing some complications. It is likely that the reverse is also true, and that genetics may also provide some people with some degree of protection against diabetes-related damage and its resulting complications.

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