Hyperglycaemia
High Blood Glucose Levels
High blood glucose (sugar) levels — known as hyperglycaemia — play a major role in the development of diabetes-related complications.
Research consistently shows that keeping blood glucose levels within target ranges can significantly reduce the risk of complications over time.
Why does hyperglycaemia matter?
Persistently high blood glucose can damage blood vessels throughout the body.
Small blood vessel damage (microvascular complications)
These are diabetes-specific complications affecting:
These complications are mainly caused by damage to small blood vessels.
Large blood vessel damage (macrovascular complications)
Hyperglycaemia also contributes to conditions such as:
Unlike microvascular complications, these conditions are influenced by several factors, including:
How does high blood glucose cause 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. The interplay of genetics and the environment is likely responsible for individual variation…
Microvascular damage
High blood glucose levels – hyperglycaemia – can 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! |
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. So the investigation of potential aldose reductase inhibitors (ARIs) remains an ongoing area in diabetes research.
Reactive oxygen species (ROS)
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
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.
Protein kinase C
Protein kinase C (PKC) is an enzyme that can be found throughout the body and is involved in signal transduction pathways; 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
This basically affects blood vessels by:
- Thickening vessel walls
- Increasing leakage from vessels
- Reducing blood flow
- Increasing substances that cause constriction of blood vessels
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 may still be out’ on this one.
Macrovascular Damage
High blood glucose levels also contributes to large blood vessel disease, increasing the risk of:
However, these risks are also strongly influenced by:
More on these topics can be found in the sections, ‘Heart Disease‘ and ‘Feet and Legs‘.
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.
Current treatments and emerging research
Researchers are exploring ways to reduce diabetes-related damage by targeting the pathways involved in hyperglycaemia.
Medications with protective effects beyond glucose lowering
Some modern diabetes medications appear to protect blood vessels and organs in ways that go beyond lowering blood glucose:
- Empagliflozin (and other SGLT2 inhibitors)
May help:- Protect kidney function
- Reduce cardiovascular risk
- Reduce oxidative stress
- Semaglutide (and other GLP-1 receptor agonists)
May help:- Improve blood vessel function
- Reduce inflammation
- Lower cardiovascular risk
Targeting specific pathways
AGE inhibitors
Drugs that aim to:
- Reduce AGE formation
- Block AGE receptors (RAGE)
- Break AGE cross-links
An early example, Aminoguanidine, showed promise but had side effects in human trials.
Research continues into safer approaches. There is also growing interest in:
- Dietary sources of AGEs (e.g. highly processed or browned foods)
- The impact of smoking on AGE formation
Aldose reductase inhibitors (polyol pathway)
These drugs aim to reduce sorbitol build-up by blocking the enzyme aldose reductase.
- Epalrestat has been used in some countries for diabetic neuropathy
Newer versions are being studied, although effectiveness and side effects remain challenges.
PKC inhibitors
Drugs targeting PKC activation have been explored.
- Ruboxistaurin showed some promise in early studies (particularly for eye and nerve disease), but is not widely used in clinical practice
Other areas of research
Additional areas being explored include:
- Antioxidants to reduce oxidative stress
- Anti-inflammatory therapies
- Mitochondrial protection (supporting the cell’s energy systems)
- Improving blood vessel (endothelial) function
Emerging understanding: metabolic memory
Research suggests that the body can “remember” periods of high blood glucose.
This means:
- Previous hyperglycaemia may continue to influence complication risk
- Early glucose management is particularly important
- Improvements in glucose levels are still beneficial at any stage
IN SUMMARY
Hyperglycaemia affects the body through multiple interconnected pathways.
The most important message is that
Reducing exposure to high blood glucose over time lowers the risk of complications
Even small, sustained improvements in glucose levels can make a meaningful difference.
Page Updated May 2026
| LEGAL DISCLAIMER: The information on this website is provided for general educational purposes only and is intended for a New Zealand audience. It is not a substitute for professional medical advice, diagnosis, or treatment. While I strive to ensure accuracy and relevance, please always seek guidance from your healthcare provider for personal medical decisions. Use of the content is at your own risk. Links to other sites are for convenience and do not imply endorsement. |
Search
Deep Dives into Diabetes
YOUR Diabetes YOUR Life!
Articles and Posts
- Is Being Māori a Risk Factor for Diabetes?
- Understanding Pharmac’s Proposed Changes to Type 2 Diabetes Medication Funding
- The National Diabetes Roadmap 2026
- Changing Insulin – What Your Doctor May Not Have Told You
- Type 5 Diabetes
- Discussion Paper – Understanding Diabetes Beyond the Labels
- Diabetes and Inequities Among Māori and Pacific Peoples in Aotearoa