Monitoring and Complications of Diabetes
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We treat diabetes to reduce the risk of the complications of diabetes. Cardiovascular disease is the leading cause of death of people with diabetes.

So it is important to monitor that treatment is effective, and to closely watch for any of the effects of the complications of diabetes.

Targets for the lifestyle factors, blood pressure control and lipids should be set for patients and monitored. Of note, is that the recommended BP for all diabetic patients – 130/80 is lower than for non-diabetic patients – 140/90.

The main complications of diabetes can be divided into macrovascular complications and microvascular complications:

Microvascular complications

Damage to the larger (macro) blood vessels

  • Cardiovascular disease
    • Increased risk of stroke and myocardial infarction

Microvascular complications

Damage to the smaller (micro) blood vessels

  • Peripheral neuropathy
    • Occurs in about 10% of patients with diabetes
  • Diabetic retinopathy
  • Diabetic nephropathy
    • Occurs in 3% of men and 11% of women with diabetes


Monitoring diabetic control

Basic principles: Monitor;
  • Wellbeing and weight
  • Urine glucose
    • Imprecise, but useful as a ‘traffic light’
  • Blood glucose
    • For self regulation. However, its only really people on insulin who can benefit from this.
  • Haemoglobin A1c (HbA1c)
    • For risk assessment. Everyone with diabetes should have this measured at least twice a year!
  • Blood glucose monitoring – this can be done quickly and easily by measuring a tiny amount of blood. It is an essential skill for all involved in diabetic care, and for many diabetic patients themselves. The testing equipment contains glucose oxidase which catalyses the reaction of glucose to gluconic acid, and a detection system that detects the products of this reaction. The detection is either done electrochemically, or colorimetrically (using dyes). Then this signal is either read electrically or by a reflective material, and this signal converted to a number corresponding to glucose concentration. Some more basic tests may involve a colour strip that changes colour.
    • The sample is obtained by pricking the sides of the finger (not the pad – which is more sensitive)
    • Blood must cover the whole of the test area, and the result must be taken after an exact amount of time – many modern kits do this by themselves now – however in cases where they don’t inaccurate readings are common.
    • These tests are accurate enough for the purposes of self monitoring, but are not accurate enough for diagnosis.
  • Urinary (micro)albumin:creatinine ratio (ACR)
  • eGFR
    • Both of these tests screen for the presence of nephropathy
  • Cholesterol profile
    • This should be treated aggressively to reduce the risk of cardiovascular disease

Monitoring schedules

These will depend on the treatment. Type 2 diabetes treated by diet and oral agents can get away with measuring their levels once or twice a week. These patients should check their fasting glucose levels.
Patients on insulin need to monitor much more carefully, in order to adjust the dose of insulin. There are two types of insulin – short acting and long acting. Long acting insulin has be monitored typically 12 hours after it was administrated, whilst short acting insulin should be monitored 90 to 120 minutes after administration. Patients should check their glucose levels regularly. This could consist of checking twice every day, or it ay be that they check 4 times a day, but only on a couple of days each week.
  • Patients should be encouraged to record their glucose levels, as this makes it easier to spot any abnormalities. They should also be encouraged to check their glucose frequently when they feel unwell.
  • Patients on insulin are encouraged to alter their own regimen from their glucose level results, although a clinician should always be available via telephone for advice.
  • These home testing kits also require that the patient has been taught how to use them properly!
As a doctor, it is also important to check the patients monitoring technique, and make sure they have an action plan for what to do if they get readings outside of the normal level.

HbA1c and fructose amide

HbA1c is glycated haemoglobin. It is formed slowly when haemoglobin comes into contact with glucose, via a non-enzymatic pathway.

This process occurs all the time, but the rate of the reaction is proportional to the concentration of glucose.

  • When this process occurs via an enzymatic pathway, as part of a deliberate physiological process, we call it glycosylation. Some medical textbooks fail to make this distinction and refer to HbA1c as “glycosylated” rather than “glycated” which is technically incorrect.
During its 120 day lifecycle, a red blood cell comes into contact with glucose. Some of this glucose will become joined to haemoglobin within the red cell through glycation. In individuals with poorly controlled glucose, the haemoglobin is more likely to come into contact with a glucose molecule, and thus more HbA1c is formed!
  • Once a haemoglobin is glycated it stays like that forever.
  • Therefore, this method of monitoring shows us the level of glucose in the blood over the last 4-12 weeks. Many experts believe that the value is weighted towards glucose levels of the last 2-4 weeks.
  • A good target rate is 4-7%. This percentage value is a percentage of the total amount of Hb. The levels in a normal individual are 4-6.5%.
  • The value can be misleading if there is thalassaemia, or reduced red cell lifespan, or something affecting haemoglobin.
Fructosamide can be used in similar tests – in this case fructose reacts with albumin to produce fructosamide. This is generally used in situations where HbA1c cannot be tested, such as:
Glycation is the process by which a protein or lipid molecule will bind to a sugar molecule (such as glucose or fructose) without enzymatic control. Glycation is usually an unwanted process in the body because it impairs the functioning of normal molecules. At certain specific sites in the body, glycation occurs under the control of enzymes for a specific purpose, and under these circumstances it is called glycosylation.

AGEs – advanced glycation end products. Some AGE’s are benign whilst the production of some others can predispose to certain conditions such as;

  • cardiovascular diseases (fibrinogen, collagen and endotherlium are all damaged by AGE’s). Collagen will be stiffened and weakened. This results in increased blood pressure (due to stiffening) and increased risk of aneurysms (due to weakening). These aneurysms can result in stroke. Glycation products can also be the basis of the formation of atherosclerotic plaques.
  • Alzheimer’s disease (amyloid plaques are side products in the production of AGE’s)
  • cancer (acylamide and other AGE side products are released)
  • peripheral neuropathy (myelin is affected), blindness (due to microvascular damage to the retina).
This damage results from the production of highly oxidising products such as hydrogen peroxide.
Glycated products are removed very slowly from the body – they are removed by the kidney. Glycated products take about twice as long to remove from the body as the average red blood cell life cycle.
Long lasting cells of the body – such as nerve cells, beta cells and retinal cells are most likely to be affected by the damage of AGE’s.

Monitoring urine glucose and ketones

You can measure glucose leves in the urine, but this isn’t much use, because it is affected by the renal threshold (which can be anywhere between 7 and 11mmol/L – note also that the renal threshold rises with age. The mean level is 10 mmol/L), urine output and time since the bladder was last emptied. Hypoglycaemia cannot be detected – because urine glucose gives no idea ofglucose levels once they are below the renal threshold.

Therefore in patients where this is used as the main monitoring method, consistent negative results, and no symptoms of hypoglycaemia will usually confirm that the disease is being well controlled.

In some circumstances urinary glucose may be acceptable – this is in type 2 diabetic patients who refuse to prick their fingers, who have a normal renal threshold, and who are not on hypoglycaemic medications (insulin or suulphonylureas).
Changes in urine glucose are also slow to appear after changes in blood glucose have occurred.
Ketone monitoring may be useful for those with diabetes in times of illness, when glucose levels may become higher than normal. This test will then predict when ketoacidosis may be about to take place.

Monitoring risk factors

To reduce the risk of complications, there are several risk factors that should be monitored and brought under control. These are summarised below. Some patients will achieve these levels but many will not. Achievable targets should be discussed and encouraged with individual patients. The longer the disease goes on, the harder it is to get these levels under control. Eating, lifestyle, and reducing weight are the main ways theses value can be brought under control. Obviously, for many patients, there will also be specific treatments, such as insulin or metformin. The benefits of attaining these values are the same, irrespective of the method used to attain them (i.e which treatment they are on)
These levels are the same irrespective of which type of diabetes you have.
BP (mmHg)
Total Cholesterol (mmol/L)

Managing Hypertension

First line therapy for management of hypertension in diabetic patients should involve the use of an ACE-inhibitor or angiotensin-receptor blocker (ARB). If this is insufficient, add a calcium channel blocker.

he use of ACE-i or ARB is associated with decreased rate of progression to albuminurea in T2DM. 

  • ACE-i and ARBs should not be used in combination

Managing Lipids

This is much the same as lipid lowering therapy for non-diabetic patients. Statins are the first line treatment.

The use of other cholesterol lowering medication can be controversial. There is not good evidence that any other medications (except perhaps for Ezetemibe) used to lower cholesterol actually reduce the risk of cardiovascular disease (despite lowering cholesterol).

Fibrates (e.g. fenofibrate), nicotinic acid and bile-acid resins are all treatemnts that have been show to lower cholesterol, but their cardiovascular disease benefit is doubtful.

Complications of diabetes

The duration and degree of hyperglycaemia is directly related to the severity of the disease.
Good diabetic control can directly reduce the risk of complications; in studies when the HbA1c was kept below 7%, the risk of developing complications was reduced by 60% over 9 years.
Treated patients still have a lower life-expectancy than non diabetic patients. In the case of insulin dependent diabetes, death is usually due to :

  • Cardiovascular disease (70%)
  • Renal failure (10%)
  • Infection (6%)
  • Other (14%)

i.e. 86% of insulin treated patients die as a result of their diabetes

Generally complications cannot be reversed by good control after they have taken hold, however, some patients in the very early stages of complications may benefit from early treatment. Therefore, for microvascular damage in particular it appears there is a threshold level for damage, and when this is reached, the damage is irreversible.
There are also problems in controlling diabetes. The better your control, the more likely you are to suffer episodes of hypoglycaemia and to gain weight, however the less likely you are to suffer from the microvascular complications of diabetes. So you have to have a balance. Obviously gaining weight increases your risk of macrovascular complications.
Thus in those patients:

  • Who are at very high risk of cardiovascular complications (e.g. family history of MI, obese)
  • Are very young or very old

Then the best method for managing their disease is NOT to have the strictest possible control. However, in all other cases, strict control will yield better long term outcome.

The mechanisms leading to the following complications are not well understood. They may involve some of the following consequences of hyperglycaemia:
Non-enzymatic glycosylation (glycation) – this leads to accumulation of AGE’s all over the body. Not only can these cause direct damage (as described above in section on HbA1c), but they can also set off the inflammatory reaction.
Polyol pathway – (akak sorbitol aldose reductase pathway) – this becomes active when intracellular levels of glucose are elevated. Glucose that can’t be metabolised in the normal way (TCA cycle), will enter the polyol pathway. Aldose reductase will reduce glucose to sorbitol, and then sorbitol to fructose.

  • This mechanism is favoured as a cause of diabetic complications because most cells require insulin for glucose to enter, however, cells of the retina, kidney and nerves DO NOT REQUIRE INSULIN for glucose to enter the cell. Thus these cells can get a high intra-cellular concentration of glucose, when glucose levels are raised in the blood. Any glucose that cannot be utilised in the normal way will enter the polyol pathway, and produce sorbitol.
  • Sorbitol cannot cross the cell membrane and thus water is drawn into the cell via osmosis. Fructose also has a similar effect. This then alters cell permeability to various other ions and compounds, and thus may alter cell functioning
  • The sorbitol pathway also produces reactive oxygen species. These can directly lead to cell damage.
  • There is research that has been conducted in animals that shows that by giving them modified aldose reductase enzymes, that don’t produce the same products as those in the normal pathway, many microvascular complications are prevented. Thus this mechanism of damage is probably the most important.

Abndormal microvascular blood flow – this impairs the supply of nutrients and oxygen. Microvascular occlusion is due to release of vasoconstrictors, such as endothelins and thrombogenesis, and over a prolonged period of time this can cause permanent endothelial damage.

  • Other factors – excess growth factors, particularly things like VEGF (vascular endothelial growth factor) are produced by ischaemic tissues in diabetics. This will cause endothelial cells to proliferate, and thus exaggerate and accelerate the microvascular damage.
  • Activation of protein kinase C.


Macrovascular complications

Diabetes is a risk factor in atherosclerosisThis risk is in relation to the background population. For example, Japanese diabetics are more likely to suffer MI than non-diabetic Japanese, however their risk is far lower than diabetic Europeans. Generally, the risks are:

  • Stroke – 2x as likely
  • MI – 3-5x as likely- women also lose their pre-menopausal protection
  • Amputation of a foot due to gangrene is 50x as likely.

Cardiovascular risks are barely affected even by aggressive treatment – thus they remain very high. Therefore, when treating diabetes it is very important to tackle the cardiovascular risk factors individually, and not just focus on the blood glucose.
The sort of risks that need to be aggressively tackled are:

  • Hypertension – this will probably need treatment by at least 2 drugs in conjunction. 1/3 of diabetics will need treatment by 3 or more drugs.
  • Smoking
  • Lipid abnormalities – there is no safe cut-off point, and so you should try and get the lipid concentration down as low as possible! In practice this means virtually all diabetics are on a statin.
  • Low dose aspirin – this will lower cardiovascular risk, but is obvious associated with GI bleeding. The cardiovascular benefits outweigh the risk of bleeding when the cardiovascular 10 year risk is >30%. This risk level is present in:
  • People under 45, with 3+ strong additional risk factors
  • People 45-54, with 3 additional risk factors
  • People 55-64, with 2 additional risk factors
  • People 65+, with 1 additional risk factor
  • ACE inhibitors – treating people with diabetes with at least one additional cardiovascular risk factor with ACE inhibitors reduces the risk of cardiovascular complications by 25-35%. They also greatly reduce the risk of nephropathy.

So we can see that people with diabetes require a lot of basic treatments!

Microvascular complications

These are specific to diabetes – which is in contrast to macrovascular disease, which is prevalent in the west in general.
Small blood vessels throughout the body are in danger, however, there are 3 sites at particular risk; the retina, the kidney and the nerve sheaths.
These side effects will manifest about 10-20 years after initial diagnosis. They will present sooner in older patients, probably because these patients have gone longer before having their diabetes diagnosed.
Genetic factors seem also to be involved. Siblings of those with diabetic microvascular complications have 3-5x greater chance of developing the complications than those with diabetes but without sibling involvement.
Nephropathy is also more common in certain races, including Hispanic, and black.

Diabetic eye complications

Diabetes is the most common cause of blindness under the age of 65. Diabetes can effect the eyes in many ways, but diabetic retinopathy is the most common mechanism. Young patients with diabetes have a 1/3 chance of developing some form of this.
5% of diabetic patients can become blind as a result of retinopathy.

Other types of diabetic eye damage include:

  • Lens damage – this can be due to reversible osmotic changes in patients with acute hyperglycaemia. It may also be due to cataracts.
  • New vessel formation – this can occur in the iris is late stage diabetes. It can result in glaucoma
  • External ocular palsies – these commonly occur in the 6th cranial nerve and effects motor movements of the eye.

Pathology of retinopathy
Diabetes causes thickening of the basement membrane and increased permeability of retinal arteries. This can result in two types of damage – occlusion, or aneurysm formation. The increased permeability of cells results in the formation of exudates. Flourescin angiography is the best way of detecting these changes early (see below).

  • After 20 years of type I diabetes, almost all patients will have some type of retinopathy, and 60% will progress to sight threatening proliferative retinopathy. Without treatment, 50% of cases of proliferative retinopathy will become blind within 5 years.
  • After 20 years of type 2 diabetes, 58% of patients will have some form of retinopathy.

Non-proliferative / background retinopathy
The first abnormality visible through the ophthalmoscope is ‘dot haemorrhage’. These are not actually haemorrhages, but are in fact, small aneurysms. Fluid may leak from these into deeper parts of the retina causing blot haemorrhages. These are also responsible for the formation of hard exudates. These will usually be present in patients 10-20 years after diagnosis. They are rarely present in young patients. This type of damage does not itself impair vision, however it can progress to maculopathy or proliferative retinopathy.
Diabetic maculopathy This can lead to blindness, even in the absence of proliferation. It tends to affect older patients with type 2 diabetes.
Macular oedema is the first sign of this, and this in itself can cause permanent damage if not treated quickly enough.
The main symptom of this is decreasing visual acuity. You need to look at the retina (photography of ophthalmoscopy) to be able to diagnose this. This is why it is essential to regularly test the visual acuity of all diabetics.
The later stages of this disease will result in hard exudates being deposited on the macular area.

Pre-proliferative retinopathy
This is a stage inbetween background retinopathy and proliferative retinopathy. Many patients will not progress to this stage. The earliest sign of this is cotton wool spots. Sometimes people use the term ‘soft exudates’ to refer to cotton wool spots, but its use is gradually being discouraged. Hypertensive retinopathy may also cause cotton wool spots. Unlike the appearance of exudates, these have a matt finish, and the boarders tend to be less well defined. They are larger and more white in colour than hard exudates.
There may also be venous bleeding, and the appearance of venous loops on the retina.

Proliferative retinopathy
This involves the proliferation of new blood vessels. Hypoxia is though to be the signal for the proliferation of new blood vessels. These lie superficially, and will grow forwards into the vitreous. They resemble bundles of seaweed! They are very fragile and bleed eaily, as they lack supporting connective tissue. Haemorrhages can be either in the retina or sometimes even into the vitreous.

  • The haemorrhage will be notices as a possible loss of vision in one eye, or less severely, as a floating shadow effecting the field of vision. Generally, partial or even full recovery of vision will be seen as the blood is reabsorbed, but rebleeds tend to occur often.
  • Loss of vision can also occur from fibrous proliferation that is associated with the proliferation in blood vessels. This can form traction bands which will contract over the course of time, and can result in retinal detachment.
Fundoscopy image (photo of the retina) showing changes of diabetic retinopathy.
Fundoscopy image (photo of the retina) showing changes of diabetic retinopathy. Note: hard exudates (scattered yellowish dots), microaneurysms (bulges off some blood vessels), and small hemorrhages (blurry red dots)
Fundoscopy image showing scarring caused by laser surgery
Fundoscopy image showing scarring caused by laser surgery

Senile cataracts tend to develop 10-15 years earlier in diabetic patients than in the general population. As well as this, there are two further types of lens problem associated with diabetes:

  • Juvenile (‘snowflake’) cataracts – these are rare, but develop very quickly in ssome people with poorly controlled diabetes.
  • Cloudyness in the lens is a feature of the hyperosmolar state, but this will correct itself with time.

Treatment is most effective when given early – usually when the patient is symptomless. This means that you have to constantly monitor the patients for any signs of eye problems and initiate treatment immediately as soon as you recognize any. This involves regularly checking the retina (fundus). There are several ways of doing this.

Visual acuity should be tested, along with a good view of the retina. To obtain a good view of the retina, you need to dilate the pupil; and this can be achieved within 15-30minutes by the drug tropicamide.
You need to be careful because dilating drugs shouldn’t be used in patients with a history of glaucoma.
It is important to sketch or photograph any abnormalities you find in the notes for future reference.
Fluorescein angiography – a fluorescent dye is injected into a vein in the arm. You can then view and photograph this as it flows through the arteries in the patient’s retina.
Using a retinoscope – When examining the fundus you should look for:
Exudates – these are very common in diabetes and are also seen sometimes in hypertension. They are little white dots on the retina. They are caused by blood plasma leaking out of blood vessels. They coincide with areas of retinal damage – and thus are useful to show where the damage is occurring. They are most common in the perimacular area. If they are close to the macula they are far more dangerous. To measure how close to the macula they are, we say they are ‘within one disc diameter’ referring to the diameter of the optic disc as a reference for size. Another measurement would be ‘within the arcades’ – this means ‘within the two main arcing blood vessels’ that arc around the macula.
Exudates are actually collections of lipid that gloop together from the leaking blood plasma.  

Fatty deposits can sometimes look like exudates. They are generally a big bigger and more yellow than exudates. The main cause of these is diet. Food known to stave these off are blackberries and spinach.

There is no specific treatment for background retinopathy, but smoking and hypertension worsen the prognosis. All patients with retinopathy need to be examined regularly by a diabetologist or ophthalmologist.
In severe non-proliferative and proliferative retinopathy, photocoagulation is the treatment of choice. In this treatment, a laser is used to clot blood vessels. It is used in many different eye diseases. In diabetic retinopathy, this treatment will be used to:

  • Destroy areas of ischaemic tissue – as it is thought that these play a vital role in neovascularisation.
  • Seal microanearysms and thus reduce oedema

The procedure carries very little risk and can be done under local anaesthetic. It reduces visual loss by up to 90% – this is only 50% of patients with maculopathy.
Patients have to be regularly monitored to check for new growths, and may require repeat treatment. Extensive bilateral photocoagulation can reduce the visual field, and affect driving and night vision.

Diabetic nephropathy

The kidney can by damaged by three mechanisms in diabetes:

  • Glomerular damage
  • Ischemia caused by damage to efferent and afferent arterioles.
  • Ascending infection – remember that the immune system of diabetic patients if often compromised, thus resulting in a greater risk of UTI.

Kidney damage in diabetes is a very important cause of morbidity and mortality. It is also one of the most common causes of end-stage renal failure (ESRF) in developed countries.
As with a lot of things to do with diabetes, management is difficult, and thus prevention is very beneficial.
Nephropathy usually presents as a result of glomerular damage about 15-25 years after diagnosis.
It affects 25-35% of patients diagnosed before the age of 30
It is primarily a disease of younger diabetics, and the incidence is lower in older patients.
Incidence if type 1 diabetes has been falling, and it is thought this can be attributed to good diabetic control. However, it is expected that diabetic nephropathy will rise as more and more younger people become affected by type 2 diabetes.

There are several different effects that diabetes can exert on the kidney:

Renal hypertrophy
The first pathological abnormality will be renal hypertrophy. This is associated with a raised GFR. This often presents soon after diagnosis, and is a direct result of hyperglycaemia. The mechanism for this is as follows. The afferent arteriole will become more dilated than the efferent arteriole. This results in an increased intraglomerular filtration pressure, and this will further damage glomerular capillaries. The shearing forces that occur locally will also contribute to mesangial cell hypertrophy, and will cause mesangial cells to secrete more extracellular matrix. This eventually leads to glomerular sclerosis. There is thickening of the basement membrane, and disruptions in the linkages between cells – this ultimately means that larger molecules are allowed to be filtered that normally wouldn’t be so.

This is the first detectable marker of diabetic nephropathy. Initially, only microalbuminurea is present – this means amounts of albumin that are so small they cannot be detected by normal dipstick, and special tests have to be performed. It not only is a sign that the kidney is heading towards nephropathy, but also (in type 2 diabetes) of increased cardiovascular risk.
Somewhere down the line, the pateint may enter the territory of persistent proteinurea. At this stage, plasma creatinine may be normal, but the patient may only be 5-10 years from end stage renal failure.
Transient nephrotic syndrome may also exists – which will induce oedema, and lead to hypoalbuminurea.
Patients with nephropathy tend to have a normocytic normochromic anaemia, and may also be hypertensive – which itself can further damage the kidney.
ESR will be raised.

Screening for microalbuminurea is an important marker in the development of kidney damage. Note also that if kidney damage does not present within 20 years of diagnosis, then the risk of developing it is very low (<1% per year)

  • Type 1 diabetic patients annually from 5 years after diagnosis. In these patients, this test is pretty much diagnostic of microalbuminurea.
  • Type 2 diabetic patients annually from diagnosis. In these patients, microalbuminurea may be contributed to by many other factors.

The risk of progression can be reduced by:

  • Aggressively tacking cardiovascular risk factors (particularly hypertension)
  • Giving ACE-inhibitor therapy
  • Strictly controlling glucose.

Usually diabetic retinopathy is present with nephropathy. So if it is not, you may suspect another cause for the nephropathy.

Ischaemic lesions
These are similar to those that occur in hypertension and are a result of hypertrophy and hyalinization of blood vessels.

Infective lesions UTI’s are more common in women with diabetes, but not more common in men. Ascending infection can be a result of bladder stasis resulting from autonomic neuropathy. Infections can also become more easily established in damaged renal tissue. Autopsy shows that there is evidence of infective lesions in many diabetic patients – however these can often be difficult to determine from ischaemic lesions, and thus the true prevelance of pyelonephritis in diabetes is uncertain.

Aside from the preventative measures, there is not much you can do. You need to avoid any diabetes treatments that involve excretion by the kidney (such as glibenclamide), and also a reduction in insulin therapy is probably useful, as insulin sensitivity tends to increase.
There is often an associated rapid progression with retinopathy once we reach the stage of nephropathy.
Management of end-stage disease is difficult due to the presence of other complications, such as blindness, cardiovascular disease and neuropathy. Haemodialysis is not that useful as shunts tend to calcify very quickly.
Renal transplant is an often, but is not as successful as in non-diabetic patients. Often this may be carried out in conjunction with a pancreatic transplant, that in many cases will give the patient freedom from insulin therapy for a year or so.

Diabetic neuropathy

It is directly related to the duration and degree of abnormal metabolic control.
It tends to occur relatively early on in the progression of the disease, although many patients will be symptomless.
The mechanism of this is not entirely clear, however it is though to be due to metabolic disturbances. One of the most common theories is that Schwann cells are affected. It is thought that accumulation of fructose and sorbitol in schwann cells leads to their degradation.

The first sign in diabetic neuropathy is delayed nerve signal transit time. This is a direct result of demyelination, as a result of damage to schwann cells. At this stage, the axon itself is still intact, and thus the potential for repair is still present. At a later stage, the axons become damaged, and here irreversible damage has occurred. There are several type of neuropathy in diabetes:

  • Symmetrical, mainly sensory neuropathy in distal regions
  • Acute painful neuropathy
  • Mononeuropathy and mononeuritis multiplex. This can occur either to cranial nerves, or to individual peripheral nerves
  • Diabetic amyotrophy – this is progressive wasting of muscle tissues
  • Autonomic neuropathy

Symmetrical mainly sensory neuropathy
This is generally not recognised by the patient in the early stages. The first signs are loss of pain, temperature and vibration feelings. You lose the deep sensation before the superficial, and the first place this tends to happen is in the feet.
Later patients may begin to notice these sensations and often describe them as ‘walking on cotton wool’. They may lose their balance whilst washing the face, or walking in the dark due to reduced proprioception.

  • Involvement of the hands does occur but it is much less common. Sensation is lost in a ‘stocking and glove’ pattern. When the hands are involved, there may be wasting of the muscles of the hand. However this is rare, and should be distinguished from carpal tunnel syndrome, which is common in diabetes.
  • This is important due to complications – often patients will suffer from unrecognised trauma. The most common thing is that a patient will get a blister, and they won’t notice, and it will develop into a leg ulcer.
  • Sequelae (consequence) of neuropathy – motor neurones to the interosseous muscles of the foot can also be involved. This leads to wasting of these muscles, and this then alters how other muscles act on the foot. This gives rise to a classic foot shape of a high arch and clawing toes. This alters the weight distribution on the foot, and can lead to calluses and ulcer formation.

Acute painful neuropathy
This is less common than the symptoms described above. Patients will describe this as a very strong burning or crawling pain often felt in the shins and feet. It is often worse at night, and the pressure from bed clothes may be unbearable. It often develops after sudden improvement in glycaemic control (i.e. the patient starts insulin). it often disappears, but will return within 3-12 months, even in the case of good control.
Late on in the disease a chronic form may develop which is virtually resistant to all therapies.
Muscle wasting is not usually present, and objective signs can be hard to find.
Sometimes, all patients need is reassurance and a good explanation of what is going on.
Gabapentin, carbamezipine and tricyclic antidepressants can reduce the pain, but often not as much as the patient would like.
TENS and acupuncture have been known to be beneficial.

Mononeuritis and mononeuritis multiplex
This can affect any nerve in the body at any stage of diabetes. The onset is often sudden and painful. The most common involvement is with the 3rd and 6th cranial nerves, thus resulting in reduced ocular movement. Most instances will have a full spontaneous recovery. Lesions are more common at sites that have external compression. Carpal tunnel syndrome is also more common in diabetes, and does not respond as well to decompression as carpel tunnel syndrome in the general population.

Diabetic amyotrophy
This tends to be seen in older men with diabetes. Presentation tends to be with painful wasting of the quadriceps muscles. The wasting can be very marked, and the knee reflexes are often absent. Amyotrophic events in diabetes are often associated with poor glycaemic control, and this condition may be present at diagnosis. The events tend to rectify themselves if a strict control regimen is adhered to.
Autonomic neuropathy
Asymptomatic neuropathy can be demonstrated in many diabetic patients, but it is rare to find it presenting with symptoms. It affects both the sympathetic and parasympathetic nervous systems, and can be disabling.

  • Cardiovascular problems – vagal neuropathy can result in a tachycardia and loss of sinus arrhythmia. Postural hypotension may also occur. A warm foot with a bounding pulse is sometimes seen in polyneuropathy as a result of peripheral vasodilation.
  • Silent MI– The patient has a heart attack, but doesn’t feel it. They just get a bit breathless. The heart attack is caused by the increased risk of macrovascular complications, but the important part is that you don’t feel the heart attack due to autonomic neuropathy of the vagus nerves.
  • Gastrointestinal problems – vagal damage can also lead to gastroparesis. In many cases this is asymptomatic but in some cases it may cause intractable vomiting. Autonomic diarrhoea may also occur at night, and is accompanied by urgency and incontinence. Diarrhoea steatorrhea can also occur as a result of overgrowth of bacteria. This is treated with antibiotics.
  • Bladder problems – autonomic damage of the nerves to the bladder can result in incomplete stasis and emptying. Not only does this predispose to infection, but also can lead to painless distended bladder.
  • Erectile dysfunction – this is very common – the first manifestation is incomplete erection, which often progresses to total failure. There can be many causes, including; anxiety, depression, alcohol, drugs, primary or seconday gonadal failure, hypothyroidism, inadequate vascular supply. You should try to pick out a cause during history taking and examination.

You should take blood tests for LH, FSH, testosterone, prolactin and thyroid function.
Phosphodiesterare type-5 inhibitors will increase the effect of nitrous oxide on smooth muscle, and thus can increase penile blood flow, and can be given to patients who aren’t taking nitrates e.g. for angina.
If this therapy works, it is worth discontinuing it after a few months, as after this time, confidence returns, and patients may no longer require treatment.
Side effects include headaches, and a green tinge to vision the next day.
60% of diabetic patients will benefit from this therapy.
There are also several other treatments available, but these tend to have lower efficacy and worse side effects.

Diabetic Foot (peripheral neuropathy)

Educate patients about the principles of foot care. Older or high risk patients should visit a chiropodist / podiatrist regularly and may be advised not cut their own toe nails.

Foot pain is a major cause of morbidly amongst patients with peripheral neuropathy. Agents known to be effective against neuropathic pain include:

  • Amitriptyline – a tricyclic antidepressant. Should be used first line
  • Pregabalin (Lyrica®) – may be considered in cases resistant to amitriptyline
  • Gabapentin

Once tissue damage has occurred, then the main aim is preservation of viable tissue.
There are four main threats to viable tissue:

  1. Infection – this takes hold very quickly, and you need early antibiotic treatment. Treatment should be modified in the light of culture results. The organisms grown from the skin may not be the organisms causing deeper skin infection. Excisions of bone may be needed if the infection spreads this far. Regular x-rays of the foot are needed to check the progress of this.
  2. Ischaemia – the blood flow to the foot should be assessed with Doppler ultrasound. Femoral angiography is sometimes used to locate areas of occlusion, and in very rare cases, the leg may need amputation. Sometimes surgery to treat occlusion may be necessary, however, the risks of this are high, and so this is not often performed.
  3. Abnormal pressure – you need to keep pressure off an ulcerated area. You may need to rest the affected leg, and wear special shoes / insoles. Even after healing these special shoes and insoles are still recommended to prevent repeated damage to the affected area. In some cases a chiropodist should be involved, and this helps prevent calluses that can distort normal foot architecture, and can itself lead to wound damage.
  4. Wound management- you need to keep the wound moist, remove exudates and protect from external factors. Also keeping pressure around the affected area can help reduce the risk of oedema. Many new types of dressing contain growth factors and other molecules designed to aid healing, however, these are often expensive, and their role in treatment is yet unclear.

Foot problems are the major cause of admission for diabetic patients. When arterial occlusion is present, it is often quicker and kinder to amputate the affected area than subject the patient to a successive sequence of conservative procedures.

An example of a severe diabetic foot.
An example of a severe diabetic foot. Note the missing toe – likely amputated due to gangrene, and the poorly healing ulcers on the base

There is actually no evidence that diabetic patients with good glycaemic control are subject to more infections that the general population.
However – there is evidence that patients with poor glycaemic control are at greater risk. The mechanism for this is not fully understood however, it is thought that high glucose concentrations impairs the production of superoxides by leucocytes, and thus chemotaxis and phagocytosis are reduced.

  • In an exaggerating effect, infections can also lead to a loss of glycaemic control, and are a very common cause of ketoacidosis.
  • Insulin patients should increase insulin dose by 25% during infection, and non-insulin treated patients may need insulin during their period of illness.
  • Diabetic patients should have the flu vaccine, and pneumococcal vaccine.

Skin and joints
The skin of diabetic patients may be thickened, particularly on the back of the fingers. This condition is not progressive.
Also, diabetes in childhood can affect the joints. You can notice this if you ask the patient to put their hands together as if in prayer. The patient will not be able to oppose the interphalangeal joints or metacarpophalangeal joints.

Diabetes and Driving

It is necessary for all patients requiring tablet or insulin therapy to inform the DVLA. There is a risk of hypoglycaemia at the wheel – which could result in an RTA. However, they will not be prevented from driving. In many countries, the driver will have to go for assessment every few years to check they are fit to drive, and commercial driving is usually not allowed.
Blurred vision may also be an issue, but is not as dangerous


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Dr Tom Leach

Dr Tom Leach MBChB DCH EMCert(ACEM) FRACGP currently works as a GP and an Emergency Department CMO in Australia. He is also a Clinical Associate Lecturer at the Australian National University, and is studying for a Masters of Sports Medicine at the University of Queensland. After graduating from his medical degree at the University of Manchester in 2011, Tom completed his Foundation Training at Bolton Royal Hospital, before moving to Australia in 2013. He started almostadoctor whilst a third year medical student in 2009. Read full bio

This Post Has 2 Comments

  1. Rosie

    I think HbA1c is glycated Haemaglobin not glycosylated haemoglobin?


  2. Dr Tom Leach

    Hi Rosie, you are right. I’ve edited the article to clear this up.

    It seems that several medical textbooks don’t make this distinction very clear. But there are numerous discussions and articles online, such as this one, which explain the difference.

    It seems that both processes involve the reaction of glucose with a protein, but that glycosylation is a deliberate physiological process controlled by enzymatic actions, whereas glycation is a non-enzymatic reaction, and in this context (in diabetes) is physiologically unhelpful.

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