Dramatic rise in childhood diabetes

A disease which lasts for life

(Below these notes is a full discussion of the nature of diabetes for interested readers.)

Incidence of Diabetes in Children and Adolescents During the COVID-19 Pandemic

A Systematic Review and Meta-Analysis

This is the video on the dramatic rise in the incidence of type I diabetes.

30^th June 2023, Toronto based study

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2806712?utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_term=063023

Key Points from the study

Analysis of 42 studies

N = 102,984 youths (<19 years)

Incidence of type 1 diabetes was higher during the COVID-19 pandemic compared with before the pandemic.

The findings suggest the need to elucidate possible underlying mechanisms to explain temporal changes

Synthesize estimates of changes in incidence rates

Minimum observation period of 12 months during and 12 months before the pandemic

(Also looked at incidence of DKA in new-onset diabetes during the pandemic.)

Results, Type 1 diabetes incidence rates

N = 38,149 youths

First year of the pandemic, incidence rate ratio = 1.14

During months 13 to 24, incidence rate ratio = 1.27

(Expected 3% to 4% annual increase trends in Europe)

Results, Type 2 diabetes incidence rates

Ten studies reported incident in both periods.

Eight studies, an increase incident of type 2 diabetes

Results, DKA incidence rates

Fifteen studies

Incidence rate ratio = 1.26

Conclusions

Future studies are needed to assess whether this trend persists,

and may help elucidate possible underlying mechanisms to explain temporal changes.

More from the study

Some studies reported an association between SARS-CoV-2 infection and new-onset diabetes.

However, (challenges in SARS-CoV-2 diagnosis), concerns about the validity of these studies.

Data sets used in other studies did not capture asymptomatic SARS-CoV-2

There is no clear mechanism by which COVID-19 could directly or indirectly lead to new-onset type 1 or 2 diabetes.

Purported direct mechanisms

SARS-CoV-2 entry receptor ACE2 is expressed on insulin-producing β cells

There is no clear underlying mechanism explaining the association between SARS-CoV-2 infection and subsequent increased risk of diabetes.

Population-based studies suggest…. that the increase in incidence may be due to an immune-mediated mechanism.

Proposed indirect effects of the COVID-19 pandemic and containment measures that may be associated with diabetes

(contrary to what would be expected based on the decrease in viral infections among children)

‘Catch-up’ could only influence the first year of the pandemic

Detailed notes on diabetes

Pathophysiology

The key feature of diabetes mellitus is a raised blood glucose level. There is a chronic hyperglycaemia which may be caused by a lack of insulin. Alternatively there may be a reduced ability of body cells to use the insulin which is present in the blood; this is called insulin resistance.

Types of diabetes mellitus (DM)

Two forms of diabetes mellitus are currently recognised, simply referred to as types 1 and 2.

Type 1

Type 1 DM is associated with complete destruction of the beta cells and an absolute insulin deficiency. Type 1 diabetics are always insulin dependent; it is an IDDM (insulin dependent diabetes mellitus).

Type 2

In established cases of type 2 DM there is a reduced level of beta cell function. However, the disease process starts with the insulin receptors; these do not work properly or are reduced in numbers. This means that even though insulin is produced, the receptors are unable to make use of it. This situation is described as insulin resistance. These patients can often be managed without using insulin i.e. type 2 diabetes may be a NIDDM (non insulin dependent diabetes mellitus). However type 2 diabetes may progress to become insulin dependent, and so may become an IDDM. Type 2 disease is the most common form of diabetes mellitus.

Type 1 diabetes mellitus

Aetiology

Type 1 DM is a progressive autoimmune disorder mediated through T lymphocytes (i.e. a type IV hypersensitivity reaction). Pancreatic biopsy, shortly after diagnosis, typically shows the presence of lymphocytes, natural killer (NK) cells and activated macrophages with inflammatory oedema in the pancreatic islets. These features illustrate how the body’s own immune system is mistakenly activated against it’s own beta cells. The efficiency of the immune system means that the total beta cell mass is progressively but completely destroyed. This pathological autoimmune process is probably initially triggered by a viral infection acting on predisposing factors. Additional evidence for the autoimmune nature of type 1 DM comes from autoantibodies which have been detected in the blood of 90% of newly diagnosed patients. Studies have recently demonstrated the presence of autoantibodies in children during the first few years of life; these children go on to develop DM type 1 several years later. Further support for the autoimmune explanation of the pathogenesis comes from observations that beta cell survival is prolonged if patients are given immunosuppressant drugs.

The incidence of type 1 DM is increasing in Europe by as much as 3-4% per year. Much of the increase is in very young children. Currently, approximately 10% of diabetics have type 1 DM. There is also a genetic predisposition to type 1 DM which increases susceptibility to the disorder. Siblings of a type 1 diabetic child have approximately a 16% chance of developing the disease. Predisposition also increases with a diabetic parent; if a father is type 1 diabetic the chances of a child developing DM by the age of 20 years is about 9%, while a type 1 diabetic mother is associated with a risk of 3%. Monozygotic twins who are genetically identical have a concordance rate of 30-50%.

Environmental factors also interact with the genetic susceptibility to the immune dysfunction seen in type 1 DM. The hygiene hypothesis suggests that because children are kept in very clean environments their immune systems fail to learn the difference between foreign antigens (such as bacteria or viruses) and the body’s own tissue. However, children exposed to soil bacteria experience a healthy immune challenge which improves the future performance of the immune system making type 1 DM less likely to develop. If babies are exposed to cow’s milk, some of the bovine serum albumin (cow protein) may be directly absorbed into the baby’s blood leading to increased susceptibility. This is because the gut is partly permeable to non-digested proteins in the first year of life. Once in the blood these bovine (i.e. cow) proteins can trigger the production of antibodies which may go on to attack the beta cells. Circumstantial evidence also suggests young children should not be fed cured and smoked meats or coffee. Subclinical deficiency of vitamin D (i.e. a deficiency which is not severe enough to cause rickets) also seems to significantly increase the risk of a child developing type 1 DM. An understanding of these environmental risk factors clearly indicates areas for health education and promotion.

Because type 1 DM is an autoimmune disease, patients with the condition are at increased risk of developing other autoimmune pathologies. This explains the increased incidence of coeliac disease, pernicious anaemia, adrenal or thyroid insufficiency, and vitiligo. Vitiligo describes white areas of the skin where the melanocytes are lost, presumably as a result of autoimmune destruction.

Pathophysiology

In type 1 DM the insulin receptors are completely normal; the pathology is restricted to the beta cells. Loss of these cells means insulin is not produced. Destruction of the beta cells takes place over a period of time, probably years. When 70-90% of the beta cells have been eradicated there will no longer be sufficient insulin producing capacity to prevent hyperglycaemia and the other presenting clinical features of type 1 DM. Initially there will be impaired glucose tolerance and then overt symptomatic diabetes mellitus.

Presentation in type 1 diabetes mellitus

Classic triad

Type 1 DM typically has a juvenile onset, often around the time of puberty, although it may start at any time of life. The classic triad of presenting features are polyuria (producing large volumes of urine), thirst and weight loss. In an acute presentation there is normally a clinical history of about 2-6 weeks. On examination there will be glucosuria and elevated serum glucose.

Polyuria and glucosuria

Polyuria occurs as a result of an osmotic diuresis. This is a diuresis that occurs for osmotic reasons. Diuresis means an abnormally large volume of urine is produced. When the level of glucose in the blood increases there is an equivalent increase in the concentration of glucose in glomerular filtrate. The quantity of glucose the renal tubules are able to reabsorb is limited. In health, when blood glucose levels are normal, all of the glucose in the filtrate is reabsorbed; this means physiologically there is no glucose at all in urine. However, when glucose glomerular filtrate levels are abnormally high it cannot all be reabsorbed. This will result in glucose passing straight through the tubule into the urine.

When glucose is found in urine, the renal threshold for glucose has been exceeded. For most people the renal threshold is 11 mmol L (millimoles of glucose per litre of blood). This means that plasma concentrations greater than 11 mmol L will result in the appearance of glucose in the urine; below these levels it will not. In fact about 1% of the population may have glucosuria with normal serum levels of glucose; these individuals have a genetically low renal threshold for glucose. You can always check for this by comparing blood glucose levels with urine levels.

When abnormally large amounts of glucose are present in glomerular filtrate the osmotic potential of this fluid is increased. This happens because glucose is an osmotic molecule; it attracts water through a semi-permeable membrane. Glucose present in filtrate therefore osmotically attracts water, increasing the volume of the glomerular filtrate. As any filtrate which is not reabsorbed from the nephrons becomes urine, the urine volumes increase. The result of these processes is an osmotic diuresis of sweet urine.

Thirst

Thirst can be excessive in an acute presentation, leading to excessive drinking (sometimes called polydipsia). This is simply explained by systemic dehydration caused by the osmotic diuresis and subsequent polyuria. Despite excessive drinking, some patients presenting with type 1 DM are hypovolaemic, with consequent tachycardia and hypotension.

Weight loss

Weight loss may partly be as a result of dehydration. However, insulin promotes protein synthesis, therefore if it is absent, less protein will be built up into muscle. Insulin also prevents protein breakdown, so if insulin is absent more protein will be broken down. This will reduce the amount of protein present in the body and so reduce weight. Also, as glucose is not transported across cell membranes, cells are obliged to use fatty aids as a fuel rather than glucose; this will progressively deplete fat reserves, again resulting in weight loss. Stored fatty acids are also converted to ketone bodies which can also be used by mitochondria to produce energy.

Ketosis

Ketosis refers to abnormally high levels of ketone bodies in the blood. ‘Ketone bodies’ is a collective term used to describe acetone and 2 organic keto type acidic compounds which are produced as a result of excessive fat metabolism. As the body cells are unable to utilise glucose, stored fatty acids are converted into ketone bodies, which are used as a fuel by the mitochondria, in place of the glucose they would prefer. (Ketosis is normal in starvation, when the body is obliged to use stored fats as an energy source.)

In addition to occurring in previously undiagnosed patients, ketosis may occur if insulin therapy is interrupted. This is another good reason why insulin therapy should never be stopped in type 1 DM. If no insulin is available, most tissues will switch to fat metabolism as they are unable to metabolise carbohydrates. It is this fat metabolism by the mitochondria, mostly in the liver, which generates the ketone bodies. Increased levels of acetone are formed in ketosis and accumulate in the blood. Acetone is a volatile substance and some of it is blown off in the expired air from the lungs. This causes the breath to smell of acetone; a smell usually described as being like ‘pear drops’. Like most smells, once you have experienced it the first time you will immediately recognise it again.

If diabetes is not treated for a period of time the ketosis will worsen. As two of the ketone bodies produced by excessive fat metabolism are acids, the acidity of the patient’s blood will progressively increase as the pH falls. This gives rise to the condition called ketoacidosis. In order to try and compensate for the acidosis the respiratory centre initiates hyperventilation. This will have the effect of somewhat lowering blood acidity by reducing levels of carbonic acid as a result of exhaling more carbon dioxide. This effect gives rise to the classical feature of ‘air hunger’ (Kussmaul respirations). This is an example of an attempted compensatory mechanism; in this case an attempted respiratory compensation for a metabolic acidosis.

Diagnosis

The World Health Organisation has suggested that diabetes is diagnosed when fasting plasma glucose is greater than 7.0 mmol L or when random levels exceed 11.1 mmol L. (These relatively low diagnostic levels illustrate how finely homeostatically controlled blood glucose levels are in normal physiology). In a patient without symptoms the test should be repeated to confirm the diagnosis. To diagnose gestational diabetes or borderline cases a glucose tolerance test may be used. This involves testing for fasting levels of plasma glucose then giving 75g of glucose in 300 mls of water and retesting after 2 hours. In normal patients the levels will have dropped to less than 7.8 mmol L, whereas in diabetes they will remain at 11.1 mmol L or more. Another method of diagnosis is to simply take blood and examine how much glucose has been absorbed into the haemoglobin in the red blood cells. The higher the average levels of blood glucose the more will absorb into the haemoglobin. This is called glycosylated haemoglobin and is tested for with the HbA1C test. A value of greater that 6.5% indicates probable diabetes mellitus.

It is important to realise there is no such thing as ‘mild’ diabetes mellitus. Any individual who has blood glucose levels at or above these diagnostic criteria is at risk of developing long term complications.

Type 2 diabetes mellitus

Aetiology

This disorder typically develops in middle life and so is sometimes referred to as maturity onset diabetes. It is caused by the interaction of environmental (life style) and genetic factors. Environmentally, the incidence of the disorder increases with the degree of obesity (in the UK 80% of type 2 diabetics are obese), with abdominal fat being a significant risk factor. The risk of developing type 2 disease increases 10 fold with a body mass index (BMI) of 30 or over. Overeating increases risk. Increasing age and lack of exercise are also risk factors. Consumption of sugary foods increases risk by increasing the demand for insulin secretion. This increases the amount of insulin in the blood which then contributes to the overuse of the insulin receptors. Fatty foods are also a risk. This is because fats are metabolized by the body cells, meaning they require less glucose, which is then left to accumulate in the blood.

Lack of physical exercise is a risk factor. If a person is physically active their muscles will use up sugar in the blood, lowering levels. As blood sugar levels are lowered so is the demand for insulin. These points are important to understand as people at risk of developing type 2 DM can change their lifestyle to eat less, lose weight and exercise more. People who do a lot of physical work and have limited access to calorie rich food develop significantly less type 2 DM than those who live a typical affluent western lifestyle. In some genetically predisposed individuals this may prevent the development of the condition. Even if the disease is not prevented, taking plenty of exercise and keeping slim will delay the onset of the disease, probably by many years.

Like type 1 DM there is a genetic component in the aetiology. Type 2 DM is much more common in people of African, Arab and South Asian extraction who live a western lifestyle than it is in equivalent white people. Further evidence for a genetic component in type 2 aetiology is a very high (often approaching 100%) concordance rate between identical monozygotic twins. Even between siblings the chances of a person developing type 2, if a brother or sister is affected, is 15-20%. While no single gene is responsible for causing type 2 DM, it seems that three principle genes each increase the risk of developing the disease by about 20% each. However, several other genes may also play a smaller role in causing type 2 disease making the aetiology polygenic (caused by many genes).

Babies who have low birth weight and children with a low weight at one year of age also seem more likely to develop type 2 DM in later life, this is sometimes called the ‘bad start hypothesis’. Risk for such people is increased if they later become overweight. This illustrates the importance of giving mothers good nutrition during pregnancy and feeding young children well.

Pathophysiology

In type 1 disease the pathophysiology begins with the beta cells. Conversely, in type 2 DM the pathophysiology begins with the insulin receptors located on the cell surfaces, mostly on liver and skeletal muscle cells. As the insulin receptors

are over-used over many years they begin to fail. It is useful to think of the insulin receptors as ‘wearing out’. In addition to the insulin receptors, it may be that the intracellular secondary messenger systems, which are normally activated by the insulin-receptor complex, do not work properly, partly for genetic reasons. This abnormality contributes to insulin resistance, in other words a given dose of insulin has less effect than it would if the receptors and cells were healthy. This means a particular dose of insulin will have a reduced hypoglycaemic effect.

In the early stages of developing type 2 DM blood glucose levels will start to rise slightly. However, in this early stage, the beta cells detect the increase in blood glucose levels and are able to increase insulin production to compensate. This means more use is made of any healthy insulin receptors which remain. For a period of time this relative hyperinsulinaemia will maintain essentially normal blood glucose levels, i.e. a euglycaemia will be maintained. However, over time this obligatory high insulin output wears out the beta cells resulting in a progressive decline in beta cell function and mass. Once the disease process has been developing over several years the total number of beta cells might be reduced by 30%. These factors mean that the levels of insulin in the blood progressively drop. This results in a combination of reduced insulin secretion and reduced insulin sensitivity. This reduction in blood insulin levels, in combination with the increased insulin resistance caused by defective insulin receptor function, means that blood glucose levels will progressively rise. Firstly there will be impaired glucose tolerance, followed by overt diabetes mellitus.

Presentation

The presenting features in type 2 DM are similar to those in type 1, but the onset may be over months or even years. However, as some insulin is still produced, some glucose is still transported into the cells for the mitochondria to use. This means that fats are not metabolized in the absence of carbohydrates so production of ketones is uncommon. This explains why ketoacidosis is unlikely in type 2 disease, but will occur in the absolute insulin deficiency found in untreated type 1 DM. Even the reduced amounts of insulin in type 2 DM are usually enough to suppress the metabolism of fats and proteins by the mitochondria, explaining why weight loss is uncommon in early type 2 DM. As the condition progresses and insulin production falls there may be increased metabolism of fats and proteins resulting in weight loss. Also over time the kidneys increase the amount of glucose they are able to reabsorb meaning that dehydration and thirst are less pronounced than in a type 1 presentation. Often the main feature which patients complain of is fatigue.

One of the problems with type 2 DM is that the patient may develop the disease and not be aware of any symptoms. Frequently, the condition is detected by the presence of glucose in urine (glycosuria) or elevated serum glucose, often while the patient is being investigated for some other complaint. This is one reason why urinalysis should be part of any routine health check. Despite an undiagnosed patient having no symptoms the chronic hyperglycaemia can be damaging several body tissues and organs, contributing to the development of the long term complications of diabetes. Part of this is that any insulin lack will lead to accelerated development of atheroma.

Metabolic syndrome

Type 2 DM is often associated with a group of other medical conditions. There may be dyslipidaemia with low levels of protective HDL and increased levels of LDL cholesterol and triglycerides. Hypertension and central obesity are also frequently present. This cluster of conditions is sometimes called metabolic or insulin resistance syndrome. These features all contribute to the formation of atheroma, leading to atherosclerosis of the large arteries. Each of the features of metabolic syndrome should be treated. Weight loss by diet and exercise is vital. Statins are needed to lower LDL cholesterol and hypotensive medications such as ACE inhibitors are needed to lower blood pressure.

Maturity onset diabetes of the young (MODY)

This condition sounds like a contradiction in terms but actually describes an uncommon variant of type 2 diabetes mellitus which presents in young people. The aetiology of this disorder is an autosomal dominant gene which gives a genetic predisposition. This is then acted on by poor life style factors such as over eating, obesity and lack of exercise.

Long term complications

Improvements in short term treatments of diabetes mean that patients should no longer die from hyperglycaemia or ketoacidotic coma. However, over time long term complications of diabetes may develop in type 1 and type 2 DM. The likelihood that long term complications occur largely depends on the degree of glycaemic control that can be achieved. In addition, it is important to control other risk factors such as obesity, dyslipidaemia and hypertension. With good control and life style the development of long term complications can be delayed or even prevented.

Macrovascular disease

Macrovascular disease affects the large arteries. It has been suggested that atheroma formation in diabetes is triggered by glucose levels in the blood being raised over a period of time. This allows glucose to migrate into the inner lining of arterial walls. Harmful low density lipoproteins seem to adhere to tissues which contain higher than normal levels of glucose, resulting in fatty accumulations in the vessel lumens. This process is then developed by higher levels of fatty material in the blood caused by the insulin lack mechanism already discussed.

The presence of fatty deposits in turn leads to the deposition of fibrous collagen and the development of atheromatous plaques.

Whatever the precise reasons, diabetics often develop more advanced atheroma than other people of the same age and sex. The development of atherosclerosis is accelerated in diabetes. Atherosclerosis affects the coronary arteries leading to angina and myocardial infarction. Coronary heart disease is the leading cause of morbidity and mortality in people with DM, accounting for up to 70% of deaths. Atheroma in the vessels supplying the brain leads to cerebral ischaemia and possible cerebrovascular accident. In the peripheral vessels atheroma will result in peripheral vascular disease. This leads to ischaemia and possible gangrene (areas of necrosis) in more advanced cases, explaining why lower limb amputations are significantly more common in diabetics compared to non-diabetics. Renal arterial involvement contributes to chronic nephron ischaemia.

Smoking will potentiate the development of macrovascular atheroma so it is particularly important that diabetics do not smoke. Serum cholesterol should be kept at low levels using statins as required. Blood pressure should also be closely monitored and lowered as necessary.

Microvascular complications

Smaller blood vessels such as arterioles and capillaries are also affected in diabetes mellitus. In these small vessels there is a progressive thickening and increase in rigidity of the basement membranes; this results in a narrowed lumen and loss of elasticity. These complications in turn lead to localised tissue ischaemia and hypoxia. When this ischaemia is compounded by macrovascular ischaemia the viability of tissues can be seriously compromised. Microvascular disease leads to complications affecting the kidneys, eyes and peripheral nerves. It is known that good glycaemic control, with a HbA1C of 7% or less significantly reduces the development of the microvascular complications.

Renal failure (diabetic nephropathy)

In the glomeruli of the kidneys there is microvascular basement membrane thickening and hardening (glomerulosclerosis). Despite the basement membrane of the glomerular capillaries being thicker, it is of reduced quality and becomes progressively more permeable to proteins. This leads to proteins passing from the blood into the glomerular filtrate. (In health protein molecules are much too large to be filtered into the glomerular filtrate). Initially this results in very small amounts of albumin passing into the glomerular filtrate and the development of microalbuminuria. This term describes the loss of very small volumes of albumin in urine not detectable by ward based ‘dip stick’ testing. However, even loss of such small amounts of protein is a predictor of subsequent more serious renal involvement. As the basement membrane thickening progresses there is loss of increasing volumes of albumin in the urine which may reach the nephrotic range. (In nephrotic syndrome substantial amounts of

protein are lost in the urine resulting in a lowered osmotic potential of the blood plasma which can lead to oedema formation.) As the glomerulosclerosis develops the glomeruli are progressively lost leading to decreased renal function and eventual end stage renal failure (ESRF). In most western countries diabetic nephropathy is the most common cause of ESRF.

This pathology affecting the capillaries of the glomerulus can be complicated by hardening of the afferent and efferent arterioles. Other factors such as ischaemia caused by macrovascular atheroma and repeated urinary tract infections may also contribute to development of chronic irreversible renal failure. Hypertension is another risk factor for the development of diabetic nephropathy. Vigorous efforts should be made to prevent progression of nephropathy in patients presenting with microalbuminuria. Glycaemic control should be very good and there should be aggressive reduction in blood pressure, probably using ACE inhibitors.

Blindness

Microvascular disease of the retina occurs as a result of basement membrane thickening. Retinal arterioles narrow and may become completely occluded. These changes lead to hypoxia in ischaemic areas of the retina. Chronic retinal hypoxia results in the release of growth factors including a factor which stimulates the rapid generation of new blood vessels. More blood vessels could carry more blood to the area and so counter the hypoxia. However there is a problem. In the retina the excessive growth of new small blood vessels is called proliferate retinopathy. These new vessels have fragile walls which can rupture and bleed; this will cause retinal haemorrhages which cause progressive damage to the light sensitive cells. Regular retinal examination and possible photocoagulation can cauterise new vessels before they have time to haemorrhage, this can prevent or delay the development of blindness. Poor glycaemic control, with hyperglycaemia is a definite risk factor for diabetic retinopathy. From this it is clear that good levels of glycaemic control reduce the probability of this complication developing. Hypertension is another risk factor for diabetic retinopathy which should therefore be managed. Diabetics are also more prone to cataracts (opacity of the lens) and glaucoma (increased pressure within the eyeball).

Neuropathy

Part of the cause of diabetic peripheral neuropathy is damage to the Schwann cells which form the myelin sheath around peripheral nerves. Schwann cell damage probably occurs for metabolic reasons and can lead to areas of demyelination. As part of the function of Schwann cells is to protect and nourish the nerve fibres there will be progressive fibre degeneration. In peripheral nerves the microvascular changes already described are likely to be an additional factor in the development of peripheral neuropathy. Ischaemia of peripheral nerves will lead to hypoxic damage as neurones are very sensitive to oxygen lack. Evidence for this comes from the fact that unmyelinated nerve fibres are affected as well as the myelinated fibres. Initially there will be shrinkage of axons followed by fragmentation. Neuropathy can lead to sensory and motor deficiency in the legs and often presents with tingling and numbness. Sensory neuropathy is the most common presentation resulting is reduced sensation and pain awareness from the feet. This can result in the patient being unaware of developing injuries to the feet. Bladder problems and impotence may also be caused by peripheral nerve defects.

Congestive cardiac failure

Poor glycaemic control is likely to be a risk factor for the development of congestive heart failure. Heart failure may be directly caused by glycosylation of heart muscle proteins. Glycosylation describes the addition of sugar molecules to proteins and lipids. Macro and microvascular disease will also contribute to congestive cardiac failure.

Predisposition to infections

Bacterial and fungal infections are more likely to occur in diabetics with high levels of blood glucose. These are likely to affect the skin, mucous membranes and urinary tract. For example, they are prone to develop staphylococcal skin lesions such as boils. Cellulitis is also a risk. Mucous membrane infections, affecting the mouth or genitals may be caused by the fungal infection Candida.

Increased problems with infections may simply be caused by higher levels of glucose in the tissue fluids which provide potential infecting bacteria and fungi with a ready supply of nutrition. In addition migration of phagocytes is inhibited by high levels of glucose in tissue fluids. This reduces the efficiency of this important part of the immune process. It also seems that microvascular basement membrane thickening decreases blood and oxygen supplies to areas of injury and infection, reducing the efficiency of the immune response. Increased rigidity of microvascular basement membranes also inhibits a normal inflammatory vasodilatory response. As the inflammatory response is necessary to combat infection and start the healing process, both of these are inhibited.

It is therefore important to monitor diabetics for the early signs and symptoms of infection so these can receive prompt treatment; this will prevent infections becoming more severe. Early infection is often more difficult to detect in diabetics as the normal inflammatory response to the presence of microorganisms is inhibited as just described. Internal infections may also occur; a urinary tract infection may develop into a potentially serious pyelonephritis (infection of the kidney tissue). Pneumonia is also a risk in poorly controlled patients.

Foot and leg problems

Macro and microvascular disease can lead to distal ischaemia eventually resulting in gangrene. As sensory neuropathy can lead to foot desensitisation, patients may not be aware of pressure effects from shoes, this can result in callous

formation. Further pressure on hard areas of callous can lead to necrotic damage of underlying tissue. This occurs largely as a result of pressure from overlying callous impeding the blood supply, essentially leading to a pressure ulcer. These ulcers which develop under callous are prone to infection which may migrate down into the bone. This is why diabetic feet should be regularly inspected and areas of callous removed. Care must be taken when removing callous not to damage healthy underlying tissue as such injuries are prone to infection. If an ulcer does form under an area of callous there should be sharp debridement and the ulcer encouraged to heal by secondary intention.

Diagram

Review of the possible long-term complications of poorly controlled diabetes mellitus.