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Diabetes mellitus refers to a metabolic condition characterised by raised blood glucose levels or hyperglycaemia. The term diabetes literally refers to ‘excess urine’, a common symptom of poor glucose control. Mellitus is derived from the old word for honey as originally medical practitioners made a diagnosis of the condition based upon sweet tasting urine. This distinguished the condition from the excessive urine produced by a patient with a rare condition affecting the anti-diuretic hormone (diabetes insipidus), which is tasteless.

Though better knowledge of the condition has improved the prognosis for diabetes, the long-term effects of poor glucose control result in the disruption of perfusion through the vascular system and leads to coronary artery disease, peripheral vascular disease and problems in highly vascular tissues such as the retina and the kidney. The condition is usually irreversible and so, even with good control, late complications lead to a considerably higher risk reduced life expectancy.

Diagnosed diabetes mellitus accounts for around 4 per cent of the UK population and this figure has worryingly doubled over the past decade with most projections suggesting a further increased incidence. There is a new diagnosis at least every five minutes and this results in over 5 per cent of the NHS budget going to the treatment and management of diabetes and its consequences. Each year in the UK, around 20,000 people die as a result of diabetes, and there are nearly 10,000 amputations and 2,500 lose vision due to the disease.

The disease process

Diabetes mellitus (henceforth described merely as diabetes) is essentially a problem with the hormone insulin and it either no longer being able to function effectively or normally, or not being produced.

Insulin

Insulin is a hormone synthesised in small clusters of beta cells in the Islets of Langerhans within the pancreas.

Initially the hormone is produced as proinsulin and stored in the cell membrane of the beta cells. During secretion, an inert peptide chain (peptide C) breaks off leaving active insulin, and both enter the circulation in equal amounts. Insulin enters the portal circulation and passes to the liver, its main organ target. About half of the hormone is broken down by the liver while the remainder is dealt with by the kidneys. C-peptide is only partially extracted by the liver and dealt with mainly by the kidney. This does make it a useful indicator of insulin secretion.

Insulin binds to receptors found on cell membranes throughout the body. The receptors consist of alpha and beta subunits. The insulin binds to the extracellular alpha unit while the beta subunit crosses the plasma membrane to allow the intracellular portion to initiate some of the activities the hormone triggers (see Figure 1 for a schematic representation). The combination of insulin and receptor promotes glucose uptake by the cell which is the essential source of energy for metabolic activity.

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The DNA sequence for the receptor has been established and found to occur on the short arm of chromosome 19 which improves the chance of genetic therapy for diabetes in the future.

Normal glucose metabolism

Despite the variable nature of glucose consumption in the diet and the variation in energy demand by the challenges of life, the healthy human body is able to maintain a surprisingly constant level of blood glucose which rarely strays outside 3.5-8.0mmol per litre. This homeostasis is achieved primarily by the liver which absorbs and stores glucose (in the form of glycogen) and releases it in between meals into the circulation to match as closely as possible the various demands of the peripheral tissues.

Around 200g of glucose is produced and used each day. Around 90 per cent of this is from the liver (three quarters of which is from stored glycogen and a quarter from glucose production within the liver) and the remaining 10 per cent is produced in the kidney.1

The major consumer of glucose is the brain and, because this is a non-negotiable use essential for life, this is a process that does not rely on insulin. Other tissues, however, such as muscle and fat, rely on variable glucose consumption. After meals, insulin facilitates the movement into these tissues of glucose.

In muscle tissue the glucose is mainly converted to glycogen as a store for energy production where it may then convert to lactic acid which may then re-enter the circulation where some is retaken up by the liver and reconverted back to glucose. Excess lactic acid build-up causes cramp. Glucose is used by fat as an energy source and to synthesise triglycerides. Breakdown products include glycerol which again may be used by the liver in gluconeogenesis.

Insulin is the major regulator of intermediary metabolism and is itself regulated by the action of other hormones. When insulin levels are low, glucose production is maximal and usage low. As levels rise to intermediate levels, glucose production is suppressed while usage is still kept low. It is this suppression that allows the use of low dose insulin in cases of ketoacidosis (see later). Hormones having an antagonistic effect to insulin include glucagon and adrenaline. They promote glucose production from the liver, inhibit use of glucose by muscles and fat tissue, and instead promote lipolysis and ketogenesis.

In summary, insulin promotes use of glucose by muscle and fatty tissues, glucagon and adrenaline (among other hormones) oppose this. It should now be clear that if there is an inadequate supply of insulin or the insulin that is present is unable to act at the receptors adequately, the result will be erratic supply of glucose to the tissues and poor regulation or homeostasis of blood glucose levels.

Classification of diabetes

Diabetes may be primary or secondary. Possible causes of secondary diabetes include:

  • Liver disease – cirrhosis

  • Pancreatic disease – cystic fibrosis, alcohol induced chronic pancreatitis, carcinoma of the pancreas

  • Hormonal diseases – thyrotoxicosis, acromegaly, Cushing’s syndrome

  • Drug responses – steroid therapy

  • Receptor diseases

  • Genetic anomalies – Friedrich’s ataxia.

These should not be confused with risk factors, such as obesity and pregnancy, known to predispose to primary diabetes (as discussed later). Whether primary or secondary, diabetes is usually classified into two types:

  • Type 1 – this is often still referred to as insulin dependent diabetes mellitus (IDDM) and describes the condition where there is a near complete loss of pancreatic insulin secretion. This results in hyperglycaemia and ketoacidosis and is symptomatic until controlled. Approaching 10 per cent of diabetics in the UK are described as having this type of diabetes.2 This rarely presents undiagnosed to an optometrist as ocular complications rarely precede systemic events.

  • Type 2 – often referred to as non-insulin dependent diabetes mellitus (NIDDM) even though therapy may involve the use of insulin. Most patients retain some degree of endogenous pancreatic production but this is not adequate to cope with the resistance to insulin activity these patients suffer from and hence they exhibit poor control of blood glucose levels. The more insidious nature of this disease means that it may go undetected for some time. Furthermore, the reduced risk of significant systemic symptoms means that in some cases ocular consequences may be detected by an optometrist prior to diagnosis by a general medical clinician.

This two disease classification is somewhat controversial and increasing numbers of clinicians now think of diabetes as a spectrum with absolute absence of insulin production at one end and resistance to insulin activity (though it is still being produced) at the other. Patients may present at any point along this spectrum and, indeed, pass along the spectrum depending on management and extraneous influences.

Most authorities, based upon the changing profile of the disease over the last decades, now specify a number of further classifications as follows:

  • Prediabetes. This term, as you might expect, is used to describe those people in whom glucose levels are elevated but as yet have not reached any of the benchmarks making diabetes diagnosis possible. Diabetes UK has recently suggested the condition to be found in a third of the adult UK population. Prediabetes increases the risk of developing type 2 diabetes. Because glucose levels are higher than normal it is possible to be diagnosed as prediabetic and be given advice regarding diet and exercise and so significantly reduce the chance of going on to develop type 2 diabetes. The condition is sometimes known by other names including borderline diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), impaired glucose regulation (IGR), and non-diabetic hyperglycaemia (NDH). The crystalline lens degrades throughout life and, as it does so, produces breakdown products that autofluoresce. As this process happens at a greater rate in prediabetics, clinical tests exist which may improve the early detection of prediabetes using a simple non-contact ocular screening method (a review of this technique will appear in Optician in two weeks’ time)

  • MODY (maturity onset diabetes in the young). This affects around 2 per cent of people with diabetes and often goes undiagnosed. It results from a mutation resulting in beta cell destruction and seems to have an autosomal dominant inheritance pattern (so family history is important). There is therefore a 50 per cent chance of MODY appearing in offspring. Also, it may be diagnosed by a genetic test. It can lead to some of the familiar diabetic complications so MODY patients need to be vigilant with their glucose control.

  • Gestational diabetes. Some women develop diabetes during pregnancy. It may be that the extra glucose demands from the foetus highlight an already present diabetes (in which case it usually appears during the first trimester), but in many it appears during the final three months as a result of insufficient response by the mother to extra foetal glucose demand. It usually goes away after birth but, again, glucose control must be monitored. In a few cases, the extra glucose production by the mother results in increased insulin production by the foetus leading to increased fat deposition in the neonate resulting in increased birthweight (macrosomia) and a post-natal hypoglycaemia (Figure 2).

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Aetiology

Type 1 diabetes

Type 1 disease is thought to be primarily immune in nature resulting from an autoimmune attack upon the beta cells of the pancreas. Indeed, antibodies to these cells are frequently detectable around the time of diagnosis. Heredity plays a part with a child more likely to develop the disease if of type 1 parents (interestingly the risk appears greater, one in 20-40, if the father is type 1 rather than if the mother is type 1, one in 40-80). The genetic component is multiple and there is only around 30 per cent concordance between identical twins. The majority (95 per cent) of type 1 patients carry similar human leukocyte antigen (HLA) profiles, again suggesting a strong genetic component to the disorder. Though theories abound about the disease expression, many believe that there is a trigger, possibly viral, that results in the genetic expression of the disease. This is given weight by testing for positive viral presence at diagnosis. Also, there appears to be more presentations during the spring and autumn than the summer when viral prevalence tends to be greater.

Type 2 diabetes

Type 2 disease appears to have a stronger concordance, with twins showing near 100 per cent concordance.  Unlike type 1, there is no evidence of any immunological involvement and frustratingly no single gene has been found to be involved. The expression of the condition is triggered by a number of identified risk factors including:

  • Age

  • Obesity

  • Family history

  • Hypertension

  • Previous gestational diabetes (see earlier)

  • Low birthweight infants are predisposed to later type 2 development.

Figure 3 shows a suggested sequence for type 2 diabetes and may be the course for prediabetes to lead to diagnosable type 2 disease. Increased insulin resistance and a subsequent hyperinsulinaemia leads to raised glucose levels after a meal (hyperglycaemia and impaired glucose tolerance). As time progresses, hyperglycaemia may be found irrespective of mealtimes (fasting hyperglycaemia) and hence glucose levels that may be diagnosable as type 2 diabetes.

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Table 1 summarises the differences between the two diseases when diagnosing from blood.

Table-1

Symptoms

As already emphasised, the symptoms of type 1 are much more apparent while type 2 diabetes is far more insidious in progression and may go unreported for some time. The classic symptoms of diabetes in general are lethargy, thirst, excessive urination and weight loss. They may be subdivided further as follows:

  • Acute presentation

– Polyuria – high blood glucose levels result in osmotic influence promoting urination

– Polydipsia – resulting fluid loss leads to excess thirst

– Weight loss – fluid depletion and fat and muscle breakdown

– Ketoacidosis – shortage of insulin (typically in type 1 disease) results in the body metabolising fatty tissues releasing ketone bodies into the blood stream which may lead to nausea, vomiting and even coma and death. This is the reason for the sweetness of urine and also, in some, a ketotic or sweetness of the breath. In around one third of children presenting for the first time with type 1 disease ketoacidosis is detectable and one of its consequences may sometimes be the first presenting feature if none of the other symptoms mentioned are reported.

Note how coma may result from three different situations – ketoacidosis (as mentioned above), hypoglycaemia due to insulin or missed meals, and severe hyperglycaemia usually in old people.

Table-2

  • Subacute presentation

– Acute symptoms, though less marked

– Itchiness of genitals, typically due to Candida (thrush)

– Blurred vision and refractive changes. Increased glucose in the aqueous results in loss of water from the crystalline lens resulting in hypertonicity of the lens due to sorbitol leading to water uptake and so on. This variation in lens volume leads to myopic, hyperopic and astigmatic shifts often in the space of hours and days. This variation is likely to be the main contribution to the increased prevalence of mixed cataract in diabetics at an earlier age. True diabetic cataract may present (rarely) at this stage as a reversible ‘snowflake’ like opacity.

  • Complications

– Recurrent or persistent skin infections, typically Staphylococcal

– Retinopathy (see later article in this series)

– Neuropathy. Ischaemia of nerves results in tingling and numbness, most typically in the feet. If left untreated, this may lead to ulceration and in a few cases infection, possible gangrene and subsequent tissue loss. Concurrent microvascular disease in these cases is an indication for amputations to prevent infection spread. In a few cases, neuropathy may affect joints (so-called Charcot’s joints) which cause discomfort and sometimes deformity and an impact on movement

– Nephropathy. Around one third of type 1 and 5 to 10 per cent of type 2 diabetics may develop kidney disease typically after 10-15 years. It is detected by the presence of protein in the urine (usually using urine testing strips). It is accelerated by hypertension and, if left untreated, can eventually lead to kidney failure. Early detection and treatment with ACE-inhibitors may stall this progression

– Other microvascular events. In theory, vessel shutdown or leakage, as occurs in retinopathy, may result in occlusion damaging function of many structures, It is this that may cause transient nerve palsies, such as of the VI, IV or III nerves (in the latter this often affects the lid and motility but the mydriasis is absent). Interruption in flow to the optic nerve head may lead to a diabetic papillopathy and subsequent sight loss.

Table 3 summarises non-retinal findings.

Table-3

Normal values and testing

As stated, glucose levels should lie somewhere between 3.5 and 8.0mmol/l depending on food intake, fasting and exercise. Diagnosis and monitoring of diabetes is generally based on glucose measurements, either in the blood or bound to haemoglobin. As again already mentioned, other tests such as the presence of protein in the urine or ketones aid diagnosis. Presence of glucose in the urine (glycosuria) is not diagnostic but indicates monitoring is a good idea.

Diagnosis is relatively simple. Because the body is normally very efficient at maintaining constant glucose levels then any measurable fluctuation out of the expected is suspicious.

  • In symptomatic patients any single reliable elevated glucose measurement is adequate for diagnosis

  • In mildly or asymptomatic patients diagnosis is made on fasting venous blood levels above 6.7mmols/l  (7.8mmol/l plasma levels) and random venous whole blood levels of over 10mmol/l (11.1mmol/l venous plasma levels)1

Oral glucose tolerance test (OGTT)

A glucose tolerance test is unnecessary when the above criteria are met but is useful in borderline cases. This is a blood glucose measurement carried out after three days of unrestricted diet and usual activity and then 8-14 hours overnight fasting (water is allowed but no smoking). Possible influences must be noted (such as any infections or the influence of medications). The sample is taken after this fast when 75g glucose in 250-300ml water are taken and an immediate reading found. If the patient is asymptomatic, any suspiciously raised reading must be repeatable before the diagnosis confirmed.

HbA1c

Glucose in the blood attaches to the terminal valine of the b-chain of the haemoglobin molecule and measurement of this glycosylated haemoglobin (HbA1c) provides a mechanism of assessing blood sugar control. The HbA1c test (haemoglobin A1c test, glycosylated haemoglobin A1c test, glycohaemoglobin A1c test, or A1c test) is a laboratory test which reveals average blood glucose over a period of 2-3 months. It determines the average blood sugar level over last 2-3 months expressed as a percentage (3.8 to 6.4 per cent is usually considered normal). The HbA1c represents a useful ‘big picture’ to complement day to day tests. It is useful to inquire of this value from a patient during a consultation as it may reflect control over time irrespective of local variations of control.

Treatment options

All diabetics need diet therapy. When insulin and medication is required, they are unlikely to be successful unless diet is also controlled. Unless there is a requirement for medical intervention, as in the case of ketoacidosis, diet alone is the best first approach to managing diabetes in older patients (over 40). The diet for a diabetic should be no different from a healthy diet but needs to be tailored to the patients presenting weight, bearing in mind that obesity is an issue with type 2 disease particularly.

When diet fails, thin patients are usually treated with a sulphonylurea drug while obese patients are given a biguanide (such as metformin). Initial poor response to the drug is termed ‘primary failure’ while many patients may initially respond well with a drug but less well later (secondary failure). Insulin, which is required anyway in ketoacidosis presentations, may be the next approach.

Insulin is now pure and antibody formation is rare and inconsequential. The main issue is one of patient compliance and good education about injection technique and sterility and dosage is essential. The thigh or abdomen is usually the chosen sight for injection and vectors vary from the traditional hypodermic to controlled dose electronic infusion appliances. Obesity may confer some degree of insulin resistance so combination of treatment with diet and careful glucose monitoring is always recommended.  This is usually by glucose testing, urine testing and HbA1c as already described.

Read more

A practitioner’s perspective: Diabetic retinopathy screening

Diabetes part 2 – Screening

Diabetes part 3 – The English Grading Scheme

Diabetic retinopathy VRICS

Diabetic retinopathy VRICS – part 2

Model answers

Which of the following represents a normal blood glucose level (in mmol/l)

C 10

Which of the following has the greatest glucose requirement?

A Brain

Which of the following statements about type I diabetes is false?

D It has a higher twin concordance than type II diabetes

Which of the following is NOT a known risk factor for type II diabetes?

C High birthweight

Why does poor glucose control cause transient visual blur?

B Sorbitol concentration in the lens induces osmotis changing the shape of the lens

Which of the following statements about HbA1c is false?

A It is based on urine analysis

References

1 Kumar PJ, Clark ML. Clinical Medicine. Bailliere Tindall, 1999.

2 Pinkney J. Diabetes Mellitus – a clinical overview. In Diabetes CPD. Association of Optometrists and City University, 1997.