Diabetic retinopathy

Diabetic retinal disease is the commonest cause of visual impairment in patients with type 1 diabetes. Diabetic retinopathy is more than likely to occur in patients who have poorly controlled diabetes and its prevalence increases with the duration of diabetes. Fifty per cent of patients with type 1 diabetes will have some form of retinopathy after 10 years. Approximately 5–10% of patients with type 2 diabetes will present with retinopathy (with a small number having sight-threatening retinopathy).

The following risk factors have been shown to determine the development and progression of diabetic retinal disease:

Clinically significant macular oedema and hard exudate formation but not proliferative retinopathy or retinopathy progression appears to be associated with total, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol levels.

Patients with multiple risk factors should be considered at particularly high risk of developing diabetic retinal disease.

Direct ophthalmoscopy

The direct ophthalmoscope is the instrument of choice for fundus examination by medical students and physicians. It allows for a magnified, monocular image of the retina and optic disc.

Non-mydriatic camera

A non-mydriatic camera does not usually require the patient’s eyes to be dilated; however, a much greater success rate can be achieved if tropicamide or similar mydriatic eye drops are used. Non-mydriatic cameras operate by using an infrared-sensitive video camera image to position and focus the image of the retina. As no visible light is used, the patient’s pupil will not constrict, and a photograph can then be taken using the built-in flash. The flash duration is so short that the exposure is made before the pupil can react.

The Scottish Diabetic Retinal Screening programme uses the Topcon TRC-NW6, which incorporates one central and eight fixed peripheral internal fixation points. Using each of these fixation points will cover 85° of the retina. The central fixation point allows a repeatable photograph of the posterior pole.

Grading and quality assurance

Retinal photographs should be graded using digital images by an appropriately trained grader to facilitate quality assurance.

Automated grading can operate as the initial screener to exclude a majority of images with ‘no retinopathy’ before manual grading. The specificity of automated grading is lower than for manual grading, for equivalent sensitivity. Automated grading may be used for distinguishing no retinopathy from any retinopathy in a screening programme providing validated software is used. It has a similar sensitivity for detecting referable retinopathy, but may be less sensitive at detecting diabetic maculopathy (Table 5.3).

Table 5.3 Systematic screening for diabetic retinal disease

Either one-field 45–50° retinal photography or multiple-field photography can be used for screening purposes.

Glycaemic control

Tight glycaemic control reduces the risk of onset and progression of diabetic eye disease in type 1 and 2 diabetes. The Diabetes Control and Complications Study (DCCT) demonstrated that intensive glycaemic control reduces the risk of onset of diabetic retinopathy, progression of pre-existing retinopathy, and the need for laser for patients with type 1 diabetes. The UK Prospective Diabetes Study (UKPDS) demonstrated similar reduction in the risk of onset and progression in diabetic retinopathy in patients with type 2 diabetes.

Control of blood pressure

The UKPDS demonstrated that the risk of progression of diabetic retinopathy was decreased with tight control of BP (with either captopril or atenolol) and led to an almost 35% relative reduction in the need for retinal photocoagulation. Data from the UKPDS suggests that BP lowering rather than use of a specific agent may be responsible for the benefits. The EURODIAB Controlled Trial of Lisinopril in Insulin-dependent Diabetes (EUCLID) study (using lisinopril) and the Diabetic Retinopathy Candesartan Trials (DIRECT) demonstrated delay in the progression of retinopathy using drugs that act on the renin–angiotensin–aldosterone axis.

Management of dyslipidaemia

The Early Treatment Diabetic Retinal Screening (ETDRS) and DCCT revealed that raised serum cholesterol concentration was related to the development and progression of diabetic maculopathy. Recent studies suggest that aggressive lipid lowering is beneficial in prevention of progression of maculopathy.

Multifactorial risk reduction

The Steno-2 trial and other studies have shown the benefit of multiple interventions, which included behavioural therapy (dietary intervention, exercise and smoking cessation) and pharmacological intervention (reduction of BP, improvement in glycaemic control and lipid modification).

Reducing glycated haemoglobin (HbA1c) by 1.5% (16.4 mmol/mol) and, if possible, to 7% (53 mmol/mol) in type 1 and 2 diabetes plus reducing BP to 144/82 mmHg significantly reduces the incidence and progression of sight-threatening diabetic eye disease. There is no evidence to suggest that lowering BP to a level below 130/75 mmHg has a deleterious impact on retinopathy progression. Therefore, reducing BP and HbA1c below these targets is likely to reduce the risk of eye disease further. Microvascular endpoints (including retinopathy) are decreased:

Rapid improvement of glycaemic control can result in short-term worsening of diabetic retinal disease, although the long-term outcomes remain beneficial. This is often seen in the rapid improvement of glycaemic control in the first trimester of pregnancy. However, pregnancy is in itself is considered an independent risk factor for the progression of diabetic retinopathy.

Laser photocoagulation, if required, should be completed before any rapid improvements in glycaemic control are achieved.

Classification of neuropathy

A generally accepted classification of peripheral diabetic neuropathies divides them broadly into symmetrical and asymmetrical neuropathies. Development of symptoms depends on total hyperglycaemic exposure plus other risk factors such as raised lipid levels, BP, smoking, and high exposure to other potentially neurotoxic agents such as ethanol. Establishing the diagnosis requires careful evaluation, as patients with diabetes may present with a neuropathy from another cause.

Physical signs

The clinical signs and symptoms are usually in keeping with where the neuropathy fits into the classification described above.

Distal symmetrical sensorimotor polyneuropathy due to diabetes must occur in the presence of diabetes as outlined by the American Diabetes Association or World Health Organization. The severity of polyneuropathy should be commensurate with the duration and severity of the diabetes, and other causes of sensorimotor polyneuropathy should be excluded. Longer nerve fibres are affected to a greater degree than shorter ones, because nerve conduction velocity is slowed in proportion to a nerve’s length.

The first clinical signs that usually develop is decrease or loss of vibratory and pinprick sensation over the toes. As disease progresses, the level of decreased sensation may move upward into the legs and then into the hands and arms, a pattern often referred to as ‘stocking and glove’ sensory loss. A glove–stocking distribution of numbness, sensory loss, dysaesthesia and night-time pain may develop. The pain can feel like burning, pricking sensation, achy or dull. Pins and needles sensation is common. Loss of proprioception, the sense of where a limb is in space, is affected early. These patients cannot feel when they are stepping on a foreign body, such as a splinter, or when they are developing a callous from an ill-fitting shoe. Consequently, they are at risk for developing ulcers and infections on the feet and legs.

Very severely affected patients may lose sensation in a shield distribution on the chest. Deep tendon reflexes are commonly hypoactive or absent, and weakness of small foot muscles may develop. More focal findings may be seen with injury to specific nerves as described above. Loss of motor function results in dorsiflexion, contractures of the toes and loss of the interosseous muscle function, and leads to contraction of the digits, so-called ‘hammer toes’. These contractures occur not only in the foot but also in the hand, where the loss of the musculature makes the hand appear gaunt and skeletal.

Treatment

Despite advances in the understanding of the metabolic causes of neuropathy, treatments aimed at interrupting these pathological processes have been limited. Thus, with the exception of tight glucose control, treatments are for reducing pain and other symptoms.

Options for pain control include tricyclic antidepressants (TCAs), serotonin reuptake inhibitors (SSRIs) and antiepileptic drugs (AEDs). It is suggested that TCAs and traditional anticonvulsants are better for short-term pain relief than newer-generation anticonvulsants. A combination of medication may be superior to a single agent.

The only two drugs approved by the US Food and Drug Administration (FDA) for diabetic peripheral neuropathy are the antidepressant duloxetine and the anticonvulsant pregabalin (Fig. 5.1). Before trying a systemic medication, people with localized diabetic periperal neuropathy occasionally get relief from their symptoms with lidocaine patches.

Figure 5.1 Treatment algorithm for management of painful diabetic peripheral neuropathy. TCA, tricyclic antidepressant.

(Source: Wong et al (2007). Reproduced with permission.)

In addition to pharmacological treatment there are several other modalities that help some patients. These have been shown to reduce pain and improve quality of life, particularly for patients with chronic neuropathic pain: interferential stimulation, acupuncture, meditation, cognitive therapy, and prescribed exercise.

Prognosis

The mechanisms of diabetic neuropathy remain poorly understood. However, the process is generally progressive.

At present, treatment alleviates pain and can control some associated symptoms. As a complication, there is an increased risk of injury to the feet because of loss of sensation. Minor infections can progress to ulceration, and this may lead to amputation.

Diabetic autonomic neuropathy

Autonomic dysfunction accounts for the most troublesome symptoms due to diabetic neuropathy. It can present with symptoms that affect cardiovascular, urogenital, gastrointestinal, pupillomotor regulatory and sudomotor functions. Simple non-invasive and sometimes bedside tests can help to diagnose autonomic dysfunction. In select cases highly specialized testing is required.

Evaluation/screening of patients of the diabetic foot

Patients with diabetic foot problems need to be assessed thoroughly in order to plan an appropriate management strategy. The medical history should include questions on previous ulcer/amputation, peripheral neuropathic symptoms, visual acuity, renal replacement therapy and smoking. General inspection should take place in a well-lit room and should include dermatological and musculoskeletal assessment. The patient’s footwear should also be assessed, particularly for size and excessive wear. Sometimes just getting the patients to take their socks off can impress on them the importance of their feet in the context of diabetes.

Previous ulceration is particularly important, as recurrence is very common. Elderly, socially isolated patients who perhaps cannot inspect or even physically reach their feet are also at high risk. Oedema, from congestive cardiac failure, nephropathy, immobility or calcium antagonists, renders feet vulnerable.

The nature of the local pathology (both wound and the associated limb), assessment of the severity of infection, and presence of systemic illness each affect the ultimate outcome in an individual case. Earlier classification systems such as the Wagner dysvascular foot classification included all infections within a single category. More recently, the consensus classification developed by the International Working Group on the Diabetic Foot (Table 5.7) uses grades of severity as a tool in classifying the foot infections. Successful management of diabetic foot infections involves recognition that infection is by no means one entity. Rather, this patient-centred approach lays great emphasis on making distinctions based on response to infection, and not infection itself. For example, systemic illness categorizes patients in grade 4 severity although the local wound may be only moderately inflamed. This classification also removes ambiguity with regards to terms such as ‘complicated’ wound.

Table 5.7 Clinical classification of diabetic foot infection

^* PEDIS is an acronym for perfusion, extent, depth, infection, sensation.

Although very difficult to include in any classification, malodour can reflect poor hygiene and/or severe infection including anaerobic infection.

Preventive management

Management of active foot disease

Charcot neuroarthropathy of the foot

Charcot neuroarthropathy of the foot is a neuroarthropathic process with osteoporosis, fracture, acute inflammation and disorganization of foot architecture.

During the acute phase, Charcot neuroarthropathy of the foot can be difficult to distinguish from infection. The clinical diagnosis of acute Charcot neuroarthropathy is based on the appearance of a red, swollen, oedematous and possibly painful foot in the absence of infection. The foot skin temperature is often 2–8 °C higher than that of the contralateral foot.

Acute Charcot neuroarthropathy is associated with increased bone blood flow, osteopenia, and fracture or dislocation. The disease process can progress with increased bone formation, osteosclerosis, spontaneous arthrodesis and ankylosis.

Diagnosis of Charcot neuroarthropathy of the foot should be made by clinical examination. Magnetic resonance imaging (MRI) cannot reliably distinguish early changes of Charcot neuroarthropathy from osteomyelitis. However, it may provide information that cannot be identified by X-ray (especially the presence of marrow oedema).

Suspected Charcot neuroarthropathy of the foot is an emergency and the patient should be referred immediately to the multidisciplinary foot team. Treatment of patients with contact casting is associated with a reduction in skin temperature, in bone activity and fewer diabetic foot deformities. Intravenous bisphosphonate therapy may reduce skin temperature and bone turnover in active Charcot neuroarthropathy.

Prevention of recurrence

Education of the patient and the relevant carers, provision of special footwear, home help and careful follow-up in the foot clinic helps to prevent recurrence. For patients with severe deformities, assessment by an orthotist is essential. Ready-to-wear boots may be helpful in the short term but are unaesthetic. Shoes made to order may be required to accommodate insoles. Devices are available that identify high-pressure sites, thereby aiding insole design.

Rehabilitation

Major amputation is usually a devastating event. The prospects for successful rehabilitation are often remote. Using a below-knee prosthesis, walking energy expenditure is increased by 50%, an impossible target in elderly or debilitated patients. The risk of ulceration in the contralateral foot may be increased owing to altered weight-bearing, and confinement to a wheelchair may be the unfortunate consequence.

Definitions

Diabetic kidney disease is usually classified on the basis of the extent of urine protein excretion – microalbuminuria or nephropathy.

Microalbuminuria is defined by a rise in urinary albumin loss to between 30 and 300/mg day. Timed urine collections may be inaccurate and therefore a urinary albumin/creatinine ratio (ACR) > 2.5 mg/mmol in men and > 3.5 mg/mmol in women is often used to define microalbuminuria. This is the earliest sign of diabetic kidney disease and predicts end-stage renal failure, cardiovascular morbidity and mortality, and increased total mortality.

Diabetic nephropathy is defined by a raised urinary albumin excretion of > 300 mg/day (indicating clinical proteinuria) in a patient with or without a raised serum creatinine level. Providing other causes have been excluded, an ACR > 30 mg/mmol in a spot urine sample is consistent with a diagnosis of diabetic nephropathy. This represents a more severe and established form of renal disease and is more predictive of total mortality, cardiovascular mortality and morbidity, and end-stage renal failure than microalbuminuria.

The presence of retinopathy has often been taken as a prerequisite for making a diagnosis of diabetic nephropathy, but diabetic nephropathy can occur in the absence of retinopathy. Very occasionally, patients can have persistent albuminuria and no retinopathy with glomerulonephritis or normal glomerular structure.

Glomerular filtration rate (GFR) is defined as the volume of plasma that is filtered by the glomeruli per unit of time, and is usually measured by estimating the rate of clearance of a substance from the plasma. GFR varies with body size and conventionally is corrected to a body surface area (BSA) of 1.73 m², the average BSA of a population of young men and women studied in the mid-1920s.

In most individuals the diagnosis of diabetic kidney disease is made clinically, as biopsy may not alter management. Classical diabetic kidney disease is characterized by specific glomerular pathology. It is important to note that there are other reasons why an individual with diabetes may develop proteinuria and/or a declining GFR, notably hypertensive nephropathy and renovascular disease. In many individuals, kidney disease will be due to a combination of one or more of these factors.

With the advent of reporting of estimated GFR (eGFR), increasing numbers of people are being identified with a sustained low GFR. Chronic kidney disease (CKD) in the absence of proteinuria would not previously be classified as having diabetic kidney disease (Table 5.8).

Table 5.8 Stratification of chronic kidney disease

If proteinuria (24-h urine > 1 g per day or urine protein/creatinine ratio (PCR) > 100 mg/mmol) is present, the suffix P may be added. Patients on dialysis are classified as stage 5D. The suffix T indicates patients with a functioning renal transplant (can be stages 1–5).

GFR, glomerular filtration rate.

^* Kidney damage defined as abnormalities on pathologic, urine, blood, or imaging tests.

Prevalence and progression of kidney disease in diabetes

Estimates of prevalence from individual studies must be interpreted in the context of their patient population, such as levels of deprivation and the proportion of individuals from ethnic minorities.

The racial differences in CKD are not accounted for simply by the increased risk and prevalence of diabetes in minority ethnic populations. The higher incidence of stage 4 and 5 CKD in minority ethnic populations may, in part, reflect reduced access to health care and genetic differences between populations.

The number of patients with diabetes requiring renal replacement therapy (RRT) is increasing.

Microalbuminuria and proteinuria

In people with type 1 diabetes, the cumulative incidence of microalbuminuria at 30 years’ disease duration is approximately 40%. For microalbuminuric patients, the relative risk of developing proteinuria is 9.3 compared with that in normoalbuminuric patients. Some 25% of individuals who were in the conventional arm of the Diabetes Control and Complications Trial (DCCT) had proteinuria, raised serum creatinine levels (> 177 μmol/L) and/or were on RRT after 30 years of diabetes. Data from type 2 patients is available from the UKPDS and is presented in Table 5.9.

Remission of microalbuminuria may occur, and so the presence of microalbuminuria does not necessarily imply an inexorable progression to nephropathy. There are data to suggest that there has been a decrease in the incidence of diabetic nephropathy in people with type 1 diabetes diagnosed more recently, with earlier aggressive BP and glycaemic control.

In the general population, particularly in people with diabetes, an eGFR < 60 mL per min per 1.73 m² is associated with an increased risk of the major adverse outcomes of CKD (impaired kidney function, progression to kidney failure and premature death from cardiovascular disease).

Microalbuminuria is associated with an approximately 2-fold increase in cardiovascular morbidity and mortality. The 4-year mortality rate for patients with type 2 microalbuminuria is 32%, and 50% for those with type 2 proteinuria. When proteinuria and hypertension are present, the standardized mortality ratio is increased 5-fold in men and 8-fold in women with type 2 diabetes, and 11-fold in men and 18-fold in women with type 1 diabetes.

Screening for kidney disease in diabetes

Management of diabetic nephropathy

Management of established diabetic kidney disease

Physicians need to exclude non-diabetic causes of renal disease before assuming that the cause of renal dysfunction in a diabetic individual is indeed due to diabetes. Absence of retinopathy, rapid decline in renal function, presence of systemic disorders known to cause renal dysfunction, presence of asymmetrical kidneys, presence of active sediments and short duration of type 1 diabetes all point to possible renal disorder other than that due to diabetes, and must be investigated and managed appropriately.

Cardiovascular risk modification

Aggressive cardiovascular risk modification is warranted in patients with renal dysfunction (Fig. 5.2). This includes smoking cessation, BP control, lipid modification, antiplatelet use, weight reduction and regular exercise schedule.

Figure 5.2 Increasing risk of cardiovascular disease (CVD) with the development of nephropathy in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM).

(Source: Holt et al (2010). © Wiley-Blackwell.)

Epidemiology

Morbidity and mortality from cardiovascular disease (CVD) are 2–5 times higher in patients with diabetes than in non-diabetic subjects. Women with diabetes have been shown to have a higher relative risk of death from CVD than men, although the absolute risk is lower. This excess in mortality occurs even in areas with high background death rates from CVD, and is evident in all age groups, most pronounced in young people with type 1 diabetes, and exacerbated by socioeconomic deprivation. The life expectancy of both men and women diagnosed as having type 2 diabetes at age 40 years is reduced by 8 years relative to people without diabetes. There is an increased prevalence of CVD in South Asian individuals with diabetes.

Cardiovascular risk factors

Lifestyle modification

Lifestyle modification is recommended to reduce cardiovascular risk factors. However, no studies identifying obesity as an independent risk factor in established diabetes are available.

Pharmacological therapy

Antihypertensive therapy

BP lowering in people with diabetes reduces the risk of macrovascular and microvascular disease. Hypertension should be treated aggressively with lifestyle modification and drug therapy.

The lowering of BP to 80 mmHg diastolic is of benefit in people with diabetes. In the Hypertension Optimal Treatment (HOT) study, the lowest incidence of major cardiovascular events in all patients occurred at a mean achieved diastolic BP of 82.6 mmHg, and further reduction below this BP was safe in patients with diabetes. There was a 51% reduction in major cardiovascular events in the BP target group ≤ 80 mmHg compared with the target group ≤ 90 mmHg (P  =  0.005).

Tip box

Target diastolic blood pressure in people with diabetes is < 80 mmHg.

In the HOT study, although diastolic BP was measured accurately, systolic BP was consistently underestimated. The reported achieved systolic BP of 139.7 mmHg in patients with a diastolic target of ≤ 80 mmHg is likely to have been closer to 146 mmHg. In the UKPDS, the achieved systolic BP of 144 mmHg in patients located to ‘tight control’ was observed when aiming for a systolic BP of < 150 mmHg. The long-term follow-up of these patients emphasized the need for maintenance of good BP control. In an epidemiological analysis, lowest risk was observed in those with a systolic BP < 120 mmHg.

Tip box

Target systolic blood pressure in people with diabetes is < 130 mmHg.

When starting antihypertensive treatment, calcium channel blockers, diuretics and ACE inhibitors are equally effective. There was no significant difference in outcome among the three treatment groups in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). A subgroup analysis of ALLHAT found an increase in heart failure in patients treated with an alpha-blocker as first line versus a diuretic, although this may simply reflect an increase in the prevalence of ankle swelling (relative risk of heart failure in patients with diabetes, 1.85).

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) found that amlodipine (a calcium channel blocker) based treatment (with an ACE inhibitor as add-on treatment) reduced the incidence of total cardiovascular events and procedures compared with an atenolol (beta-blocker) regimen (with a thiazide diuretic as add-on treatment). This study demonstrated increased cardiovascular mortality in patients treated with beta-blockers in comparison with those treated with renin–angiotensin blocking agents.

There is also evidence from two studies for the use of combination of ACE inhibitor and diuretic. In one study, ACE inhibitor and diuretic reduced BP (5.6/2.2 mmHg) and the relative risk for deaths, cardiovascular deaths and major vascular events by 14%, 18% and 9%, respectively, independent of the initial BP level. A second study found that ACE inhibitor and diuretic reduced BP by 9.4/4.6 mmHg. The reduction in risk of further stroke for those patients with diabetes was 38% – equivalent to one stroke avoided for every 16 patients treated for 5 years.

Angiotensin-II receptor blockers (ARBs) are equally effective alternative antihypertensive agents in patients with ACE inhibitor-induced cough or rash. They also have similar renal benefits in patients with microalbuminuria.

The British Hypertension Society A/CD algorithm (Fig. 5.3) has been accepted as the best method of defining combination drug therapy. It specifies the use of ACE inhibitors (or ARBs if intolerant), calcium channel blockers and thiazide-type diuretics.

Figure 5.3 The British Hypertension Society (BHS) A/CD algorithm. ACE, angiotensin converting enzyme; NICE, National Institute for Health and Clinical Excellence.

(Source: National Prescribing Centre, 2011. Reproduced with permission.)

Patients with diabetes requiring antihypertensive treatment should be commenced on:

• an ACE inhibitor (ARB if ACE inhibitor intolerant), or

• a calcium channel blocker, or

• a thiazide diuretic.

Beta-blockers and alpha-blockers should not normally be used in the initial management of BP in patients with diabetes.

An algorithm such as the A/CD should be followed, unless there is a specific indication that a particular specific class be used first (e.g. ACE inhibitor or ARB in those aged under 55 years or with nephropathy; beta-blockers in ischaemic heart disease). The expectation should be that most patients end up on more than one agent.

Acute coronary syndromes

Acute coronary syndromes are a common cause of death in people with diabetes. However, the case fatality rate from MI is double that in the non-diabetic population.

Congestive heart failure

Management of patients with diabetes and stable angina

Coronary revascularization

Patients with diabetes are at increased risk of complications during revascularization procedures, increased risk of death following both coronary bypass surgery and angioplasty; there is also a substantially increased risk of restenosis following angioplasty in diabetic patients, partly ameliorated by the use of coronary stents. Much of this increased risk is due to confounding associations, including female sex, diffuse coronary disease, impaired left ventricular function and renal impairment, rather than the diabetic state itself. Indications for coronary angiography in patients with diabetes with symptomatic coronary disease are similar to those in non-diabetic subjects.

Stenting improves the outcome after angioplasty. Platelet glycoprotein-IIb/IIIa receptor antagonists (e.g. abciximab) also reduce mortality after angioplasty with or without stenting in patients with diabetes.

Drug-eluting stents (DES) reduce in-stent restenosis and target lesion revascularization when compared with bare metal stents (BMS) for revascularization in patients with diabetes.

In patients with diabetes, DES are recommended rather than BMS in patients with stable CHD or non-ST elevation MI to reduce in-stent restenosis and target lesion revascularization.

Diabetic cardiomyopathy

The entity remains controversial. Patients with diabetes have greater left ventricular mass, higher resting heart rates and greater propensity for heart failure. Several metabolic abnormalities have been postulated to contribute to the development of these abnormalities. Patients with diabetes have a higher risk of:

Acute stroke

The relative risk of stroke in patients with diabetes is twice as high as in the non-diabetic population, and the mortality rate following stroke is increased compared with that in non-diabetic patients. Stroke is considered conventionally a macrovascular complication of diabetes. However, small-vessel strokes (i.e. lacunar infarcts) are the commonest subtype of stroke occurring in patients with diabetes. These tend to occur almost a decade earlier than in non-diabetic individuals. It is thought that large-vessel disease tends to unmask the small-vessel disease earlier in patients with diabetes.

Management of stroke is similar to that in non-diabetic patients. Routine glucose control should be maintained. Rehydration and intravenous insulin may also be required.

Patients with diabetes who have no cerebrovascular disease but have one or more risk factors should be advised how this may affect the likelihood of their developing cerebrovascular disease.

Patients should be given information to help them recognize the following risk factors:

Peripheral vascular disease

Peripheral vascular disease (PVD) is common in diabetes and affects up to 30% of all diabetics. Amputation is 5–8 times commoner in diabetics than in those without diabetes. The atherosclerotic lesions in diabetes are usually located more peripherally (below the knee) and therefore more difficult to treat surgically.

The World Health Organization (WHO) defines PVD using an ABPI of < 0.9. The patient may be completely asymptomatic or may complain of claudication, rest pain or non-healing ulcers.

Diagnosis is made from history and objective findings on examination. Hand-held Doppler ultrasonography helps in measuring ABPI. However, the ABPI can be falsely high in patients with diabetes owing to calcification of arteries in diabetics. Alternatively, toe pressure measurement is useful. Angiography is useful when intervention is contemplated.

Fibroproliferative disorders of soft tissue

Disorders of joints

Skeletal disease in diabetes

Muscle involvement in diabetes

Prevalence of infection and diabetes

Although fungal and bacterial infections may be encountered more frequently in diabetic patients, particularly when metabolic control is poor, it remains uncertain whether the overall incidence of infection is increased. Diabetes has long been considered a risk factor for pulmonary tuberculosis. Recurrent cutaneous or urogenital infections, such as vulvovaginal candidiasis or balanitis, may be the presenting feature of diabetes and their occurrence should prompt appropriate investigations.

Predisposing factors

Attainment of good metabolic control is therefore important in the management of infections in diabetic patients; this may necessitate temporary insulin therapy in diet- or tablet-treated patients with type 2 diabetes. The association between the rare and serious complication of invasive infection with the saprophytic Mucor species (rhinocerebral mucormycosis) with DKA (see p. 143) is noteworthy; this condition is encountered in some other states associated with severe metabolic acidosis.

Viral infections

As discussed in Section 1, some viruses (rubella, mumps, Coxsackie B4) have been implicated in the aetiology of type 1 diabetes. Intrauterine rubella infection leads to autoimmune type 1 diabetes in 20–40% of children. Recent concerns that immunization against common childhood infections might lead to an increased risk of type 1 diabetes have not been substantiated.

Periodontal disease and diabetes

Periodontal disease has been recognized as a common complication of diabetes mellitus. In fact, signs and symptoms of periodontal disease may be the first manifestation of diabetes. There are two main types of periodontal disease: gingivitis, in which the gingiva surrounding the teeth is reddened and inflamed and bleeds easily, and periodontitis, in which the infection and inflammation surrounding the teeth destroys the ligamentous attachment of the teeth as well as the alveolar bone surrounding the teeth.

Periodontal disease is commoner in diabetics, and the relationship between diabetes and periodontal disease is a two-way relationship. Diabetic patients with periodontal disease have worse glycaemic control and it has also been reported that treatment of periodontal disease leads to better glycaemic control. Recently it has been reported that periodontal disease is an independent risk factor for heart disease and stroke.