Complications of diabetes

• Despite all the treatments now available, the outcome for patients with
diabetes remains disappointing.
• Long-term complications of diabetes still cause significant morbidity and
mortality
• Excess mortality in diabetes is caused mainly by large blood vessel disease,
particularly myocardial infarction and stroke.
• Macrovascular disease also causes substantial morbidity from myocardial
infarction, stroke, angina, cardiac failure and intermittent claudication.
• The pathological changes of atherosclerosis in diabetic patients are similar
to those in the non-diabetic population but occur earlier in life and are
more extensive and severe.
• Diabetes amplifies the effects of the other major cardiovascular risk
factors: smoking, hypertension and dyslipidaemia
• Mortality statistics from the USA indicate that cardiovascular death
rates are 1.7 times higher in adults with diabetes aged 20 years or
older compared to adults in the same age group who do not have
diabetes, while similar f igures for myocardial infarction show a 1.8
times greater rate. Hospitalisation rates for stroke were 1.5 times
higher in adults with diabetes than in those without diabetes.
• addition, 60% of non-traumatic amputations among people aged 20
years or older were reported to be in people with diabetes.
• Type 1 diabetes is also associated with increased cardiovascular risk.
• Disease of small blood vessels is a specific complication of diabetes
and is termed diabetic microangiopathy.
• . It contributes to mortality through renal failure caused by diabetic
nephropathy, and is responsible for substantial morbidity and
disability: for example, blindness from diabetic retinopathy, difficulty
in walking, chronic ulceration of the feet from peripheral neuropathy,
and bowel and bladder dysfunction from autonomic neuropathy.
• The risk of microvascular disease is positively correlated with the
duration and degree of sustained hyperglycaemia, however it is
caused and at whatever age it develops.
Complications of diabetes
• Microvascular/neuropathic
• Retinopathy, cataract • Impaired vision
• Nephropathy • Renal failure
• Peripheral neuropathy
• • Sensory loss • Pain • Motor weakness
• Autonomic neuropathy
• • Gastrointestinal problems (gastroparesis; altered bowel habit)
• • Postural hypotension
• Foot disease
• • Ulceration • Arthropathy
• Macrovascular
• Coronary circulation. • Myocardial ischaemia/infarction
• Cerebral circulation
• • Transient ischaemic attack
• Peripheral circulation • Claudication • Ischaemia
Mortality in diabetes
• Risk versus non-diabetic controls (mortality ratio)
• • Overall 2.6
• • Coronary heart disease.
• Cerebrovascular disease 2.8
• Peripheral vascular disease
• • All other causes, including renal failure 2.7
• Causes of death in diabetes (approximate proportion)
• Cardiovascular disease. 70%
• • Renal failure 10%
• • Cancer. 10%
• • Infections. 6%
• • Diabetic ketoacidosis. 1%
• • Other. 3%
Risk factors for increased morbidity and
mortality in diabetes
• • Duration of diabetes
• • Early age at onset of disease
• • High glycated haemoglobin (HbA1c)
• • Raised blood pressure
• • Proteinuria; microalbuminuria
• • Dyslipidaemla
• • Obesity
Pathophysiology
• The histopathological hallmark of diabetic microangiopathy is thickening of
the capillary basement membrane, with associated increased vascular
permeability, which occurs throughout the body.

• The development of the characteristic clinical syndromes of diabetic

retinopathy, nephropathy, neuropathy and accelerated atherosclerosis is
thought to result from the local response to generalised vascular injury.
• For example, in the wall of large vessels, increased permeability of arterial
endothelium, particularly when combined with hyperinsulinaemia and
hypertension, may increase the deposition of atherogenic lipoproteins.
Preventing diabetes complications
• Glycaemic control

• The evidence that improved glycaemic control decreases the risk of

developing microvascular complications of diabetes was established by the
DCCT in type 1 diabetes and the UKPDS in type 2 diabetes
• The DCCT was a large study that lasted 9 years; it randomised patients
with type 1 diabetes to intensive treatment (mean HbA1c 53 mmol/mol)
and conventional treatment (mean HbA1c 75 mmol/mol). There was a 60%
overall reduction in the risk of developing diabetic complications in
patients with type 1 diabetes on intensive therapy with strict glycaemic
control, compared with those on conventional therapy.
• The UKPDS randomised patients to intensive treatment (mean HbA1c 53
mmol/mol) versus conventional treatment (mean HbA1c 64 mmol/mol).
This study showed that, in type 2 diabetes, the frequency of diabetic
complications is lower and progression is slower with good glycaemic
control and effective treatment of hypertension, irrespective of the type of
therapy used.
• Extrapolation from the UKPDS suggests that, for every 11 mmol/mol
reduction in HbA1c, there is a 21% reduction in death related to diabetes, a
14% reduction in myocardial infarction and 30–40% reduction in risk of
microvascular complications
• These landmark trials demonstrated that diabetic complications are
preventable and that the aim of treatment should be ‘nearnormal’
glycaemia.
• Control of other risk factors
• Randomised controlled trials have shown that aggressive
management of blood pressure minimises the microvascular and
macrovascular complications of diabetes.
• Angiotensin-converting enzyme (ACE) inhibitors are valuable in
improving outcome in heart disease and in treating diabetic
nephropathy . The management of dyslipidaemia with a statin limits
macrovascular disease in people with diabetes
Diabetic retinopathy
• Diabetic retinopathy is one of the most common causes of visual
impairment in people of working age in developed countries.
• The prevalence of diabetic retinopathy increases with the duration of
diabetes. Almost all individuals with type 1 diabetes, and most of those
with type 2 diabetes, will have some degree of retinopathy after 20 years.
• Pathogenesis
• The underlying pathogenesis of diabetic retinopathy is local vascular
endothelial growth factor production initiated by hyperglycaemia-induced
capillary occlusion.
• This occlusion stimulates increased production of retinal vascular
endothelial growth factor, which not only increases capillary permeability,
leading to retinal oedema, but also stimulates angiogenesis, leading to new
vessel formation.
Clinical features

• The initial clinical feature of diabetic retinopathy, capillary occlusion, is

visible only on retinal angiography. Capillaries adjacent to the occluded
capillary form discrete swellings (microaneurysms), which leak fluid and
blood, causing oedema and retinal haemorrhages
• Clinically, microaneurysms appear as isolated red dots, the capillaries being
too small to visualise. At the edge of any leaking fluid, lipids precipitate out
to form exudate, like the tidemark of the sea.
• capillaries with microaneurysms also occlude, their microaneurysms
turning white before disappearing entirely from clinical view.
• As more and more capillaries occlude, larger patches of retinal ischaemia
form, leading to sufficient vascular endothelial growth factor production to
induce the growth of new vessels at the border of diseased and undiseased
retina.
• Within patches of retinal ischaemia, diseased remnants of partially
perfused capillaries form intraretinal microvascular abnormalities
(IRMAs) and retinal veins develop multiple diffuse swellings (venous
beading). These signs are best seen on f luorescein angiography.
• New vessels and their glial tissue (like a cabbage leaf) grow from
retinal veins, through the overlying internal limiting membrane into
the vitreous, triggering local inflammation and contracting scars.
• If the scarring is sufficient, then tractional retinal detachment and
complete blindness may occur
• Other retinal lesions, not unique to capillary occlusion, are also seen
in diabetic retinopathy.
• These include flame haemorrhages and cotton wool spots (soft
exudates).
• Cotton wool spots are also situated in the nerve-fibre layer and are
usually most numerous nasal to the optic disc, where the nerve fibres
crowd together.
Management of proliferative diabetic
retinopathy
• If untreated, proliferative retinopathy eventually causes severe visual
impairment through recurrent vitreous haemorrhage and retinal
detachment.
• Pan-retinal laser photocoagulation therapy is extremely effective at
preserving vision, if applied before complications set in.
• Intravitreal injections of anti-vascular endothelial growth factor (e.g.
ranibizumab, aflibercept, bevacizumab) also cause temporary
regression of proliferative retinopathy, whereas, after pan-retinal
laser therapy, background and proliferative types of retinopathy
regress permanently. I
• Management of diabetic macular oedema
• Traditionally, oedema seen on slit-lamp biomicroscopy was categorised
according to three patterns of leakage elucidated from fluorescein
angiogram studies:
• • focal leakage from microaneurysms
• • diffuse leakage from diseased capillaries
• • ischaemia (no leakage) from thrombosis of the perifoveal capillaries.
• Laser was applied, either directly on leaking microaneurysms or empirically
by placing a grid of burns on the affected macula, to reduce leakage. The
main aim was to treat oedema before the fovea was affected, as laser
therapy for oedema affecting the fovea was never particularly effective.
• Prevention
• There is a clear relationship between glycaemic control and the incidence
of diabetic retinopathy. A combination of good glycaemic and blood
pressure control also slows the progression Of retinopathy
• . When blood glucose is rapidly lowered in patients with type 1 diabetes,
however, there can be a transient deterioration of retinopathy,
predominantly in the form of cotton wool spot formation, but occasionally
triggering new vessel formation.
• ideally, any improvement in glycaemic control should be gradual, in many
circumstances this is hard to achieve, particularly if the patient suddenly
decides to comply with treatment, leading to dramatic improvement in
glycaemic control.
Screening
• Systematic screening for asymptomatic proliferative retinopathy has
been shown to be cost-effective.
• Historically, annual screening has been advocated. However,
evidence now indicates that patients with repeated normal screens,
particularly those with type 2 diabetes, can be safely screened every 2
years.
• In pregnancy, the placenta is a source of angiogenic growth factors.
For this reason, although the risk of developing significant retinopathy
during pregnancy remains low, pregnant women should be screened
every trimester until the placenta is delivered.
Other causes of visual loss in people with
diabetes
• Around 50% of visual loss in people with type 2 diabetes results from
causes other than diabetic retinopathy.
• These include
• cataract,
• age-related macular degeneration,
• retinal vein occlusion,
• retinal arterial occlusion,
• non-arteritic ischaemic optic neuropathy and glaucoma.
Diabetic nephropathy
• Diabetic nephropathy is an important cause of morbidity and mortality in both
type 1 and type 2 diabetes.
• It is now the most common cause of end-stage renal failure in developed
countries and accounts for between 20% and 50% of patients starting renal
replacement therapy.
• About 30% of patients with type 1 diabetes have developed diabetic nephropathy
20 years after diagnosis, but the risk after this time falls to less than 1% per year,
and from the outset the risk is not equal in all patients
• The risk of nephropathy in Caucasian populations with type 2 diabetes is similar
to those with type 1 diabetes but the rate of progression may be exacerbated by
concomitant obesity and other risk factors.
• The risk of nephropathy is much greater in some ethnic groups, with epigenetic
and genetic factors thought to influence this increased risk.
• The pathophysiology is not fully understood and there are several
postulated mechanisms by which hyperglycaemia causes the pathological
changes seen in diabetic nephropathy.
• The central features are activation of the renin–angiotensin system, leading
to both intrarenal and systemic effects, as well as direct toxic effects of
prolonged hyperglycaemia, leading to renal inflammation and fibrosis.
• Pathologically, the first changes coincide with the onset of
microalbuminuria and include thickening of the glomerular basement
membrane and accumulation of matrix material in the mesangium.
• Subsequently, nodular deposits are characteristic, and glomerulosclerosis
worsens as heavy proteinuria develops, until glomeruli are progressively
lost and renal function deteriorates.
Risk factors for diabetic nephropathy
• • Poor glycaemic control
• • Long duration of diabetes
• • Presence of other microvascular complications
• • Ethnicity (e.g. Asians, Pima Indians)
• • Pre-existing hypertension
• • Family history of diabetic nephropathy
• • Family history of hypertension
Diagnosis and screening
• Microalbuminuria is the presence in the urine of small amounts of
albumin, at a concentration below that detectable using a standard
urine dipstick.
• Overt nephropathy is defined as the presence of macroalbuminuria
(urinary albumin > 300 mg/24 hrs, detectable on urine dipstick).
• Microalbuminuria is a good predictor of progression to nephropathy
in type 1 diabetes. It is a less reliable predictor of nephropathy in
older patients with type 2 diabetes, in whom it may be accounted for
by other diseases although it is a potentially useful marker of an
increased risk of macrovascular disease.
Screening for microalbuminuria
• • Screening identifies incipient nephropathy in type 1 and type 2 diabetes;
is an independent predictor of macrovascular disease in type 2 diabetes
• • Risk factors include high blood pressure, poor glycaemic control and
smoking
• • Early morning urine is measured for the albumin:creatinine ratio (ACR).
Microalbuminuria is present if:
• Male ACR 2.5–30 mg/mmol creatinine
• Female ACR 3.5–30 mg/mmol creatinine
• • An elevated ACR should be followed by a repeat test:
• There is established microalbuminuria if 2 out of 3 tests are positive
• An ACR > 30 mg/mmol creatinine is consistent with overt nephropathy
Management
• The presence of established microalbuminuria or overt nephropathy should prompt vigorous efforts to reduce the risk of
progression of nephropathy and of cardiovascular disease by:
• • aggressive reduction of blood pressure
• • aggressive reduction of cardiovascular risk factors
• • optimisation of glycaemic control
• Blockade of the renin–angiotensin system using either ACE inhibitors or angiotensin 2 receptor blockers (ARBs) has been shown to
have an additional benefit over similar levels of blood pressure control achieved with other antihypertensive agents and is
recommended as first-line therapy.
• The addition of a diuretic and/or salt restriction increase both the anti-proteinuric and antihypertensive effect of angiotensin
blockade and therefore constitute an ideal second-line treatment.
• Halving the amount of albuminuria with an ACE inhibitor or ARB results in a nearly 50% reduction in long-term risk of progression
to end-stage renal disease.
• Renal replacement therapy is often required at a higher eGFR than in other causes of renal failure, due to fluid overload or
symptomatic uraemia.
• Renal transplantation dramatically improves the life of many, and any recurrence of diabetic nephropathy in the allograft is usually
too slow to be a serious problem; associated macrovascular and microvascular disease elsewhere may still progress, however.
Diabetic neuropathy
• Diabetic neuropathy causes substantial morbidity and increases
mortality.
• It is diagnosed on the basis of symptoms and signs, after the
exclusion of other causes of neuropathy
• Depending on the criteria used for diagnosis, it affects between 50%
and 90% of patients with diabetes, and of these, 15–30% will have
painful diabetic neuropathy (PDN).
• Like retinopathy, neuropathy occurs secondary to metabolic
disturbance, and prevalence is related to the duration of diabetes and
the degree of metabolic control.
• Pathological features can occur in any peripheral nerves. They include
axonal degeneration of both myelinated and unmyelinated f ibres,
with thickening of the Schwann cell basal lamina, patchy segmental
demyelination and abnormal intraneural capillaries (with basement
membrane thickening and microthrombi).
• Various classifications of diabetic neuropathy have been proposed.
• motor, sensory and autonomic nerves may be involved in varying
combinations, so that clinically mixed syndromes usually occur.
Clinical features
Symmetrical sensory polyneuropathy
• This is frequently asymptomatic. The most common clinical signs are diminished
perception of vibration sensation distally, ‘glove and stocking’ impairment of all other
modalities of sensationand loss of tendon reflexes in the lower limbs.
• Symptoms include paraesthesiae in the feet , pain in the lower limbsburning sensations
in the soles of the feet, cutaneous hyperaesthesia and, when severe, an abnormal gait
• Weakness and atrophy, in particular of the interosseous muscles, develops, leading to
structural changes in the foot with loss of lateral and transverse arches, clawing of the
toes and exposure of the metatarsal heads.
• Electrophysiological tests demonstrate slowing of both motor and sensory conduction,
and tests of vibration sensitivity and thermal thresholds are abnormal.
• A diffuse small-fibre neuropathy causes altered perception of pain and temperature, and
is associated with symptomatic autonomic neuropathy; characteristic features include
foot ulcers and Charcot neuroarthropathy.
Asymmetrical motor diabetic neuropathy
• Sometimes called diabetic amyotrophy, this presents as severe and
progressive weakness and wasting of the proximal muscles of the lower
(and occasionally the upper) limbs .
• accompanied by severe pain, felt mainly on the anterior aspect of the leg,
and hyperaesthesia and paraesthesiae.
• Sometimes there may also be marked loss of weight (‘neuropathic
cachexia’).
• Tendon reflexes may be absent on the affected side(s).
• This condition is thought to involve acute infarction of the lower motor
neurons of the lumbosacral plexus.
• Although recovery usually occurs within 12 months, some deficits are
permanent. Management is mainly supportive.
Mononeuropathy
• Either motor or sensory function can be affected within a single
peripheral or cranial nerve.
• mononeuropathies are severe and of rapid onset, but they eventually
recover.
• The nerves most commonly affected are the 3rd and 6th cranial
nerves (resulting in diplopia), and the femoral and sciatic nerves.
• Nerve compression palsies are more common in diabetes, frequently
affecting the median nerve and giving the clinical picture of carpal
tunnel syndrome, and less commonly the ulnar nerve.
Autonomic neuropathy
• Parasympathetic or sympathetic nerves may be predominantly
affected in one or more visceral systems.
• The development of autonomic neuropathy is related to poor
metabolic control less clearly than to somatic neuropathy, and
improved control rarely results in improved symptoms.
• Within 10 years of developing overt symptoms of autonomic
neuropathy, 30–50% of patients are dead, many from sudden
cardiorespiratory arrest.
• Patients with postural hypotension (a drop in systolic pressure of 30
mmHg or more on standing from the supine position) have the
highest subsequent mortality.
Clinical features of autonomic neuropathy
• Cardiovascular • Postural hypotension • Resting tachycardia • Fixed heart rate
• Gastrointestinal
• • Dysphagia, due to oesophageal atony
• • Abdominal fullness, nausea and vomiting, unstable glycaemia, due to delayed
gastric emptying (‘gastroparesis’)
• • Nocturnal diarrhoea ± faecal incontinence
• • Constipation, due to colonic atony
• Genitourinary
• • Difficulty in micturition, urinary incontinence, recurrent infection, due to atonic
bladder
• • Erectile dysfunction and retrograde ejaculation
• Sudomotor
• • Nocturnal sweats without hypoglycaemia
• • Gustatory sweating
• • Anhidrosis; fissures in the feet
• Vasomotor
• • Feet feel cold, due to loss of skin vasomotor responses
• • Dependent oedema, due to loss of vasomotor tone and increased vascular
permeability
• • Bulla formation
• Pupillary
• • Decreased pupil size
• • Resistance to mydriatics
Gastroparesis
• Gastroparesis is diagnosed when there is an objectively measured delay in gastric
emptying in the absence of mechanical obstruction.
• The main symptoms are chronic nausea, vomiting (especially of undigested food),
abdominal pain and a feeling of fullness/early satiety.
• Diagnosis is most commonly made by 99m-technetium scintigraphy following a
solid-phase meal with standard imaging over 4 hours.
• Management is difficult, with glucose levels directly impacting on gastric motility
and, conversely, gastroparesis affecting absorption of ingested carbohydrate.
• Insulin pump therapy may be especially useful in this context; patients on
conventional injection therapy may benefit from injecting rapid-acting insulin
after a meal rather than before.
• Recommended dietary changes include following low-fibre and low-residue diets,
as well as eating smaller amounts more frequently.
Erectile dysfunction
• Erectile failure (impotence) affects 30% of diabetic males and is often
multifactorial.
• Although neuropathy and vascular causes are common, psychological
factors, including depression, anxiety and reduced libido, may be
partly responsible.
Management options for peripheral
sensorimotor and autonomic neuropathies
• Pain and paraesthesiae from peripheral somatic neuropathies
• • Intensive insulin therapy (strict glycaemic control)
• • Anticonvulsants (gabapentin, pregabalin, carbamazepine, phenytoin)
• • Tricyclic antidepressants (amitriptyline, imipramine)
• • Other antidepressants (duloxetine)
• • Substance P depleter (capsaicin – topical)
• • Opiates (tramadol, oxycodone)
• • Membrane stabilisers (mexiletine, IV lidocaine)
• • Antioxidant (α-lipoic acid)
• Postural hypotension
• • Support stockings • Fludrocortisone • NSAIDs
• • α-adrenoceptor agonist (midodrine)
• Gastroparesis
• • Dopamine antagonists (metoclopramide, domperidone)
• • Erythromycin
• • Botulinum toxin
• • Gastric pacemaker; percutaneous enteral (jejunal) feeding
• Diarrhoea
• • Loperamide • Broad-spectrum antibiotics
• • Clonidine • Octreotide
• Constipation
• • Stimulant laxatives (senna)
• Atonic bladder
• • Intermittent self-catheterisation
• Excessive sweating
• • Anticholinergic drugs (propantheline, poldine, oxybutinin)
• • Topical antimuscarinic agent (glycopyrrolate cream)
• • Clonidine
• Erectile dysfunction
• Phosphodiesterase type 5 inhibitors (sildenafil, vardenafil, tadalafil) – oral
• • Dopamine agonist (apomorphine) – sublingual
• Prostaglandin E1 (alprostadil) – injected into corpus cavernosum or intra-urethral administration of pellets
• Vacuum tumescence devices
• • Implanted penile prosthesis
• Psychological counselling; psychosexual therapy
The diabetic foot
• Foot ulceration occurs as a result of trauma (often trivial) in the presence
of neuropathy and/or peripheral vascular disease with infection is a
secondary phenomenon following disruption of the protective epidermis.
• Most ulcers develop at the site of a plaque of callus skin, beneath which
tissue necrosis occurs and eventually breaks through to the surface.
• Ischaemia alone accounts for a minority of foot ulcers in diabetic patients,
with most being either neuropathic or neuro-ischaemic.
• Charcot neuroarthropathy is a progressive condition affecting the bones
and joints of the foot; it is characterised by early inflammation and then
joint dislocation, subluxation and pathological fractures of the foot of
neuropathic patients, often resulting in debilitating deformity
Management
• Management can be divided into primary prevention and treatment
of an active problem. All patients should be educated in preventative
measures
• The feet of people with diabetes should be screened annually
• Two simple tests are required to grade risk: a 10 g monofilament
should be used to assess sensation at f ive points on each foot, and
foot pulses should be palpated (dorsalis pedis and/or posterior tibial).
• Removal of callus skin with a scalpel is best done by a podiatrist who
has specialist training and experience in diabetic foot problems.
 Foot ulcer
• Once a foot ulcer develops, patients should ideally be referred to a
multidisciplinary foot team, involving a diabetes specialist, a podiatrist, a vascular
surgeon and an orthotist.
• Treatment involves: débridement of dead tissue; prompt, often prolonged,
treatment with antibiotics if required, as infection can accelerate tissue necrosis
and lead to gangrene; and pressure relief using customised insoles, specialised
orthotic footwear and sometimes total contact plaster cast or an irremovable
aircast boot.
• If an ulcer is neuro-ischaemic, a vascular assessment is often carried out, by
ultrasound or angiography, as revascularisation by angioplasty or surgery may be
required to allow the ulcer to heal.
• In cases of severe secondary infection or gangrene, an amputation may be
required. This can be limited to the affected toe or involve more extensive limb
amputation.
• Charcot neuroarthropathy
• Acute Charcot neuroarthropathy almost always presents with signs of
inflammation – a hot, red, swollen foot.
• The initial X-ray may show bony destruction but is often normal.
• As about 40% of patients with a Charcot joint also have a foot ulcer, it can be
difficult to differentiate from osteomyelitis.
• Magnetic resonance imaging (MRI) of the foot is often helpful.
• The mainstay of treatment for an active Charcot foot is immobilisation and,
ideally, avoidance of weight-bearing on the affected foot.
• Immobilisation is often achieved by a total contact plaster cast or ‘aircast’ boot.
• The acute phase frequently lasts 3–6 months and sometimes longer. In the post-
acute phase, there is consolidation and remodelling of fracture fragments,
eventually resulting in a stable foot.