29th May 2025

Complications of Type 2 Diabetes

Hypoglycaemia

In T2DM, hypoglycaemia is usually seen as a result of taking either insulin or sulfonylureas, although it can occur without these medications. It is defined as a blood glucose level <3.5mmol/L and can be classified by severity according to the symptoms experienced:

• Mild – hunger, anxiety, palpitations, sweating, perioral paraesthesia. 
• Moderate – headache, impaired cognition, reduced level of awareness, drowsiness and features of mild hypoglycaemia.
• Severe – seizures, loss of consciousness and coma.

Some patients will only experience symptoms at a very low blood glucose level, meaning they have impaired hypoglycaemia awareness (IHA). This is especially observed in patients who have had repeated episodes of hypoglycaemia and patients taking certain medications, including beta-adrenergic antagonists (e.g., bisoprolol), beta-adrenergic agonists (e.g. terbutaline), serotonin receptor reuptake inhibitors (e.g. serotonin) and methylxanthines (e.g. caffeine). Patients and, where appropriate, relatives and carers should be educated about the symptoms of hypoglycaemia and advised on emergency management. This is especially important in patients with known IHA as they are more liable to progress to severe hypoglycaemia and will therefore be unable to administer emergency treatment. 

The management of hypoglycaemia involves increasing the circulating glucose level as quickly as possible and there are several ways this can be achieved:

• Oral fast-acting carbohydrate – Conscious patients, who can swallow, with blood glucose <4mmol/L with or without symptoms of hypoglycaemia should be given a fast-acting oral carbohydrate such as 40% glucose gel, glucose tablets or glucose liquid. In the community, if these agents are unavailable, then any accessible sugary foods should be used, such as orange juice or candies. The treatment may be repeated up to 3 times at 15-minute intervals if there is not a satisfactory response. 
• IM Glucagon – If there is no response to oral agents and the patient doesn’t have intravenous access then they should be given glucagon via intramuscular injection. Glucagon should also be given to unconscious patients and can be administered by appropriately trained family members. Glucagon doesn’t increase the total amount of glucose in the body, rather mobilising stored glucose in the liver, and therefore will be ineffective in patients that have depleted glucose stores. It should therefore be avoided in patients who have undergone a prolonged fast, have adrenal insufficiency or have alcohol-induced hypoglycaemia. It is also less effective in patients who take a sulfonylurea. 
• IV Glucose infusion – Patients who have not responded to oral agents and have intravenous access should be started on either a 10% or 20% glucose infusion. 50% glucose should be avoided as it is a hypertonic solution.  Patients who are unconscious and haven’t responded to or aren’t suitable for IM glucagon should also be treated with IV glucose. Alcoholic patients should be co-administered IV thiamine to reduce the risk of Wernicke’s encephalopathy (thiamine plays an important role in the intracellular metabolism of glucose). 

Once blood glucose >4mmol/L the patient should be given a source of long-acting carbohydrate (such as a slice of toast, 2 biscuits or a glass of milk) if able to eat. Patients who are NBM should be started on a 10% insulin infusion. In T2DM, since most hypoglycemia is seen in response to a sulfonylurea or insulin, the hypoglycaemia can persist for up to 36 hours so blood glucose should be monitored closely.

Diabetic kidney disease (DKD)

Chronic hyperglycemia causes vascular calcification and endothelial damage, contributing to many of the complications seen in T2DM. In DKD, microvascular damage to the nephron arterioles and overstimulation of the local renin-angiotensin system, causing efferent arteriole constriction, leads to intraglomerular hypertension and glomerular hyperfiltration, manifesting as microalbuminuria. The hyperglycaemic environment also triggers intracellular pathways, including through activation of protein kinase C, causing an increase in the production of advanced glycation end products, which lead to oxidative stress and cellular damage. DKD affects all renal cell types, resulting in thickening of the glomerular and tubular basement membranes, mesangial expansion through both proliferation and hypertrophy, tubular hypertrophy and afferent arteriole thickening with endothelial effacement. Clinically, it presents as gradually deteriorating renal function, progressing towards end-stage renal failure. 

Unlike in T1DM, where DKD occurs after a long duration of the disease (usually >10 years), DKD may be present on diagnosis with T2DM as it may be undiagnosed for many years. DKD is defined by the presence of albuminuria and deterioration in the estimated glomerular filtration rate (eGFR) without another cause for renal impairment. Not all diabetics will develop DKD, the most notable risk factors are: 

• Chronically poor glycaemic control
• Hypertension
• Dyslipidemia 
• Family history
• Smoking
• Increasing age 
• Race – Afro-Caribbean, Mexican-American and Pima Indian are at an increased risk

DKD usually remains symptom-less until severe, when patients may experience peripheral oedema, anaemia, fatigue, haematuria and progression to end-stage renal failure.  Patients are screened on diagnosis using:

• Urinary albumin-creatinine ratio (ACR) – normal ACR is <3mg/mmol. Patients with DKD are categorised into microalbuminuria with an ACR of 3-30mg/g, or macroalbuminuria (overt nephropathy) with an ACR <30mg/mmol. The result should be repeatable on 2 separate occasions.
• eGFR – DKD patients will see a gradual deterioration in eGFR as seen in chronic kidney disease, it can be graded according to the regular CKD values:

Table 2: Staging of chronic kidney disease

Adapted from table in NICE CKD treatment summary: https://www.nice.org.uk/guidance/ng203/chapter/Recommendations#classification-of-ckd-in-adults

Definitive diagnosis can be made by renal biopsy but this is not routinely offered to patients and they are normally diagnosed using ACR and clinical assessment to rule out other causes of renal disease. When a biopsy is performed, characteristic changes include mesangial expansion, thickening of the basement membrane and nodular glomerulosclerosis.

Patients diagnosed with DKD (ACR >3mg/mmol) should be offered either an angiotensin-converting enzyme inhibitor (ACEi) (such as ramipril) or an angiotensin receptor blocker (ARB) (such as candesartan), titrated up to the highest dose the patient can tolerate. An SGLT-2 inhibitor should be added when ACR>30mg/mmol and may be considered earlier, they are effective in slowing the progression of DKD. Control of dyslipidaemia, good glycaemic control and smoking cessation are all important in preventing the progression of DKD.

Diabetic eye disease

Patients diagnosed with T2DM should be immediately referred to their local eye screening service. Diabetic retinopathy presents as gradually decreasing visual acuity but in cases where vitreous haemorrhage occurs, patients will experience a sudden partial or complete loss of vision. Several complications of diabetic retinopathy may occur, which are discussed below.

Diabetic retinopathy is caused by progressive microvascular damage in the eye due to chronic hyperglycaemia. Several observable changes are seen in fundoscopy:

• Arteriole microaneurysms – The earliest visible manifestation of diabetic retinopathy, appearing as small red dots on the retina.
• Blot haemorrhages – Weakened capillary walls are more liable to rupture. Haemorrhages may be indistinguishable from microaneurysms by fundoscopy but sometimes have more irregular borders. Fundus fluoresceine angiogram can be used to distinguish between haemorrhages and microaneurysms.
• Hard exudates – It is theorised that increased capillary permeability allows leakage of lipoproteins through the vessel wall to form hard exudates, seen as yellow patches on fundoscopy.
• Cotton wool spots – Small arteriole infarcts result in patches of retinal non-perfusion, seen as white/yellow patches on fundoscopy.
• Intraretinal microvascular abnormalities – communications between arterioles and venules, bypassing capillary beds.
• Venous beading – intermittent dilatations in the retinal venules producing an appearance of beads on a string.
• Neovascularisation – chronic retinal hypoperfusion simulates the production of vascular endothelial growth factor A, which over time will lead to the formation of vessels to supply the retina.
• Vitreous haemorrhage – The new vessels produced are more fragile and liable to larger haemorrhage into the vitreous cavity.

Diabetic retinopathy is categorised by the International Clinical Diabetic Retinopathy Disease Severity Scale:

Table 3: Staging of diabetic retinopathy

Adapted from StatPearls: https://www.ncbi.nlm.nih.gov/books/NBK560805/

Patients with diabetic retinopathy may develop several other ophthalmological pathologies:

• Diabetic macular oedema (DMO) – Increased capillary permeability can lead to the accumulation of exudative fluid in the macula, leading to deterioration in central vision. DMO can lead to blindness.
• Posterior vitreous detachment – The detachment of the vitreous membrane from the retina causes the patient reduced visual acuity, floaters and flashers.
• Retinal detachment – Producing a dark shadow to fall over the patient’s vision, which they often describe as curtain-like.
• Amaurosis fugax – Describes a sudden but transient monocular loss of vision due to retinal ischaemia. Diabetic retinopathy increases the risk of retinal artery and vein occlusion, as well as atherosclerosis and dissection.
• Cataracts – Diabetic patients are at a much greater risk of developing cataracts, where the lens becomes thickened and opaque leading to reduced visual acuity and clouding of vision.

Diabetics should be encouraged to attend screening annually and should be referred urgently if they experience a sudden visual loss or neovascularisation or vitreous haemorrhage is seen on fundoscopy. Management of NPDR involves good glycaemic control and modulation of risk factors to prevent progression. Patients with severe NPDR should be considered for anti-VEGF therapy to prevent progression to proliferative retinopathy. Pan-retinal laser photocoagulation can be used once neovascularisation occurs to destroy the vessels before they bleed. Surgery may be offered to relieve intraocular pressure caused by a large vitreous haemorrhage, as well as for cataracts and retinal/vitreous detachment.

Diabetic neuropathy

Damage to the vessels that supply the nerves in the body, through the same mechanism outlined above, leads to diabetic neuropathy affecting both the somatic and autonomic systems. Damage to sensory nerves can cause problems in the feet, making patients more likely to develop ulcers or Charcot arthropathy, discussed in more detail in the diabetic foot disease section. Patients may experience painful neuropathy, typically in the extremities, which should be managed in the same way as neuropathic pain in non-diabetics. They should be offered one of the following: amitriptyline, gabapentin, pregabalin or duloxetine. If one agent is not effective even when titrated to a maximum dose then it should be substituted for an alternative. Patients with severe pain that limits their daily activities (such as sleep) or that causes a deterioration in a comorbidity should be referred to a specialist pain team.

Autonomic neuropathy can cause a variety of symptoms, which can be managed with specific interventions. Other causes of these symptoms must be ruled out before a diagnosis of diabetic autonomic neuropathy can be made:

• Cardiovascular autonomic dysfunction (CAN) – Causing resting tachycardia, reduced heart rate variability, exercise intolerance, orthostatic hypotension, dizziness and syncope. CAN increases an individual’s risk of developing cardiovascular disease, including silent myocardial infarction. ACE inhibitors and beta-blockers are effective treatment options. 
• Orthostatic hypotension – Medications should be reviewed as many can exacerbate hypotension, including antihypertensive medications, nitrates, diuretics, alpha-adrenergic blockers (such as tamsulosin), levodopa and tricyclic antidepressants. Other medications that increase the risk of falls should also be reviewed such as opioids, benzodiazepines, ‘Z-drugs’ (zopiclone and zolpidem) and anticholinergics. Patients can be encouraged to increase fluid and salt intake to expand their circulating volume. Medications such as fludrocortisone may be used if the hypotension is symptomatic and resistant to non-pharmacological methods.
• Constipation or diarrhoea – May be treated using laxatives and loperamide respectively and where appropriate. 
• Gastroparesis – Causing erratic blood sugars, abdominal bloating and vomiting. There is unfortunately limited evidence for the use of antiemetics for gastroparesis with the most evidence for domperidone. It is recommended that erythromycin and metoclopramide be alternated and domperidone only used in exceptional circumstances given its significant cardiac risk profile and potential interactions with other medications.
• Erectile dysfunction – Men should be offered a phosphodiesterase-5 inhibitor, such as sildenafil, if they have problematic erectile dysfunction. 
• Impaired hypoglycaemic awareness – Hypoglycaemic episodes can disrupt autonomic pathways and thereby inhibit the associated neurogenic symptoms.
• Reduced sweating – This leads to dry skin, which can crack and allow entry of microorganisms, causing infections. 
• Neurogenic bladder – Patients may have difficulty emptying their bladder, which can cause recurrent urinary tract infections or incontinence.

Diabetic foot disease

Vascular and neurovascular damage associated with T2DM can lead to several problems in the feet and patients must have their feet assessed on diagnosis with T2DM and then annually thereafter. If deemed to be at risk of developing problems, they should be referred to the local foot protection service to be seen 2-8 weeks according to severity. Life-threatening foot problems, requiring immediate referral to the hospital, include ulcers with signs of sepsis or limb ischaemia, evidence of deep-seated soft tissue or bone infection, or gangrene.  

Problems that can arise include:

• Peripheral neuropathy – Crude touch, proprioception, fine touch and pain sensation should all be checked as well as motor function. Sensory deficit can lead to unknown injury and development of ulcers, Charcot arthropathy and skin infections. 
• Limb ischaemia – The lower limbs should be checked for vascular insufficiency including all pulses. Ankle-brachial pressure index (ABPI) can be used to assess evidence of arterial disease, but results must be viewed in the context of diabetes where calcification of vessels can elevate the measurement. Vascular insufficiency, either arterial or venous, leads to poorer wound healing and exacerbates problems such as ulceration and wound infections.
• Ulceration – A combination of neuropathy and vascular disease can lead to the formation of neuropathic, venous and arterial ulcers. A summary of the difference can be found in the table below.

Table 4: Types of diabetic Ulcers

Adapted from NICE CKS Diabetic foot problem – prevention and management: https://www.nice.org.uk/guidance/ng19/chapter/Recommendations#diabetic-foot-ulcer, and Dermnet.nz – Diabetic foot ulcers: https://dermnetnz.org/topics/diabetic-foot-ulcer

• Charcot Arthropathy – Loss of sensation allows recurrent small traumas to occur to the foot, which over time cause destruction of the joint. Charcot will present as a unilateral red, hot and swollen joint that can be mistaken for DVT or cellulitis. Imaging will show bony destruction and general inflammation, similar in appearance to osteomyelitis. Due to the loss of sensation, the foot will be much less painful than should be expected or may be completely painless. Management in the acute phase involves immobilising the foot and avoidance of weight-bearing. Surgery may also be considered, although there is no consensus as to whether this should take place in the acute phase or its resolution. The overall aim of treatment is to limit deformity and allow the patient to walk on the affected foot.
• Gangrene – Both wet and dry gangrene may occur. These patients should be referred to vascular surgery for consideration of debridement and amputation whilst being treated with antibiotics.

When a diabetic foot infection is suspected, a sample should be taken from as deep in the wound as possible, ideally a soft tissue or bone sample but failing this a deep swab. X-rays should be taken to assess the extent of the infection and MRI should be used if there is concern about osteomyelitis. Antibiotics should be given empirically until wound samples have been processed:

Table 5: Choosing the right antibiotic for diabetic foot disease

Adapted form NICE CKS Diabetic foot problem – prevention and management: https://www.nice.org.uk/guidance/ng19/chapter/Recommendations#diabetic-foot-ulcer

Macrovascular complications

As discussed previously, hyperglycaemia and insulin resistance lead to an increase in the production of reactive oxygen advanced glycation end products which cause oxidative stress and modulate intracellular signalling. The resulting increase in inflammatory compounds accelerates the formation of atherosclerosis and creates a prothrombin state. Other important risk factors for cardiovascular disease such as obesity and lipid dysregulation are commonly associated with T2DM. These elements lead to a significant increase in risk of:

• Coronary artery disease – including myocardial infarction and heart failure. 
• Cerebrovascular disease – including strokes and TIAs.
• Peripheral artery disease – including critical ischaemic limb, acute limb ischaemia and intermittent claudications.

The specific management of these conditions remains the same as for individuals without T2DM and details can be found in their corresponding chapters. From diagnosis, the risk of T2DM patients developing these conditions should be assessed and steps taken to modulate factors such as obesity, glycaemic control, hypertension, smoking and lipid dysregulation.

Skin and mucosal disease

T2DM is associated with several different dermatological pathologies:

• Diabetic dermopathy – Small, slightly indented, red/brown patches that develop on the shins in roughly 1/3rd of diabetic patients. They are benign and can disappear if good glycaemic control is achieved.
• Diabetic bullae – Blistering lesions that can develop typically on the hands and feet and can grow to be quite large. They are benign and self-limiting.
• Acanthosis nigricans – Dark skin discolouration present in the skin folds, for example, the axillae or groin caused by insulin resistance.
• Necrobiosis lipoidica – Waxy, yellow, granulomatous plaques that form on the shins and can develop into ulcers or squamous cell lung cancer.
• Candida infection – Oral, genital and candida intertrigo are all more common in diabetic patients. 
• Periodontitis – Microvascular damage at the gums puts diabetics at a higher risk of periodontitis and they should attend regular checks at the dentist.