Complications of diabetes mellitus

Complications of diabetes mellitus can occur in patients with long-standing diabetes mellitus and are divided into macrovascular complications (e.g., coronary artery disease, stroke, peripheral artery disease) and microvascular complications (e.g., diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, diabetic foot). Diabetic nephropathy is a chronic kidney disease that results from glomerular damage induced by plasma hyperfiltration and glycosylation of the basement membrane. It is often asymptomatic in the early stages, but urine studies can show findings of microalbuminuria. In later stages, patients develop nephrotic syndrome with macroalbuminuria, foamy urine, and progressive hypertension. Diabetic retinopathy is a vascular disease of the retina that is classified as nonproliferative diabetic retinopathy, proliferative diabetic retinopathy, or diabetic maculopathy. Loss of vision is typically insidious, but acute loss of vision may occasionally result from retinal detachment, vitreous hemorrhage, or macular edema. Dilated and comprehensive eye examination help diagnose and distinguish between the subtypes. Diabetic neuropathy is characterized by damage to nerve fibers, which most commonly manifests as distal symmetrical sensory loss in the lower extremities and painful paresthesias that gradually ascend in a stocking and glove distribution. Patients often have a decreased sense of vibration on tuning fork test and a decreased sense of pressure on monofilament test. The two types of diabetic foot are neuropathic diabetic foot (due to peripheral neuropathy) and ischemic diabetic foot (due to diabetes-induced peripheral artery disease). Both manifest with recurrent infections and a painless ulcer that is typically located on the sole of the foot. Additional manifestations of neuropathic diabetic foot include warm, dry skin and palpable foot pulses, while ischemic diabetic foot also manifests with cool, pale skin and no palpable pulses. Treatment of all complications mainly comprises stringent glycemic control. In diabetic nephropathy, antihypertensive treatment is necessary to prevent further damage to the kidneys. Diabetic retinopathy is treated with laser panretinal photocoagulation or injections of intravitreal anti-vascular endothelial growth factor (VEGF). Pain management (e.g., tricyclic antidepressants, selective serotonin norepinephrine reuptake inhibitors) is used in diabetic neuropathy. Foot ulcers are treated with surgical debridement and regular wound dressing.

Acute complications

• Hyperglycemic crisis: undiagnosed or insufficiently treated diabetes mellitus may result in severe hyperglycemia, potentially culminating in a crisis
  • Hyperosmolar hyperglycemic state (HHS)
  • Diabetic ketoacidosis (DKA)
• Life-threatening hypoglycemia: secondary to inappropriate insulin therapy

Long-term complications ^[1]

Macrovascular disease (atherosclerosis)

• Prevalence: more common in patients with type 2 diabetes
• Risk factors: : The major determinants are metabolic risk factors, which include obesity, dyslipidemia, and arterial hypertension. Hyperglycemia may be less related to the development of macrovascular disease.
• Manifestations
  • Coronary heart disease (most common cause of death)
  • Cerebrovascular disease
  • Peripheral artery disease (possible loss of limb)
  • Gangrene
  • Monckeberg arteriosclerosis
    • A form of arteriosclerosis characterized by calcification of the media and internal elastic lamina that do not cause significant arterial stenosis ^[2]
    • Associated with diabetes mellitus and/or progressive kidney disease
    • Usually affects small and medium size arteries in the extremities
    • Diagnostics:
      • PAD diagnostic tools are unreliable in patients with Monckeberg arteriosclerosis: The commonly used ankle-brachial index (ABI) produces falsely elevated pressure values because of the additional pressure needed to compress the stiff arterial walls.
      • X-rays show long, pipestem arteries or “railroad tracks” (calcifications)
    • In general, the disease is asymptomatic and does not require treatment. However, it is often accompanied by PAD and is therefore relevant in clinical practice.

Microvascular disease

• Onset: typically arises 5–10 years after onset of disease
• Pathophysiology: chronic hyperglycemia → nonenzymatic glycation of proteins and lipids → thickening of the basal membrane with progressive function impairment and tissue damage
• Manifestations
  • Diabetic nephropathy
  • Diabetic retinopathy, glaucoma
  • Diabetic neuropathy: motor, sensory, and autonomic nerves degeneration
  • Diabetic foot

Strict glycemic control is crucial in preventing microvascular disease

Other complications

• Necrobiosis lipoidica
• Mucormycosis (zygomycosis)
• Diabetic cardiomyopathy: a disorder of the myocardium seen in patients with diabetes ^[3]
  • Chronic hyperglycemia results in altered metabolism of glucose and fatty acids, microangiopathy with endothelial dysfunction, and autonomic neuropathy, which collectively results in cardiomyocyte hypertrophy, myocardial fibrosis, ventricular dilation, and ultimately in systolic and/or diastolic heart failure.
  • This disorder may or may not be accompanied by CVD and hypertension.
• Osmotic damage: occurs in tissues with high aldolase reductase activity and low/absent sorbitol dehydrogenase activity (e.g., eyes, peripheral nerves) → cataracts, neuropathy
• Diabetic fatty liver disease
• Hyporeninemic hypoaldosteronism ^[4]
  • Hypoaldosteronism that is caused by decreased renin activity
  • Most commonly caused by diabetic nephropathy or chronic interstitial nephritis
  • Patients present with features of hypoaldosteronism, i.e., hypotension, hyponatremia, and type 4 renal tubular acidosis.
• Limited joint mobility syndrome (formerly known as diabetic cheiroarthropathy) ^[5]
  • Manifested as stiffness of the small joints of the hand
  • Tight waxy skin, particularly on the dorsal surface of the fingers, is common.
  • Positive prayer sign: inability to approximate the palms due to flexion contractures of the PIP and MCP joints ^[6]
  • Positive tabletop test: inability to flatten the palm against the surface of a table due to the contractures in the metacarpophalangeal joints
• Sialadenosis
• Increased risk of infection

Insulin purging ^[7]

• Definition: attempting to lose weight by purposefully not injecting insulin after meals
• Population: young patients with type 1 diabetes with eating disorders use insulin purging as an alternative to fasting, vomiting, and other methods of weight loss
• Result: self-induced insulin deficiency → ↓ insulin-dependent glucose uptake in cells → ↓ anabolic effect of insulin → weight loss (no weight gain)
  • Poor glycemic control
  • Increased risk of hyperglycemic crises

Diabetic nephropathy is a major cause of end stage renal disease (ESRD).

• Pathophysiology ^[8]
  • Seen in patients with diabetes for > 10 years
  • Chronic hyperglycemia → glycation (also called non-enzymatic glycosylation or NEG) of the basement membrane (protein glycation) → increased permeability and thickening of the basement membrane and stiffening of the efferent arteriole → hyperfiltration (increase in GFR) → increase in intraglomerular pressure; → progressive glomerular hypertrophy, increase in renal size, and glomerular scarring (glomerulosclerosis) → worsening of filtration capacity
• Pathology: Three major histological changes can be seen on light microscopy. ^[9]
  • Mesangial expansion
  • Glomerular basement membrane thickening
  • Glomerulosclerosis (later stages)
    • Diffuse hyalinization (most common) or
    • Pathognomonic nodular glomerulosclerosis (Kimmelstiel-Wilson nodules):
      • Glomerular capillary hypertension and hyperfiltration → increase in mesangial matrix → eosinophilic hyaline material in the area of glomerular capillary loops
      • Can progressively consume the entire glomerulus → hypofiltration (↓ GFR) ^[10]
• Clinical features
  • Often asymptomatic; patients may complain of foamy urine
  • Progressive diabetic kidney disease with signs of renal failure and risk of uremia (e.g., uremic polyneuropathy)
  • Arterial hypertension
• Urine analysis: proteinuria ^[11][12][13]
  • Initially moderately increased albuminuria (microalbuminuria) ,
  • Eventually significantly increased albuminuria (macroproteinuria): nephrotic syndrome may develop.
• Differential diagnoses: other causes of chronic kidney disease (e.g., hypertensive nephropathy) and nephrotic syndrome
• Prevention and management
  • Stringent glycemic control
  • Antihypertensive treatment
    • ACE inhibitors OR angiotensin-receptor blockers are the first-line antihypertensive drugs in patients with diabetes.
    • Second line agents to be added to ACE inhibitors or ARBs to further control hypertension include diuretics or calcium channel blockers
  • Dietary modification: daily salt intake < 5–6 g/day; phosphorus and potassium intake restriction in advanced nephropathy; protein restriction

Microalbuminuria is the earliest clinical sign of diabetic nephropathy. The extent of albuminuria correlates with the risk of cardiovascular disease.

Early antihypertensive treatment delays the progression of diabetic nephropathy.

• Epidemiology
  • After 15 years with disease, approx. 90% of patients with type 1 diabetes and approx. 25% of patients with type 2 diabetes develop diabetic retinopathy.
  • The most common cause of visual impairment and blindness in patients aged 25–74 years in the US
• Clinical features
  • Asymptomatic until very late stages of disease
  • Visual impairment
  • Progression to blindness
• Classification ^[14]

• Screening
  • Type 1 DM: initial dilated and comprehensive eye examination within 5 years after the onset of diabetes and then annually
  • Type 2 DM: initial dilated and comprehensive eye examination at the time of the diabetes diagnosis and then annually
• Management ^[15]
  • General measurements
    • Blood sugar control
    • Blood pressure and serum lipid control to reduce the risk or slow the progression of diabetic retinopathy
  • Invasive treatment
    • Laser panretinal photocoagulation over the course of numerous appointments if the patient has severe nonproliferative retinopathy or proliferative retinopathy
    • Intravitreal anti-vascular endothelial growth factor (VEGF) injection
    • Vitrectomy rarely done in case of traction retinal detachment and vitreal hemorrhage

Distal symmetric polyneuropathy ^[16]

• Pathophysiology: : Chronic hyperglycemia causes glycation of axon proteins with subsequent development of progressive sensomotoric neuropathy; typically affects multiple peripheral nerves
• Epidemiology: Diabetic polyneuropathy is the most common form of polyneuropathy in the US.
• Clinical features
  • Early: progressive symmetric loss of sensation in the distal lower extremities
    • A stocking glove sensory loss pattern with proximal progression is typical.
    • Dysesthesia (burning feet) may occur
    • A similar sensory loss pattern may occur in the upper extremities.
  • Late: pain at rest and at night (painful diabetic neuropathy), but also decreased pain perception, motor weakness, and areflexia
• Types
  • Mononeuropathy
    • Cranial mononeuropathy
    • Peripheral mononeuropathy
    • Mononeuropathy multiplex: asymmetric neuropathy, affecting the multiple peripheral and cranial nerves
    • Diabetic truncal neuropathy
  • Diabetic lumbosacral plexopathy
    • A form of lumbosacral plexus injury caused by diabetes mellitus
    • Microvasculitis causes damage to the plexus formed by the spinal roots T12-S4, which results in a variety of symptoms, including pain in the lower back and legs and progressive weakness of the proximal legs.
• Screening
  • Tuning fork: decreased vibration sense
  • Monofilament test: decreased pressure sense
  • Pinprick (pain assessment) or temperature assessment: decreased sensation
• Treatment
  • Optimal glycemic control
  • Pain management
    • Anticonvulsants: pregabalin (most effective; usually first-choice), gabapentin, and sodium valproate
    • Antidepressants
      • Tricyclic antidepressants: amitriptyline
      • SNRI: duloxetine, venlafaxine
    • Miscellaneous: lidocaine patch, capsaicin spray, isosorbide dinitrate spray
    • Opioids: dextromethorphan, morphine sulfate, tramadol, and oxycodone

Autonomic neuropathy ^[17]

• Urogenital system
  • Erectile dysfunction (most common)
  • Bladder dysfunction: urinary retention, incomplete bladder emptying, bladder distention, overflow incontinence, poor urinary stream
• Cardiovascular system
  • Silent myocardial infarction
  • Orthostatic hypotension
  • Decreased heart variability or fixed rhythm
  • Persistent sinus tachycardia
  • Ventricular arrhythmia
• Gastrointestinal system: diabetic gastroparesis
  • Definition: delayed gastric emptying due to nonmechanical obstruction ^[18]
  • Risk factors ^[19]
    • Impaired neural control of gastric function (e.g., interstitial cells of Cajal dysfunction, abnormal myenteric neurotransmission, vagal dysfunction) → antral motor coordination and function abnormalities
    • Poor glycemic control, sustained hyperglycemia > 200 mg/dL ^[20]
  • Pathophysiology ^[19][20]
    • Poor glycemic control, sustained hyperglycemia > 200 mg/dL → neuronal damage → impaired neural control of gastric function (e.g., interstitial cells of Cajal dysfunction, abnormal myenteric neurotransmission, smooth muscle dysfunction, vagal dysfunction) → antral motor coordination and function abnormalities (↓ antral contractions, pyloric spams, abnormal antroduodenal contractions) → delayed gastric emptying
    • Abnormal small bowel motility → ↑ or ↓ gastric compliance → delayed gastric emptying
    • Autonomic neuropathy → abnormal gastric electrical activity and visceral perception
  • Clinical features
    • Nausea, vomiting
    • Bloating, upper abdominal pain
    • Loss of appetite, early satiety
  • Physical examination finding: succussion splash
  • Diagnostics: based on clinical features
    • Endoscopy: exclude mechanical obstruction
    • Scintigraphic gastric emptying (confirmatory test): shows delayed gastric emptying
    • CT or MRI: if endoscopy is inconclusive
  • Treatment
    • Conservative (first-line)
      • Glycemic control, dietary modifications
      • Prokinetics (e.g., metoclopramide) and antiemetics (e.g., diphenhydramine, ondansetron)
    • Invasive (e.g., decompressive endoscopy): if conservative treatment fails
    • Surgery (e.g., venting gastrostomy or jejunostomy): refractory symptoms
  • Complications: electrolyte imbalance, malnutrition, increased risk of postprandial hypoglycemia
• Other manifestations
  • Sweat gland dysfunction associated with heat intolerance
  • Pupillary dysfunction ^[21]
  • Risk of hypoglycemia due to absence of hormonal counterregulation (secretion of cortisol, glucagon, and catecholamines)

• Classification
  • Neuropathic diabetic foot: diabetes-induced peripheral neuropathy ^[22]
  • Ischemic diabetic foot: diabetes-induced peripheral artery disease
• Clinical features
  • Recurrent foot infections (e.g., athlete's foot, cellulitis) and cutaneous lesions that may be painless
  • Malum perforans: painless neuropathic ulcers (usually located on the plantar pressure points of the foot; over the head of the metatarsal bones or the heel)
    • Major risk factors include peripheral sensory neuropathy, autonomic neuropathy, microvascular changes, as well as macrovascular disease.
    • Complex, multifactorial pathophysiology
  • Foot deformities (e.g., hammer toe, hallux valgus)
• Diagnostics
  • Physical examination
    • Neuropathic diabetic foot: warm, dry skin, foot pulses are palpable
    • Ischemic diabetic foot: cool, pale foot with no palpable pulses
  • Neurological examinations: evaluation of peripheral neuropathy
  • Examination for peripheral artery disease: ankle-brachial index testing
  • Foot ulcer risk assessment: See “Screening” in “Diabetic polyneuropathy” above.
• Treatment
  • Surgical debridement
  • Regular wound dressing
  • Mechanical offloading: fitting of therapeutic footwear or total contact cast
  • Antibiotic therapy if foot ulcers become infected
  • Interventional or surgical revascularization: in patients with underlying peripheral artery disease
  • Amputation if all else fails or severe life-threatening complications arise (e.g., osteomyelitis)
• Complications
  • Secondary infection of foot ulcers: may lead to cellulitis and acute or chronic osteomyelitis
    • Osteomyelitis should be suspected in any patient with an ulcer and one or more of the following features:
      • Local signs of infection (e.g., erythema, pus)
      • Ulcer size > 2 cm² and/or ulcer depth > 3 mm
      • Exposed bone tissue
      • Positive probe-to-bone test
        • A clinical test to evaluate for osteomyelitis related to chronic ulcers
        • A sterile blunt probe is inserted into the ulcer → direct contact of the probe to bone indicates potential underlying osteomyelitis
      • Chronic (≥ 4 weeks) and/or treatment-resistant ulcers
      • An ulcer overlying a bony prominence
      • Markedly increased ESR without explanation
  • Diabetic neuropathic arthropathy (Charcot foot)
    • Exact cause is unknown
    • Decreased pain and pressure perception, abnormal strain and weight distribution, as well as autonomic neuropathy that increases perfusion with a subsequent "washing out" of bone substance is suspected
    • Deformation of joints and bones; tarsus and tarsometatarsal joints most commonly affected.
      • Acute: swelling, warmth, erythema
      • Chronic: painless bony deformities, midfoot collapse, osteolysis, risk of fractures
• Prevention
  • Glycemic control
  • Regular foot examinations
  • Self-monitoring and proper foot care

In about one third of patients with diabetic foot, the underlying cause is both ischemic and neuropathic.