Hyperglycaemia contributes to the pathogenesis of neuropathy in both type 1 and type 2 diabetes. Other metabolic and vascular factors, particularly hypertriglyceridaemia, are important.
The clinical presentation comprises a broad constellation of symptoms and deficits, involving sensory, motor, and autonomic nerve fibres, and multiple organ systems.
Diabetic peripheral neuropathy is the most common chronic complication of diabetes, characterised by the presence of peripheral nerve dysfunction, diagnosed after the exclusion of other causes. Pain is the outstanding complaint in most patients, but many patients are completely asymptomatic.
Treatment has traditionally focused on control of hyperglycaemia as a means of slowing progression or delaying onset, on targeting potential pathogenic mechanisms, and on pain reduction.
Although pain is generated principally by peripheral nerve injury, there is recent evidence that the central nervous system may play a significant role in the disinhibition and amplification of pain. Indeed, the most effective drugs in treating painful diabetic neuropathy are centrally acting. Pregabalin (a voltage-gated calcium channel modulator), duloxetine (a selective dual serotonin-noradrenaline reuptake inhibitor), and tapentadol (an agonist of the mu-opioid receptor and noradrenaline reuptake inhibitor) are the only prescription drugs currently approved for treating painful diabetic neuropathy in some countries.
Diabetic neuropathy (DN) is a highly prevalent complication of diabetes (type 1 or type 2) and is characterised by the presence of symptoms and/or signs of peripheral nerve dysfunction and/or autonomic nerve dysfunction. It is diagnosed after the exclusion of other causes. Frequently, however, people with DN are asymptomatic.
History and exam
- presence of risk factors
- pain (peripheral)
- loss of sensation (peripheral)
- dysaesthesia (peripheral)
- reduced or absent ankle reflexes (peripheral)
- painless injuries (peripheral)
- resting tachycardia (autonomic)
- impaired heart rate variability (autonomic)
- urinary frequency, urgency, nocturia, incontinence, hesitancy, weak stream, or retention (autonomic)
- erectile dysfunction (autonomic)
- decreased sexual desire and increased pain during intercourse (autonomic)
- orthostatic hypotension (autonomic)
- constipation (autonomic)
- faecal incontinence (autonomic)
- anhidrosis, heat intolerance, dry skin, or hyperhidrosis (autonomic)
- hypoglycaemia unawareness (autonomic)
- weakness (peripheral)
- history of recent falls (peripheral)
- gait ataxia (peripheral)
- nausea, postprandial vomiting, bloating, loss of appetite, early satiety (autonomic)
- heartburn and dysphagia for solids (autonomic)
- profuse and watery diarrhoea (autonomic)
- specific mononeuropathy (peripheral)
- cranial neuropathy (peripheral)
- pain over lower thoracic or abdominal wall (peripheral)
- thigh muscle atrophy, pain, and weakness (peripheral)
- poorly controlled hyperglycaemia
- prolonged duration of diabetes
- older age (e.g., >70 years)
- tall stature
- dyslipidaemia with elevated triglycerides
- co-existence of multiple cardiovascular disease (CVD) risk factors (type 2 diabetes)
- immune dysregulation
- clinical diagnosis
- fasting blood glucose
- serum thyroid-stimulating hormone
- serum vitamin B12
- electrolytes, urea, creatinine
- serum lipid profile
- FBC and erythrocyte sedimentation rate
- serum/urine immunoelectrophoresis
- corneal confocal microscopy
- oral glucose tolerance test
- nerve conduction studies (nerve conduction velocity [NCV])
- electromyography (EMG)
- quantitative sensory testing (QST)
- skin biopsy
- cardiovascular reflex testing
- heart rate variability (HRV)
- gastric emptying studies
- surface electrogastrography
- barium meal
- gastrointestinal manometry
- hydrogen breath tests
- gastric ultrasonography
- gastric MRI
- anorectal manometry
- faecal fat
- d-xylose test
- urine culture
- cystometry, voiding cystometrogram
- post-void urinary tract ultrasound
- measurement of nocturnal penile tumescence and of penile and brachial BP
- serum LH, testosterone, free testosterone, prolactin (morning tests, 8.00-9.00 a.m.)
- sudomotor function tests
- scintigraphic studies
- assessment of sympathetic muscle activity
- cardiac vagal baroreflex sensitivity testing
- 24-hour BP profile
Rayaz A. Malik, BSc (Hons), MSc, MBChB, FRCP, PhD
Professor of Medicine
Organizational Official for the Human Research Protection Program
Weill Cornell Medicine - Qatar
RAM is on speaker panels for Eli Lilly, Novo Nordisk, and Pfizer; he is on advisory boards for Novo Nordisk and Pfizer. RAM is an author of a number of references cited in this topic.
Uazman Alam, BSc, MBChB, MPHe, PhD
Senior Lecturer and Consultant Physician
University of Liverpool
UA serves on advisory boards for Eli Lilly.
Shazli Azmi, MBchB, MRCP
Diabetes and Endocrinology
Central Manchester Foundation Trust
University of Manchester Manchester
SA declares that she has no competing interests.
Dr Rayaz Malik, Dr Uazman Alam, and Dr Shazli Azmi would like to gratefully acknowledge Dr Rodica Pop-Busui and Dr Eva Feldman, the previous contributors to this topic.
RPB declares that she has received speaking honoraria from Pfizer and research support from Amylin Pharmaceuticals; National Institutes of Health/National Heart, Lung, and Blood Institute; National Institute of Health/National Institute of Diabetes and Digestive and Kidney Diseases; American Diabetes Association; and Juvenile Diabetes Research Foundation. RPB and EF are authors of references cited in this topic.
Zachary T. Bloomgarden, MD
Department of Medicine
Mount Sinai School of Medicine
ZTB declares that he has no competing interests.
Rajesh K. Garg, MD
Assistant Professor of Medicine
Harvard Medical School
Division of Endocrinology
Diabetes and Hypertension
Brigham and Women's Hospital
RKG has received consultant fees from Aventis and Novartis, and speaker fees from Novartis.
Edward Jude, MBBS, MD, MRCP, DNB
Consultant and Honorary Senior Lecturer
Tameside General Hospital
Ashton Under Lyne
EJ has received funding for conferences and lectures from Pfizer and Boehringer Ingelheim.
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