Last reviewed: 25 Sep 2021
Last updated: 07 Apr 2021



History and exam

Key diagnostic factors

  • asymptomatic
  • pain (peripheral)
  • loss of sensation (peripheral)
  • dysesthesia (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)

Other diagnostic factors

  • constipation (autonomic)
  • fecal incontinence (autonomic)
  • anhidrosis, heat intolerance, dry skin, or hyperhidrosis (autonomic)
  • hypoglycemia 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 diarrhea (autonomic)
  • specific mononeuropathy (peripheral)
  • cranial neuropathy (peripheral)
  • pain over lower thoracic or abdominal wall (peripheral)
  • thigh muscle atrophy, pain, and weakness (peripheral)

Risk factors

  • poorly controlled hyperglycemia
  • prolonged duration of diabetes
  • older age (e.g., >70 years)
  • tall stature
  • hypertension
  • dyslipidemia with elevated triglycerides
  • co-existence of multiple cardiovascular disease (CVD) risk factors (type 2 diabetes)
  • obesity
  • immune dysregulation
  • smoking

Diagnostic investigations

1st investigations to order

  • clinical diagnosis
  • fasting blood glucose
  • HbA1c
  • serum thyroid-stimulating hormone
  • serum vitamin B12
  • electrolytes, BUN, creatinine
  • serum lipid profile
  • LFTs
  • CBC and erythrocyte sedimentation rate
  • serum/urine immunoelectrophoresis
  • corneal confocal microscopy

Investigations to consider

  • 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
  • gastroduodenoscopy
  • surface electrogastrography
  • barium meal
  • gastrointestinal manometry
  • hydrogen breath tests
  • gastric ultrasonography
  • gastric MRI
  • anorectal manometry
  • fecal fat
  • d-xylose test
  • urine culture
  • cystometry, voiding cystometrogram
  • postvoid urinary tract ultrasound
  • video-urodynamics
  • 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
  • microneurography

Treatment algorithm



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 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

Consultant Physician

Diabetes and Endocrinology

Central Manchester Foundation Trust

University of 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.

Peer reviewers

Zachary T. Bloomgarden, MD

Clinical Professor

Department of Medicine

Mount Sinai School of Medicine

New York



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

Diabetes Centre

Ashton Under Lyne




EJ has received funding for conferences and lectures from Pfizer and Boehringer Ingelheim.

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