TABLE 1.

Diagnostic Steps and Management Recommendations for Diabetic Neuropathy

Type of Neuropathy	Symptoms	Clinical Signs		Diagnosis	Management Recommendations
DSPN	Burning pain	Tests for small-fiber unction:		Assess symptoms (history taking)	Prevention
	Lancinating or shooting pain	Pinprick (push pin)		Assess clinical signs	Glucose control targeting near-normal glycemia: strong evidence for type 1 diabetes; modest data for type 2 diabetes
	Paresthesias (tingling and prickling sensation)	Temperature sensation discrimination		Confirm pattern for symptoms and signs:	Lifestyle modifications: emerging as effective treatment strategies in patients with IGT/metabolic syndrome or type 2 diabetes
	Hyperalgesia (exaggerated response to painful stimuli)	Tests for large-fiber function:		Distal-to-proximal (stocking-glove)	Prevention of foot complications
	Allodynia (pain evoked by light touch)	Vibration perception (128-Hz tuning fork)		Symmetrical	Pain treatment (see Figure 1)
	Note. Neuropathic pain may be the first symptom that prompts patients to seek medical care.	Proprioception		Combine at least two of the small- and large-fiber tests listed in the previous column (e.g., pinprick plus vibration) for higher sensitivity and specificity	Anticonvulsants:
		Light touch to 10-g monofilament (on dorsal aspect of the great toe bilaterally)		Differential (as applicable):	Pregabalin* 150–600 mg/day
		Ankle reflexes		Family/medication history	Gabapentin 1,800–3,600 mg/day
				Serum B12	Monoamine reuptake inhibitors:
				Folic acid	• Selective norepinephrine-serotonin reuptake inhibitors
				Thyroid function	Duloxetine* 60–120 mg/day
				Complete blood count	Venlafaxine 150–225 mg/day
				Metabolic panel	Tricyclic antidepressants
				Serum protein immunoelectrophoresis	Amitriptyline 25–100 mg/day (with titration)
		Note. Electrophysiological testing or referral to a neurologist is rarely needed in clinical practice except for situations in which clinical features are atypical and a different etiology is suspected (i.e., motor greater than sensory neuropathy, asymmetry of symptoms and signs, or rapid progression).			Nortriptyline 25–100 mg/day (with titration)
					Desipramine titrate from 12.5 to 100–150 mg/day
					Warning. Opioids are not recommended for DSPN pain as first-, second-, or third-line agents given their high risk of addiction, abuse, and serious adverse events.
Diabetic autonomic neuropathies
CAN	Lightheadedness	Reduced HRV	Document symptoms		Prevention
	Weakness	Resting tachycardia (>100 bpm)	Document signs		Glucose control targeting near-normal glycemia: strong evidence for type 1 diabetes, controversial data for type 2 diabetes
	Faintness	Exercise intolerance	Consider ECG recordings with deep breathing		Lifestyle modifications: emerging as effective treatment strategies in patients with impaired glucose tolerance/metabolic syndrome, and type 2 diabetes
	Palpitations	Orthostatic hypotension (a fall in systolic or diastolic blood pressure of >20 or >10 mmHg, respectively, upon standing)	Differential (as applicable):		Treatment for orthostatic hypotension
	Syncope		Anemia		Non-pharmacological:
	Note. All symptoms occur upon standing.		Hyperthyroidism		Physical activity
			Dehydration		Volume repletion with fluids
			Adrenal insufficiency		Pharmacological:
			Smoking		Midodrine* (peripheral, selective, direct α1-adrenoreceptor agonist); 2.5–10 mg up to 3 times/day, with titration; use lowest effective dose, first dose before arising
			Alcohol		Droxidopa** (α/β adrenergic agonist)
			Caffeine		Dietary changes
			Medications (e.g., sympathomimetics, over-the-counter cold agents containing ephedrine or pseudoephedrine, recreational drugs, and dietary supplements)		Eating multiple small meals
Gastrointestinal neuropathy (gastroparesis)	Early satiety	Clinically silent in the majority of cases	Careful medication history		Decreasing fat and fiber intake
	Fullness and bloating	Glucose variability and unexplained hypoglycemia (due to the dissociation between food absorption and the pharmacokinetic profiles of insulin and other agents)	Esophagogastroduodenoscopy or barium study to exclude organic causes of gastric outlet obstruction or peptic ulcer disease		Withdrawing drugs with effects on motility: opioids, anticholinergics, tricyclic antidepressants, GLP-1 receptor agonists, pramlintide
	Nausea, vomiting, or dyspepsia		Gastric emptying with scintigraphy of digestible solids (gold standard if above tests are negative)		Medication
	Abdominal pain		13C-octanoic acid breath test (emerged as an easier alternative)		Metoclopramide*** 5–10 mg 3–4 times/day (prokinetic agent, weak evidence, risk of serious adverse effects, tardive dyskinesia)
	Note. Symptoms are nonspecific and do not correspond with severity of gastroparesis or abnormal gastric emptying

Adapted from ref. 1.

^*FDA-approved.

^**FDA-approved for the treatment of neurogenic orthostatic hypotension but not specifically for orthostatic hypotension due to diabetes.

^***FDA-approved for up to 5 days of use.