Non-Diabetic hypoglycemia– Causes, Symptoms, Diagnosis, Treatment and Ongoing care



  • Hypoglycemia defined by Whipple triad:
    • Low plasma glucose level (≤60 mg/dL)
    • Hypoglycemic symptoms that are relieved when glucose level is corrected
    • Occurs commonly in patients with diabetes receiving sulfonylurea or insulins; less commonly in patients without diabetes
  • Reactive hypoglycemia:
    • Occurs in response to a meal, drugs, herbal substances or nutrients
    • May occur 2–3 hours postprandially or later
    • Symptoms generally observed with serum glucose ≤60 mg/dL, lower in patients with hypoglycemic unawareness
    • Also seen after gastrointestinal surgery (in association with dumping syndrome in some patients)
  • Spontaneous (fasting) hypoglycemia:
    • May be associated with a primary condition, including hypopituitarism, Addison disease, myxedema, or in disorders related to hepatic dysfunction or renal failure
    • If hypoglycemia presents as a primary disorder, consider hyperinsulinism, and extrapancreatic tumors.



  • True incidence is unknown.
  • 8.6% of hospitalized inpatients ≥65 years old:
    • Asymptomatic in 25% of cases


True prevalence is unknown.

  • Predominant age: Older adult
  • Predominant sex: Female > male

Risk Factors

Refer to “Etiology”


Some aspects may involve genetics (e.g., hereditary fructose intolerance).

General Prevention

  • Follow dietary and exercise guidelines
  • Patient recognition of early symptoms and knowledge of corrective action


  • Reactive, postprandial:
    • Alimentary hyperinsulinism
    • Meals high in refined carbohydrate
    • Certain nutrients including fructose, galactose, leucine
    • Glucose intolerance (prediabetes)
    • Gastrointestinal surgery
    • Idiopathic (unknown cause)
  • Spontaneous
    • Fasting
    • Alcohol or medication (insulin, sulfonylureas, thiazolidinediones, beta-blockers, salicylates, quinine, hydroxychloroquine, fluoroquinones, doxycycline, sertraline, disopyramide, pentamidine)
    • Consider medication errors as a source of unexplained hypoglycemia even in patients without diabetes
    • Surreptitious drug use (self-injection of insulin or ingestion of oral hypoglycemic medications in patients with diabetes
    • Natural medicines or herbs (bitter melon, caffeine, cassia cinnamon, chromium, fenugreek, ginseng, guarana, mate, stevia, vanadium)
    • Post surgical (e.g., gastrectomy, Roux-en-Y) hypoglycemia/dumping syndrome
    • Islet cell hyperplasia or tumor (insulinoma)
    • Extrapancreatic insulin secreting tumor
    • Hepatic disease
    • Glucagon deficiency
    • Adrenal insufficiency
    • Catecholamine deficiency
    • Hypopituitarism
    • Hypothyroidism
    • Eating disorders
    • Exercise
    • Fever
    • Pregnancy
    • Renal glycosuria
    • Large tumors
    • Ketotic hypoglycemia of childhood
    • Enzyme deficiencies or defects
    • Severe malnutrition
    • Sepsis
    • Total parenteral nutrition therapy
    • Hemodialysis

Pediatric Considerations

  • Usually divided into 2 syndromes
  • Transient neonatal hypoglycemia
  • Hypoglycemia of infancy and childhood
  • Screening infants for hypoglycemia is appropriate when pregnancy was complicated by maternal diabetes.

Geriatric Considerations

  • More likely to have underlying disorders or be causative medications
  • Iatrogenic hypoglycemia is common in the hospitalized elderly with renal insufficiency.

Commonly Associated Conditions

  • Severe liver disease; alcoholism
  • Addison disease; adrenocortical insufficiency
  • Myxedema
  • Malnutrition (patients with renal failure)
  • Gastrointestinal surgery
  • Panhypopituitarism
  • Insulinoma

Diabetes mellitus, Endocrine Disorders, hereditary fructose intolerance, plasma glucose, addison disease, dumping syndrome, renal failure,



  • Central nervous system (CNS; neuroglycopenic) symptoms predominate with gradual glucose reduction:
    • Headache
    • Confusion
    • Lightheadedness
    • Fatigue and weakness
    • Visual disturbances
    • Changes in personality
  • Adrenergic symptoms: More prominent in acute drop in glucose:
    • Anxiety
    • Tremulousness
    • Dizziness
    • Diaphoresis
    • Warmth/flushing
    • Heart palpitations
  • Gastrointestinal symptoms:
    • Hunger
    • Nausea
    • Belching

Physical Exam

  • CNS (neuroglycopenic) symptoms predominate with gradual glucose reduction:
    • Convulsions
    • Coma
    • Hypotension
  • Adrenergic symptoms: More prominent in acute drop in glucose:
    • Tremulousness
    • Diaphoresis
    • Warmth/flushing
    • Heart palpitations

Diagnostic Tests & Interpretation


Initial lab tests

Blood glucose ≤45 mg/dL (≤2.5 mmol/L) when symptomatic followed by symptom resolution with feeding (1,2)[C]

  • Plasma glucose overnight fasting: ≤60 mg/dL (≤3.33 mmol/L); confirm on 2 or more occasions (2)[C]
  • Plasma glucose 72-hour fasting: ≤45 mg/dL (≤2.5 mmol/L) for females; ≤55 mg/dL (≤3.05 mmol/L) for males; fast may be ended when Whipple triad is achieved or hypoglycemia is demonstrated (2)[C]

Follow-Up & Special Considerations

  • Oral glucose tolerance: ≤50 mg/dL (≤2.78 mmol/L) (1,2)[C]
  • Misinterpretation of glucose tolerance tests may lead to misdiagnosis of hypoglycemia; ≥1/3 of normal patients have hypoglycemia with or without symptoms during the 4-hour glucose tolerance test. These patients may be at future risk for type 2 diabetes.
  • C-peptide measurement (2)[C]
  • Check liver studies, serum insulin, ACTH, and cortisol. Serum insulin should be suppressed when glucose is <60 mg/dL (2)[C].
  • Serum b-hydroxybutyrate
  • Insulin radioimmunoassay: Elevated insulin levels suggest islet cell hyperplasia or tumor (2)[C].
  • Drugs may alter lab results: Many drugs can affect glucose levels; refer to drug or laboratory reference (2)[C].


Initial approach

Abdominal CT to rule out abdominal tumor

Diagnostic Procedures/Surgery

For definitive diagnosis patient should have:

  • Documented low glucose levels (2)
  • Symptoms when glucose levels are low (2)
  • Evidence that symptoms are relieved specifically by ingestion of sugar or other food (2)
  • Identification of the specific type of hypoglycemia (2)
  • Serum b-hydroxybutyrate <2.7 mg/dL in the presence of high serum insulin, C-peptide, and low serum glucose suggests excessive insulin production

Differential Diagnosis

CNS disorders

  • Psychogenic
  • Pseudohypoglycemia: Symptoms of hypoglycemia or self-diagnosis in patients in whom low blood glucose may not be detectable and who may be impossible to convince that they do not suffer from hypoglycemia after all tests are found to be normal.



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  • Once diagnosis is established, begin therapy appropriate to underlying disorder.
  • If unable to swallow: Glucagon 1mg (1unit) IM or SC. If no response, give IV bolus of 25–50 g of 50% glucose solution followed by continuous infusion until patient able to take by mouth (1)[C].
  • Postsurgical gastrectomy patients unresponsive to diet changes may benefit from propantheline, psyllium, fiber or oat bran, which delays gastric emptying (1)[C].
  • Insulinoma: See separate topic.

Additional Treatment

General Measures

  • Outpatient except for severe cases; may also be inpatient for testing
  • Oral carbohydrate for alert patient without drug overdose (2–3 tablespoons of sugar in glass of water or fruit juice, 1–2 cups of milk, piece of fruit, or several soda crackers) (1)[C]
  • If unable to swallow: Use glucagon IM or SC (1)[C].
  • If caused by medication or nutrients: Avoid or control causative agents (1)[C].
  • If triggered by meals: Try high-protein diet with carbohydrate restriction (1)[C].
  • Nonhypoglycemic hypoglycemia or pseudohypoglycemia:
    • Many patients (often females, aged 20–45) present with diagnosis of reactive hypoglycemia (self-diagnosed or misinterpretation of tests)
    • Symptoms may pertain to chronic fatigue and somatic complaints (stress often playing a role in these symptoms)
    • Management difficult, listening is important. Try 120 g carbohydrate diet (1)[C].
    • Counseling may be useful for stress and other problems

Surgery/Other Procedures

If Islet cell tumor (insulinoma) or other insulin secreting tumor, surgery is treatment of choice. If inoperable, diazoxide may relieve symptoms.

In-Patient Considerations

Admission Criteria

Hypoglycemia unresponsive to oral intake

Ongoing Care

Follow-Up Recommendations

  • Exercise routine or daily activity may need to be reevaluated.
  • Patients with recurrent hypoglycemia should have glucose source at hand for immediate ingestion during symptoms.

Patient Monitoring

  • Depends on type and severity of symptoms and treatment of underlying cause
  • Hypoglycemia from sulfonylureas can last for hours to days depending on half-life and renal function.


  • High protein, low carbohydrate
  • Frequent small feedings (6 daily)
  • Avoid fasting

Patient Education

  • Dietary instruction
  • Counseling for stress, if appropriate
  • Recognition of early symptoms of hypoglycemia and how to take corrective action


Favorable, with appropriate treatment


  • Insulinoma: If tumor identified and removed, some surgical risk is involved.
  • Organic brain syndrome: May occur with extensive, prolonged hypoglycemia


1. Carroll MF, Burge MR, Schade DS. Severe hypoglycemia in adults. Rev Endocr Meta Dis. 2003;4(2):149–57.

2. Service FJ. Classification of hypoglycemic disorders. Endocrinol Metab Clin North Am. 1999;28:501–17, vi.

Additional Reading

Burmeister JE, Scapini A, da Rosa Miltersteiner D et al. Glucose-added dialysis fluid prevents asymptomatic hypoglycaemia in regular haemodialysis. Nephrol Dial Transplant. 2007;22:1184–9.

Cansu DU, Korkmaz C. Hypoglycaemia induced by hydroxychloroquine in a non-diabetic patient treated for RA. Rheumatology (Oxford). 2008;47:378–9.

Lawrence KR, Adra M, Keir C. Hypoglycemia-induced anoxic brain injury possibly associated with levofloxacin. J Infect. 2006;52:e177–80.

Pollak PT, Mukherjee SD, Fraser AD. Sertraline-induced hypoglycemia. Ann Pharmacother. 2001;35:1371–4.

Singh M, Jacob JJ, Kapoor R, et al. Fatal hypoglycemia with levofloxacin use in an elderly patient in the post-operative period. Langenbecks Arch Surg. 2008;393:235–8.

Yamada C, Nagashima K, Takahashi A, et al. Gatifloxacin acutely stimulates insulin secretion and chronically suppresses insulin biosynthesis. Eur J Pharmacol. 2006;553:67–72.

See Also (Topic, Algorithm, Electronic Media Element)

Hypoglycemia, Diabetic; Insulinoma

Algorithm: Hypoglycemia



251.2 Hypoglycemia, unspecified


237637005 non-diabetic hypoglycemia (disorder)

Clinical Pearls

  • Symptoms coincide with low blood glucose levels.
  • Symptoms resolve with oral/intravenous glucose or glucagon.
  • Avoid known agents/nutrients that trigger hypoglycemia.
  • Treat underlying cause.

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