Hyperinsulinemic Hypoglycemia

  • Diagnosis
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Symptomatic hypoglycemia without other evident etiology

Laboratory Testing

  • Classic lab finding is hypoketotic hypo-fatty-acidemic hypoglycemia
  • Random blood sugar
    • Cutoffs used vary by guideline
      • Typical definition – glucose ≤60 mg/dL
    • Patient may need to be fasting to detect hypoglycemia
    • Confirm hypoglycemia with at least two additional tests
  • Insulin – random or fasting; fasting preferred
    • Inappropriate insulin level during episode of hypoglycemia suggests diagnosis
    • Low or undetectable insulin virtually excludes diagnosis
    • If clinical picture is neonatal hyperinsulinemic hypoglycemia (HH), then consider rarer disorders (AKT2 hypoinsulinemic hypoglycemia)
    • Insulin alone may not be informative and should be considered in conjunction with C-peptide
  • C-peptide – usually ≥0.6 ng/mL (elevated)
    • Low C-peptide, markedly elevated insulin – suggests exogenous insulin
    • High C-peptide, elevated insulin – insulinoma or exogenous use of sulfonylureas or metformin
      • Perform serum/urine sulfonylureas and metformin testing
  • Beta hydroxybutyrate and free fatty acids  – typically low (suppressed values)
    • If elevated, consider testing for fatty acid oxidation disorders
  • Provocative fasting for infants and children may be useful – requires close monitoring
  • Glucagon provocation testing
    • When diagnosis is in doubt and usually in adults
      • Injection of 0.5-1 mg (IV or IM) of glucagon with pre- and post-glucose levels
      • Increase in plasma glucose >30 mg/dL post-glucagon administration confirms hyperinsulinemic hypoglycemia
  • Genetic testing for infantile forms – treatment response is often gene-dependent
    • KCNJI1, ABCC8 mutations
      • Most common genetic causes
      • Poor response to diazoxide – often requires surgery
    • GLUD1, HADH, and HNF4A mutations – good response to diazoxide

Differential Diagnosis

  • Postprandial hyperinsulinemic hypoglycemia
    • Dumping syndrome
    • Post-gastric bypass surgery
    • Insulin autoimmune syndrome
  • Insulinoma
  • Drugs
    • Surreptitious use of oral antihyperglycemics or insulin
    • Beta blockers
    • Antiarrhythmics
    • Interferon
    • Triptan
  • Adrenal insufficiency
  • Unusual
    • Maternal DM
    • Perinatal asphyxiation
    • Intrauterine growth restriction
    • Rhesus isoimmunization
    • ​Hypoinsulinemic hypoglycemia (AKT2 mutation)

Hypoglycemia may constitute a medical emergency because it can result in permanent neurologic defects.

Epidemiology

  • Incidence of hypoglycemia
    • Newborns – 1-3/1,000 live births
    • Familial forms – 1/50,000 in sporadic populations (higher incidence in Ashkenazi Jews)
    • Diabetic patients
      • Type 1 – 10-30% annually
      • Type 2 – 1-2% annually
  • Age
    • Neonatal forms – infancy
    • Adult forms – 25-45 years; depends on risk factors
  • Definition of hypoglycemia
    • Glucose <50 mg/dL
    • Glucose <60 mg/dL plus signs and symptoms of hypoglycemia

Risk Factors

  • Infants or newborns
    • Previous hyperinsulinemic hypoglycemia (HH)
    • Genetic
      • Identified gene defects – ABCC8KCNJ11GLUD1GCKHADH, SLC16A1HNF4A, HNF1A, UCP2
        • ABCC8 and KCNJ11 most common
      • Developmental syndromes associated with HH (Arnoux, 2011)
        • Beckwith-Wiedemann syndrome (BWS)
        • Sotos syndrome
        • Simpson-Golabi-Behmel syndrome
        • Perlmann syndrome
        • Ondine syndrome
        • Kabuki syndrome
        • Costello syndrome
        • Timothy syndrome
        • Usher syndrome 1c
        • Congenital disorder of glycosylation syndrome (1a and 1b)
    • Perinatal stress (eg,intrauterine growth retardation, maternal preeclampsia)
    • Maternal diabetes mellitus (DM)
    • Premature or postmature delivery
  • Children
    • DM – highest risk in patients receiving insulin
    • Medication abuse
      • Insulin
      • Oral hypoglycemic agents
  • Adults
    • DM – highest risk in patients receiving insulin
    • Medication abuse
      • Insulin
      • Oral hypoglycemic agents
    • Insulinoma
    • Insulin autoantibodies
    • Autoimmune diseases
    • Post bariatric surgery patients (gastric bypass procedures)
    • Diffuse nesidioblastosis

Pathophysiology

  • Dysregulated insulin secretion with defects in glucose counter-regulatory hormones
  • Insulin drives glucose into sensitive tissues (liver, adipose, skeletal muscle), which can cause profound hypoglycemia
  • Simultaneous inhibition of glycogenolysis, gluconeogenesis, lipolysis and ketogenesis
  • Nesidioblastosis (abnormally enlarged islets, hypertrophic beta cells, and periductal cells in the pancreas) is the likely explanation for pathology in gastric bypass patients

Clinical Presentation

  • Adults and children
    • Lethargy, confusion, anxiety, sweating
    • Nausea
    • Focal neurologic defects
    • Seizures
    • Gastric bypass patients may experience symptoms as late as 1-2 years post procedure and usually 1-3 hours postprandially
  • Infants and newborns
    • Lethargy, floppiness, sweating
    • Poor feeding, apnea, seizures, coma
    • Recurrent hypoglycemia can cause neurologic damage
    • BWS infants – omphalocele, macrosomia, macroglossia, microcephaly, visceromegaly
      • 50% have hyperinsulinemic hypoglycemia – usually transient and resolves by 3-6 months
    • Hypoglycemias associated with nongenetic disorders tend to be transient and resolve spontaneously after several months
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Glucose, Plasma or Serum 0020024
Method: Quantitative Enzymatic

Insulin, Fasting 0070063
Method: Quantitative Chemiluminescent Immunoassay

C-Peptide, Serum or Plasma 0070103
Method: Quantitative Chemiluminescent Immunoassay

Beta-Hydroxybutyric Acid 0080045
Method: Quantitative Enzymatic

Fatty Acids, Free 0080120
Method: Quantitative Spectrophotometry

Hypoglycemia Panel, Sulfonylureas Qualitative, Serum or Plasma 2010292
Method: Qualitative Liquid Chromatography-Tandem Mass Spectrometry

Limitations 

Cutoff concentrations vary by drug

Sulfonylurea Hypoglycemia Panel, Quantitative, Urine 0091100
Method: Quantitative Liquid Chromatography/Tandem Mass Spectrometry

Metformin Quantitative, Serum or Plasma 0092390
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Metformin Quantitation, Urine 2002928
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Proinsulin, Intact 0070112
Method: Quantitative Chemiluminescent Immunoassay

Guidelines

Thornton PS, Stanley CA, De León DD, Harris D, Haymond MW, Hussain K, Levitsky LL, Murad MH, Rozance PJ, Simmons RA, Sperling MA, Weinstein DA, White NH, Wolfsdorf JI, Pediatric Endocrine Society. Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children. J Pediatr. 2015; 167(2): 238-45. PubMed

General References

Arnoux J, Verkarre V, Saint-Martin C, Montravers F, Brassier A, Valayannopoulos V, Brunelle F, Fournet J, Robert J, Aigrain Y, Bellanné-Chantelot C, de Lonlay P. Congenital hyperinsulinism: current trends in diagnosis and therapy. Orphanet J Rare Dis. 2011; 6: 63. PubMed

Arya VBhushan, Flanagan SE, Schober E, Rami-Merhar B, Ellard S, Hussain K. Activating AKT2 mutation: hypoinsulinemic hypoketotic hypoglycemia. J Clin Endocrinol Metab. 2014; 99(2): 391-4. PubMed

De León DD, Stanley CA. Determination of insulin for the diagnosis of hyperinsulinemic hypoglycemia. Best Pract Res Clin Endocrinol Metab. 2013; 27(6): 763-9. PubMed

Flanagan SE, Kapoor RR, Hussain K. Genetics of congenital hyperinsulinemic hypoglycemia. Semin Pediatr Surg. 2011; 20(1): 13-7. PubMed

Güemes M, Hussain K. Hyperinsulinemic Hypoglycemia. Pediatr Clin North Am. 2015; 62(4): 1017-36. PubMed

Kapoor RR, James C, Hussain K. Advances in the diagnosis and management of hyperinsulinemic hypoglycemia. Nat Clin Pract Endocrinol Metab. 2009; 5(2): 101-12. PubMed

Raffel A, M MKrausch, Anlauf M, Wieben D, Braunstein S, Klöppel G, Röher H, Knoefel WTrudo. Diffuse nesidioblastosis as a cause of hyperinsulinemic hypoglycemia in adults: a diagnostic and therapeutic challenge. Surgery. 2007; 141(2): 179-84; discussion 185-6. PubMed

Medical Reviewers

Last Update: August 2016