Hyperinsulinemic Hypoglycemia

Symptomatic hypoglycemia that is corrected with the administration of glucose is characteristic of hyperinsulinemic hypoglycemia. The cause should be investigated so that underlying conditions can be corrected. Hypoglycemia may constitute a medical emergency, as it can result in permanent neurologic defects or death. Patient history (eg, diabetes, drug history) should guide the investigation. Laboratory testing includes plasma glucose, insulin, proinsulin, insulin antibodies, C-peptide, beta-hydroxybutyrate, fatty acids, and therapeutic drug testing. A classic lab finding is hypoketotic hypo-fatty-acidemic hypoglycemia.

Diagnosis

Indications for Testing

  • Whipple’s triad
    • Symptomatic hypoglycemia
    • Documented low plasma glucose with validated test during symptomatic episode
    • Correction of symptoms with administration of glucose

Laboratory Testing

  • Testing in presence of symptoms – may require fast (up to 72 hours) to reproduce symptoms (see table below), which requires close monitoring
    • Plasma glucose
    • Insulin
    • C-peptide
    • Beta-hydroxybutyrate
    • Free fatty acids
  • Glucagon provocation testing
    • When diagnosis is in doubt and usually in adults
      • Injection (intravenous or intramuscular) of 0.5-1 mg of glucagon, with pre- and postglucose levels
      • Increase in plasma glucose >30 mg/dL after glucagon administration confirms hyperinsulinemic hypoglycemia
  • Genetic testing for infantile forms
    • Treatment response is often gene dependent
    • KCNJI1, ABCC8 variants
      • Most common genetic causes
      • Associated with poor response to diazoxide – often requires surgery, such as (partial) pancreactecomy
    • GLUD1, HADH, HNF4A variants
      • Associated with good response to diazoxide
  • Additional testing
    • Drug testing (see Etiologies)
      • Sulfonylureas
      • Metformin
    • Proinsulin
      • Assists with diagnosis of insulinoma
    • Cortisol
      • Assess possible adrenal insufficiency
    • Insulin antibodies
      • Presence suggests administration of insulin, rather than endogenous insulin such as that secreted by insulinoma
Usual Laboratory Test Results in Endogenous Hyperinsulinemic Hypoglycemia
Laboratory Test Result

Plasma glucose

<55 mg/dL

Insulin

≥3.0 µU/mL

C-peptide

≥0.6 ng/mL

Proinsulin

≥5.0 pmol/L

Beta-hydroxybutyrate

≤2.7 mmol/L

Increase in plasma glucose with IV glucagon

25 mg/dL

aIn patient with signs and/or symptoms of hypoglycemia after a 72-hour fast or mixed meal and IV glucagon infusion, these results together indicate presence of insulin (eg, produced by insulinoma).

Source: Cryer, Endocrine Society, 2009

Etiologies

  • Postprandial hyperinsulinemic hypoglycemia
    • Dumping syndrome
    • Postgastric bypass surgery
    • Insulin autoimmune syndrome
  • Insulinoma
  • Medications
    • Surreptitious use of oral antihyperglycemics or insulin
    • Accidental or malicious misuse of oral antihyperglycemics or insulin
    • Other medications with moderate quality of evidence for causing hypoglycemia include cibenzoline, gatifloxacin, pentamidine, quinine, indomethacin, glucagon (Cryer, Endocrine Society, 2009)
  • Adrenal insufficiency
  • Unusual causes

Background

Epidemiology

  • Incidence of hypoglycemia
    • Newborns – 1-3/1,000 live births
    • Familial forms – 1/50,000 in sporadic populations (higher incidence in Ashkenazi Jews)
    • Patients with diabetes
      • 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
    • Genetic factors
      • Identified gene defects in ABCC8KCNJ11GLUD1GCKHADH, SLC16A1HNF4A, HNF1A, UCP2
        • ABCC8 and KCNJ11 defects most common
      • Developmental syndromes associated with hyperinsulinemic hypoglycemia (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 DM
    • Premature or postmature delivery
  • Children
    • DM – patients receiving insulin at highest risk
    • Medication abuse (eg, of insulin or oral hypoglycemic agents)
  • Adults
    • DM – patients receiving insulin at highest risk
    • Medication abuse (eg, of insulin or oral hypoglycemic agents)
    • Insulinoma
    • Insulin autoantibodies
    • Autoimmune diseases
    • Bariatric surgery (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 patients who have undergone gastric bypass

Clinical Presentation

  • Adults and children
    • Lethargy, confusion, anxiety, sweating
    • Nausea
    • Focal neurologic defects
    • Seizures
    • Patients who have undergone gastric bypass may experience symptoms as late as 1-2 years after procedure and usually 1-3 hours postprandially
  • Infants and newborns
    • Lethargy, floppiness, sweating
    • Poor feeding, apnea, seizures, coma
    • Recurrent hypoglycemia can cause neurologic damage
    • In Beckwith-Wiedemann syndrome – 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

ARUP Lab Tests

Screen for hyperinsulinemic hypoglycemia

Aid in evaluation of hyperinsulinemic hypoglycemia

Quantitative test to evaluate if etiology of hypoglycemia is a result of sulfonylurea exposure

Cutoff concentrations vary by drug

Useful in evaluating if etiology of hypoglycemia is a result of sulfonylurea exposure

Serum or plasma is the preferred specimen (refer to hypoglycemia panel, serum or plasma)

Panel includes chlorpropamide, tolazamide, glyburide, acetohexamide, glimepiride, nateglinide, repaglinide

Preferred test when determining if hypoglycemia is from exposure to metformin

Serum or plasma is the preferred specimen for correlating drug use with hypoglycemia

Aid in the detection of insulinomas

Screen and diagnose primary and secondary adrenal insufficiency

Use to determine presence of antibodies to endogenous insulin or exogenous insulin analogues

Testing not recommended for patients receiving insulin for >2 weeks, as insulin antibody formation may occur

Related Tests

Aid in the detection of insulinoma

May aid in distinguishing type 1 from type 2 diabetes mellitus (DM) in ambiguous cases

Do not use to diagnose DM

Medical Experts

Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®