Hyperinsulinemic 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

Etiologies

• Postprandial hyperinsulinemic hypoglycemia
  • Dumping syndrome
  • Postgastric bypass surgery
  • Insulin autoimmune syndrome
• Insulinoma
  • Sporadic
  • Multiple endocrine neoplasias subtype 1
• 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
  • Maternal diabetes mellitus (DM)
  • Perinatal asphyxiation
  • Intrauterine growth restriction
  • Rhesus isoimmunization
  • ​Hypoinsulinemic hypoglycemia (AKT2 mutation)

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 ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A, 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