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.

Tabs Content

Clinical Overview

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
- 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

ARUP Lab Tests

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

Recommended Use

Screen for hyperinsulinemic hypoglycemia

Insulin, Fasting 0070063
Method: Quantitative Chemiluminescent Immunoassay

Recommended Use

Aid in evaluation of hyperinsulinemic hypoglycemia

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

Recommended Use

Aid in evaluation of hyperinsulinemic hypoglycemia

Beta-Hydroxybutyric Acid 0080045
Method: Quantitative Enzymatic

Recommended Use

Aid in evaluation of hyperinsulinemic hypoglycemia

Fatty Acids, Free 0080120
Method: Quantitative Spectrophotometry

Recommended Use

Aid in evaluation of hyperinsulinemic hypoglycemia

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

Recommended Use

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

Limitations

Cutoff concentrations vary by drug

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

Recommended Use

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

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

Recommended Use

Preferred test when determining if hypoglycemia is from exposure to metformin

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

Proinsulin, Intact 0070112
Method: Quantitative Chemiluminescent Immunoassay

Recommended Use

Aid in the detection of insulinomas

Cortisol, Serum 0070030
Method: Quantitative Chemiluminescent Immunoassay

Recommended Use

Screen and diagnose primary and secondary adrenal insufficiency

Insulin Antibody 0099228
Method: Semi-Quantitative Radioimmunoassay

Recommended Use

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

Medical Experts

Johnson-Davis, Kamisha, PhD, DABCC, FAACC, Medical Director, Clinical Toxicology at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Straseski, Joely A., PhD, MS, MT(ASCP), DABCC, Medical Director, Endocrinology and Automated Core Laboratory at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

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
Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, Service J, Endocrine Society. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009; 94(3): 709-28. 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 VB, 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 MK, Anlauf M, Wieben D, Braunstein S, Klöppel G, Röher H, Knoefel WT. 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

Roženková K, Güemes M, Shah P, Hussain K. The diagnosis and management of hyperinsulinaemic hypoglycaemia. J Clin Res Pediatr Endocrinol. 2015; 7(2): 86-97. PubMed

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Yang HS, Wu AH, Johnson-Davis KL, Lynch KL. Development and validation of an LC-MS/MS sulfonylurea assay for hypoglycemia cases in the emergency department. Clin Chim Acta. 2016; 454: 130-4. PubMed

Content Review:

May 2018

Last Update: December 2018

Hyperinsulinemic Hypoglycemia

Diagnosis

Indications for Testing

Laboratory Testing

Etiologies

Background

Epidemiology

Risk Factors

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult


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Hyperinsulinemic Hypoglycemia

Diagnosis

Indications for Testing

Laboratory Testing

Etiologies

Background

Epidemiology

Risk Factors

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult