Hyperinsulinism Clinical Presentation
- Author: Sunil Sinha, MD; Chief Editor: Stephen Kemp, MD, PhD more...
Pregnancy and birth history may reveal risk factors that could predispose an infant to hyperinsulinism. Maternal diabetes, poor fetal growth, and birth asphyxia all can lead to excessive insulin release.
Signs and symptoms associated with hyperinsulinemic hypoglycemia result from 2 physiologic processes: hypoglycemia triggers autonomic nervous system activation and epinephrine release, and CNS glucopenia leads to neurologic manifestations.
Infants may present with cyanosis, respiratory distress, apnea, lethargy, sweating, hypothermia, jitteriness, irritability, poor feeding, seizures, tachycardia, and vomiting.
Older children may present with sweating, shakiness, anxiety, hunger and increased appetite, staring or strabismus, lethargy, nausea and vomiting, headache, behavior and mental status changes, inattention, loss of consciousness, tachycardia, hypothermia, and seizures.
Macrosomia reflects the anabolic effects of prolonged hyperinsulinemia in utero in infants who are large for their gestational age and in infants of diabetic mothers.
Microsomia can occur in infants who are small for gestational age (SGA), particularly those who have experienced maternal toxemia. Infants with microsomia may require high rates of glucose infusion initially to maintain euglycemia.
Some neonates have physical signs consistent with Beckwith-Wiedemann syndrome. Signs may include fetal overgrowth, omphalocele, macroglossia, visceromegaly, and creases of the ear lobe.
Classification of hyperinsulinism in infancy is described below.
Transient hyperinsulinism of infancy causes include the following:
Infant of a mother with diabetes
Infant who is SGA
Drug-induced hyperinsulinism, as follows:
- Surreptitious insulin administration
- Oral hypoglycemic ingestion
- Blood transfusion
Umbilical artery catheter placement
Persistent, congenital hyperinsulinism is also recognized.
Focal inborn error of insulin release (loss of heterozygosity with paternal-specific mutation) causes include the following:
Loss of heterozygosity with mutation of SUR1 or Kir6.2
Diffuse inborn error of insulin release (autosomal dominant or autosomal recessive)
Loss of functioning SUR1
Loss of functioning inward rectifying potassium channel (Kir6.2)
Loss of allosteric inhibition in glutamate dehydrogenase–1 (GLUD1), the cause of the hyperinsulinism-hyperammonemia syndrome
Activating glucokinase mutation (low intrinsic Km [Michaelis-Menten constant]) (GCK)
A useful classification of acquired hyperinsulinism beyond infancy is as follows:
Surreptitious insulin administration
Oral hypoglycemic ingestion
Transient causes include the following:
Infants of mothers with diabetes: During gestation, glucose is freely transferred across the placenta. Prolonged hyperglycemia in poorly controlled maternal diabetes results in fetal hyperglycemia. Fetal hyperglycemia induces fetal pancreatic beta-cell hyperplasia with resultant hyperinsulinemia and macrosomia. Withdrawal of the transplacental supply of glucose after birth leads to a precipitous drop in the concentration of glucose. When neonates present with signs and symptoms of hypoglycemia, many require infusion of large quantities of glucose to maintain normal blood glucose levels. Hyperinsulinism typically resolves within 1-2 days following birth (see Infant of Diabetic Mother).
Prolonged hyperinsulinism in infants who are SGA and asphyxiated newborns: Infants who are SGA, experience maternal toxemia, or have birth asphyxia are at increased risk for developing hypoglycemia. These infants have high rates of glucose metabolism and may require dextrose infusions as high as 20 mg/kg/min to maintain euglycemia. Some evidence suggests that this may be due to hyperinsulinemia, although the exact mechanisms are still unclear. These patients may have prolonged hypoglycemia for as long as 2-4 weeks following birth. Afterward, the hypoglycemia appears to resolve completely.
Erythroblastosis fetalis: Neonates with severe Rh isoimmunization have islet cell hyperplasia and hyperinsulinism. The cause of hyperinsulinism is unknown. Researchers hypothesize that elevated levels of glutathione from massive hemolysis may serve as a stimulus for insulin release.
Drug-induced hyperinsulinism includes the following:
Surreptitious insulin administration: This phenomenon is rare but may occur in the setting of Munchausen syndrome by proxy. The timing of hypoglycemia is unpredictable and occurs when the offender has access to the patient. Laboratory evaluation reveals elevated insulin levels and a low serum C-peptide level.
Ingestion of oral hypoglycemic agents: Toddlers may accidentally ingest drugs prescribed for adult diabetics (eg, sulfonylureas). Depending on the half-life of the preparation ingested, the duration of hypoglycemia varies. Glucose infusion (to maintain normoglycemia) is the treatment of choice. On rare occasions, diazoxide may be needed to suppress insulin secretion.
Blood transfusion: Certain preparations of blood products (eg, citrated blood) have large amounts of dextrose. During transfusion, the high glucose load triggers insulin secretion. Problems arise when the transfusion is completed. Elevated insulin levels could lead to a precipitous drop in blood glucose levels. This fall typically occurs about 2 hours after transfusion.
Malposition of the umbilical artery catheter in neonates may be associated with hypoglycemia and hyperinsulinemia. Repositioning of the catheter usually resolves the hypoglycemia and hyperinsulinemia. Theoretically, this problem may be caused by a high glucose load administered to the celiac axis. Localized hyperglycemia would induce insulin secretion and result in hypoglycemia in the systemic circulation.
Congenital causes include the following:
Beckwith-Wiedemann syndrome includes symptoms of omphalocele, macroglossia, and visceromegaly.
These infants have generalized islet cell hyperplasia.
Hyperinsulinemic hypoglycemia may be difficult to control. These patients require large quantities of glucose. Treatment with diazoxide is often needed to control hyperinsulinemia. Hyperinsulinism usually spontaneously resolves when the infant is aged several weeks or months.
Focal causes include the following:
Focal disease was formerly called nesidioblastosis, islet adenomatosis, or beta-cell adenoma. Dozens of patients with congenital hyperinsulinism demonstrate focal histologic abnormalities, which most pathologists label as islet adenomatosis or beta-cell adenoma. As patients present with hyperinsulinemic hypoglycemia at older ages (>1 y), they are increasingly more likely to have the focal form of hyperinsulinism.
Unfortunately, many infants with hyperinsulinism remain undiagnosed, misdiagnosed, or inadequately treated for several months before definitive management. Currently, definitive care is available at Le Bonheur Children's Hospital (Memphis, Tennessee), The Children's Hospital of Philadelphia (Philadelphia, Pennsylvania), Great Ormond Street Children's Hospital (London, England), Necker-Enfants Malades Hospital (Paris, France), Hadassah–Hebrew University Medical Center (Jerusalem, Israel), and The Children's Hospital (Helsinki, Finland). As with most rare diseases in children, timely referral to such centers provides optimal management.
A study that used preoperative pancreatic catheterization and intraoperative histologic studies suggested that as many as half of all neonates presenting with congenital hyperinsulinism have focal islet cell hyperplasia. Focal causes of hyperinsulinism can be treated, and possibly cured, with partial pancreatectomy.
Patients with inborn genetic defects of insulin release have congenital hyperinsulinism. Other terms for this disorder that have fallen out of favor include persistent hyperinsulinemic hypoglycemia of infancy (PHHI), leucine-sensitive hypoglycemia, islet cell dysmaturation syndrome, and nesidioblastosis.
Genetic causes include the following:
Pancreatic β-cell KATP channel defects are recognized.
Recessive mutations on chromosome 11 lead to alterations in the potassium channel on the plasma membrane of pancreatic beta cells. Mutations in the SUR1 and Kir6.2 genes create a nonfunctional potassium channel with membrane depolarization and unchecked insulin secretion. Mutations of the SUR1 gene are more common than mutations of the Kir6.2 gene. SUR1 mutations have been found more frequently in the less heterogeneous populations of Saudi Arabia and Ashkenazi Jews.
Patients with the autosomal recessive disorder present with high birth weights from the anabolic effects of insulin in utero. These disorders cannot be controlled with diazoxide, which binds to the cell surface of SUR1 to suppress insulin secretion. Thus, pancreatectomy is often required. For this subset of patients, near-total pancreatectomy achieves the best glycemic control during infancy.
GCK (encoding glucokinase) mutations: Mutations of the GCK gene can be autosomal dominant or recessive. The GCK mutations increase the affinity of glucokinase for glucose (ie, lower intrinsic Km for the glucose binding site). Accelerated rates of glycolysis result in an increased ATP/ADP ratio and increased insulin secretion. Patients with these mutations have a milder form of hyperinsulinism than patients with potassium channel defects. These patients also respond well to diazoxide treatment. In some patients, treatment can be discontinued after several years.
Hyperinsulinism-hyperammonemia (HH) syndrome due to GLUD1 mutation, as follows:
- GLUD1 mutations reported to date have been transmitted in an autosomal dominant inheritance. Early in infancy, patients with this genetic mutation present with hypoglycemic seizures, which are unrelated to the hyperammonemia per se. Delayed diagnosis and definitive care is unfortunately common because of the rarity of this disease.
- GLUD1 mutation affects both hepatocytic and islet function. Two metabolic pathways use glutamate dehydrogenase: leucine glutamate dehydrogenase–mediated oxidation in beta cells produces ATP, which induces insulin release; glutamate dehydrogenase also reduces intrahepatocytic glutamate concentration, and glutamate depletion downregulates the first step of the urea cycle to convert ammonium to urea.
- Excessive activity of glutamate dehydrogenase thus increases the rate of insulin release by beta cells in the pancreas and impairs the detoxification of ammonia by hepatocytes in the liver. Patients with one of these GLUD1 gene mutations present with low blood glucose levels and persistent mild elevations of serum ammonia to 100-200 µmol/L. This hyperammonemia is not affected by fasting, intravenous L-leucine challenge, oral L-leucine challenge, or glycemic control by medication. Indeed, the hyperammonemia itself has not been associated with clinical consequences, in contrast to the hypoglycemia that can cause permanent brain damage. GLUD1 mutations tend to display less severe hypoglycemia and respond to diazoxide.
Exercise-induced hyperinsulinism (EIHI): Exercise-induced hyperinsulinism (EIHI) is characterized by inappropriate insulin secretion that leads to hypoglycemia during exercise. Promoter-activating mutations of SLC16A1 gene encoding a monocarboxylate transporter (MCT1) that mediates the movement of lactate and pyruvate across cell membranes and causes anaerobic exercise-induced hypoglycemia as a dominantly inherited trait. Patients typically become hypoglycemic 30-45 minutes after a period of intensive exercise.
Uncoupling protein 2 (UCP2): Loss-of-function mutations encoding UCP2 leads to an increased ATP synthesis and enhanced glucose-stimulated insulin secretion. Diazoxide responsive this rare form of defuse HH syndrome is thought to be transient.
3-Hydroxyacyl-CoA Dehydrogenase (HADH): HADH (formerly known as short chain L-3-hydroxyacyl-CoA dehydrogenase) inherited as an autosomal recessive manner. Diazoxide responsive this rare disorder characterized by increased levels of 3-hydroxybutyryl-carnitine in blood and 3-hydroxyglutaric acid in urine. However precise mechanism of hyperinsulinism in patients with a HADH deficiency is not well understood.
HNF-4A: Hepatocyte nuclear factor 4 alpha (HNF-4 encoded by the HNF4A gene) is a transcription factor that plays important role in pancreatic development, maintenance of β-cell mass and regulation of insulin secretion. HNF4A gene mutations can cause increased birth weight, macrosomia, and transient HH syndrome in the neonatal period, which evolves to decreased insulin secretion and maturity-onset diabetes of the young type 1 (MODY1) later in life. 
Yorifuji T. Congenital hyperinsulinism: current status and future perspectives. Ann Pediatr Endocrinol Metab. 2014 Jun. 19 (2):57-68. [Medline].
Abdulhadi-Atwan M, Bushmann J, et al. Novel de novo mutation in sulfonylurea receptor 1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence. Diabetes. 2008 Jul. 57(7):1935-40. [Medline].
Arbizu Lostao J, Fernandez-Marmiesse A, Garrastachu Zumarran P, et al. [18F-fluoro-L-DOPA PET-CT imaging combined with genetic analysis for optimal classification and treatment in a child with severe congenital hyperinsulinism.]. An Pediatr (Barc). 2008 May. 68(5):481-5. [Medline].
Glaser B, Kesavan P, Heyman M, et al. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med. 1998. 338:226-30. [Medline].
Grimberg A, Ferry RJ Jr, Kelly A, et al. Dysregulation of insulin secretion in children with congenital hyperinsulinism due to sulfonylurea receptor mutations. Diabetes. 2001. 50:322-8. [Medline].
Shah JH, Maguire DJ, Munce TB, Cotterill A. Alanine in HI: a silent mutation cries out!. Adv Exp Med Biol. 2008. 614:145-50. [Medline].
Stanley CA, Baker L. The causes of neonatal hypoglycemia. N Engl J Med. 1999 Apr 15. 340(15):1200-1. [Medline].
Stanley CA, Lieu YK, Hsu BY, et al. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med. 1998. 338:1352-7. [Medline].
Suchi M, MacMullen CM, Thornton PS. Molecular and immunohistochemical analyses of the focal form of congenital hyperinsulinism. Mod Pathol. 2006. 19:122-9. [Medline].
Thomas PM, Cote GJ, Wohllk N, et al. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science. 1995. 268:426-9. [Medline].
Hardy OT, Hernandez-Pampaloni M, Saffer JR, et al. Accuracy of [18F]fluorodopa positron emission tomography for diagnosing and localizing focal congenital hyperinsulinism. J Clin Endocrinol Metab. 2007. 92:4706-11. [Medline].
Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, Hughes N, et al. Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. J Clin Endocrinol Metab. 2013 Feb. 98(2):E355-63. [Medline]. [Full Text].
Kapoor RR, Flanagan SE, Arya VB, Shield JP, Ellard S, Hussain K. Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism. Eur J Endocrinol. 2013 Apr. 168(4):557-64. [Medline]. [Full Text].
Lord K, Radcliffe J, Gallagher PR, Adzick NS, Stanley CA, De León DD. High risk of diabetes and neurobehavioral deficits in individuals with surgically treated hyperinsulinism. J Clin Endocrinol Metab. 2015 Sep 1. jc20152539. [Medline].
Lord K, Dzata E, Snider KE, Gallagher PR, De León DD. Clinical presentation and management of children with diffuse and focal hyperinsulinism: a review of 223 cases. J Clin Endocrinol Metab. 2013 Nov. 98(11):E1786-9. [Medline]. [Full Text].
Khawash P, Hussain K, Flanagan SE, Chatterjee S, Basak D. Nifedipine in Congenital Hyperinsulinism-A Case Report. J Clin Res Pediatr Endocrinol. 2015 Jun 5. 7 (2):151-4. [Medline].
Cherubini V, Bagalini LS, Ianilli A, Marigliano M, Biagioni M, Carnielli V, et al. Rapid genetic analysis, imaging with 18F-DOPA-PET/CT scan and laparoscopic surgery in congenital hyperinsulinism. J Pediatr Endocrinol Metab. 2010. 23:171-7. [Medline].
Craver RD, Hill CB. Cure of hypoglycemic hyperinsulinism by enucleation of a focal islet cell adenomatous hyperplasia. J Pediatr Surg. 1997. 32:1526-7. [Medline].
Cucchiaro G, Markowitz SD, Kaye R, et al. Blood glucose control during selective arterial stimulation and venous sampling for localization of focal hyperinsulinism lesions in anesthetized children. Anesth Analg. 2004. 99:1044-8, table of contents. [Medline].
[Guideline] De Leon DD, Stanley CA. Mechanisms of Disease: advances in diagnosis and treatment of hyperinsulinism in neonates. Nat Clin Pract Endocrinol Metab. 2007. 3:57-68. [Medline].
de Lonlay-Debeney P, Poggi-Travert F, Fournet JC. Clinical features of 52 neonates with hyperinsulinism. N Engl J Med. 1999. 340:1169-75. [Medline].
Ferry RJ Jr, Franklin SL, Geffner ME. Hypoglycemia. Kappy MS, Allen DB, Geffner ME, eds. Principles and Practice of Pediatric Endocrinology. Springfield, Ill: Charles C Thomas Publisher, Ltd; 2005. 607-34.
Ferry RJ Jr, Kelly A, Grimberg A, et al. Calcium-stimulated insulin secretion in diffuse and focal forms of congenital hyperinsulinism. J Pediatr. 2000. 137:239-46. [Medline].
Hoe FM, Thornton PS, Wanner LA. Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism. J Pediatr. 2006 Feb. 148(2):207-12. [Medline].
Hussain K, Aynsley-Green A, Stanley CA. Medications used in the treatment of hypoglycemia due to congenital hyperinsulinism of infancy (HI). Pediatr Endocrinol Rev. 2004 Nov. 2 Suppl 1:163-7. [Medline].
Kane C, Shepherd RM, Squires PE, et al. Loss of functional KATP channels in pancreatic beta-cells causes persistent hyperinsulinemic hypoglycemia of infancy. Nat Med. 1996. 2:1344-7. [Medline].
Levitt Katz LE, Satin-Smith MS, Collett-Solberg P, et al. Insulin-like growth factor binding protein-1 levels in the diagnosis of hypoglycemia caused by hyperinsulinism. J Pediatr. 1997 Aug. 131(2):193-9. [Medline].
Lovvorn HN III, Nance ML, Ferry RJ Jr. Congenital hyperinsulinism and the surgeon: lessons learned over 35 years. J Pediatr Surg. 1999. 34:786-92; discussion 792-3. [Medline].
Palladino AA, Bennett MJ, Stanley CA. Hyperinsulinism in infancy and childhood: when an insulin level is not always enough. Clin Chem. 2008. 54:256-63. [Medline].
Stanley CA. Hyperinsulinism/hyperammonemia syndrome: insights into the regulatory role of glutamate dehydrogenase in ammonia metabolism. Mol Genet Metab. 2004 Apr. 81 Suppl 1:S45-51. [Medline].
Steinkrauss L, Lipman TH, Hendell CD. Effects of hypoglycemia on developmental outcome in children with congenital hyperinsulinism. J Pediatr Nurs. 2005 Apr. 20(2):109-18. [Medline].
Suchi M, Thornton PS, Adzick NS, et al. Congenital hyperinsulinism: intraoperative biopsy interpretation can direct the extent of pancreatectomy. Am J Surg Pathol. 2004 Oct. 28(10):1326-35. [Medline].