Skip to main content

Monogenic hyperinsulinemic hypoglycemia: current insights into the pathogenesis and management

Abstract

Hyperinsulinism (HI) is the leading cause of persistent hypoglycemia in children,which if unrecognized may lead to development delays and permanent neurologicdamage. Prompt recognition and appropriate treatment of HI are essential toavoid these sequelae. Major advances have been made over the past two decades inunderstanding the molecular basis of hyperinsulinism and mutations in nine genesare currently known to cause HI. Inactivating KATP channel mutationscause the most common and severe type of HI, which occurs in both a focal and adiffuse form. Activating mutations of glutamate dehydrogenase (GDH) lead tohyperinsulinism/hyperammonemia syndrome, while activating mutations ofglucokinase (GK), the “glucose sensor” of the beta cell, causeshyperinsulinism with a variable clinical phenotype. More recently identifiedgenetic causes include mutations in the genes encoding short-chain3-hydroxyacyl-CoA (SCHAD), uncoupling protein 2 (UCP2), hepatocyte nuclearfactor 4-alpha (HNF-4α), hepatocyte nuclear factor 1-alpha (HNF-1α),and monocarboyxlate transporter 1 (MCT-1), which results in a very rare form ofHI triggered by exercise. For a timely diagnosis, a critical sample and aglucagon stimulation test should be done when plasma glucose is < 50 mg/dL.A failure to respond to a trial of diazoxide, a KATP channel agonist,suggests a KATP defect, which frequently requires pancreatectomy.Surgery is palliative for children with diffuse KATPHI, but childrenwith focal KATPHI are cured with a limited pancreatectomy. Therefore,distinguishing between diffuse and focal disease and localizing the focal lesionin the pancreas are crucial aspects of HI management. Since 2003,18 F-DOPA PET scans have been used to differentiate diffuse andfocal disease and localize focal lesions with higher sensitivity and specificitythan more invasive interventional radiology techniques. Hyperinsulinism remainsa challenging disorder, but recent advances in the understanding of its geneticbasis and breakthroughs in management should lead to improved outcomes for thesechildren.

Introduction

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemiain infants and children, which if unrecognized may lead to development delays andpermanent neurologic damage. In general, the high risk of brain damageappears to be due to delays in diagnosis and treatment rather than a consequence ofthe genetic defects and, thus, is potentially preventable [1].

Within the last two decades, major advances have been made in understanding themolecular and genetic basis of HI. This work has helped elucidate the physiology ofbeta cell function and insulin regulation, as well as advanced clinical care forchildren with HI. Among the nine known genetic causes of HI, mutations in the genesencoding the ATP-sensitive potassium channel represent the most common defectaccounting for the majority of the cases [2]. At least 50% of the children carrying these mutations have a focal formof the disease and can be cured by surgery, thanks to the introduction of novelimaging techniques. In this article, we will review the genetic basis of HI with afocus on the recently identified genetic causes and mechanisms of disease, describethe recommended diagnostic work-up and discuss recent advances in the management ofthis challenging disorder.

Molecular genetics

Nine genes expressed in the ß-cell have been implicated in thepathophysiology of HI [Figure 1. They includeABCC8 and KCNJ11 encoding SUR-1 and Kir6.2, the twosubunits of the ATP-sensitive potassium channel (KATP channel);GLUD1 encoding glutamate dehydrogenase (GDH); GCK encodingglucokinase (GK); HADH encoding short-chain 3-hydroxyacyl-CoA (SCHAD);UCP2 encoding uncoupling protein 2 (UCP2); HNF4A andHNF1A encoding the transcription factors hepato-cyte nuclear factor4-alpha (HNF-4α) and hepatocyte nuclear factor 1-alpha (HNF-1α),respectively; and ectopic expression of monocarboxylate transporter 1 (MCT-1)encoded by SLC16A1. Many of these genes are also involved in thepathogenesis of monogenic diabetes, including ABCC8, KCNJ11,GCK, HNF4A, and HNF1A. There remain approximately50% of diazoxide-responsive cases and 10% of diazoxide-unresponsive cases of HIwith unknown genetic etiology, suggesting that additional, yet to be identifiedgenes are implicated in the pathogenesis of HI [3].

Figure 1
figure 1

Genetic defects in the beta cell leading to hyperinsulinism. Inthe pancreatic beta cell, ATP production from fuel metabolism leads toinhibition and closure of ATP-sensitive potassium channels, whichtriggers membrane depolarization and opening of voltage-dependentcalcium channels. The resulting increase in cytosolic calcium triggersinsulin secretion. Defects in this pathway can result inhyperinsulinism. The known protein defects are depicted in bold italics.Five are inactivating mutations: SUR-1 (sulfonylurea receptor), Kir6.2(potassium channel), SCHAD (short-chain 3-OH acyl-CoA dehydrogenase),UCP2 (uncoupling protein 2), HNF-4α (hepatic nuclear transcriptionfactor 4α), and HNF-1α (hepatic nuclear transcription factor1α). The last 2 are transcription factors and are not depicted inthe figure. Three are activating mutations: GK (glucokinase), GDH(glutamate dehydrogenase), MCT-1 (monocarboxylate transporter 1).Positive effects are shown by a plus arrow; negative effects by a minusarrow. Dashed arrows denote multiple steps in a pathway. G6P =glucose-6-phosphate, ATP = adenosine triphosphate, ADP = adenosinediphosphate.

KATP-hyperinsulinism

Inactivating mutations in the genes encoding the two subunits of theß-cell ATP-sensitive potassium channel (KATP channel),ABCC8 and KCNJ11 (encoding SUR-1 and Kir6.2,respectively), cause the most common and severe form of hyperinsulinism,although mutations in ABCC8 are more common [4, 5]. The effect of these mutations on channel expression and functiondetermines the clinical phenotype, particularly the response to diazoxide, aKATP channel opener used in the treatment of HI [2]. Thus, KATPHI can been classified into three subtypes:(1) recessive diazoxide-unresponsive, (2) dominant diazoxide-unresponsiveand (3) dominant diazoxide-responsive [69]. Clinically, the first two groups are undistinguishable. Thesechildren present as neonates with large for gestational age birth weightsand severe hypoglycemia that requires high glucose infusion rates and failsto respond to therapy with diazoxide, because there are no functionalKATP channels (recessive defects) or their function isseverely impaired (dominant defects) [8]. Therefore, children with recessive or dominantdiazoxide-unresponsive KATPHI, frequently require pancreatectomyto control their hypoglycemia. The third group (dominantdiazoxide-responsive) typically has less severe hypoglycemia, which may notbe noted at birth.

The pathophysiology of KATPHI is characterized by a failure tosuppress insulin secretion as glucose concentration falls, manifesting assevere fasting hypoglycemia, and a failure to increase insulin secretion inresponse to a glucose load [2]. In contrast to the impaired glucose-stimulated insulinsecretion, amino acids trigger insulin release in some individuals withKATPHI, causing severe protein-induced hypoglycemia [10].

In the 1980s, it was recognized that some patients with severehyperinsulinism were cured after a partial pancreatectomy. On histologicinspection, although the majority of their pancreas appeared normal, a focal“tumor-like” area of abnormal beta cell proliferation wasidentified. In contrast, children who were not cured with surgery had anormal number of beta cells, but these cells showed signs of hyperactivitythroughout the pancreas [11]. These findings lead to the recognition of two distincthistologic forms of HI: diffuse and focal. The molecular mechanismresponsible for these focal adenomatous lesions in which abnormal beta cellproliferation occurs in a discrete region of the pancreas was laterdescribed [12]. The pathophysiology of focal KATPHI includes a“two hits” mechanism: first, a paternally inherited recessivemutation in ABCC8 or KCNJ11; and second, a deletion of thematernally inherited 11p15 chromosomal region, compensated by paternaluniparental disomy [13]. The loss of maternally expressed genes involved in tumorsuppression explains the histological findings of focal KATPHI [12, 14].

Clinically, children with the focal form are indistinguishable from thosewith the recessive diffuse form, presenting with severe hypoglycemia andhigh glucose requirements. Unlike the diffuse form, focal KATPHImay be cured with surgical resection of the discrete lesion. Thus, therecognition of these cases prior to surgery is critical as explainedlater.

Recently, a novel “atypical” form of focal hyperinsulinismconsisting of morphologic mosaicism of pancreatic islets has been reported,which similar to focal lesions, involves only a portion of the pancreas andmay be cured with partial pancreatectomy [15]. The histology in this form shows co-existence of two abnormalislet types (large islets with occasional enlarged nuclei and shrunkenislets with small nuclei) in a limited region of the pancreas. No mutationsin ABCC8, KCNJ11 or GCK were identified in thesecases and the molecular mechanism is unknown at this time.

GDH-hyperinsulinism

The second most common form of HI is due to activating mutations of glutamatedehydrogenase (GDH), encoded by GLUD1, leading to thehyperinsulinism/hyperammonemia (HI/HA) syndrome [16]. In the beta cell, GDH is involved in amino acid-stimulatedinsulin secretion and loss of inhibitory control of GDH in HI/HA leads todysregulated insulin secretion. The majority of mutations in GLUD1occur de novo (70%) with the reminder inherited in an autosomal dominantpattern [17]. Individuals with HI/HA have fasting and protein-inducedhypoglycemia, which is easily controlled with diazoxide. Ammonia levels aretypically elevated 3–5 times the normal range, but these individualsdo not exhibit the classical symptoms associated with hyperammonia due toother causes. Children with HI/HA have increased rates of seizures, mostcommonly atypical absence, and learning disabilities [18]. These neurologic abnormalities appear to be unrelated tohypoglycemia or elevated ammonia levels.

GK-hyperinsulinism

Activating mutations in glucokinase (GK) cause an autosomal dominant form ofHI. Glucokinase, encoded by GCK, is the “glucosesensor” of the beta cell, triggering insulin secretion in response torising glucose concentration [19]. Activating mutations lower the threshold for insulin release;thus, the glucose set point for these individuals is lower. GK-HI presentswith fasting hypoglycemia of variable degrees of severity and, although theinitial reported case responded well to diazoxide, less than a third of thereported cases have been treated successfully with diazoxide [2, 20].

SCHAD-hyperinsulinism

Short-chain 3-hydroxyacyl-CoA (SCHAD) deficiency leads to an autosomalrecessive form of HI. SCHAD, encoded by HADH, catalyzes a step inthe fatty acid oxidation (FAO) cycle [21]. Although FAO defects are well known to cause hypoglycemia, theconnection between an enzyme in the FAO cycle and HI was unclear.Subsequently, it was shown that SCHAD is an inhibitory regulator of GDH, theenzyme involved in amino-acid stimulated insulin secretion, and loss ofGDH’s inhibition due to SCHAD deficiency results in insulindysregulation [22]. Children with SCHAD-HI have fasting and protein-inducedhypoglycemia and similar to patients with HI/HA, they respond well todiazoxide therapy. Biochemical markers of SCHAD-HI include increasedconcentration of 3-hydroxybutyrylcarnitine in plasma and 3-hydroxyglutaricacid in urine. These children do not exhibit the cardiac, skeletal orhepatic dysfunction associated with FAO disorders.

UCP2-Hyperinsulinism

Uncoupling protein 2 (UCP2), a membranous mitochondrial carrier, acts as anegative regulator of insulin secretion in the beta cells. Recently, loss offunction mutations in UCP2 have been described that result inhyperinsulinism [23]. UCP2 mutations are inherited in an autosomal dominant manner andhave been identified in children responding to diazoxide. The reported caseshave resolution of HI by 7 months to 6 years of age, which suggests thatUCP2-HI is a transient disorder [2].

HNF4A and HNF1A-hyperinsulinism

Hepatocyte nuclear factor 4-alpha (HNF-4α), a transcription factorinvolved in pancreatic development and function, has been classically linkedto a monogenic form of early-onset diabetes, MODY1 [24]. Mutations in HNF4A, which encodes HNF-4α, have anautosomal dominant pattern of inheritance. A study of families with MODY1found that carriers of HNF4A mutations were born macrosomic and 8carriers had transient neonatal hypoglycemia with hyperinsulinism identifiedin 3 of the 8 [25]. Further studies demonstrated HNF4A mutations inchildren presenting with diazoxide-responsive HI [26]. Patients with HNF4A mutations respond well to diazoxideand the HI resolves within the first year of life in the majority of cases,although cases of persistent HI caused by HNF4A mutations have beenreported [27]. The phenotype in these cases is complex and may involve theliver and kidney [28]. Recently, mutations in the transcription factor, hepatocytenuclear factor 1-alpha (HNF-1α), encoded by HNF1A and known tocause MODY3, have been shown to also present with hyperinsulinism in infancy [28]. The mechanism by which loss of function mutations inHNF4A and HNF1A can lead to this dual phenotype withhypoglycemia in early life and diabetes later, has not been elucidated, butlikely implies a changing pattern of gene expression regulation by thesetranscription factors throughout the life of an individual.

MCT1-Hyperinsulinism

Aberrant expression of monocarboxylate transporter 1 (MCT-1) leads to a veryrare and unusual form of hyperinsulinism, which is triggered by exercise.Identified in two Finnish families, exercise-induced hyperinsulinism (EIHI)is characterized by episodes of hypoglycemia associated with elevatedinsulin levels at the time of anaerobic exercise [29]. Autosomal dominant mutations in the regulatory regions of theSLC16A1 gene, which encodes MCT-1, have been identified [30]. In normal individuals, MCT-1, a transporter of pyruvate andlactate, is not expressed on beta cells, but in EIHI, mutations in theregulatory regions of SLC16A1 lead to expression of MCT-1 on betacells. The presence of MCT-1 allows pyruvate, elevated during anaerobicexercise, to enter the beta cell and through the triggering pathway(KATP-mediated), increase insulin release resulting inhypoglycemia [31]. The degree of hypoglycemia associated with exercise is variableand is only partially responsive to diazoxide.

Diagnosis

For children presenting with hypoglycemia (plasma glucose < 70 mg/dL), promptdiagnosis and establishment of effective treatment is essential to avoidneurologic sequelae. Clinical clues to the diagnosis of the HI include large forgestational age birth weight and severe, persistent hypoglycemia requiring highglucose infusion rates (> 10 mg/kg/min). However, the clinical phenotype ofhyperinsulinism is a spectrum and infants with HI can also present with normalbirth weights and lower glucose requirements.

The diagnosis of hyperinsulinism is made based on the critical sample obtainedduring a spontaneous or provoked hypoglycemic event. The threshold blood glucoseto obtain the critical sample by convention is set low at < 50 mg/dL todecrease the likelihood of false positive results. If a diagnostic fast isneeded to obtain the critical sample, close monitoring of blood glucose, vitalsigns and mental status is essential to ensure the patient’s safety.Parental dextrose, as well as all appropriate specimen collection tubes, shouldbe at the bedside prior to the start of the fast. Upon completion of diagnostictesting, blood glucoses should be monitored every 10–15 min until they arereliably above 70 mg/dL.

In addition to obtaining the critical sample, the glycemic response to glucagonshould be evaluated [Table 1. A detectable insulin levelis inappropriate at the time of hypoglycemia and is consistent with insulinexcess. A common pitfall in the diagnosis of HI is that insulin concentration isnot always elevated, even at the time of hypoglycemia, thus the diagnosis shouldbe based on other indicators of increased insulin action [32]. Laboratories consistent with excess insulin action includesuppressed beta-hydroxybutyrate and free fatty acid concentrations as well as aninappropriate glycemic response to glucagon of 30 mg/dL or more at the time ofhypoglycemia [33].

Table 1 Criteria for diagnosing hyperinsulinism

In cases with overgrowth and failure to respond to diazoxide and octreotide,activating mutations in AKT2 should be considered in the differential diagnosis [34]. Beckwith-Wiedemann syndrome, neonatal panhypopituitarism andcongenital disorders of glycosylation should also be considered andappropriately evaluated if warranted by clinical features. Beckwith-Wiedemannsyndrome has significant clinical heterogeneity and is characterized byhemihypertrophy, macrosomia, macroglossia and predisposition to embryonaltumors. Neonates with panhypopituitarism may have diagnostic findings identicalto HI with suppressed ketones and free fatty acids and a glycemic response toglucagon. Clinical features suggestive of panhypopituitarism include midlinedefects and micropenis. Congenital disorders of glycosylation are a highlyvariable group of disorders caused by abnormal glycosylation of N-linkedoligosaccharides and hypoglycemia may be found with failure to thrive and liverdysfunction. Low growth hormone and cortisol at the time of hypoglycemia are notdiagnostic of growth hormone deficiency or adrenal insufficiency and theappropriate stimulation tests should be performed to confirm those diagnoses [35]. Insulinomas should be considered in the differential diagnosis ofchildren presenting with hyperinsulinemic hypoglycemia beyond infancy,particularly during the second decade of life.

A failure to respond to maximum dose of diazoxide (15 mg/kg/day) after at least 5days of treatment, suggests a KATP channel defect as the most likelycause of hyperinsulinism. Such children are potential surgical candidates andrequire referral to a specialized HI center with 18-fluoroL-3,4-dihydroxyphenylalanine positron emission tomography(18 F-DOPA PET) scan availability [Figure 2. Commercial genetic testing is available for the four most commonHI genes (ABCC8, KCNJ11, GLUD1 and GCK) andfor the HNFs defects. As a cost-reducing measure, genetic testing should betargeted based on the clinical phenotype; for example sending for GLUD1in children who are responsive to diazoxide and have elevated ammonias. Ourrecommendation is to send genetic testing as soon as possible for the child andhis/her parents, especially for the diazoxide-unresponsive cases as thedetection of a single recessive paternal KATP mutation(ABCC8 or KCNJ11) has a positive predictive value of 94%for focal hyperinsulinism [3].

Figure 2
figure 2

Algorithm for the treatment of hyperinsulinism. Assessing theresponse to diazoxide is a critical step in the management of HI.Patients who fail to respond to diazoxide will most likely haveKATP channel defect and require referral to a specializedcenter with 18 F DOPA PET scan capability. A safetyfast should be 8 to 18 h long depending on the age of the patient. Notethat octreotide is not recommended as pre-operative treatment inneonates with HI due to high rate of treatment failure and risk ofnecrotizing enterocolitis. KATP = ATP-sensitive potassiumchannel, 18 F DOPA PET = 18-fluoroL-3,4-dihydroxyphenylalanine positron emission tomography.

Management

The therapeutic goal for hyperinsulinism as well as other hypoglycemic disordersis to achieve and maintain plasma glucoses greater than 70 mg/dL. In the 1960s,the antihypertensive, diazoxide with its known side effect of hyperglycemia, wasfirst used to treat hyperinsulinism [36]. The 1970s saw the introduction of octreotide as an HI treatment [37]. These drugs remain the mainstay of medical treatment for HI.Diazoxide acts to open the KATP channel, decreasing insulin secretionand is the first-line agent for HI, although most cases of KATPHI donot respond.

The therapeutic dose range of diazoxide is wide (5 to 15 mg/kg/day) and variesaccording to the severity of the phenotype. Patients with severe hypoglycemiaand high glucose requirements should be started on the maximum dose of diazoxideat 15 mg/kg/day. Patients with more mild disease can be started on doses of5–10 mg/kg/day, which should be increased if there is no response afterseveral days of treatment. The half-life of diazoxide in children is between9.5-24 h [38] and is unknown in neonates, leading to controversy as to whethertwice a day or three times a day dosing is appropriate. In general, we find thatfor diazoxide-responsive children, dosing twice daily is sufficient to provideappropriate control. To evaluate diazoxide’s efficacy after 5 days oftherapy, a safety fast should be performed with a duration lasting 8 to 18 hbased on the age of the patient. Continued hypoglycemia after at least 5 days ofthe maximum dose (15 mg/kg/day) is considered a treatment failure. The sideeffects of diazoxide include hypertrichosis and fluid retention. Hypertrichosisis often quite severe, but resolves after stopping the drug. Fluid retention,especially in neonates, may require the use of a diuretic, such aschlorothiazide, but stronger loop diuretics should be avoided.

The second-line agent, octreotide decreases insulin secretion throughhyperpolarization of the beta cells and inhibition of calcium channels.Octreotide is associated with frequent treatment failure due to the developmentof tachyphylaxis. More importantly, octreotide has recently been associated withthe occurrence of fatal necrotizing enterocolitis and therefore, should be usedwith caution in neonates [39]. Our center no longer recommends its use in neonates pre-operatively.It continues to be used post-operatively in children with diffuse disease whoremain hypoglycemic following subtotal pancreatectomy. Successful treatment withlong-acting formulations of octreotide has recently been reported [40, 41].

Glucagon can be used as a continuous intravenous infusion of 1 mg/day to lowerglucose infusion rate requirements in infants awaiting surgery. Trials ofglucagon as a subcutaneous infusion through a pump were largely unsuccessful dueto the drug’s lack of stability in solution [42, 43]. A new potential therapeutic approach to children withKATP defects involves inhibition of GLP-1 action, an incretinknown to increase insulin secretion and lower blood glucose. Recently, a GLP-1receptor antagonist, exendin-(9–39) has been shown to elevate fastingblood glucose in individuals with hyperinsulinism [44].

Surgical intervention is indicated in children who have a focal lesion that canbe cured with resection and in children with diffuse disease who fail medicaltherapy. Pursuing surgery in the latter group requires a careful considerationof risks and benefits. The benefit of surgery in this group is that theirhypoglycemia is often easier to manage following a pancreatectomy, but this mustbe weighed against the risks of a surgical procedure and long-termcomplications, such as diabetes. Those children with diffuse disease who havevery limited fasting tolerances (less than 2–3 h) and very high glucoseinfusion requirements will most likely require a pancreatectomy. However, somechildren with diffuse disease and longer fasting tolerances (6–8 h) may bemanaged with a combination of frequent feeds, enteral dextrose and/oroctreotide. The risks of this management approach include potentially morefrequent hypoglycemia and exposure to octreotide.

The largest advance in the management of children with HI over the past decadewas the introduction of imaging with 18 F-DOPA PET todifferentiate focal from diffuse disease and to localize focal lesions [45]. As discussed earlier, children with focal KATPHI can becured with surgical resection of the lesion. In contrast, for children withdiffuse HI, surgery is palliative. Differentiating focal from diffuse diseaseand accurately identifying the location of focal lesions in the pancreas iscrucial for ensuring that children with focal KATPHI are successfullycured. Conventional imaging techniques, such as CT or MRI, cannot identify focallesions and interventional radiology techniques, such as transhepatic portalvenous sampling or arterial calcium stimulation are highly invasive and havepoor accuracy for differentiating diffuse from focal HI and for localizing thefocal lesion [46].

The uptake of 18 F-DOPA identifies neuroendocrine tissue, whichtakes up amino acid precursors of dopamine, including DOPA. In diffuse HI, theuptake of the tracer is uniform throughout the pancreas; in contrast, a focallesion will have greater uptake in a specific region compared to the surroundingtissue [Figure 3. Since 2003, 18 F-DOPAPET scans have been used to differentiate diffuse from focal HI and to localizefocal lesions prior to surgery [47]. In the largest series to date of 50 patients who underwent18 F-DOPA PET scans, followed by surgery, the sensitivityfor diagnosing focal disease was 75% and the location of the focal was correctlyidentified in 100% of cases [45]. Similar results have been reported in smaller series [48, 49]. A meta-analysis in 2012 showed superiority of the18 F-DOPA PET scan compared to interventional radiologytechniques for diagnosing and localizing focal lesions [50].

Figure 3
figure 3

A. Frontal view of a 3D maximum intensity projection (MIP) 18-fluoroL-3,4-dihydroxyphenylalanine positron emission tomography (18F-DOPA PET) image demonstrating a focal lesion in the tail ofthe pancreas (arrow). B. A frontal view 3D MIP18 F-DOPA PET image fused with a contrast-enhanced CTshows a focal lesion in the pancreatic head (white arrow). C.Frontal view of a 3D MIP showing non-uniform pattern of uptake withincreased activity throughout the pancreas consistent with diffusedisease. Note the normal liver, kidney and bladder uptake.

Accurate localization of the focal lesion aids in pre-operative planning and inselect cases (lesions on the anterior surface of the body and tail), allows forthe use of laparoscopic techniques [2]. Intraoperative biopsies and frozen section evaluation by experiencedpathologists allows for confirmation of a focal lesion and guides the extent ofpancreatic resection. Children with diffuse HI who fail medical management willrequire a subtotal pancreatectomy and placement of a gastrostomy tube to helpwith the post-operative management since most of these children continue to havehypoglycemia, although less severe [51].

Of the surgical cases performed at the Children’s Hospital of Philadelphia,95% of patients with focal disease have been cured and the majority requiredless than a 50% pancreatectomy. In contrast, the majority of patients withdiffuse disease post-operatively required continued intervention to maintaineuglycemia. However, after surgery, their HI can be more easily medicallymanaged. For children with continued hypoglycemia, octreotide during the daycombined with continuous intragastric dextrose overnight is effective atpreventing octreotide tachyphylaxis and allows for stable glucose control. Forthe smaller subset of patients with hyperglycemia following subtotalpancreatectomy, insulin may be necessary. The long-term risk of developingdiabetes in children with diffuse disease depends on the extent of pancreaticresection [52]. In the largest published series, 91% of children who had undergone anear-total pancreatectomy in infancy required insulin therapy for diabetes bythe age of 14 years [53].

Conclusions

Congenital hyperinsulinism is one of the most complicated and challenging disordersfaced by pediatric endocrinologists. The potential for preventing permanent braindamage caused by persistent hypoglycemia, makes it extremely important to identifyand treat these children early. The past two decades has seen tremendous progress inunderstanding the genetic and molecular basis of HI. This understanding has in turnlead to advancements in management and improved outcomes, particularly through theuse of 18 F-DOPA PET scan to identify and cure focal lesions.

Abbreviations

HI:

Hyperinsulinism

KATP:

ATP-sensitive potassium channel

GDH:

Glutamatedehydrogenase

HI/HA:

Hyperinsulinism/hyperammonemia syndrome

GK:

Glucokinase

SCHAD:

Short-chain 3-hydroxyacyl-CoA

FAO:

Fatty acid oxidation disorder

UCP2:

Uncoupling protein 2

HNF-4α:

Hepatocyte nuclear factor 4-alpha

HNF-1α:

Hepatocyte nuclear factor 1-alpha

MCT1:

Monocarboxylate transporter 1

EIHI:

Exercise-induced hyperinsulinism

F-DOPA PET:

18-fluoro L-3,4-dihydroxyphenylalaninepositron emission tomography.

References

  1. Mazor-Aronovitch K, Gillis D, Lobel D, Hirsch HJ, Pinhas-Hamiel O, Modan-Moses D, Glaser B, Landau H: Long-term neurodevelopmental outcome in conservatively treated congenital hyperinsulinism. Eur J Endocrinol 2007, 157(4):491–497.

    Article  CAS  PubMed  Google Scholar 

  2. Stanley CA, De Leon DD: Monogenic Hyperinsulinemic Hypoglycemia Disorders. 1st edition. Basel: Karger; 2012.

    Book  Google Scholar 

  3. Monogenic Disorders of Insulin Secretion: Congenital Hyperinsulinism and Neonatal Diabetes March 15–16, 2012 Faculty Synopses. Pediatr Diabetes 2012, 13(4):344–368.

    Article  Google Scholar 

  4. Thomas P, Ye Y, Lightner E: Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet 1996, 5(11):1809–1812.

    Article  CAS  PubMed  Google Scholar 

  5. Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, Aguilar-Bryan L, Gagel RF, Bryan J: Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 1995, 268(5209):426–429.

    Article  CAS  PubMed  Google Scholar 

  6. Huopio H, Reimann F, Ashfield R, Komulainen J, Lenko HL, Rahier J, Vauhkonen I, Kere J, Laakso M, Ashcroft F, et al: Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1. J Clin Invest 2000, 106(7):897–906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pinney SE, MacMullen C, Becker SA, Lin YW, Hanna C, Thornton PS, Ganguly A, Shyng SL, Stanley CA: Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations. J Clin Invest 2008, 118(8):2877–2886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Macmullen CM, Zhou Q, Snider KE, Tewson PH, Becker SA, Aziz AR, Ganguly A, Shyng SL, Stanley CA: Diazoxide-unresponsive congenital hyperinsulinism in children with dominant mutations of the beta-cell sulfonylurea receptor SUR1. Diabetes 2011, 60(6):1797–1804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. De Leon DD, Stanley CA: Pathophysiology of Diffuse ATP-Sensitive Potassium Channel Hyperinsulinism. In Monogenic Hyperinsulinemic Hypoglycemia Disorders. 21st edition. Edited by De Leon DD, Stanley CA. Basel: Karger; 2012:18–29.

    Chapter  Google Scholar 

  10. Fourtner SH, Stanley CA, Kelly A: Protein-sensitive hypoglycemia without leucine sensitivity in hyperinsulinism caused by K(ATP) channel mutations. J Pediatr 2006, 149(1):47–52.

    Article  CAS  PubMed  Google Scholar 

  11. Rahier J, Falt K, Muntefering H, Becker K, Gepts W, Falkmer S: The basic structural lesion of persistent neonatal hypoglycaemia with hyperinsulinism: deficiency of pancreatic D cells or hyperactivity of B cells? Diabetologia 1984, 26(4):282–289.

    Article  CAS  PubMed  Google Scholar 

  12. De Lonlay P, Fournet JC, Rahier J, Gross-Morand MS, Poggi-Travert F, Foussier V, Bonnefont JP, Brusset MC, Brunelle F, Robert JJ, et al: Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy. J Clin Invest 1997, 100(4):802–807.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Verkarre V, Fournet JC, De Lonlay P, Gross-Morand MS, Devillers M, Rahier J, Brunelle F, Robert JJ, Nihoul-Fekete C, Saudubray JM, et al: Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia. J Clin Invest 1998, 102(7):1286–1291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Suchi M, MacMullen CM, Thornton PS, Adzick NS, Ganguly A, Ruchelli ED, Stanley CA: Molecular and immunohistochemical analyses of the focal form of congenital hyperinsulinism. Mod Pathol 2006, 19(1):122–129.

    Article  CAS  PubMed  Google Scholar 

  15. Sempoux C, Capito C, Bellanne-Chantelot C, Verkarre V, De Lonlay P, Aigrain Y, Fekete C, Guiot Y, Rahier J: Morphological Mosaicism of the Pancreatic Islets: A Novel Anatomopathological Form of Persistent Hyperinsulinemic Hypoglycemia of Infancy. J Clin Endocrinol Metab 2011, 96(12):3785–3793.

    Article  CAS  PubMed  Google Scholar 

  16. Stanley CA, Lieu YK, Hsu BY, Burlina AB, Greenberg CR, Hopwood NJ, Perlman K, Rich BH, Zammarchi E, Poncz M: Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med 1998, 338(19):1352–1357.

    Article  CAS  PubMed  Google Scholar 

  17. Palladino AA, Stanley CA: The hyperinsulinism/hyperammonemia syndrome. Rev Endocr Metab Disord 2010, 11(3):171–178.

    Article  CAS  PubMed  Google Scholar 

  18. Bahi-Buisson N, Roze E, Dionisi C, Escande F, Valayannopoulos V, Feillet F, Heinrichs C: Neurological aspects of hyperinsulinism-hyperammonaemia syndrome. Dev Med Child Neurol 2008, 50(12):945–949.

    Article  PubMed  Google Scholar 

  19. Glaser B, Kesavan P, Heyman M, Davis E, Cuesta A, Buchs A, Stanley CA, Thornton PS, Permutt MA, Matschinsky FM, et al: Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med 1998, 338(4):226–230.

    Article  CAS  PubMed  Google Scholar 

  20. Sayed S, Langdon DR, Odili S, Chen P, Buettger C, Schiffman AB, Suchi M, Taub R, Grimsby J, Matschinsky FM, et al: Extremes of Clinical and Enzymatic Phenotypes in Children With Hyperinsulinism Caused by Glucokinase Activating Mutations. Diabetes 2009, 58(6):1419–1427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Clayton PT: Hyperinsulinism in short-chain l-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. J Clin Invest 2001, 108(3):457–465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Li C, Chen P, Palladino A, Narayan S, Russell LK, Sayed S, Xiong G, Chen J, Stokes D, Butt YM: Mechanism of hyperinsulinism in short-chain 3- hydroxyacyl-CoA dehydrogenase deficiency involves activation of glutamate dehydrogenase. J Biol Chem 2010, 285(41):31806–31818.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gonzalez-Barroso MM, Giurgea I, Bouillaud F, Anedda A, Bellanne-Chantelot C, Hubert L, de Keyzer Y, de Lonlay P, Ricquier D: Mutations in UCP2 in Congenital Hyperinsulinism Reveal a Role for Regulation of Insulin Secretion. PLoS One 2008, 3(12):e3850.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, Fajans SS, Signorini S, Stoffel M, Bell GI: Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature 1996, 384(6608):458–460.

    Article  CAS  PubMed  Google Scholar 

  25. Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard S, Ferrer J, Hattersley AT: Macrosomia and Hyperinsulinaemic Hypoglycaemia in Patients with Heterozygous Mutations in the HNF4A Gene. PLoS Med 2007, 4(4):e118.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Flanagan SE, Kapoor RR, Mali G, Cody D, Murphy N, Schwahn B, Siahanidou T, Banerjee I, Akcay T, Rubio-Cabezas O, et al: Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations. Eur J Endocrinol 2010, 162(5):987–992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kapoor RR, Locke J, Colclough K, Wales J, Conn JJ, Hattersley AT, Ellard S, Hussain K: Persistent Hyperinsulinemic Hypoglycemia and Maturity-Onset Diabetes of the Young Due to Heterozygous HNF4A Mutations. Diabetes 2008, 57(6):1659–1663.

    Article  CAS  PubMed  Google Scholar 

  28. Stanescu DE, Hughes N, Kaplan B, Stanley CA, De Leon DD: Novel Presentations of Congenital Hyperinsulinism due to Mutations in the MODY genes: HNF1A and HNF4A. J Clin Endocrinol Metab 2012, 97(10):E2026–E2030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Meissner T, Otonkoski T, Feneberg R, Beinbrech B, Apostolidou S, Sipila I, Schaefer F, Mayatepek E: Exercise induced hypoglycaemic hyperinsulinism. Arch Dis Child 2001, 84(3):254–257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Otonkoski T, Jiao H, Kaminen-Ahola N, Tapia-Paez I, Ullah MS, Parton LE, Schuit F, Quintens R, Sipila I, Mayatepek E, et al: Physical Exercise.Induced Hypoglycemia Caused by Failed Silencing of Monocarboxylate Transporter 1 in Pancreatic β Cells. Am J Hum Genet 2007, 81(3):467–474.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Otonkoski T, Kaminen N, Ustinov J, Lapatto R, Meissner T, Mayatepek E, Kere J, Sipila I: Physical exercise-induced hyperinsulinemic hypoglycemia is an autosomal-dominant trait characterized by abnormal pyruvate-induced insulin release. Diabetes 2003, 52(1):199–204.

    Article  CAS  PubMed  Google Scholar 

  32. Palladino AA, Bennett MJ, Stanley CA: Hyperinsulinism in Infancy and Childhood: When an Insulin Level Is Not Always Enough. Clin Chem 2008, 54(2):256–263.

    Article  CAS  PubMed  Google Scholar 

  33. Finegold DN, Stanley CA, Baker L: Glycemic response to glucagon during fasting hypoglycemia: an aid in the diagnosis of hyperinsulinism. J Pediatr 1980, 96(2):257–259.

    Article  CAS  PubMed  Google Scholar 

  34. Hussain K, Challis B, Rocha N, Payne F, Minic M, Thompson A, Daly A, Scott C, Harris J, Smillie BJL, et al: An Activating Mutation of AKT2 and Human Hypoglycemia. Science 2011, 334(6055):474.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kelly A, Tang R, Becker S, Stanley CA: Poor Specificity of Low Growth Hormone and Cortisol Levels During Fasting Hypoglycemia for the Diagnoses of Growth Hormone Deficiency and Adrenal Insufficiency. Pediatrics 2008, 122(3):e522–e528.

    Article  PubMed  Google Scholar 

  36. Drash A, Wolff F: Drug Therapy in Leucine-Sensitive Hypoglycemia. Metab 1964, 13:487–492.

    Article  CAS  Google Scholar 

  37. Hirsch HJ, Loo S, Evans N, Crigler JF, Filler RM, Gabbay KH: Hypoglycemia of infancy and nesidioblastosis. Studies with somatostatin. N Engl J Med 1977, 296(23):1323–1326.

    Article  CAS  PubMed  Google Scholar 

  38. Dayton PG, Pruitt AW, Faraj BA, Israili ZH: Metabolism and disposition of diazoxide. A mini-review. Drug Metab Dispos 1975, 3(3):226–229.

    CAS  PubMed  Google Scholar 

  39. Laje P, Halaby L, Adzick NS, Stanley CA: Necrotizing enterocolitis in neonates receiving octreotide for the management of congenital hyperinsulinism. Pediatr Diabetes 2010, 11(2):142–147.

    Article  PubMed  Google Scholar 

  40. Modan-Moses D, Koren I, Mazor-Aronovitch K, Pinhas-Hamiel O, Landau H: Treatment of congenital hyperinsulinism with lanreotide acetate (Somatuline Autogel). J Clin Endocrinol Metab 2011, 96(8):2312–2317.

    Article  CAS  PubMed  Google Scholar 

  41. Le Quan Sang KH, Arnoux JB, Mamoune A, Saint-Martin C, Bellanné-Chantelot C, Valayannopoulos V, Brassier A, Kayirangwa H, Barbier V, Broissand C, et al: Successful treatment of congenital hyperinsulinism with long-acting release octreotide. Eur J Endocrinol 2012, 166(2):333–339.

    Article  PubMed  Google Scholar 

  42. Mohnike K, Blankenstein O, Pfuetzner A, Potzsch S, Schober E, Steiner S, Hardy OT, Grimberg A, van Waarde WM: Long-term non-surgical therapy of severe persistent congenital hyperinsulinism with glucagon. Horm Res 2008, 70(1):59–64.

    Article  CAS  PubMed  Google Scholar 

  43. Mazor-Aronovitch K, Landau H, Gillis D: Surgical versus non-surgical treatment of congenital hyperinsulinism. Pediatr Endocrinol Rev 2009, 6(3):424–430.

    PubMed  Google Scholar 

  44. Calabria AC, Li C, Gallagher PR, Stanley CA, De Leon DD: GLP-1 receptor antagonist exendin-(9-39) elevates fasting blood glucose levels in congenital hyperinsulinism owing to inactivating mutations in the ATPsensitive K+ channel. Diabetes 2012, 61(10):2585–2591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hardy OT, Hernandez-Pampaloni M, Saffer JR, Scheuermann JS, Ernst LM, Freifelder R, Zhuang H, MacMullen C, Becker S, Adzick NS, et al: Accuracy of [18 F]Fluorodopa Positron Emission Tomography for Diagnosing and Localizing Focal Congenital Hyperinsulinism. J Clin Endocrinol Metab 2007, 92(12):4706–4711.

    Article  CAS  PubMed  Google Scholar 

  46. Stanley CA, Thornton PS, Ganguly A, MacMullen C, Underwood P, Bhatia P, Steinkrauss L, Wanner L, Kaye R, Ruchelli E, et al: Preoperative evaluation of infants with focal or diffuse congenital hyperinsulinism by intravenous acute insulin response tests and selective pancreatic arterial calcium stimulation. J Clin Endocrinol Metab 2004, 89(1):288–296.

    Article  CAS  PubMed  Google Scholar 

  47. Otonkoski T, Nanto-Salonen K, Seppanen M, Veijola R, Huopio H, Hussain K, Tapanainen P, Eskola O, Parkkola R, Ekstrom K, et al: Noninvasive diagnosis of focal hyperinsulinism of infancy with [18 F]-DOPA positron emission tomography. Diabetes 2006, 55(1):13–18.

    Article  CAS  PubMed  Google Scholar 

  48. Ribeiro M-J, de Lonlay P, Delzescaux T, Boddaert N, Jaubert F, Bourgeois S, Dolle F, Nihoul-Fekete C, Syrota A, Brunelle F: Characterization of hyperinsulinism in infancy assessed with PET and 18 F-fluoro-L-DOPA. J Nucl Med 2005, 46(4):560–566.

    PubMed  Google Scholar 

  49. Zani A, Nah SA, Ron O, Totonelli G, Ismail D, Smith VV, Ashworth M, Blankenstein O, Mohnike W, De Coppi P, et al: The predictive value of preoperative fluorine-18-L-3,4-dihydroxyphenylalanine positron emission tomography-computed tomography scans in children with congenital hyperinsulinism of infancy. J Pediatr Surg 2011, 46(1):204–208.

    Article  PubMed  Google Scholar 

  50. Blomberg BA, Moghbel MC, Saboury B, Stanley CA, Alavi A: The Value of Radiologic Interventions and (18)F-DOPA PET in Diagnosing and Localizing Focal Congenital Hyperinsulinism: Systematic Review and Meta-Analysis. Mol Imaging Biol 2013, 15(1):97–105.

    Article  PubMed  Google Scholar 

  51. Palladino AA, Stanley CA: A specialized team approach to diagnosis and medical versus surgical treatment of infants with congenital hyperinsulinism. Semin Pediatr Surg 2011, 20(1):32–37.

    Article  PubMed  Google Scholar 

  52. Lovvorn HN III, Nance ML, Ferry RJ Jr, Stolte L, Baker L, O'Neill JA Jr, Schnaufer L, Stanley CA, Adzick NS: Congenital hyperinsulinism and the surgeon: lessons learned over 35 years. J Pediatr Surg 1999, 34(5):786–792. discussion 792-783.

    Article  PubMed  Google Scholar 

  53. Beltrand J, Caquard M, Arnoux JB, Laborde K, Velho G, Verkarre V, Rahier J, Brunelle F, Nihoul-Fekete C, Saudubray JM, et al: Glucose metabolism in 105 children and adolescents after pancreatectomy for congenital hyperinsulinism. Diabetes Care 2012, 35(2):198–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Diva D De León.

Electronic supplementary material

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided theoriginal work is properly cited.

Reprints and permissions

About this article

Cite this article

Lord, K., De León, D.D. Monogenic hyperinsulinemic hypoglycemia: current insights into the pathogenesis and management. Int J Pediatr Endocrinol 2013, 3 (2013). https://doi.org/10.1186/1687-9856-2013-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/1687-9856-2013-3

Keywords