Login to MyKarger

New to MyKarger? Click here to sign up.



Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or Open Athens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Mini Review

Free Access

Diagnosis and Management of Hyperinsulinaemic Hypoglycaemia of Infancy

Hussain K.

Author affiliations

London Centre for Paediatric Endocrinology and Metabolism, Great Ormond Street Hospital for Children NHS Trust, London, and Institute of Child Health, University College London, London, UK

Corresponding Author

Dr. K. Hussain

Developmental Endocrinology Research Group, Molecular Genetics Unit

Institute of Child Health, University College London, 30 Guilford Street

London WC1N 1EH (UK)

Tel. +44 (0) 20 7 905 2128, Fax +44 (0) 20 7 404 6191, E-Mail K.Hussain@ich.ucl.ac.uk

Related Articles for ""

Horm Res 2008;69:2–13

Abstract

Hyperinsulinaemic hypoglycaemia is a cause of persistent hypoglycaemia in the neonatal and infancy periods. Prompt recognition and management of patients with hyperinsulinaemic hypoglycaemia are essential, if brain damage and long-term neurological sequelae are to be avoided. Hyperinsulinaemic hypoglycaemia can be transient, prolonged, or persistent (congenital). Advances in the fields of molecular biology, genetics, and pancreatic β-cell physiology are beginning to provide novel insights into the mechanisms causing congenital forms of hyperinsulinism. So far mutations in six different genes have been described that lead to unregulated insulin secretion. The histological differentiation of focal and diffuse congenital hyperinsulinism has radically changed the surgical approach to this disease. Until recently, highly invasive investigations were performed to localize the focal lesion, but recent experience with 18F-L-dopa positron emission tomography scanning suggests that this technique is highly sensitive for differentiating diffuse from focal disease as well as for accurately locating the focal lesion. Despite recent advances, the genetic basis of congenital hyperinsulinism is still unknown in about 50% of the patients, and the management of medically unresponsive diffuse disease remains a real challenge.

© 2007 S. Karger AG, Basel


Introduction

Hyperinsulinaemic hypoglycaemia (HH) is characterized by the unregulated secretion of insulin from pancreatic β-cells in relation to the blood glucose concentration. HH is the commonest cause of persistent hypoglycaemia in the neonatal and infancy periods. As HH is a major risk factor for brain damage and subsequent neurodevelopment handicap [1,] identification and prompt management of patients with HH are essential, if brain damage is to be avoided.

HH can be either transient or persistent (congenital hyperinsulinism; CHI). Transient forms of HH are usually secondary to conditions such as maternal diabetes mellitus or intra-uterine growth retardation [2]. In contrast, recent advances in cellular physiology and molecular biology have begun to unravel the complex mechanisms that lead to congenital forms of hyperinsulinism. Pathologically, CHI can be classified into two major subgroups: ‘channelopathies’ and ‘metabolopathies’ [3]. Channelopathies refer to defects in the pancreatic β-cell ATP-sensitive potassium channels (KATP channels) that lead to unregulated insulin secretion. Metabolopathies cause CHI either by altering the concentration of intracellular signaling molecules (such as ATP/ADP) or by accumulation of intermediary metabolites.

The histological differentiation of CHI into focal and diffuse disease has radically changed the surgical management of patients with CHI [4]. Correct localization and limited excision of the focal lesion will result in complete cure of the patient. Recent advances in 18F-L-dopa PET (positron emission tomography) scanning are beginning to provide greater accuracy in pre-operative differentiation of focal and diffuse disease and in correct localization of focal lesions [5]. In contrast, medically unresponsive diffuse disease will still require a near-total pancreatectomy, greatly increasing the risk of post-pancreatectomy diabetes mellitus.

HH is also observed in several overgrowth syndromes such as Beckwith-Wiedemann and Sotos’ syndromes [6, 7], in association with rare metabolic conditions (congenital disorders of glycosylation; CDG) [8,] and several novel causes of postprandial HH have been recently reported [9, 10]. Table 1 summarizes the different causes of HH.

Table 1

Summary of the different causes of HH

http://www.karger.com/WebMaterial/ShowPic/262193

The aim of this mini review is to outline the clinical presentation, the diagnostic cascade, the pathophysiology, and the management of HH with a particular focus on CHI. Recent reviews focusing on the molecular mechanisms of HH have been published elsewhere [11].

Congenital Hyperinsulinism

Overview

CHI is an extremely heterogeneous disorder with respect to clinical presentation, pancreatic histology, and molecular biology. Both sporadic and familial variants of CHI are recognized, with sporadic forms being relatively uncommon (incidence 1/40,000 live births) and familial forms being common in communities with high rates of consanguinity; in these communities, the incidence may be as high as 1/2,500 live births [12]. The clinical severity of CHI varies mainly with age at onset of hypoglycaemia (severe hypoglycaemia in neonates) and has major consequences in terms of therapeutic outcome and genetic counseling.

Clinical Presentation and Diagnosis

CHI typically presents in the first few days after birth in term and preterm infants with symptomatic hypoglycaemia [13]. The patients may present with non-specific symptoms of hypoglycaemia such as poor feeding, lethargy, and irritability or symptoms such as seizures and coma. Subtle forms of CHI, however, may present later in infancy or even childhood. The hypoglycaemia is usually persistent, and normoglycaemia can only be achieved by giving the infant concentrated intravenous dextrose infusions. Some infants with CHI are macrosomic which may reflect their exposure to perinatal hyperinsulinaemia, but the absence of macrosomia does not exclude CHI, as not all infants with CHI are macrosomic. Some patients with CHI may have mild facial dysmorphism such as a high forehead, a small nasal tip, and short columella with a square face, although the reason for this is unclear [14].

In CHI a blood sample taken at the time of hypoglycaemia will show an inappropriately raised serum insulin level with low serum fatty acid levels and ketone bodies [15]. The low serum fatty acid levels and ketone bodies reflect the metabolic ‘footprint’ of insulin action. Unregulated insulin secretion increases the glucose consumption by insulin-sensitive tissues, such as muscle, adipose tissue, and liver, while simultaneously suppressing hepatic glucose production (both glycogenolysis and gluconeogenesis), lipolysis, and ketogenesis. Due to this metabolic ‘footprint’ of insulin action, the intravenous glucose infusion rate required to maintain normoglycaemia is increased (>8 mg/kg/min, normal 4–6 mg/kg/min). There is no correlation between the serum insulin level and the severity of hypoglycaemia. A ‘normal’ insulin level for normoglycaemia is usually inappropriate in the presence of hypoglycaemia, especially taken in the context of a high glucose requirement to maintain normoglycaemia [15].

The serum lactate level may be elevated in some forms of HH [16,] and the serum ammonia concentration must be measured in all patients presenting with HH because of the association with hyperinsulinism/hyperammoniaemia (HI/HA) syndrome [17]. Urinary organic acid and acylcarnitine analysis should also be performed, since short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency can cause CHI [18]. The serum cortisol and glucagon counterregulatory hormonal responses may be blunted in CHI, but replacement therapy with glucocorticoids does not seem to affect the severity of the disease [19, 20].

Some infants and children present with more subtle forms of CHI and require further investigations to aid in the diagnosis. In these patients other supportive evidence, such as decreased serum insulin-like growth factor binding protein-1 levels (as insulin suppresses the transcription of the IGFBP1 gene) [21] and a positive glycaemic response to intramuscular/intravenous glucagon at the time of hypoglycaemia [22,] will provide diagnostic clues. Provocation testing (such as protein or leucine loading and exercise test) will exacerbate the hypoglycaemia in those patients with protein/leucine sensitivity and exercise-induced hypoglycaemia [17, 23]. Figure 1 outlines the diagnostic and management cascade for patients with CHI.

Fig. 1

Flowchart for the diagnosis and management of CHI.

http://www.karger.com/WebMaterial/ShowPic/262191

Transient HH

Transient HH is a poorly defined term, as there is no definition of the precise duration of the hypoglycaemia. Classically transient HH is observed in newborns with intra-uterine growth retardation, in those suffering from perinatal asphyxia, in those born to insulin-dependent and gestational diabetic mothers, and in infants with Rh isoimmunization [24]. In these conditions, HH is usually a transient phenomenon and settles within a few days after delivery. However, some neonates (both intra-uterine growth retarded and appropriate weight for gestational age groups) can have prolonged HH that requires treatment with diazoxide, persists for several months, and then resolves spontaneously [25, 26].

Syndromic Forms of HH

Table 1 lists the syndromes which have been reported in association with HH [6, 7,27,28,29,30,31,32]. The mechanism/s of HH in most of these syndromes is/are not known. Beckwith-Wiedemann syndrome is the most common syndrome associated with HH. Beckwith-Wiedemann syndrome is characterized by prenatal and/or postnatal overgrowth, macroglossia, anterior abdominal wall defects, organomegaly, hemihypertrophy, ear lobe creases, helical pits, and renal tract abnormalities. The incidence of HH in children with Beckwith-Wiedemann syndrome is about 50%. This hypoglycemia can be transient, which, in the majority of infants, will be asymptomatic and resolve within the first few days of life. In about 5% of these children, the HH can be persistent and extend beyond the neonatal period, requiring either continuous feeding, medical therapy, or, in rare cases, partial pancreatectomy.

Metabolic Conditions Associated with HH

HH has been described in CDG (Congenital Disorders of Glycosylation), mostly in CDG-Ib but also as the leading symptom in CDG-Ia [8, 33]. Persistent HH as the leading symptom has recently been reported in CDG-Id associated with islet hyperplasia on postmortem examination of the pancreas [34]. Hence if CDG syndrome is suspected, a transferrin isoelectric focusing pattern should be requested. Patients with tyrosinaemia type I may also have HH with islet cell hyperplasia which is not due to impaired insulin clearance, but possibly related to the accumulation of toxic metabolites [35]. In patients with tyrosinaemia type I, urinary organic acids will show excretion of succinylacetone.

Postprandial HH

Several novel syndromes causing postprandial HH have recently been reported (table 1). A syndrome of autosomal dominant postprandial HH with onset in adolescence to adulthood and linked to a mutation (Arg1174Gln) in the insulin receptor kinase has been reported [9]. In these patients a prolonged (5 h) oral glucose tolerance test demonstrates marked postprandial HH, with clamp studies showing reduced insulin sensitivity and clearance of serum insulin in affected family members as compared with control subjects. In adults, a syndrome of ‘noninsulinoma pancreatogenous’ hypoglycaemia has been recognized [10]. These patients demonstrate neuroglycopaenic episodes from HH within 4 h of meal ingestion and have negative 72-hour fasts.

Pathophysiology of HH

Transient HH

Aetiology and the mechanisms responsible for transient forms of HH are unclear. Although the aetiology of these transient forms of HH is not thought to be genetic, recently mutations in the gene encoding the hepatic nuclear transcription factor-4α (HNF4A gene) have been reported [36]. In these patients the birth weight of the heterozygote HNF4A mutation carriers was dramatically increased. However, it is not known how mutations in HNF4A gene cause transient HH.

Congenital HH

CHI can be classified into ‘channelopathies’, where defects in the pancreatic β-cell KATP channels lead to unregulated insulin secretion, or ‘metabolopathies’, with increased β-cell ATP formation or accumulation of intermediary metabolites, triggering insulin secretion.

CHI due to Channelopathies

The commonest genetic causes of CHI are autosomal recessive mutations in the genes ABCC8 and KCNJ11 (encoding the two subunits SUR1 and KIR6.2, respectively) of the pancreatic KATP channels [37, 38]. Autosomal dominant mutations have also been described [39]. KATP channels play a pivotal role in transducing metabolic signals to electrical changes in membrane potential (fig. 2). These mutations result in differing abnormalities of recombinant KATP channels, including protein folding, protein synthesis defects, assembly and trafficking defects, and alterations in both nucleotide regulation and open-state frequency [40,41,42,43].

Fig. 2

Role of KATP channels in linking glucose metabolism to regulated insulin. KATP channels play a pivotal role in transducing metabolic signals to electrical changes in membrane potential. The metabolism of glucose in the β-cell increases the ratio of ATP/ADP which has the effect of closing the KATP channels. This in turn causes the opening up of voltage-gated calcium channels which regulate the entry of calcium into the β-cell. The entry of calcium is thought to be the final stimulus for insulin exocytosis.

http://www.karger.com/WebMaterial/ShowPic/262190

Mutations that affect the regulation of the KATP channels by altering their sensitivity to changes in ADP/ATP will also lead to an unregulated insulin secretion. Several mutations have now been described that result in the loss of ADP-dependent gating properties of the channel [39, 44, 45]. Loss of ADP-dependent gating results in the constitutive inhibition of KATP channels by ATP.

In more than 50% of the patients, screening has failed to define the genetic basis of CHI. There are families with autosomal dominantly inherited HH, but no underlying genetic defects have been found [46]. In some populations, mutations in the ABCC8 gene account for only about 20% of the cases of CHI [47,] suggesting that other genes may be involved.

CHI due to Metabolopathies

Glutamate Dehydrogenase (GDH). Activating mutations in GDH are the second commonest cause of CHI. Activating mutations in GDH underlie the molecular basis of the HI/HA syndrome and may explain the ‘leucine-sensitive’ hypoglycaemia described in previous years [17]. The HI/HA syndrome is caused by missense mutations of GDH that reduce the sensitivity of the enzyme to allosteric inhibition by the high-energy phosphates GTP and ATP. GDH is allosterically activated by leucine and inhibited by GTP [48]. Mutations which cause loss of inhibition by GTP cause leucine to increase the oxidation of glutamate, thereby raising the ratio of ATP/ADP in the pancreatic β-cell. The increased ratio of ATP/ADP then triggers closure of the KATP channel, opening the voltage-gated calcium channel, raising cytosolic calcium, and triggering the release of insulin.

Patients with the HI/HA syndrome can present with hypoglycaemia either in the neonatal period or later on in childhood. These patients also have a mildly elevated plasma ammonia concentration which appears to be asymptomatic. Patients show no signs of lethargy or headaches, typical of other forms of hyperammonaemia. The mechanism of the hyperammonaemia is still unclear at present. These patients typically demonstrate protein-induced HH (leucine sensitivity), but also have fasting hypoglycaemia.

Children with the HI/HA syndrome have an unusual frequency of absence-type seizures [49]. These children have an EEG pattern of generalized epilepsy that resembles the seizures associated with mutations of plasma membrane ion channels. It is unlikely that this seizure pattern is a manifestation of ammonia toxicity.

Glucokinase (GCK). GCK is the rate-limiting step in the metabolism of glucose and acts as the cellular sensor of glucose concentrations. Activation of GCK lowers the threshold for glucose-stimulated insulin secretion (‘resetting’ of the glucose-stimulated insulin release threshold), thus causing hypoglycaemia. The first activating mutation in the GCK gene was Val455Met which was a single-base change, resulting in the substitution of methionine for valine at codon 455 [50]. When expressed in vitro, the Val455Met mutation increased the affinity of GCK for glucose. Several other patients with activating mutations in the GCK gene have now been reported [51, 52,] all responsive to medical therapy with diazoxide. However a case of severe HH due to a ‘de novo’ mutation in GCK gene (Y214C) was reported which failed to respond to medical therapy [53]. Functional studies of this mutant showed a sixfold increase in its affinity for glucose, and histology of the resected pancreas in this patient revealed abnormally large and hyperfunctional islets. It is unclear, why this patient failed to respond to diazoxide, one possibility being that the dose of diazoxide was insufficient.

SCHAD Deficiency. SCHAD, encoded by the HADHSC gene, is an intramitochondrial enzyme that catalyzes the penultimate reaction in the β-oxidation of fatty acids, the NAD+-dependent dehydrogenation of 3-hydroxyacyl-CoA to the corresponding 3-ketoacyl-CoA. So far 3 patients with mutations in the HADHSC gene and HH have been reported [18, 54, 55]. The clinical presentation can be heterogeneous, either with mild late-onset hypoglycaemia or severe neonatal hypoglycaemia. The acylcarnitine profile in all reported patients has demonstrated raised hydroxybutyrylcarnitine levels, and urinary organic acids showed raised 3-hydroxyglutarate concentrations with decreased expression and function of SCHAD.

The mechanism of how a defect in the HADHSC gene leads to dysregulated insulin secretion is unclear at present. Fatty acids increase insulin secretion by affecting the concentrations of long-chain fatty acyl derivatives as a result of the inhibitory effect of citrate and malonyl-CoA on the rate-controlling carnitine palmitoyltransferase-1, but it is unclear how defects in SCHAD lead to unregulated insulin secretion. Interestingly, Foxa2 (HNF3β) has recently been shown to be involved in regulating the expression of the HADHSC gene, with studies in Foxa2-deficient β-cells showing a threefold downregulation of HADHSC gene transcripts along with the ability of Foxa2 to bind to and activate this gene [56]. Further studies will give new insights into how defects in the HADHSC gene lead to HH. Figure 3 summarizes the known genetic causes of HH.

Fig. 3

Summary of the known genetic causes of HH. Mutations in the genes ABCC8 and KCNJ11 (encoding SUR1 and KIR6.2, respectively, of the KATP channel) are the commonest causes of CHI. The molecular mechanisms leading to HH due to mutations in the genes HADHSC (encoding SCHAD) and HNF4alpha are still unclear. HNF4A = Hepatic nuclear transcription factor 4 alpha; NH3 = ammonia. For explanation of the other abbreviations see text.

http://www.karger.com/WebMaterial/ShowPic/262189

Exercise-Induced HH. In exercise-induced HH, strenuous physical exercise leads to inappropriate insulin release from β-cells causing postexercise hypoglycaemia [23]. These patients show an increased insulin secretion in response to intravenous pyruvate administration in comparison with control patients [23]. The molecular mechanism/s of how exogenous pyruvate triggers an inappropriate insulin secretion in these patients is/are still unclear.

Histology of CHI

Nesidioblastosis is a histological term which describes islets budding off from exocrine ducts but it is not specific for CHI [4]. It can also be observed in some normoglycaemic infants. Although two major histological forms of the disease have been described (diffuse and focal), there are still some cases which represent a diagnostic challenge, as they cannot be easily classified into focal or diffuse [57]. Both the diffuse and focal forms share a similar clinical presentation, but result from different pathphysiological and molecular mechanisms. In addition, diffuse CHI usually presents as an autosomal recessive disorder, whereas focal CHI is sporadic.

The typical diffuse form affects all the β-cells and is most commonly due to recessive mutations in the genes encoding the two subunits of the KATP channel. Typical diffuse disease is characterized by an increase in the size of the pancreatic β-cell nuclei throughout the pancreas.

The ‘focal’ form (focal adenomatous pancreatic hyperplasia) of CHI is found in about 40–50% of the children and appears to be localized to one region of the pancreas. The genetic defect in the focal form consists of germline mutations in the paternal allele of ABCC8 and KCNJ11 genes, encoding SUR1 and KIR6.2, respectively, on chromosome 11p15. In addition, the lesion exhibits a somatic loss of a part of the maternally inherited chromosome 11p which includes imprinted maternally expressed tumour suppressor genes (H19 and P57KIP2), paternally expressed insulin growth factor-2, as well as (non-imprinted) SUR1/Kir6. This results in a corresponding reduction to homozygosity of the paternal mutation, and the outcome is unregulated insulin secretion. β-Cells within the focal lesion do not express p57KIP2, but insulin growth factor-2 is mildly increased. The somatic loss of heterozygosity is associated with increased proliferation [58, 59]. The focal lesion is different from the insulinoma (also called adenoma) in histology and molecular mechanisms of insulin secretion [60].

General Management

The management of patients with HH can be extremely complicated (as they have multiple problems, such as fluid overload, cardiac failure, and sepsis). They will require frequent blood glucose monitoring and the insertion of a central venous catheter to deliver concentrated dextrose infusions. Ideally, these patients should be referred to specialized centres that have the necessary multidisciplinary team experience and expertise in managing them [15]. The treatment of HH involves medical therapy and surgery in some cases. The mainstay of initial medical treatment is the provision of adequate carbohydrate to maintain normoglycaemia (3.5–6 mmol/l). Adequate carbohydrate can be provided as intravenous glucose at high concentrations, together with a nasogastric feeding tube for regular feeds. Concentrated dextrose infusions should be delivered using a central venous catheter (Hickman line) or an umbilical venous catheter. Glucose polymer can be added to the enteral feed to increase the carbohydrate intake. Some infants may require the insertion of a gastrostomy for regular and frequent feeds.

Medical Management

Table 2 is a summary of the medications used in the treatment of CHI, their doses, side effects, and the possible mechanisms of actions. Diazoxide is the first-line treatment of choice. Diazoxide and nifedipine are given orally, whereas octreotide and glucagon are given subcutaneously or intravenously. Nifedipine is a calcium channel antagonist and has been used in some patients with CHI, although the vast majority of patients fail to show any response. Despite this, there have been several reports of nifedipine-responsive CHI patients [61, 62,] but the underlying molecular pathophysiology of CHI in these reported cases is unclear.

Table 2

Summary of the medications used in the treatment of CHI: their doses, side effects, and the possible mechanisms of action

http://www.karger.com/WebMaterial/ShowPic/262192

Diazoxide

The clinical effectiveness of diazoxide is variable [63]. Mutations in the ABCC8/KCNJ11 gene are not predictive of the response to diazoxide, and there is no correlation between the histology and the clinical efficacy of diazoxide [64]. Patients with transient and syndromic forms of HH will usually respond to diazoxide, whereas those with severe neonatal CHI will show no response.

A newer more potent synthetic diazoxide analog, 6,7-dichloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (BPDZ 154), has been evaluated [65]. In patients with CHI associated with severe loss of KATP channel function, neither diazoxide nor BPDZ 154 was effective in suppressing insulin release in vivo. In contrast, in those cases of CHI, where the KATP channel function was preserved, BPDZ 154 was able to activate KATP channels in vitro, while diazoxide had no therapeutic effect when used in vivo.

These findings imply that increasing the concentrations of diazoxide in vivo may prove beneficial, but in clinical practice increasing doses of diazoxide are associated with side effects.

Octreotide

Octreotide is a long-acting analog of the natural hormone somatostatin and is used in the short- and long-term management of CHI. In the short term (with and without glucagon), it is used to stabilize patients pending further investigations. Octreotide has been successively used in the long-term management of some CHI patients in combination with frequent feeding [66]. The long-term medical management of diffuse disease with octreotide and frequent feeding should not be taken lightly, as it may impose a huge burden and be stressful on the family. A gastrostomy is recommend in these patients, as this will allow the delivery of bolus and continuous overnight feeds.

Glucagon

Glucagon is used for the acute management of hypoglycemia, when there are adequate glycogen stores (e.g., hyperinsulinism either due to endogenous hyperinsulinemia or to exogenous insulin treatment of patients with diabetes). It is also used in the short term to stabilize patients with HH in combination with octreotide. At higher doses (>20 µg/kg/h), glucagon is a potent stimulator of insulin secretion [67].

Differentiating Focal from Diffuse CHI

Identification of those children, who have the focal form of the disease preoperatively, is a critical part of the management of patients with CHI. The preoperative localization allows radically different treatment options and medical outcomes. Focal disease is curable with limited (partial) pancreatectomy with few long-term complications. Until recently, highly invasive methods such as intrahepatic pancreatic portal venous sampling, the intra-arterial calcium stimulation/venous sampling test, and acute insulin response testing to intravenous glucose, calcium, and tolbutamide were used for identifying those children with focal and diffuse forms of the disease. More recently, 18F-L-dopa PET has been successfully used to localize the focal domain [5, 68]. The principle of this test is based on the fact that islets take up L-dopa and convert it to dopamine by dopa decarboxylase which is present in the islet cells [69]. 18F-L-dopa PET can also accurately locate ectopic focal lesions [70]. In figure 4 the 18F-L-Dopa PET/CT scan shows a focal lesion embedded in the head of the pancreas.

Fig. 4

18F-L-dopa PET/CT scan showing a focal lesion embedded in the head of the pancreas. For comparison of tracer uptake in various parts of the pancreas, standardized uptake values (SUVs) were calculated: The 18F-L-dopa uptake is greatest in the head (SUV 5.0) of the pancreas as compared with body and tail (SUV 3.2 and SUV 3.0, respectively).

http://www.karger.com/WebMaterial/ShowPic/262188

Natural History and the Role of Surgery in CHI

The role of surgery in focal CHI is relatively well defined. If a focal lesion is identified and accurately located, it should be surgically removed, as this will ‘cure’ the patient. There is early experience, showing that some focal lesions may be removed laparoscopically [71].

As diffuse CHI is a heterogeneous disorder with respect to clinical presentation and response to medical therapy, the role of surgery in those cases that are diazoxide unresponsive is not so clear. Studies of predominantly Ashkenazi Jewish children with CHI suggest that the natural history of the disease is one of progressive glucose intolerance and clinical diabetes, possibly due to a slow progressive loss of β-cell function, and this may be due to the increased β-cell apoptosis, and, therefore, surgery may not be indicated in all patients [72]. Similarly, some patients with diazoxide-responsive CHI go on to develop diabetes mellitus in adulthood [73].

Near-total pancreatectomy is a major operation and is associated with a high incidence of diabetes mellitus later in life [74]. Clearly, surgery is indicated in those patients with severe diffuse disease who fail to respond to octreotide with frequent feeding regimens, and identification of this subgroup is important. The management of post-pancreatectomy diabetes mellitus is complicated by the fact that these children have pancreatic exocrine insufficiency, glucagon deficiency, and have residual unregulated insulin secretion, and some patients show resistance to hyperketonaemia and diabetic ketoacidosis [75]. Figure 5 is a suggested outline of the long-term medical and surgical management of patients with diazoxide-unresponsive CHI.

Fig. 5

Outline of the long-term medical and surgical management of patients with diazoxide-unresponsive CHI. The broken arrow indicates that some patients may require a total pancreatectomy to control the most severe forms of CHI.

http://www.karger.com/WebMaterial/ShowPic/262187

Conclusions

HH is a major cause of hypoglycaemia in the childhood period. Recognition and appropriate management of this type of hypoglycaemia are important to avoid long-term neurological consequences. The genetic mechanisms that lead to some forms of transient and CHI are beginning to be understood. Recent experience using 18F-L-dopa PET/CT scanning to distinguish diffuse from focal hyperinsulinism has completely changed the diagnostic and management approach to these patients. For the future, the management of medically unresponsive diffuse disease remains a challenge, and identifying the genetic mechanisms leading to both transient and persistent hyperinsulinism in the remaining 50% of the patients will provide novel insights into pancreatic β-cell physiology.

Acknowledgement

Research at the Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust benefits from R & D funding received from the NHS Executive.


References

  1. Menni F, de Lonlay P, Sevin C, Touati G, Peigne C, Barbier V, Nihoul-Fékété C, Saudubray JM, Robert JJ: Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia. Pediatrics 2001;107:476–479.
  2. Collins JE, Leonard JV, Teale D, Marks V, Williams DM, Kennedy CR, Hall MA: Hyperinsulinaemic hypoglycaemia in small for dates babies. Arch Dis Child 1990;65:1118–1120.
  3. Dunne MJ, Cosgrove KE, Shepherd RM, Aynsley-Green A, Lindley KJ: Hyperinsulinism in infancy: from basic science to clinical disease. Physiol Rev 2004;84:239–275.
  4. Rahier J, Guiot Y, Sempoux C: Persistent hyperinsulinaemic hypoglycaemia of infancy: a heterogeneous syndrome unrelated to nesidioblastosis. Arch Dis Child Fetal Neonatal Ed 2002;82:F108–F112.
    External Resources
  5. Otonkoski T, Näntö-Salonen K, Seppänen M, Veijola R, Huopio H, Hussain K, Tapanainen P, Eskola O, Parkkola R, Ekström K, Guiot Y, Rahier J, Laakso M, Rintala R, Nuutila P, Minn H: Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography. Diabetes 2006;55:13–18.
  6. Hussain K, Cosgrove KE, Shepherd RM, Luharia A, Smith VV, Kassem S, Gregory JW, Sivaprasadarao A, Christesen HT, Jacobsen BB, Brusgaard K, Glaser B, Maher EA, Lindley KJ, Hindmarsh P, Dattani M, Dunne MJ: Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann syndrome due to defects in the function of pancreatic β-cell adenosine triphosphate-sensitive potassium channels. J Clin Endocrinol Metab 2005;90:4376–4382.
  7. Baujat G, Rio M, Rossignol S, Sanlaville D, Lyonnet S, Le Merrer M, Munnich A, Gicquel C, Cormier-Daire V, Colleaux L: Paradoxical NSD1 mutations in Beckwith-Wiedemann syndrome and 11p15 anomalies in Sotos’ syndrome. Am J Hum Genet 2004;74:715–720.
  8. de Lonlay P, Cuer M, Vuillaumier-Barrot S, Beaune G, Castelnau P, Kretz M, Durand G, Saudubray JM, Seta N: Hyperinsulinemic hypoglycemia as a presenting sign in phosphomannose isomerase deficiency: a new manifestation of carbohydrate-deficient glycoprotein syndrome treatable with mannose. J Pediatr 1999;135:379–383.
  9. Hojlund K, Hansen T, Lajer M, Henriksen JE, Levin K, Lindholm J, Pedersen O, Beck-Nielsen H: A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene. Diabetes 2004;53:1592–1598.
  10. Service FJ, Natt N, Thompson GB, Grant CS, van Heerden JA, Andrews JC, Lorenz E, Terzic A, Lloyd RV: Noninsulinoma pancreatogenous hypoglycemia: a novel syndrome of hyperinsulinemic hypoglycemia in adults independent of mutations in Kir6.2 and SUR1 genes. J Clin Endocrinol Metab 1999;84:1582–1589.
  11. Giurgea I, Bellanné-Chantelot C, Ribeiro M, Hubert L, Sempoux C, Robert JJ, Blankenstein O, Hussain K, Brunelle F, Nihoul-Fékété C, Rahier J, Jaubert F, de Lonlay P: Molecular mechanisms of neonatal hyperinsulinism. Horm Res 2006;66:289–296.
  12. Glaser B, Thornton P, Otonkoski T, Junien C: Genetics of neonatal hyperinsulinism. Arch Dis Child Fetal Neonatal Ed 2000;82:F79–F86.
  13. Hussain K, Aynsley-Green A: Hyperinsulinaemic hypoglycaemia in preterm neonates. Arch Dis Child Fetal Neonatal Ed 2004;89:F65–F67.
  14. de Lonlay P, Cormier-Daire V, Amiel J, Touati G, Goldenberg A, Fournet JC, Brunelle F, Nihoul-Fékété C, Rahier J, Junien C, Robert JJ, Saudubray JM: Facial appearance in persistent hyperinsulinemic hypoglycemia. Am J Med Genet 2002;111:130–133.
  15. Aynsley-Green A, Hussain K, Hall J, Saudubray JM, Nihoul-Fékété C, de Lonlay-Debeney P, Brunelle F, Otonkoski T, Thornton P, Lindley JK: Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed 2000;82:F98–F107.
  16. Hussain K, Thornton PS, Otonkoski T, Aynsley-Green A: Severe transient neonatal hyperinsulinism associated with hyperlactataemia in non-asphyxiated infants. J Pediatr Endocrinol Metab 2004;17:203–209.
  17. 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;338:1352–1357.
  18. Clayton PT, Eaton S, Aynsley-Green A, Edginton M, Hussain K, Krywawych S, Datta V, Malingre HE, Berger R, van den Berg IE: Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. J Clin Invest 2001;108:457–465.
  19. Hussain K, Hindmarsh P, Aynsley-Green A: Neonates with symptomatic hyperinsulinaemic hypoglycaemia generate inappropriately low serum cortisol counter-regulatory hormonal responses. J Clin Endocrinol Metab 2003;88:4342–4347.
  20. Hussain K, Bryan J, Christesen HT, Brusgaard K, Aguilar-Bryan L: Serum glucagon counterregulatory hormonal response to hypoglycemia is blunted in congenital hyperinsulinism. Diabetes 2005;54:2946–2951.
  21. Levitt Katz LE, Satin-Smith MS, Collet-Solberg P, Thornton PS, Baker L, Stanley CA, Cohen P: Insulin-like growth factor binding protein-1 levels in the diagnosis of hypoglycemia caused by hyperinsulinism. J Pediatr 1997;131:193–199.
  22. Finegold DN, Stanley CA, Baker L: Glycemic response to glucagon during fasting hypoglycemia: an aid in the diagnosis of hyperinsulinism. J Pediatr 1980;96:257–259.
  23. Otonkoski T, Kaminen N, Ustinov J, Lapatto R, Meissner T, Mayatepek E, Kere J, Sipilä I: Physical exercise-induced hyperinsulinemic hypoglycemia is an autosomal-dominant trait characterized by abnormal pyruvate-induced insulin release. Diabetes 2003;52:199–204.
  24. Miller HC, Johnson RD, Durlacher SH: A comparison of newborn infants with erythroblastosis fetalis with those born to diabetic mothers. J Pediatr 1944;24:603–605.
    External Resources
  25. Fafoula O, Alkhayyat H, Hussain K: Prolonged hyperinsulinaemic hypoglycaemia in newborns with intrauterine growth retardation. Arch Dis Child Fetal Neonatal Ed 2006;91:F467.
  26. Hoe FM, Thornton PS, Wanner LA, Steinkrauss L, Simmons RA, Stanley CA: Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism. J Pediatr 2006;148:207–212.
  27. Geneviève D, Amiel J, Viot G, Le Merrer M, Sanlaville D, Urtizberea A, Gérard M, Munnich A, Cormier-Daire V, Lyonnet S: Atypical findings in Kabuki syndrome: report of 8 patients in a series of 20 and review of the literature. Am J Med Genet A 2004;129:64–68.
  28. Bitner-Glindzicz M, Lindley KJ, Rutland P, Blaydon D, Smith VV, Milla PJ, Hussain K, Furth-Lavi J, Cosgrove KE, Shepherd RM, Barnes PD, O’Brien RE, Farndon PA, Sowden J, Liu XZ, Scanlan MJ, Malcolm S, Dunne MJ, Aynsley-Green A, Glaser B: A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene. Nat Genet 2000;26:56–60.
  29. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K, Tager-Flusberg H, Priori SG, Sanguinetti MC, Keating MT: Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 2004;119:19–31.
  30. Alexander S, Ramadan D, Alkhayyat H, Al-Sharkawi I, Backer KC, El-Sabban F, Hussain K: Costello syndrome and hyperinsulinemic hypoglycemia. Am J Med Genet A 2005;139:227–230.
  31. Tamame T, Hori N, Homma H, Yoshida R, Inokuchi M, Kosaki K, Takahashi T, Hasegawa T: Hyperinsulinemic hypoglycemia in a newborn infant with trisomy 13. Am J Med Genet A 2004;129:321–322.
    External Resources
  32. Alkhayyat H, Christesen HB, Steer J, Stewart H, Brusgaard K, Hussain K: Mosaic Turner syndrome and hyperinsulinaemic hypoglycaemia. J Pediatr Endocrinol Metab 2006;19:1451–1457.
  33. Böhles H, Sewell AA, Gebhardt B, Reinecke-Lüthge A, Klöppel G, Marquardt T: Hyperinsulinaemic hypoglycaemia – leading symptom in a patient with congenital disorder of glycosylation Ia (phosphomannomutase deficiency). J Inherit Metab Dis 2001;24:858–862.
  34. Sun L, Eklund EA, Chung WK, Wang C, Cohen J, Freeze HH: Congenital disorder of glycosylation id presenting with hyperinsulinemic hypoglycemia and islet cell hyperplasia. J Clin Endocrinol Metab 2005;90:4371–4375.
  35. Baumann U, Preece MA, Green A, Kelly DA, McKiernan PJ: Hyperinsulinism in tyrosinaemia type I. J Inherit Metab Dis 2005;28:131–135.
  36. 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:e118.
  37. 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;268:426–429.
  38. 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;5:1813–1822.
  39. Huopio H, Reimann F, Ashfield R, Komulainen J, Lenko HL, Rahier J, Vauhkonen I, Kere J, Laakso M, Ashcroft F, Otonkoski T: Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1. J Clin Invest 2000;106:897–906.
  40. Dunne MJ, Kane C, Shepherd RM, Sanchez JA, James RF, Johnson PR, Aynsley-Green A, Lu S, Clement JP IV, Lindley KJ, Seino S, Aguilar-Bryan L: Familial persistent hyperinsulinemic hypoglycemia of infancy and mutations in the sulfonylurea receptor. N Engl J Med 1997;336:703–706.
  41. Kane C, Shepherd RM, Squires PE, Johnson PR, James RF, Milla PJ, Aynsley-Green A, Lindley KJ, Dunne MJ: Loss of functional KATP channels in pancreatic beta-cells causes persistent hyperinsulinemic hypoglycemia of infancy. Nat Med 1996;2:1344–1347.
  42. Partridge CJ, Beech DJ, Sivaprasadarao A: Identification and pharmacological correction of a membrane trafficking defect associated with a mutation in the sulfonylurea receptor causing familial hyperinsulinism. J Biol Chem 2001;276:35947–35952.
  43. Sharma N, Crane A, Clement JP 4th, Gonzalez G, Babenko AP, Bryan J, Aguilar-Bryan L: The C terminus of SUR1 is required for trafficking of KATP channels. J Biol Chem 1999;274:20628–20632.
  44. Shyng SL, Ferrigni T, Shepard JB, Nestorowicz A, Glaser B, Permutt MA, Nichols CG: Functional analyses of novel mutations in the sulfonylurea receptor 1 associated with persistent hyperinsulinemic hypoglycemia of infancy. Diabetes 1998;47:1145–1151.
  45. Tanizawa Y, Matsuda K, Matsuo M, Ohta Y, Ochi N, Adachi M, Koga M, Mizuno S, Kajita M, Tanaka Y, Tachibana K, Inoue H, Furukawa S, Amachi T, Ueda K, Oka Y: Genetic analysis of Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy: nucleotide-binding fold-2 mutation impairs cooperative binding of adenine nucleotides to sulfonylurea receptor 1. Diabetes 2000;49:114–120.
  46. Kukuvitis A, Deal C, Arbour L, Polychronakos C: An autosomal dominant form of familial persistent hyperinsulinemic hypoglycemia of infancy, not linked to the sulfonylurea receptor locus. J Clin Endocrinol Metab 1997;82:1192–1194.
  47. Someya T, Miki T, Sugihara S, Minagawa M, Yasuda T, Kohno Y, Seino S: Characterization of genes encoding the pancreatic beta-cell ATP-sensitive K+ channel in persistent hyperinsulinemic hypoglycemia of infancy in Japanese patients. Endocr J 2000;47:715–722.
  48. MacMullen C, Fang J, Hsu BY, Kelly A, de Lonlay-Debeney P, Saudubray JM, Ganguly A, Smith TJ, Stanley CA; Hyperinsulinism/hyperammonemia Contributing Investigators: Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase. J Clin Endocrinol Metab 2001;86:1782–1787.
  49. Raizen DM, Brooks-Kayal A, Steinkrauss L, Tennekoon GI, Stanley CA, Kelly A: Central nervous system hyperexcitability associated with glutamate dehydrogenase gain of function mutations. J Pediatr 2005;146:388–394.
  50. Glaser B, Kesavan P, Heyman M, Davis E, Cuesta A, Buchs A, Stanley CA, Thornton PS, Permutt MA, Matschinsky FM, Herold KC: Familial hyperinsulinism caused by activating glucokinase mutation. N Engl J Med 1998;338:226–230.
  51. Christesen HB, Jacobsen BB, Odili S, Buettger C, Cuesta-Muñoz A, Hansen T, Brusgaard K, Massa O, Magnuson MA, Shiota C, Matschinsky FM, Barbetti F: The second activating glucokinase mutation (A456V): implications for glucose homeostasis and diabetes therapy. Diabetes 2002;51:1240–1246.
  52. Gloyn AL, Noordam K, Willemsen MA, Ellard S, Lam WW, Campbell IW, Midgley P, Shiota C, Buettger C, Magnuson MA, Matschinsky FM, Hattersley AT: Insights into the biochemical and genetic basis of glucokinase activation from naturally occurring hypoglycemia mutations. Diabetes 2003;52:2433–2440.
  53. Cuesta-Muñoz A, Huopio H, Otonkoski T, Gomez-Zumaquero JM, Näntö-Salonen K, Rahier J, López-Enriquez S, García-Gimeno MA, Sanz P, Soriguer FC, Laakso M: Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation. Diabetes 2004;53:2164–2168.
  54. Hussain K, Clayton PT, Krywawych S, Chatziandreou I, Mills P, Ginbey DW, Geboers AJ, Berger R, van den Berg IE, Eaton S: Hyperinsulinism of infancy associated with a novel splice site mutation in the SCHAD gene. J Pediatr 2005;146:706–708.
  55. Molven A, Matre GE, Duran M, Wanders RJ, Rishaug U, Njolstad PR, Jellum E, Sovik O: Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. Diabetes 2004;53:221–227.
  56. Lantz KA, Vatamaniuk MZ, Brestelli JE, Friedman JR, Matschinsky FM, Kaestner KH: Foxa2 regulates multiple pathways of insulin secretion. J Clin Invest 2004;114:512–520.
  57. Suchi M, MacMullen C, Thornton PS, Ganguly A, Stanley CA, Ruchelli ED: Histopathology of congenital hyperinsulinism: retrospective study with genotype correlations. Pediatr Dev Pathol 2003;6:322–333.
  58. de Lonlay P, Fournet JC, Rahier J, Gross-Morand MS, Poggi-Travert F, Foussier V, Bonnefont JP, Brusset MC, Brunelle F, Robert JJ, Nihoul-Fékété C, Saudubray JM, Junien C: 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;100:802–807.
  59. Verkarre V, Fournet JC, de Lonlay P, Gross-Morand MS, Devillers M, Rahier J, Brunelle F, Robert JJ, Nihoul-Fékété C, Saudubray JM, Junien C: 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;102:1286–1291.
  60. Sempoux C, Guiot Y, Lefevre A, Nihoul-Fékété C, Jaubert F, Saudubray JM, Rahier J: Neonatal hyperinsulinemic hypoglycemia: heterogeneity of the syndrome and keys for differential diagnosis. J Clin Endocrinol Metab 1998;83:1455–1461.
  61. Bas F, Darendeliler F, Demirkol D, Bundak R, Saka N, Günöz H: Successful therapy with calcium channel blocker (nifedipine) in persistent neonatal hyperinsulinemic hypoglycemia of infancy. J Pediatr Endocrinol Metab 1999;12:873–878.
  62. Shanbag P, Pathak A, Vaidya M, Shahid SK: Persistent hyperinsulinemic hypoglycemia of infancy – successful therapy with nifedipine. Indian J Pediatr 2002;69:271–272.
  63. Touati G, Poggi-Travert F, Ogier de Baulny H, Rahier J, Brunelle F, Nihoul-Fékété C, Czernichow P, Saudubray JM: Long-term treatment of persistent hyperinsulinaemic hypoglycaemia of infancy with diazoxide: a retrospective review of 77 cases and analysis of efficacy-predicting criteria. Eur J Pediatr 1998;157:628–633.
  64. Darendeliler F, Fournet JC, Bas F, Junien C, Gross MS, Bundak R, Saka N, Gunoz H: ABCC8 (SUR1) and KCNJ11 (KIR6.2) mutations in persistent hyperinsulinemic hypoglycemia of infancy and evaluation of different therapeutic measures. J Pediatr Endocrinol Metab 2002;15:993–1000.
  65. Cosgrove KE, Antoine MH, Lee AT, Barnes PD, de Tullio P, Clayton P, McCloy R, de Lonlay P, Nihoul-Fékété C, Robert JJ, Saudubray JM, Rahier J, Lindley KJ, Hussain K, Aynsley-Green A, Pirotte B, Lebrun P, Dunne MJ: BPDZ 154 activates adenosine 5′-triphosphate-sensitive potassium channels: in vitro studies using rodent insulin-secreting cells and islets isolated from patients with hyperinsulinism. J Clin Endocrinol Metab 2002;87:4860–4868.
  66. Glaser B, Landau H, Smilovici A, Nesher R: Persistent hyperinsulinaemic hypoglycaemia of infancy: long-term treatment with the somatostatin analogue Sandostatin. Clin Endocrinol (Oxf) 1989;31:71–80.
  67. Moens K, Berger V, Ahn JM, Van Schravendijk C, Hruby VJ, Pipeleers D, Schuit F: Assessment of the role of interstitial glucagon in the acute glucose secretory responsiveness of in situ pancreatic beta-cells. Diabetes 2002;51:669–675.
  68. Mohnike K, Blankenstein O, Christesen HT, de Lonlay J, Hussain K, Koopmans KP, Minn H, Mohnike W, Mutair A, Otonkoski T, Rahier J, Ribeiro M, Schoenle E, Fékété C: Proposal for a standardized protocol for 18F-DOPA-PET (PET/CT) in congenital hyperinsulinism. Horm Res 2006;66:40–42.
  69. Pearse AG: Islet cell precursors are neurons. Nature 1982; 259:96–97.
    External Resources
  70. Hussain K, Seppänen M, Näntö-Salonen K, Adzick NS, Stanley CA, Thornton P, Minn H: The diagnosis of ectopic focal hyperinsulinism of infancy with [18F]-dopa positron emission tomography. J Clin Endocrinol Metab 2006;91:2839–2842.
  71. De Vroede M, Bax NM, Brusgaard K, Dunne MJ, Groenendaal F: Laparoscopic diagnosis and cure of hyperinsulinism in two cases of focal adenomatous hyperplasia in infancy. Pediatrics 2004;114:e520–e522.
  72. Kassem SA, Ariel I, Thornton P, Scheimberg I, Glaser B: Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Diabetes 2000;49:1325–1333.
  73. Huopio H, Otonkoski T, Vauhkonen I, Reimann F, Ashcroft FM, Laakso M: A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1. Lancet 2003;361:301–307.
  74. Leibowitz G, Glaser B, Higazi AA, Salameh M, Cerasi E, Landau H: Hyperinsulinemic hypoglycemia of infancy (nesidioblastosis) in clinical remission: high incidence of diabetes mellitus and persistent beta-cell dysfunction at long-term follow-up. J Clin Endocrinol Metab 1995;80:386–392.
  75. Greene SA, Aynsley-Green A, Soltesz G, Baum JD: Management of secondary diabetes mellitus after pancreatectomy in infancy. Arch Dis Child 1984;59:356–359.
  76. Service GJ, Thompson GB, Service FJ, Andrews JC, Collazo-Clavell ML, Lloyd RV: Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric bypass surgery. N Engl J Med 2005;353:249–254.

Author Contacts

Dr. K. Hussain

Developmental Endocrinology Research Group, Molecular Genetics Unit

Institute of Child Health, University College London, 30 Guilford Street

London WC1N 1EH (UK)

Tel. +44 (0) 20 7 905 2128, Fax +44 (0) 20 7 404 6191, E-Mail K.Hussain@ich.ucl.ac.uk


Article / Publication Details

First-Page Preview
Abstract of Mini Review

Received: September 07, 2006
Accepted: July 27, 2007
Published online: December 04, 2007
Issue release date: December 2007

Number of Print Pages: 12
Number of Figures: 5
Number of Tables: 2

ISSN: 1663-2818 (Print)
eISSN: 1663-2826 (Online)

For additional information: https://www.karger.com/HRP


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Menni F, de Lonlay P, Sevin C, Touati G, Peigne C, Barbier V, Nihoul-Fékété C, Saudubray JM, Robert JJ: Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia. Pediatrics 2001;107:476–479.
  2. Collins JE, Leonard JV, Teale D, Marks V, Williams DM, Kennedy CR, Hall MA: Hyperinsulinaemic hypoglycaemia in small for dates babies. Arch Dis Child 1990;65:1118–1120.
  3. Dunne MJ, Cosgrove KE, Shepherd RM, Aynsley-Green A, Lindley KJ: Hyperinsulinism in infancy: from basic science to clinical disease. Physiol Rev 2004;84:239–275.
  4. Rahier J, Guiot Y, Sempoux C: Persistent hyperinsulinaemic hypoglycaemia of infancy: a heterogeneous syndrome unrelated to nesidioblastosis. Arch Dis Child Fetal Neonatal Ed 2002;82:F108–F112.
    External Resources
  5. Otonkoski T, Näntö-Salonen K, Seppänen M, Veijola R, Huopio H, Hussain K, Tapanainen P, Eskola O, Parkkola R, Ekström K, Guiot Y, Rahier J, Laakso M, Rintala R, Nuutila P, Minn H: Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography. Diabetes 2006;55:13–18.
  6. Hussain K, Cosgrove KE, Shepherd RM, Luharia A, Smith VV, Kassem S, Gregory JW, Sivaprasadarao A, Christesen HT, Jacobsen BB, Brusgaard K, Glaser B, Maher EA, Lindley KJ, Hindmarsh P, Dattani M, Dunne MJ: Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann syndrome due to defects in the function of pancreatic β-cell adenosine triphosphate-sensitive potassium channels. J Clin Endocrinol Metab 2005;90:4376–4382.
  7. Baujat G, Rio M, Rossignol S, Sanlaville D, Lyonnet S, Le Merrer M, Munnich A, Gicquel C, Cormier-Daire V, Colleaux L: Paradoxical NSD1 mutations in Beckwith-Wiedemann syndrome and 11p15 anomalies in Sotos’ syndrome. Am J Hum Genet 2004;74:715–720.
  8. de Lonlay P, Cuer M, Vuillaumier-Barrot S, Beaune G, Castelnau P, Kretz M, Durand G, Saudubray JM, Seta N: Hyperinsulinemic hypoglycemia as a presenting sign in phosphomannose isomerase deficiency: a new manifestation of carbohydrate-deficient glycoprotein syndrome treatable with mannose. J Pediatr 1999;135:379–383.
  9. Hojlund K, Hansen T, Lajer M, Henriksen JE, Levin K, Lindholm J, Pedersen O, Beck-Nielsen H: A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene. Diabetes 2004;53:1592–1598.
  10. Service FJ, Natt N, Thompson GB, Grant CS, van Heerden JA, Andrews JC, Lorenz E, Terzic A, Lloyd RV: Noninsulinoma pancreatogenous hypoglycemia: a novel syndrome of hyperinsulinemic hypoglycemia in adults independent of mutations in Kir6.2 and SUR1 genes. J Clin Endocrinol Metab 1999;84:1582–1589.
  11. Giurgea I, Bellanné-Chantelot C, Ribeiro M, Hubert L, Sempoux C, Robert JJ, Blankenstein O, Hussain K, Brunelle F, Nihoul-Fékété C, Rahier J, Jaubert F, de Lonlay P: Molecular mechanisms of neonatal hyperinsulinism. Horm Res 2006;66:289–296.
  12. Glaser B, Thornton P, Otonkoski T, Junien C: Genetics of neonatal hyperinsulinism. Arch Dis Child Fetal Neonatal Ed 2000;82:F79–F86.
  13. Hussain K, Aynsley-Green A: Hyperinsulinaemic hypoglycaemia in preterm neonates. Arch Dis Child Fetal Neonatal Ed 2004;89:F65–F67.
  14. de Lonlay P, Cormier-Daire V, Amiel J, Touati G, Goldenberg A, Fournet JC, Brunelle F, Nihoul-Fékété C, Rahier J, Junien C, Robert JJ, Saudubray JM: Facial appearance in persistent hyperinsulinemic hypoglycemia. Am J Med Genet 2002;111:130–133.
  15. Aynsley-Green A, Hussain K, Hall J, Saudubray JM, Nihoul-Fékété C, de Lonlay-Debeney P, Brunelle F, Otonkoski T, Thornton P, Lindley JK: Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed 2000;82:F98–F107.
  16. Hussain K, Thornton PS, Otonkoski T, Aynsley-Green A: Severe transient neonatal hyperinsulinism associated with hyperlactataemia in non-asphyxiated infants. J Pediatr Endocrinol Metab 2004;17:203–209.
  17. 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;338:1352–1357.
  18. Clayton PT, Eaton S, Aynsley-Green A, Edginton M, Hussain K, Krywawych S, Datta V, Malingre HE, Berger R, van den Berg IE: Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. J Clin Invest 2001;108:457–465.
  19. Hussain K, Hindmarsh P, Aynsley-Green A: Neonates with symptomatic hyperinsulinaemic hypoglycaemia generate inappropriately low serum cortisol counter-regulatory hormonal responses. J Clin Endocrinol Metab 2003;88:4342–4347.
  20. Hussain K, Bryan J, Christesen HT, Brusgaard K, Aguilar-Bryan L: Serum glucagon counterregulatory hormonal response to hypoglycemia is blunted in congenital hyperinsulinism. Diabetes 2005;54:2946–2951.
  21. Levitt Katz LE, Satin-Smith MS, Collet-Solberg P, Thornton PS, Baker L, Stanley CA, Cohen P: Insulin-like growth factor binding protein-1 levels in the diagnosis of hypoglycemia caused by hyperinsulinism. J Pediatr 1997;131:193–199.
  22. Finegold DN, Stanley CA, Baker L: Glycemic response to glucagon during fasting hypoglycemia: an aid in the diagnosis of hyperinsulinism. J Pediatr 1980;96:257–259.
  23. Otonkoski T, Kaminen N, Ustinov J, Lapatto R, Meissner T, Mayatepek E, Kere J, Sipilä I: Physical exercise-induced hyperinsulinemic hypoglycemia is an autosomal-dominant trait characterized by abnormal pyruvate-induced insulin release. Diabetes 2003;52:199–204.
  24. Miller HC, Johnson RD, Durlacher SH: A comparison of newborn infants with erythroblastosis fetalis with those born to diabetic mothers. J Pediatr 1944;24:603–605.
    External Resources
  25. Fafoula O, Alkhayyat H, Hussain K: Prolonged hyperinsulinaemic hypoglycaemia in newborns with intrauterine growth retardation. Arch Dis Child Fetal Neonatal Ed 2006;91:F467.
  26. Hoe FM, Thornton PS, Wanner LA, Steinkrauss L, Simmons RA, Stanley CA: Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism. J Pediatr 2006;148:207–212.
  27. Geneviève D, Amiel J, Viot G, Le Merrer M, Sanlaville D, Urtizberea A, Gérard M, Munnich A, Cormier-Daire V, Lyonnet S: Atypical findings in Kabuki syndrome: report of 8 patients in a series of 20 and review of the literature. Am J Med Genet A 2004;129:64–68.
  28. Bitner-Glindzicz M, Lindley KJ, Rutland P, Blaydon D, Smith VV, Milla PJ, Hussain K, Furth-Lavi J, Cosgrove KE, Shepherd RM, Barnes PD, O’Brien RE, Farndon PA, Sowden J, Liu XZ, Scanlan MJ, Malcolm S, Dunne MJ, Aynsley-Green A, Glaser B: A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene. Nat Genet 2000;26:56–60.
  29. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K, Tager-Flusberg H, Priori SG, Sanguinetti MC, Keating MT: Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 2004;119:19–31.
  30. Alexander S, Ramadan D, Alkhayyat H, Al-Sharkawi I, Backer KC, El-Sabban F, Hussain K: Costello syndrome and hyperinsulinemic hypoglycemia. Am J Med Genet A 2005;139:227–230.
  31. Tamame T, Hori N, Homma H, Yoshida R, Inokuchi M, Kosaki K, Takahashi T, Hasegawa T: Hyperinsulinemic hypoglycemia in a newborn infant with trisomy 13. Am J Med Genet A 2004;129:321–322.
    External Resources
  32. Alkhayyat H, Christesen HB, Steer J, Stewart H, Brusgaard K, Hussain K: Mosaic Turner syndrome and hyperinsulinaemic hypoglycaemia. J Pediatr Endocrinol Metab 2006;19:1451–1457.
  33. Böhles H, Sewell AA, Gebhardt B, Reinecke-Lüthge A, Klöppel G, Marquardt T: Hyperinsulinaemic hypoglycaemia – leading symptom in a patient with congenital disorder of glycosylation Ia (phosphomannomutase deficiency). J Inherit Metab Dis 2001;24:858–862.
  34. Sun L, Eklund EA, Chung WK, Wang C, Cohen J, Freeze HH: Congenital disorder of glycosylation id presenting with hyperinsulinemic hypoglycemia and islet cell hyperplasia. J Clin Endocrinol Metab 2005;90:4371–4375.
  35. Baumann U, Preece MA, Green A, Kelly DA, McKiernan PJ: Hyperinsulinism in tyrosinaemia type I. J Inherit Metab Dis 2005;28:131–135.
  36. 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:e118.
  37. 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;268:426–429.
  38. 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;5:1813–1822.
  39. Huopio H, Reimann F, Ashfield R, Komulainen J, Lenko HL, Rahier J, Vauhkonen I, Kere J, Laakso M, Ashcroft F, Otonkoski T: Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1. J Clin Invest 2000;106:897–906.
  40. Dunne MJ, Kane C, Shepherd RM, Sanchez JA, James RF, Johnson PR, Aynsley-Green A, Lu S, Clement JP IV, Lindley KJ, Seino S, Aguilar-Bryan L: Familial persistent hyperinsulinemic hypoglycemia of infancy and mutations in the sulfonylurea receptor. N Engl J Med 1997;336:703–706.
  41. Kane C, Shepherd RM, Squires PE, Johnson PR, James RF, Milla PJ, Aynsley-Green A, Lindley KJ, Dunne MJ: Loss of functional KATP channels in pancreatic beta-cells causes persistent hyperinsulinemic hypoglycemia of infancy. Nat Med 1996;2:1344–1347.
  42. Partridge CJ, Beech DJ, Sivaprasadarao A: Identification and pharmacological correction of a membrane trafficking defect associated with a mutation in the sulfonylurea receptor causing familial hyperinsulinism. J Biol Chem 2001;276:35947–35952.
  43. Sharma N, Crane A, Clement JP 4th, Gonzalez G, Babenko AP, Bryan J, Aguilar-Bryan L: The C terminus of SUR1 is required for trafficking of KATP channels. J Biol Chem 1999;274:20628–20632.
  44. Shyng SL, Ferrigni T, Shepard JB, Nestorowicz A, Glaser B, Permutt MA, Nichols CG: Functional analyses of novel mutations in the sulfonylurea receptor 1 associated with persistent hyperinsulinemic hypoglycemia of infancy. Diabetes 1998;47:1145–1151.
  45. Tanizawa Y, Matsuda K, Matsuo M, Ohta Y, Ochi N, Adachi M, Koga M, Mizuno S, Kajita M, Tanaka Y, Tachibana K, Inoue H, Furukawa S, Amachi T, Ueda K, Oka Y: Genetic analysis of Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy: nucleotide-binding fold-2 mutation impairs cooperative binding of adenine nucleotides to sulfonylurea receptor 1. Diabetes 2000;49:114–120.
  46. Kukuvitis A, Deal C, Arbour L, Polychronakos C: An autosomal dominant form of familial persistent hyperinsulinemic hypoglycemia of infancy, not linked to the sulfonylurea receptor locus. J Clin Endocrinol Metab 1997;82:1192–1194.
  47. Someya T, Miki T, Sugihara S, Minagawa M, Yasuda T, Kohno Y, Seino S: Characterization of genes encoding the pancreatic beta-cell ATP-sensitive K+ channel in persistent hyperinsulinemic hypoglycemia of infancy in Japanese patients. Endocr J 2000;47:715–722.
  48. MacMullen C, Fang J, Hsu BY, Kelly A, de Lonlay-Debeney P, Saudubray JM, Ganguly A, Smith TJ, Stanley CA; Hyperinsulinism/hyperammonemia Contributing Investigators: Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase. J Clin Endocrinol Metab 2001;86:1782–1787.
  49. Raizen DM, Brooks-Kayal A, Steinkrauss L, Tennekoon GI, Stanley CA, Kelly A: Central nervous system hyperexcitability associated with glutamate dehydrogenase gain of function mutations. J Pediatr 2005;146:388–394.
  50. Glaser B, Kesavan P, Heyman M, Davis E, Cuesta A, Buchs A, Stanley CA, Thornton PS, Permutt MA, Matschinsky FM, Herold KC: Familial hyperinsulinism caused by activating glucokinase mutation. N Engl J Med 1998;338:226–230.
  51. Christesen HB, Jacobsen BB, Odili S, Buettger C, Cuesta-Muñoz A, Hansen T, Brusgaard K, Massa O, Magnuson MA, Shiota C, Matschinsky FM, Barbetti F: The second activating glucokinase mutation (A456V): implications for glucose homeostasis and diabetes therapy. Diabetes 2002;51:1240–1246.
  52. Gloyn AL, Noordam K, Willemsen MA, Ellard S, Lam WW, Campbell IW, Midgley P, Shiota C, Buettger C, Magnuson MA, Matschinsky FM, Hattersley AT: Insights into the biochemical and genetic basis of glucokinase activation from naturally occurring hypoglycemia mutations. Diabetes 2003;52:2433–2440.
  53. Cuesta-Muñoz A, Huopio H, Otonkoski T, Gomez-Zumaquero JM, Näntö-Salonen K, Rahier J, López-Enriquez S, García-Gimeno MA, Sanz P, Soriguer FC, Laakso M: Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation. Diabetes 2004;53:2164–2168.
  54. Hussain K, Clayton PT, Krywawych S, Chatziandreou I, Mills P, Ginbey DW, Geboers AJ, Berger R, van den Berg IE, Eaton S: Hyperinsulinism of infancy associated with a novel splice site mutation in the SCHAD gene. J Pediatr 2005;146:706–708.
  55. Molven A, Matre GE, Duran M, Wanders RJ, Rishaug U, Njolstad PR, Jellum E, Sovik O: Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. Diabetes 2004;53:221–227.
  56. Lantz KA, Vatamaniuk MZ, Brestelli JE, Friedman JR, Matschinsky FM, Kaestner KH: Foxa2 regulates multiple pathways of insulin secretion. J Clin Invest 2004;114:512–520.
  57. Suchi M, MacMullen C, Thornton PS, Ganguly A, Stanley CA, Ruchelli ED: Histopathology of congenital hyperinsulinism: retrospective study with genotype correlations. Pediatr Dev Pathol 2003;6:322–333.
  58. de Lonlay P, Fournet JC, Rahier J, Gross-Morand MS, Poggi-Travert F, Foussier V, Bonnefont JP, Brusset MC, Brunelle F, Robert JJ, Nihoul-Fékété C, Saudubray JM, Junien C: 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;100:802–807.
  59. Verkarre V, Fournet JC, de Lonlay P, Gross-Morand MS, Devillers M, Rahier J, Brunelle F, Robert JJ, Nihoul-Fékété C, Saudubray JM, Junien C: 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;102:1286–1291.
  60. Sempoux C, Guiot Y, Lefevre A, Nihoul-Fékété C, Jaubert F, Saudubray JM, Rahier J: Neonatal hyperinsulinemic hypoglycemia: heterogeneity of the syndrome and keys for differential diagnosis. J Clin Endocrinol Metab 1998;83:1455–1461.
  61. Bas F, Darendeliler F, Demirkol D, Bundak R, Saka N, Günöz H: Successful therapy with calcium channel blocker (nifedipine) in persistent neonatal hyperinsulinemic hypoglycemia of infancy. J Pediatr Endocrinol Metab 1999;12:873–878.
  62. Shanbag P, Pathak A, Vaidya M, Shahid SK: Persistent hyperinsulinemic hypoglycemia of infancy – successful therapy with nifedipine. Indian J Pediatr 2002;69:271–272.
  63. Touati G, Poggi-Travert F, Ogier de Baulny H, Rahier J, Brunelle F, Nihoul-Fékété C, Czernichow P, Saudubray JM: Long-term treatment of persistent hyperinsulinaemic hypoglycaemia of infancy with diazoxide: a retrospective review of 77 cases and analysis of efficacy-predicting criteria. Eur J Pediatr 1998;157:628–633.
  64. Darendeliler F, Fournet JC, Bas F, Junien C, Gross MS, Bundak R, Saka N, Gunoz H: ABCC8 (SUR1) and KCNJ11 (KIR6.2) mutations in persistent hyperinsulinemic hypoglycemia of infancy and evaluation of different therapeutic measures. J Pediatr Endocrinol Metab 2002;15:993–1000.
  65. Cosgrove KE, Antoine MH, Lee AT, Barnes PD, de Tullio P, Clayton P, McCloy R, de Lonlay P, Nihoul-Fékété C, Robert JJ, Saudubray JM, Rahier J, Lindley KJ, Hussain K, Aynsley-Green A, Pirotte B, Lebrun P, Dunne MJ: BPDZ 154 activates adenosine 5′-triphosphate-sensitive potassium channels: in vitro studies using rodent insulin-secreting cells and islets isolated from patients with hyperinsulinism. J Clin Endocrinol Metab 2002;87:4860–4868.
  66. Glaser B, Landau H, Smilovici A, Nesher R: Persistent hyperinsulinaemic hypoglycaemia of infancy: long-term treatment with the somatostatin analogue Sandostatin. Clin Endocrinol (Oxf) 1989;31:71–80.
  67. Moens K, Berger V, Ahn JM, Van Schravendijk C, Hruby VJ, Pipeleers D, Schuit F: Assessment of the role of interstitial glucagon in the acute glucose secretory responsiveness of in situ pancreatic beta-cells. Diabetes 2002;51:669–675.
  68. Mohnike K, Blankenstein O, Christesen HT, de Lonlay J, Hussain K, Koopmans KP, Minn H, Mohnike W, Mutair A, Otonkoski T, Rahier J, Ribeiro M, Schoenle E, Fékété C: Proposal for a standardized protocol for 18F-DOPA-PET (PET/CT) in congenital hyperinsulinism. Horm Res 2006;66:40–42.
  69. Pearse AG: Islet cell precursors are neurons. Nature 1982; 259:96–97.
    External Resources
  70. Hussain K, Seppänen M, Näntö-Salonen K, Adzick NS, Stanley CA, Thornton P, Minn H: The diagnosis of ectopic focal hyperinsulinism of infancy with [18F]-dopa positron emission tomography. J Clin Endocrinol Metab 2006;91:2839–2842.
  71. De Vroede M, Bax NM, Brusgaard K, Dunne MJ, Groenendaal F: Laparoscopic diagnosis and cure of hyperinsulinism in two cases of focal adenomatous hyperplasia in infancy. Pediatrics 2004;114:e520–e522.
  72. Kassem SA, Ariel I, Thornton P, Scheimberg I, Glaser B: Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Diabetes 2000;49:1325–1333.
  73. Huopio H, Otonkoski T, Vauhkonen I, Reimann F, Ashcroft FM, Laakso M: A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1. Lancet 2003;361:301–307.
  74. Leibowitz G, Glaser B, Higazi AA, Salameh M, Cerasi E, Landau H: Hyperinsulinemic hypoglycemia of infancy (nesidioblastosis) in clinical remission: high incidence of diabetes mellitus and persistent beta-cell dysfunction at long-term follow-up. J Clin Endocrinol Metab 1995;80:386–392.
  75. Greene SA, Aynsley-Green A, Soltesz G, Baum JD: Management of secondary diabetes mellitus after pancreatectomy in infancy. Arch Dis Child 1984;59:356–359.
  76. Service GJ, Thompson GB, Service FJ, Andrews JC, Collazo-Clavell ML, Lloyd RV: Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric bypass surgery. N Engl J Med 2005;353:249–254.
ppt logo Download Images (.pptx)


Figures
Thumbnail
Thumbnail
Thumbnail
Thumbnail
Thumbnail

Tables
Thumbnail
Thumbnail