Dunne, Mark J., Karen E. Cosgrove, Ruth M. Shepherd, Albert Aynsley-Green, and Keith J. Lindley. Hyperinsulinism in Infancy: From Basic Science to Clinical Disease. Physiol Rev 84: 239–275, 2004; 10.1152/physrev.00022.2003.—Ion channelopathies have now been described in many well-characterized cell types including neurons, myocytes, epithelial cells, and endocrine cells. However, in only a few cases has the relationship between altered ion channel function, cell biology, and clinical disease been defined. Hyperinsulinism in infancy (HI) is a rare, potentially lethal condition of the newborn and early childhood. The causes of HI are varied and numerous, but in almost all cases they share a common target protein, the ATP-sensitive K+ channel. From gene defects in ion channel subunits to defects in β-cell metabolism and anaplerosis, this review describes the relationship between pathogenesis and clinical medicine. Until recently, HI was generally considered an orphan disease, but as parallel defects in ion channels, enzymes, and metabolic pathways also give rise to diabetes and impaired insulin release, the HI paradigm has wider implications for more common disorders of the endocrine pancreas and the molecular physiology of ion transport.

Usher syndrome type 1 describes the association of profound, congenital sensorineural deafness, vestibular hypofunction and childhood onset retinitis pigmentosa. It is an autosomal recessive condition and is subdivided on the basis of linkage analysis into types 1A through 1E. Usher type 1C maps to the region containing the genes ABCC8 and KCNJ11 (encoding components of ATP-sensitive K + (KATP) channels), which may be mutated in patients with hyperinsulinism. We identified three individuals from two consanguineous families with severe hyperinsulinism, profound congenital sensorineural deafness, enteropathy and renal tubular dysfunction. The molecular basis of the disorder is a homozygous 122-kb deletion of 11p14-15, which includes part of ABCC8 and overlaps with the locus for Usher syndrome type 1C and DFNB18. The centromeric boundary of this deletion includes part of a gene shown to be mutated in families with type 1C Usher syndrome, and is hence assigned the name USH1C. The pattern of expression of the USH1C protein is consistent with the clinical features exhibited by individuals with the contiguous gene deletion and with isolated Usher type 1C.

Congenital hyperinsulinism is a rare disease, but is the most frequent cause of persistent and severe hypoglycaemia in early childhood. Hypoglycaemia caused by excessive and dysregulated insulin secretion (hyperinsulinism) from disordered pancreatic β cells can often lead to irreversible brain damage with lifelong neurodisability. Although congenital hyperinsulinism has a genetic cause in a significant proportion (40%) of children, often being the result of mutations in the genes encoding the KATP channel (ABCC8 and KCNJ11), not all children have severe and persistent forms of the disease. In approximately half of those without a genetic mutation, hyperinsulinism may resolve, although timescales are unpredictable. From a histopathology perspective, congenital hyperinsulinism is broadly grouped into diffuse and focal forms, with surgical lesionectomy being the preferred choice of treatment in the latter. In contrast, in diffuse congenital hyperinsulinism, medical treatment is the best option if conservative management is safe and effective. In such cases, children receiving treatment with drugs, such as diazoxide and octreotide, should be monitored for side effects and for signs of reduction in disease severity. If hypoglycaemia is not safely managed by medical therapy, subtotal pancreatectomy may be required; however, persistent hypoglycaemia may continue after surgery and diabetes is an inevitable consequence in later life. It is important to recognize the negative cognitive impact of early‐life hypoglycaemia which affects half of all children with congenital hyperinsulinism. Treatment options should be individualized to the child/young person with congenital hyperinsulinism, with full discussion regarding efficacy, side effects, outcomes and later life impact.

Mutations in genes encoding the ATP-regulated potassium (K(ATP)) channels of the pancreatic beta-cell (SUR1 and Kir6.2) are the major known cause of persistent hyperinsulinemic hypoglycemia of infancy (PHHI). We collected all cases of PHHI diagnosed in Finland between 1983 and 1997 (n = 24). The overall incidence was 1:40,400, but in one area of Central Finland it was as high as 1:3,200. Haplotype analysis using polymorphic markers spanning the SUR1/Kir6.2 gene cluster confirmed linkage to the 11p region. Sequence analysis revealed a novel point mutation in exon 4 of SUR1, predicting a valine to aspartic acid change at amino acid 187 (V187D). Of the total cases, 15 affected individuals harbored this mutation in heterozygous or homozygous form, and all of these had severe hyperinsulinemia that responded poorly to medical treatment and required subtotal pancreatectomy. No K(ATP) channel activity was observed in beta-cells isolated from a homozygous patient or after coexpression of recombinant Kir6.2 and SUR1 carrying the V187D mutation. Thus, the mutation produces a nonfunctional channel and, thereby, continuous insulin secretion. This unique SUR1 mutation explains the majority of PHHI cases in Finland and is strongly associated with a severe form of the disease. These findings provide diagnostic and prognostic utility for suspected PHHI patients.

Introduction: Neuroglycopenia is recognized to be associated with abnormal neurodevelopmental outcomes in 26–44% of children with persistent congenital hyperinsulinism (P-CHI). The prevalence of abnormal neurodevelopment in transient CHI (T-CHI) is not known. We have aimed to investigate abnormal neurodevelopment and associated factors in T-CHI and P-CHI.Materials and Methods: A cohort of children with CHI (n = 67, age 2.5–5 years) was assessed at follow-up review and noted to have normal or abnormal (mild or severe) neurodevelopmental outcomes for the domains of speech and language, motor, and vision. Children were classified as P-CHI (n = 33), if they had undergone surgery or remained on medical therapy, or T-CHI (n = 34), if medical treatment for hypoglycemia was stopped.Results: Overall, abnormal neurodevelopment was present in 26 (39%) children with CHI, of whom 18 (69%) were severe. Importantly, the incidence of abnormal neurodevelopment in T-CHI was similar to that in P-CHI (30 vs. 47% respectively, p = 0.16). The prevalence of severe abnormal neurodevelopment in speech, motor, and vision domains was similar in both T-CHI and P-CHI children. For this cohort, we found that the severity of disease [based upon maximal diazoxide dose (odds ratio 95% confidence intervals) 1.3 (1.1; 1.5), p = 0.03], and early presentation of CHI <7 days following birth [5.9 (1.3; 27.8), p = 0.02] were significantly associated with abnormal neurodevelopment. There was no significant association with gender, genotype, or the histopathological basis of CHI.Conclusion: Abnormal neurodevelopment was evident in one third of children with both T-CHI and P-CHI, early presentation and severe CHI being risk factors. Early recognition and rapid correction of hypoglycemia are advocated to avoid abnormal neurodevelopment in children with CHI.

Objective: In children with congenital hyperinsulinism (CHI), K ATP channel genes (ABCC8 and KCNJ11) can be screened rapidly for potential pathogenic mutations. We aimed to assess the contribution of rapid genetic testing to the clinical management of CHI. Design: Follow-up observational study at two CHI referral hospitals. Methods: Clinical outcomes such as subtotal pancreatectomy, 18 F-Dopa positron emission tomography-computed tomography (PET-CT) scanning, stability on medical treatment and remission were assessed in a cohort of 101 children with CHI. Results: In total, 32 (32%) children had pathogenic mutations in K ATP channel genes (27 in ABCC8 and five in KCNJ11), of which 11 (34%) were novel. In those negative at initial screening, other mutations (GLUD1, GCK, and HNF4A) were identified in three children. Those with homozygous/compound heterozygous ABCC8/KCNJ11 mutations were more likely to require a subtotal pancreatectomy CHI (7/10, 70%). Those with paternal heterozygous mutations were investigated with 18 F-Dopa PET-CT scanning and 7/13 (54%) had a focal lesionectomy, whereas four (31%) required subtotal pancreatectomy for diffuse CHI. Those with maternal heterozygous mutations were most likely to achieve remission (5/5, 100%). In 66 with no identified mutation, 43 (65%) achieved remission, 22 (33%) were stable on medical treatment and only one child required a subtotal pancreatectomy. Conclusions: Rapid genetic analysis is important in the management pathway of CHI; it provides aetiological confirmation of the diagnosis, indicates the likely need for a subtotal pancreatectomy and identifies those who require 18 F-Dopa PET-CT scanning. In the absence of a mutation, reassurance of a favourable outcome can be given early in the course of CHI.

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a neonatal disease characterized by dysregulation of insulin secretion accompanied by profound hypoglycemia. We have discovered that islet cells, isolated from the pancreas of a PHHI patient, proliferate in culture while maintaining a beta celllike phenotype. The PHHI-derived cell line (NES2Y) exhibits insulin secretory characteristics typical of islet cells derived from these patients, i.e. they have no K ATP channel activity and as a consequence secrete insulin at constitutively high levels in the absence of glucose. In addition, they exhibit impaired expression of the homeodomain transcription factor PDX1, which is a key component of the signaling pathway linking nutrient metabolism to the regulation of insulin gene expression. To repair these defects NES2Y cells were triple-transfected with cDNAs encoding the two components of the K ATP channel (SUR1 and Kir6.2) and PDX1. One selected clonal cell line (NISK9) had normal K ATP channel activity, and as a result of changes in intracellular Ca 2؉ homeostasis ([Ca 2؉ ] i ) secreted insulin within the physiological range of glucose concentrations. This approach to engineering PHHI-derived islet cells may be of use in gene therapy for PHHI and in cell engineering techniques for administering insulin for the treatment of diabetes mellitus. Persistent hyperinsulinemic hypoglycemia of infancy (PHHI)1 is a potentially lethal disease of the newborn. It is characterized by inappropriate insulin release in relation to the corresponding levels of glycemia (1, 2). Affected children run the risk of severe neurological damage unless immediate and adequate steps are taken to avoid profound hypoglycemia. Treatment involves administration of glucose along with drugs such as diazoxide and somatostatin that inhibit insulin secretion. However, in many cases this is not effective, and within the first few weeks of birth a near total (ϳ95%) pancreatectomy is required to control blood glucose levels.Recently, it has been shown that PHHI arises from defects in the regulation of insulin secretion. This is due principally to the loss of function of ATP-regulated potassium (K ATP ) channels. Genetic linkage has identified a susceptibility locus for PHHI within a region of chromosome 11 that encodes subunits of these channels (3, 4), while direct recordings of beta cells isolated from PHHI patients (following pancreatectomy) have documented the absence of K ATP channels (5). In beta cells these channels are composed of at least two subunits as follows: a K ϩ channel pore, Kir6.2, and an ATP-binding cassette protein, SUR1 (6, 7). Open K ATP channels set the resting membrane potential for the beta cell and a change in the intracellular ATP/ADP ratio following glucose metabolism results in their closure and the initiation of a depolarization of the cell membrane. This in turn activates voltage-dependent calcium channels and the ensuing influx of calcium stimulates membrane docking and fusion of preformed insulin granules resulting ...

Hyperinsulinism of infancy (HI) is a congenital defect in the regulated release of insulin from pancreaticH yperinsulinism of infancy (HI) (congenital hyperinsulinism) is a consequence of unregulated insulin release. The disease is clinically heterogeneous, with highly variable age of onset, severity, and responsiveness to medical treatments (1). Mutations in four different genes have been identified: the ATP-sensitive K + channel (K ATP channel) genes SUR1 and Kir6.2, glucokinase (GK), and glutamate dehydrogenase (GLUD1). Despite this, in as many as 60% of patients, the genetic basis of the condition has not been elucidated (2). The most common and most severe forms of HI arise from SUR1 and/or Kir6.2 gene defects (HI-SUR1 and HI-Kir6.2, respectively, also termed persistent hyperinsulinemic hypoglycemia of infancy [PHHI]) (2). These patients commonly exhibit symptomatic hypoglycemia soon after birth, are largely unresponsive to inhibitors of insulin release such as diazoxide and somatostatin, and require subtotal (95%) resection of the pancreas to alleviate hypoglycemia (1). For individuals with the rarer forms (HI-GK or HI-GLUD1), surgical resection of the pancreas is not usually necessary because hyperinsulinism is avoided by managing nutrition or by inhibiting insulin secretion with the K ATP channel activator diazoxide (3,4).The genetic basis of HI-K ATP is heterogeneous; more than 40 mutations in SUR1 have been identified, and 3 mutations in Kir6.2 have been described (2). Using both recombinant expression systems (5-8) and ␤-cells isolated from patients after surgery (6-10), investigators have shown these mutations to lead to impaired trafficking or assembly of K ATP channels or to cause defects in the ADP-dependent regulation of channel activity. Functional studies on ␤-cells isolated from patients with HI have further demonstrated that loss of operational channels results in depolarized ␤-cells with unregulated Ca 2+ channel activity (9). However, whereas these studies have provided a means of correlating the genetics of HI