ABCC8 Mutations Research Articles

Mutations of the same conserved glutamate residue in NBD2 of the sulfonylurea receptor 1 subunit of the KATP channel can result in either hyperinsulinism or neonatal diabetes.

OBJECTIVETwo novel mutations (E1506D, E1506G) in the nucleotide-binding domain 2 (NBD2) of the ATP-sensitive K+ channel (KATP channel) sulfonylurea receptor 1 (SUR1) subunit were detected heterozygously in patients with neonatal diabetes. A mutation at the same residue (E1506K) was previously shown to cause congenital hyperinsulinemia. We sought to understand why mutations at the same residue can cause either neonatal diabetes or hyperinsulinemia.RESEARCH DESIGN AND METHODSNeonatal diabetic patients were sequenced for mutations in ABCC8 (SUR1) and KCNJ11 (Kir6.2). Wild-type and mutant KATP channels were expressed in Xenopus laevis oocytes and studied with electrophysiological methods.RESULTSOocytes expressing neonatal diabetes mutant channels had larger resting whole-cell KATP currents than wild-type, consistent with the patients’ diabetes. Conversely, no E1506K currents were recorded at rest or after metabolic inhibition, as expected for a mutation causing hyperinsulinemia. KATP channels are activated by Mg-nucleotides (via SUR1) and blocked by ATP (via Kir6.2). All mutations decreased channel activation by MgADP but had little effect on MgATP activation, as assessed using an ATP-insensitive Kir6.2 subunit. Importantly, using wild-type Kir6.2, a 30-s preconditioning exposure to physiological MgATP concentrations (>300 µmol/L) caused a marked reduction in the ATP sensitivity of neonatal diabetic channels, a small decrease in that of wild-type channels, and no change for E1506K channels. This difference in MgATP inhibition may explain the difference in resting whole-cell currents found for the neonatal diabetes and hyperinsulinemia mutations.CONCLUSIONSMutations in the same residue can cause either hyperinsulinemia or neonatal diabetes. Differentially altered nucleotide regulation by NBD2 of SUR1 can explain the respective clinical phenotypes.

Molecular-genetic verification and treatment of neonatal diabetes mellitus related to the defects in ATP-dependent potassium channels: Results of the observation of 9 patients and the first description of ABCC8 gene mutations in Russia

Introduction of the methods for molecular-genetic analysis into clinical practice has opened up new prospects for both diagnosis and pathogenetically sound therapy of neonatal diabetes mellitus. It is currently known that the overwhelming majority of the cases of diabetes mellitus developing in children during the first six month of life are associated with defects of the genes controlling formation, development, and functional activity of pancreatic beta-cells whereas type 1 diabetes mellitus of autoimmune origin accounts for less than 1% of this pathology. This paper reports the results of a molecular-genetic study of 14 patients presenting with neonatal diabetes mellitus. Nine cases are shown to have developed as a result of mutations in KCNJ11 and ABCC8 genes. ABCC8 mutations are described for the first time in Russia. Analysis of clinical forms of neonatal diabetes mellitus revealed correlation between the type of mutations, clinical features of the disease, and susceptibility of the patients to sulfonylurea drugs.

Role of molecular genetics in transforming diagnosis of diabetes mellitus

Most common diseases also run in families as rare, monogenic forms. Diabetes is no exception. Mutations in approximately 20 different genes are now known to cause monogenic diabetes, a disease group that can be subclassified into maturity-onset diabetes of the young, neonatal diabetes and mitochondrial diabetes. In some families, additional features, such as urogenital malformations, exocrine pancreatic dysfunction and neurological abnormalities, are present and may aid the diagnostic classification. The finding of a mutation in monogenic diabetes may have implications for the prediction of prognosis and choice of treatment. Mutations in the GCK gene cause a mild form of diabetes, which seldom needs insulin and has a low risk for complications. By contrast, HNF1A mutations lead to a diabetes form that in severity, treatment and complication risk resembles Type 1 diabetes, although these patients may experience a good effect of sulfonylurea treatment. The majority of neonatal diabetes cases are caused by mutations in the KATP channel genes ABCC8 and KCNJ11, and sulfonylurea therapy is then usually superior to insulin. Diseases with a considerable genetic component may now be explored by genome-wide approaches using next-generation DNA sequencing technology. We expect that within a few years important breakthroughs will be made in mapping cases of diabetes with a suspected, but still unsolved monogenic basis.

In vitro recovery of ATP-sensitive potassium channels in β-cells from patients with congenital hyperinsulinism of infancy.

OBJECTIVECongenital hyperinsulinism in infancy (CHI) is characterized by unregulated insulin secretion from pancreatic β-cells; severe forms are associated with defects in ABCC8 and KCNJ11 genes encoding sulfonylurea receptor 1 (SUR1) and Kir6.2 subunits, which form ATP-sensitive K+ (KATP) channels in β-cells. Diazoxide therapy often fails in the treatment of CHI and may be a result of reduced cell surface expression of KATP channels. We hypothesized that conditions known to facilitate trafficking of cystic fibrosis transmembrane regulator (CFTR) and other proteins in recombinant expression systems might increase surface expression of KATP channels in native CHI β-cells.RESEARCH DESIGN AND METHODSTissue was isolated during pancreatectomy from eight patients with CHI and from adult cadaver organ donors. Patients were screened for mutations in ABCC8 and KCNJ11. Isolated β-cells were maintained at 37°C or 25°C and in the presence of 1) phorbol myristic acid, forskolin and 3-isobutyl-1-methylxanthine, 2) BPDZ 154, or 3) 4-phenylbutyrate. Surface expression of functional channels was assessed by patch-clamp electrophysiology.RESULTSMutations in ABCC8 were detected for all patients tested (n = 7/8) and included three novel mutations. In five of eight patients, no changes in KATP channel activity were observed under different cell culture conditions. However, in three patients, in vitro recovery of functional KATP channels occurred. Here, we report the first cases of recovery of defective KATP channels in human β-cells using modified cell culture conditions.CONCLUSIONSOur study establishes the principle that chemical modification of KATP channel subunit trafficking could be of benefit for the future treatment of CHI.

Characterization of ABCC8 and KCNJ11 gene mutations and phenotypes in Korean patients with congenital hyperinsulinism

Congenital hyperinsulinism (CHI) is characterized by persistent hypoglycemia due to the inappropriate insulin secretion. Inactivating mutations in the ABCC8 and KCNJ11 genes, which encode the sulfonylurea receptor 1 and Kir6.2 subunits of the ATP-sensitive K(+) (K(ATP)) channel in pancreatic β-cell, are the most common cause of CHI. We studied the genetic etiology and phenotypes of CHI in Korean patients. ABCC8 and KCNJ11 mutational analysis was performed in 17 patients with CHI. Medical records were retrospectively reviewed to identify phenotypes. Mutations (12 ABCC8 and three KCNJ11) were identified in 82% (14/17) of patients. Of these, nine ABCC8 mutations (E100X, W430X, c.1630+1G>C, D813N, Q923X, E1087_A1094delinsDKSDT, Q1134H, H1135W, and E1209Rfs) and one KCNJ11 mutation (W91X) were novel. Of the 14 patients, four had confirming recessively inherited CHI. The remaining ten patients had single heterozygous mutations. The majority (12/17) of patients were medically responsive. Of the five diazoxide-responsive patients, four had an ABCC8 mutation. The five patients unresponsive to medical management and one diazoxide-responsive patient underwent pancreatectomy and had diffuse histology. Of the operated six patients, two had recessively inherited mutations; three patients had a single heterozygous mutation (one maternally and two paternally inherited); and one patient had no identifiable K(ATP) channel mutation. This is the first study to report genotype and phenotype correlations among Korean patients with CHI. Mutations in ABCC8 and KCNJ11 are the most common causes of CHI in Korean patients. Similar to other studies, there is marked genetic heterogeneity and no clear genotype-phenotype correlation.

Genetics and pathophysiology of neonatal diabetes mellitus.

Neonatal diabetes mellitus (NDM) is the term commonly used to describe diabetes with onset before 6 months-of-age. It occurs in approximately one out of every 100,000-300,000 live births. Although this term encompasses diabetes of any etiology, it is recognized that NDM diagnosed before 6 months-of-age is most often monogenic in nature. Clinically, NDM subgroups include transient (TNDM) and permanent NDM (PNDM), as well as syndromic cases of NDM. TNDM often develops within the first few weeks of life and remits by a few months of age. However, relapse occurs in 50% of cases, typically in adolescence or adulthood. TNDM is most frequently caused by abnormalities in the imprinted region of chromosome 6q24, leading to overexpression of paternally derived genes. Mutations in KCNJ11 and ABCC8, encoding the two subunits of the adenosine triphosphate-sensitive potassium channel on the β-cell membrane, can cause TNDM, but more often result in PNDM. NDM as a result of mutations in KCNJ11 and ABCC8 often responds to sulfonylureas, allowing transition from insulin therapy. Mutations in other genes important to β-cell function and regulation, and in the insulin gene itself, also cause NDM. In 40% of NDM cases, the genetic cause remains unknown. Correctly identifying monogenic NDM has important implications for appropriate treatment, expected disease course and associated conditions, and genetic testing for at-risk family members. Early recognition of monogenic NDM allows for the implementation of appropriate therapy, leading to improved outcomes and potential societal cost savings. (J Diabetes Invest, doi:10.1111/j.2040-1124.2011.00106.x, 2011).

Macrosomia, transient neonatal hypoglycemia, and monogenic diabetes in a family with heterozygous mutation R154X of HNF4A gene

252 Congenital hyperinsulinemic hypoglycemia (CHI) is a potentially life-threatening condition which is often caused by loss-of-function mutations in ABCC8 and KCNJ11 genes, that encode for the ATP-sensitive potassium channel of the pancreatic β cell. Recently, it has been shown that in families with monogenic diabetes due to genetic defects of the transcription factor HNF4A [known as Maturity Onset Diabetes of the Young type 1 (MODY1)] mutation carriers can present neonatal hypoglycemia and macrosomia (1). Here we report about a girl born large for gestational age, who showed severe neonatal hypoglycemia (day 1 of life) treated with glucose infusion (Table 1). She had a second hypoglycemic episode at day 9, treated again with glucose infusion for 2 days. Her younger sister, who was delivered by cesarean section because of macrosomia and polyhydramnios at 34 weeks of gestation, also presented with mild, transient neonatal hypoglycemia. Both were referred to us for molecular genetic screening. Family history disclosed early-onset Type 2 diabetes in the mother and in the maternal grandfather. In particular, the mother had been diagnosed with gestational diabetes – treated with insulin – during her second pregnancy (35 yr of age) and, after a year free of therapy, started on oral hypoglycemic agents. These data combined prompted us to screen directly the HNF4A gene in this family. We identified a C>T substitution at position 460 (c.460C>T), resulting in the already described mutation arginine→stop at codon 154 (p.R154X) (Table 1) in the proband, her sister, and her mother. DNA of maternal grandfather, deceased, was not available. The proband, now almost 15 yr old (pubertal stage: Ph5,B5), and a bit overweight, has shown at the last visit above normal glycated hemoglobin value compatible with recently proposed criteria for diagnosis of diabetes (2). This finding is in line with what is usually seen in patients with heterozygous mutations of HNF4A gene or TCF1/HNF1A (so-called MODY 3), who present with diabetes at adolescence or as young adults.

Nesidioblastosis No Longer! It's All about Genetics

The past two decades have witnessed rapid advances in elucidating genetic forms of hyperinsulinemic hypoglycemia that have dramatically eclipsed our previous concepts about congenital hyperinsulinism in infants and children. Before this time, persistent hypoglycemia in infants, a disorder first described as “idiopathic hypoglycemia of infancy” in the mid-1950s (1), was attributed to nesidioblastosis, a supposed disturbance in embryonic morphogenesis in which insulin cells continued to bud off pancreatic ducts beyond the time of birth (2). This increase in -cell mass was presumed to explain hypoglycemia in infants affected with nesidioblastosis. By the mid1980s, however, studies by Rahier et al. (3) and other pathologists had convincingly proven that nesidioblastosis is merely a normal feature of the pancreas in early infancy. In pediatrics, use of the term has fortunately been abandoned. Interestingly, nesidioblastosis continues to be mentioned in adults as if it were still a specific entity. For example, patients with hypoglycemia post gastric bypass surgery have recently been labeled as having nesidioblastosis (4). The recognition of a genetic, as opposed to an embryological, basis for congenital hyperinsulinism evolved from the recognition of familial cases with either dominant or recessive patterns of inheritance (5). Currently, thanks to work by many investigators, eight different loci have been associated with hyperinsulinism: ABCC8, KCNJ11, HADH1, GCK, GLUD1, SLC16A1, UCP2, and HNF4a (Table 1). Mutations of these loci have significant differences in phenotype and inheritance pattern that can be helpful in differentiation and management. The first defects to be discovered, and still the most common genes associated with hyperinsulinism, involve the ABCC8 and KCNJ11 genes that are located together on the short arm of chromosome 11 and encode the two subunits of the -cell ATP-dependent potassium channel: SUR1 and Kir6.2. Recessive mutations of these genes cause a severe form of neonatal hypoglycemia that frequently requires near-total pancreatectomy. In addition, these mutations are responsible for the focal form of congenital hyperinsulinism, caused by isodisomy for a paternally transmitted ABCC8 or KCNJ11 mutation. Dominant missense mutations of these genes have also been discovered that can be associated with either medically controllable or medically unresponsive hyperinsulinism (6, 7). Mutations in HADH1, which encodes SCHAD, a fatty acid oxidation enzyme, cause the only other recessive form of hyperinsulinism (8). Dominant, activating mutations of GCK, which encodes glucokinase, can cause hyperinsulinism that responds poorly to medical therapy. Other dominant forms of hyperinsulinism include activating mutations of GLUD1, which encodes glutamate dehydrogenase, a key step in amino acidstimulated insulin secretion; inactivating mutations of UCP2, a mitochondrial uncoupling protein; activating mutations of SLC16A1 (encodes MCT1), a plasma membrane pyruvate transporter; and inactivating mutations of HNF4a, a nuclear transcription factor also associated with maturity-onset diabetes of the young 1, a form of monogenic diabetes of youth. Phenotypic features that distinguish some of these disorders can be helpful in suggesting the likely gene involved. Large birth weight is common in ABCC8, KCNJ11, GCK, and HNF4a defects. Hyperammonemia is a distinctive feature of GLUD1 mutations [“hyperinsulinism/hyperammonemia (HI/HA) syndrome”]. Protein-sensitive hypoglycemia occurs in HI/HA and SCHAD hyperinsulinism, due to hypersensitivity to leucine stimulation of insulin release. Protein sensitivity also occurs with mutations of ABCC8 and KCNJ11, but it is not due to leucine sensitivity. Hypoglycemia after ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2011 by The Endocrine Society doi: 10.1210/jc.2011-0164 Received January 19, 2011. Accepted January 28, 2011.

The Predominant Mechanisms of Pathogenic Hyperactivity of Mutant ABCC8/KCNJ11-Coded KATP Channels

We discovered numerous congenital diabetes (CD), insulin release-inhibiting mutations in ABCC8/KCNJ11 genes coding for the pancreatic beta-cell (SUR1/Kir6.2)4 KATP channel (Diabetes 53:2719; N Engl J Med 355:456; Diabetes 56:1737; J Biol Chem 283:8778; reviewed in Endocr Rev 29:265). Based on FEBS Lett 445:131; 459:367 and subsequent structure-activity analyses and mechanistic models of KATP channels (reviewed in J Mol Cell Cardiol 39:79), Babenko predicted three possible mechanisms of KATP hyperactivation by mutations in ABCC8 and started testing the hypothesis (DK077827 R01 project ABCC8/KCNJ11 Mechanisms and Diabetes). Following the analysis described in N Engl J Med 355:456 and J Biol Chem 283:8778, we established that the majority of CD mutations which map to the canonical ABC exporter core increase the open channel probability (Po) in intact cells by enhancing the MgATP/ADP-dependent stimulatory action of SUR1 on the channel, without affecting its maximal Po in the absence of nucleotides (Pomax) or its Mg-independent sensitivity to inhibitory ATP, IC50(ATP). This is called the A-type mechanism of KATP hyperactivation. The majority of CD mutations which map to the non-canonical, TMD0-L0 “gatekeeper” (J Biol Chem 278:41577) domain of SUR1 increase Pomax and apparent IC50(ATP). Single-channel kinetics analysis reveals that this effect is due to reciprocal changes in the rates of channel transitions to and from its long-lived closed state with the lowest apparent Kd(ATP) for the inhibitory nucleotide. This establishes the second, or B-type, mechanism of KATP hyperactivity. Although our search for the third, Kd(ATP)-increasing type mutations in ABCC8 continues, we are in the position to conclude that A/B-mechanisms cause the majority of CD-KATP cases and our refined Sav1866/MsbA / KcsA/Kir3.1/BacKir/Chimera-based models of KATP channels help correctly predict the principal effect of the majority of diabetogenic mutations in ABCC8/KCNJ11 on KATP gating.

Familial mild hyperglycemia associated with a novel ABCC8-V84I mutation within three generations

We present a unique case of a 19-year-old man with a positive family history of persistent mild hyperglycemia and a novel V84I mutation in ABCC8. The proband was initially detected to have fasting hyperglycemia (ranging 6.1-6.4 mmol/L) at the age of 12 years. Increased fasting blood glucose was also subsequently detected in five additional family members (in his twin brother, sister, mother, maternal aunt, and grandfather). The grandfather has been known to have mild diabetes since 30 years and has never been treated. After having excluded a causative mutation in five maturity-onset diabetes of the young genes (MODY1-4 and 6), we identified a novel ABCC8 V84I mutation, which segregated with autosomal dominant transmission of mild hyperglycemia within three generations. This mutation that is located in a conserved area of transmembrane domain TMD0 seems to be a rare cause of clinical phenotype resembling glucokinase-deficient diabetes.

Clinical characteristics of recessive and dominant congenital hyperinsulinism due to mutation(s) in the ABCC8/KCNJ11 genes encoding the ATP-sensitive potasium channel in the pancreatic beta cell

Recessive mutations in ABCC8/KCNJ11 of beta-cell K(ATP) channel generally cause severe medically unresponsive hyperinsulinemic hypoglycemia (HH). Rarer dominant mutations in these genes have been described that mostly cause milder, medically responsive congenital hyperinsulinism. Rarer dominant mutations in these genes have been described that mostly cause milder, medically responsive congenital hyperinsulinism. To date the phenotype of patients with dominant mutations seems to be different from those with recessive mutations as the majority of patients are responsive to diazoxide therapy. Controversy exists on whether these dominant ABCC8 or KCNJ11 genes mutations predispose to diabetes mellitus in adulthood or not. We report the clinical and genetic characteristics of five patients with neonatal HH, three had recessively inherited K(ATP) channel mutations and two with a dominantly acting mutation. As a result of failure to medical therapy, patients with recessive K(ATP) channel mutations underwent a near total pancreatectomy. Two siblings with a novel dominant mutation showed good response to medical treatment. Although the HH remitted in early infancy, they became diabetic at the prepubertal age. Their mother, maternal aunt and maternal grandfather had the same mutation without any medical history of neonatal HH. The clinical presentation of our two patients with a dominant ABCC8 mutation was milder than that of patients with the resessive form of the disease as they responded well to medical management.

KATP channel mutations in congenital hyperinsulinism

Adenosine triphosphate (ATP)-sensitive potassium channels (K(ATP) channels) have a central role in the regulation of insulin secretion in pancreatic β cells. They are octameric complexes organized around the central core constituted by the Kir6.2 subunits. The regulation of the channel itself takes place on the sulfonylurea receptor-1 subunit. The channel opens and closes according to the balance between adenine nucleotide ATP and adenosine diphosphate. Hyperinsulinemic hypoglycemia (also named congenital hyperinsulinism, or CHI) is associated with loss-of-function K(ATP) channel mutations. Their frequency depends on the histopathological form and the responsiveness of CHI patients to diazoxide. ABCC8/KCNJ11 defects are identified in approximately 80% of patients with CHI refractory to diazoxide. Within this group, focal forms are related to a paternally inherited KCNJ11 or ABCC8 mutation and the loss of the corresponding maternal allele in some pancreatic β cells leading to a focal lesion. Diffuse forms are mostly associated with recessively inherited mutations. Some patients with diffuse forms also carried a single K(ATP) channel mutation. In contrast, K(ATP) mutations are involved in 15% of diazoxide-responsive CHI cases that are either sporadic or dominantly inherited.

Successful transfer to sulfonylurea therapy in an infant with developmental delay, epilepsy and neonatal diabetes (DEND) syndrome and a novel ABCC8 gene mutation

Successful transfer to sulfonylurea therapy in an infant with developmental delay, epilepsy and neonatal diabetes (DEND) syndrome and a novel ABCC8 gene mutation

The molecular mechanisms and pharmacotherapy of ATP-sensitive potassium channel gene mutations underlying neonatal diabetes.

Neonatal diabetes mellitus (NDM) is a monogenic disorder caused by mutations in genes involved in regulation of insulin secretion from pancreatic β-cells. Mutations in the KCNJ11 and ABCC8 genes, encoding the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel Kir6.2 and SUR1 subunits, respectively, are found in ∼50% of NDM patients. In the pancreatic β-cell, KATP channel activity couples glucose metabolism to insulin secretion via cellular excitability and mutations in either KCNJ11 or ABCC8 genes alter KATP channel activity, leading to faulty insulin secretion. Inactivation mutations decrease KATP channel activity and stimulate excessive insulin secretion, leading to hyperinsulinism of infancy. In direct contrast, activation mutations increase KATP channel activity, resulting in impaired insulin secretion, NDM, and in severe cases, developmental delay and epilepsy. Many NDM patients with KCNJ11 and ABCC8 mutations can be successfully treated with sulfonylureas (SUs) that inhibit the KATP channel, thus replacing the need for daily insulin injections. There is also strong evidence indicating that SU therapy ameliorates some of the neurological defects observed in patients with more severe forms of NDM. This review focuses on the molecular and cellular mechanisms of mutations in the KATP channel that underlie NDM. SU pharmacogenomics is also discussed with respect to evaluating whether patients with certain KATP channel activation mutations can be successfully switched to SU therapy.

Molecular Diagnosis of Neonatal Diabetes Mellitus Using Next-Generation Sequencing of the Whole Exome

BackgroundAccurate molecular diagnosis of monogenic non-autoimmune neonatal diabetes mellitus (NDM) is critical for patient care, as patients carrying a mutation in KCNJ11 or ABCC8 can be treated by oral sulfonylurea drugs instead of insulin therapy. This diagnosis is currently based on Sanger sequencing of at least 42 PCR fragments from the KCNJ11, ABCC8, and INS genes. Here, we assessed the feasibility of using the next-generation whole exome sequencing (WES) for the NDM molecular diagnosis.Methodology/Principal FindingsWe carried out WES for a patient presenting with permanent NDM, for whom mutations in KCNJ11, ABCC8 and INS and abnormalities in chromosome 6q24 had been previously excluded. A solution hybridization selection was performed to generate WES in 76 bp paired-end reads, by using two channels of the sequencing instrument. WES quality was assessed using a high-resolution oligonucleotide whole-genome genotyping array. From our WES with high-quality reads, we identified a novel non-synonymous mutation in ABCC8 (c.1455G>C/p.Q485H), despite a previous negative sequencing of this gene. This mutation, confirmed by Sanger sequencing, was not present in 348 controls and in the patient's mother, father and young brother, all of whom are normoglycemic.Conclusions/SignificanceWES identified a novel de novo ABCC8 mutation in a NDM patient. Compared to the current Sanger protocol, WES is a comprehensive, cost-efficient and rapid method to identify mutations in NDM patients. We suggest WES as a near future tool of choice for further molecular diagnosis of NDM cases, negative for chr6q24, KCNJ11 and INS abnormalities.

Familial Focal Congenital Hyperinsulinism

Congenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia. Histologically, there are two subgroups, diffuse and focal. Focal CHI is a consequence of two independent events, inheritance of a paternal mutation in ABCC8/KCNJ11 and paternal uniparental isodisomy of chromosome 11p15 within the embryonic pancreas, leading to an imbalance in the expression of imprinted genes. The probability of both events occurring within siblings is rare. We describe the first familial form of focal CHI in two siblings. The proband presented with medically unresponsive CHI. He underwent pancreatic venous sampling and Fluorine-18-L-dihydroxyphenylalanine positron emission tomography scan, which localized a 5-mm focal lesion in the isthmus of the pancreas. The sibling presented 8 yr later also with medically unresponsive CHI. An Fluorine-18-L-dihydroxyphenylalanine positron emission-computerised tomography scan showed a 7-mm focal lesion in the posterior section of the head of the pancreas. Both siblings were found to be heterozygous for two paternally inherited ABCC8 mutations, A355T and R1494W. Surgical removal of the focal lesions in both siblings cured the Hyperinsulinaemic hypoglycaemia. This is the first report of focal CHI occurring in siblings. Genetic counseling for families of patients with focal CHI should be recommended, despite the rare risk of recurrence of this disease.

Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies

BackgroundTo investigate disease progression the first 12 months after diagnosis in children with type 1 diabetes negative (AAB negative) for pancreatic autoantibodies [islet cell autoantibodies(ICA), glutamic acid decarboxylase antibodies (GADA) and insulinoma-associated antigen-2 antibodies (IA-2A)]. Furthermore the study aimed at determining whether mutations in KCNJ11, ABCC8, HNF1A, HNF4A or INS are common in AAB negative diabetes.Materials and methodsIn 261 newly diagnosed children with type 1 diabetes, we measured residual β-cell function, ICA, GADA, and IA-2A at 1, 6 and 12 months after diagnosis. The genes KCNJ11, ABCC8, HNF1A, HNF4A and INS were sequenced in subjects AAB negative at diagnosis. We expressed recombinant K-ATP channels in Xenopus oocytes to analyse the functional effects of an ABCC8 mutation.ResultsTwenty-four patients (9.1%) tested AAB negative after one month. Patients, who were AAB-negative throughout the 12-month period, had higher residual β-cell function (P = 0.002), lower blood glucose (P = 0.004), received less insulin (P = 0.05) and had lower HbA1c (P = 0.02) 12 months after diagnosis. One patient had a heterozygous mutation leading to the substitution of arginine at residue 1530 of SUR1 (ABCC8) by cysteine. Functional analyses of recombinant K-ATP channels showed that R1530C markedly reduced the sensitivity of the K-ATP channel to inhibition by MgATP. Morover, the channel was highly sensitive to sulphonylureas. However, there was no effect of sulfonylurea treatment after four weeks on 1.0-1.2 mg/kg/24 h glibenclamide.ConclusionGAD, IA-2A, and ICA negative children with new onset type 1 diabetes have slower disease progression as assessed by residual beta-cell function and improved glycemic control 12 months after diagnosis. One out of 24 had a mutation in ABCC8, suggesting that screening of ABCC8 should be considered in patients with AAB negative type 1 diabetes.

Permanent neonatal diabetes due to activating mutations in ABCC8 and KCNJ11

The ATP-sensitive potassium (K(ATP)) channel is composed of two subunits SUR1 and Kir6.2. The channel is key for glucose stimulated insulin release from the pancreatic beta cell. Activating mutations have been identified in the genes encoding these subunits, ABCC8 and KCNJ11, and account for approximately 40% of permanent neonatal diabetes cases. The majority of patients with a K(ATP) mutation present with isolated diabetes however some have presented with the Developmental delay, Epilepsy and Neonatal Diabetes syndrome. This review focuses on mutations in the K(ATP) channel which result in permanent neonatal diabetes, we review the clinical and functional effects as well as the implications for treatment.

ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism

BackgroundCongenital hyperinsulinism (CHI) is characterised by an over secretion of insulin by the pancreatic β-cells. This condition is mostly caused by mutations in ABCC8 or KCNJ11 genes encoding the SUR1...

Successful transfer from insulin to oral sulfonylurea in a 3-year-old girl with a mutation in the KCNJ11 gene

Neonatal diabetes mellitus is considered a rare disease that is diagnosed in the first six months of life, and can be either transient or permanent. Recent advances in molecular genetics have shown that activating mutations in KCNJ11 (the gene that encodes for the Kir6.2 subunit of the KATP potassium channel of the pancreatic β-cell) is a common cause of permanent neonatal diabetes mellitus. Patients with mutations in this gene may respond to oral sulfonyureas. We describe a 3-year-old girl with permanent neonatal diabetes mellitus with a mutation in the KCNJ11 gene (R201H), who was successfully transferred from subcutaneous insulin to oral glibenclamide, with a marked improvement in glycemic control. This is the first successful switch from insulin to oral sulfonylurea in a patient with R201H mutation, in the Arabian Gulf.