Charles A Stanley

The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

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Publications (201)1182.7 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondrial GTP (mtGTP)-insensitive mutations in glutamate dehydrogenase (GDH(H454Y)) result in fasting and amino acid-induced hypoglycemia in Hyperinsulinemia Hyperammonemia (HI/HA). Surprisingly, hypoglycemia may occur in this disorder despite appropriately suppressed insulin. To better understand the islet-specific contribution transgenic mice expressing the human activating mutation in beta-cells (H454Y mice) were characterized in vivo. As in the humans with HI/HA, H454Y mice had fasting hypoglycemia but plasma insulin concentrations were similar to the controls. Paradoxically, both glucose- and glutamine-stimulated insulin secretion were severely impaired in H454Y mice. Instead, lack of a glucagon response during hypoglycemic clamps identified impaired counter regulation. Moreover, both insulin and glucagon secretion were impaired in perifused islets. Acute pharmacologic inhibition of GDH restored both insulin and glucagon secretion and normalized glucose tolerance in vivo. These studies support the presence of a mtGTP-dependent signal generated via beta-cell GDH that inhibits alpha-cells. As such, in children with activating GDH mutations of HI/HA this insulin-independent glucagon suppression may contribute importantly to symptomatic hypoglycemia. The identification of a human mutation causing congenital hypoglucagonemic hypoglycemia highlights a central role of the mtGTP-GDH-glucagon axis in glucose homeostasis.
    Diabetes 07/2014; · 7.90 Impact Factor
  • Colin P. Hawkes, Charles A. Stanley
    The Journal of Pediatrics. 01/2014; 164(6):1310.
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    ABSTRACT: β cell failure in type 2 diabetes (T2D) is associated with hyperglycemia, but the mechanisms are not fully understood. Congenital hyperinsulinism caused by glucokinase mutations (GCK-CHI) is associated with β cell replication and apoptosis. Here, we show that genetic activation of β cell glucokinase, initially triggering replication, causes apoptosis associated with DNA double-strand breaks and activation of the tumor suppressor p53. ATP-sensitive potassium channels (KATP channels) and calcineurin mediate this toxic effect. Toxicity of long-term glucokinase overactivity was confirmed by finding late-onset diabetes in older members of a GCK-CHI family. Glucagon-like peptide-1 (GLP-1) mimetic treatment or p53 deletion rescues β cells from glucokinase-induced death, but only GLP-1 analog rescues β cell function. DNA damage and p53 activity in T2D suggest shared mechanisms of β cell failure in hyperglycemia and CHI. Our results reveal membrane depolarization via KATP channels, calcineurin signaling, DNA breaks, and p53 as determinants of β cell glucotoxicity and suggest pharmacological approaches to enhance β cell survival in diabetes.
    Cell metabolism 12/2013; · 17.35 Impact Factor
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    ABSTRACT: To present our experience in the care of infants with Beckwith-Wiedemann syndrome (BWS) who required pancreatectomy for the management of severe Congenital Hyperinsulinism (HI). We did a retrospective chart review of patients with BWS who underwent pancreatectomy between 2009 and 2012. Four patients with BWS and severe HI underwent pancreatectomy, 3 females and one male. Eight other BWS patients with HI could be managed medically. The diagnosis of BWS was established by the presence of mosaic 11p15 loss of heterozygosity and uniparental disomy in peripheral blood and/or pancreatic tissue. All patients had hypoglycemia since birth that did not respond to medical management with diazoxide or octreotide, and required glucose infusion rates of up to 30mg/kg/min. Preoperative 18-F-DOPA PET/CT scans showed diffuse uptake of the radiotracer throughout an enlarged pancreas in three patients and a normal sized pancreas with a large area of focal uptake in the pancreatic body in one patient. None of the patients had mutations in the ABCC8 or KCNJ1 genes that are typically associated with diazoxide-resistant HI. Age at surgery was 1, 2, 4, and 12months and the procedures were 85%, 95%, 90%, and 75% pancreatectomy, respectively, with the pancreatectomy extent tailored to HI severity. Pathologic analysis revealed marked diffuse endocrine proliferation throughout the pancreas that occupied up to 80% of the parenchyma with scattered islet cell nucleomegaly. One patient had a small pancreatoblastoma in the pancreatectomy specimen. The HI improved in all cases after the pancreatectomy, with patients being able to fast safely for more than 8h. All patients are under close surveillance for embryonal tumors. One patient developed a hepatoblastoma at age 2. The pathophysiology of HI in BWS patients is likely multifactorial and is associated with a dramatic increase in pancreatic endocrine tissue. Severe cases of HI that do not respond to medical therapy improve when the mass of endocrine tissue is reduced by subtotal or near-total pancreatectomy.
    Journal of Pediatric Surgery 12/2013; 48(12):2511-6. · 1.38 Impact Factor
  • Diva D De León, Charles A Stanley
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    ABSTRACT: Hyperinsulinemic hypoglycemia is the most common cause of persistent hypoglycemia in children and adults. The diagnosis of hyperinsulinemic hypoglycemia relies on the evaluation of the biochemical profile at the time of hypoglycemia, however, contrary to common perception, plasma insulin is not always elevated. Thus, the diagnosis must often be based on the examination of other physiologic manifestations of excessive insulin secretion, such as suppression of glycogenolysis, lipolysis and ketogenesis, which can be inferred by the finding of a glycemic response to glucagon, and the suppression of plasma free fatty acids and beta-hydroxybutyrate concentrations during hypoglycemia.
    Best practice & research. Clinical endocrinology & metabolism. 12/2013; 27(6):763-9.
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    ABSTRACT: Insulinomas are rare pediatric tumors for which optimal localization studies and management remain undetermined. We present our experience with surgical management of insulinomas during childhood. A retrospective review was performed of patients who underwent surgical management for an insulinoma from 1999 to 2012. The study included eight patients. Preoperative localization was successful with abdominal ultrasound, abdominal CT, endoscopic ultrasound, or MRI in only 20%, 28.6%, 40%, and 50% of patients, respectively. Octreotide scan was non-diagnostic in 4 patients. For diagnostic failure, selective utilization of 18-Fluoro-DOPA PET/CT scanning, arterial stimulation/venous sampling, or transhepatic portal venous sampling were successful in insulinoma localization. Intraoperatively, all lesions were identified by palpation or with the assistance of intraoperative ultrasound. Surgical resection using pancreas sparing techniques (enucleation or distal pancreatectomy) resulted in a cure in all patients. Postoperative complications included a pancreatic fistula in two patients and an additional missed insulinoma in a patient with MEN-1 requiring successful reoperation. Preoperative tumor localization may require many imaging modalities to avoid unsuccessful blind pancreatectomy. Intraoperative palpation with the assistance of ultrasound offers a reliable method to precisely locate the insulinoma. Complete surgical resection results in a cure. Recurrent symptoms warrant evaluation for additional lesions.
    Journal of Pediatric Surgery 12/2013; 48(12):2517-24. · 1.38 Impact Factor
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    ABSTRACT: Glutamate dehydrogenase (GDH) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of L-glutamate to 2-oxoglutarate. Only in the animal kingdom is this enzyme heavily allosterically regulated by a wide array of metabolites. The major activators are ADP and leucine and inhibitors include GTP, palmitoyl CoA, and ATP. Spontaneous mutations in the GTP inhibitory site that lead to the hyperinsulinism/hyperammonemia (HHS) syndrome have shed light as to why mammalian GDH is so tightly regulated. Patients with HHS exhibit hypersecretion of insulin upon consumption of protein and concomitantly extremely high levels of ammonium in the serum. The atomic structures of four new inhibitors complexed with GDH complexes have identified three different allosteric binding sites. Using a transgenic mouse model expressing the human HHS form of GDH, at least three of these compounds blocked the dysregulated form of GDH in pancreatic tissue. EGCG from green tea prevented the hyper-response to amino acids in whole animals and improved basal serum glucose levels. The atomic structure of the ECG-GDH complex and mutagenesis studies is directing structure-based drug design using these polyphenols as a base scaffold. In addition, all of these allosteric inhibitors are elucidating the atomic mechanisms of allostery in this complex enzyme.
    Neurochemical Research 10/2013; · 2.13 Impact Factor
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    ABSTRACT: Background/Aims: In a family with congenital hyperinsulinism (HI), first described in the 1950s by McQuarrie, we examined the genetic locus and clinical phenotype of a novel form of dominant HI. Methods: We surveyed 25 affected individuals, 7 of whom participated in tests of insulin dysregulation (24-hour fasting, oral glucose and protein tolerance tests). To identify the disease locus and potential disease-associated mutations we performed linkage analysis, whole transcriptome sequencing, whole genome sequencing, gene capture, and next generation sequencing. Results: Most affecteds were diagnosed with HI before age one and 40% presented with a seizure. All affecteds responded well to diazoxide. Affecteds failed to adequately suppress insulin secretion following oral glucose tolerance test or prolonged fasting; none had protein-sensitive hypoglycemia. Linkage analysis mapped the HI locus to Chr10q21-22, a region containing 48 genes. Three novel noncoding variants were found in hexokinase 1 (HK1) and one missense variant in the coding region of DNA2. Conclusion: Dominant, diazoxide-responsive HI in this family maps to a novel locus on Chr10q21-22. HK1 is the more attractive disease gene candidate since a mutation interfering with the normal suppression of HK1 expression in beta-cells could readily explain the hypoglycemia phenotype of this pedigree.
    Hormone Research in Paediatrics 07/2013; · 1.55 Impact Factor
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    ABSTRACT: Abstract Insulin autoimmune syndrome (IAS) or Hirata's disease is a rare cause of hyperinsulinemic hypoglycemia. We report the case of a child with a mild, atypical presentation of IAS. A previously healthy girl, aged 7 years old, developed non-ketotic fasting hypoglycemia during treatment for pneumonia. Laboratory evaluation during hypoglycemia showed the following results: serum glucose, 32 mg/dL (1.8 mmol/L); insulin, 5.6 μIU/mL (38.9 pmol/L); C-peptide, 1.4 ng/mL (0.47 nmol/L); anti-insulin antibody, 6.2% (normal, <2.4%); absence of ketonuria; and positive glucagon stimulation test result. Search for mutation in genes ABCC8, KCNJ11, GLUD1 and MEN1 was negative. Human leukocyte antigen (HLA) typing was HLA-DRB1*1104. Computed tomography scan of the abdomen showed a normal result. The patient evolved with spontaneous resolution of the hypoglycemia, within 30 days, with normalization of serum anti-insulin titers. The serum levels of insulin and anti-insulin antibodies in the patient of this report were not extremely high as previously reported. This novel, mild, or forme fruste presentation of IAS expands the previously reported spectrum of this disease.
    Journal of pediatric endocrinology & metabolism: JPEM 07/2013; · 0.75 Impact Factor
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    ABSTRACT: The purpose of the study was to determine the sensitivity of the (18)fluoro-dihydroxyphenylalanine positron emission tomography/computed tomography scan (18F-PET/CT) in the diagnosis of focal congenital hyperinsulinism (HI). A retrospective review of children with HI who underwent a preoperative 18F-PET/CT scan was performed. Between 1/2008 and 2/2012 we performed 105 consecutive 18F-PET/CT scans on infants with HI. Fifty-three patients had focal HI. Of those fifty-three patients, eight had a preoperative 18F-PET/CT scan read as "diffuse disease". The sensitivity of the study in the diagnosis of focal HI was 85%. The location of the eight missed focal lesions was: head (3), body (2), and tail (3). The 18F-PET/CT of the missed head lesions showed homogeneous tracer uptake (n =2) or heterogeneous uptake throughout the pancreas (n=1). The 18F-PET/CT of the 2 missed body lesions and 1 missed tail lesion showed heterogeneous uptake throughout the pancreas. The 18F-PET/CT of the other 2 missed tail lesions showed lesions adjacent to and obscured by the signal of the upper renal pole, identified retrospectively by closer observation. Fifty-two of the 105 patients had diffuse HI. Two of them had 18F-PET/CT studies read as "focal disease". Therefore, the specificity of the study was 96%. Of the forty-seven 18F-PET/CT studies read as "focal disease", forty-five had true focal HI. Therefore, the positive predictive value of the study in the diagnosis of focal HI was 96%. The sensitivity and specificity of 18 F-PET/CT can be affected by certain anatomic features of the pancreas, by the location of the lesion, and by the reader's experience.
    Journal of Pediatric Surgery 02/2013; 48(2):388-93. · 1.38 Impact Factor
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    ABSTRACT: INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is a well-recognised complication in infants of diabetic mothers and is attributed to a compensatory increase in fetal insulin secretion. Infants with congenital hyperinsulinism have excessive prenatal and postnatal insulin secretion due to defects in pathways of insulin secretion (most commonly the K(ATP) channel). HCM has been reported in a few neonates with hyperinsulinism, but its extent and risk factors for its development have not been evaluated. METHODS: Retrospective chart review of infants, age <3 months, with congenital hyperinsulinism managed by Children's Hospital of Philadelphia over a 3.5-year period. DATA: Gestational age, birth weight, hyperinsulinism form and treatments, echocardiogram results, cardiac/respiratory complications. RESULTS: 68 infants were included, 58 requiring pancreatectomy for diffuse (n=28) or focal (n=30) disease, 10 were diazoxide-sensitive. Twenty-five had echocardiograms performed. Ten had HCM, all of whom required pancreatectomy and eight of whom had confirmed ATP-sensitive potassium-hyperinsulinism. Subjects with HCM had younger gestational age 36(32, 38) than their surgical counterparts without HCM 38 (31.6, 43), p=0.02. DISCUSSION: HCM appears common in infants with severe hyperinsulinism. Routine echocardiogram and EKG of at-risk newborns should be considered. Fetal hyperinsulinism is the likely mediating factor for HCM in HI infants.
    Archives of Disease in Childhood - Fetal and Neonatal Edition 02/2013; · 3.45 Impact Factor
  • Diva D De León, Charles Stanley
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    ABSTRACT: Hyperinsulinemic hypoglycemia is the most common cause of persistent hypoglycemia in children and adults. The diagnosis of hyperinsulinemic hypoglycemia relies on the evaluation of the biochemical profile at the time of hypoglycemia, however, contrary to common perception, plasma insulin is not always elevated. Thus, the diagnosis must often be based on the examination of other physiologic manifestations of excessive insulin secretion, such as suppression of glycogenolysis, lipolysis and ketogenesis, which can be inferred by the finding of a glycemic response to glucagon, and the suppression of plasma free fatty acids and beta-hydroxybutyrate concentrations during hypoglycemia.
    Best Practice & Research: Clinical Endocrinology & Metabolism 01/2013; · 4.91 Impact Factor
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    ABSTRACT: Context:Hypoglycemia due to congenital hyperinsulinism (HI) is caused by mutations in 9 genes.Objective:Our objective was to correlate genotype with phenotype in 417 children with HI.Methods:Mutation analysis was carried out for the ATP-sensitive potassium (KATP) channel genes (ABCC8 and KCNJ11), GLUD1, and GCK with supplemental screening of rarer genes, HADH, UCP2, HNF4A, HNF1A, and SLC16A1.Results:Mutations were identified in 91% (272 of 298) of diazoxide-unresponsive probands (ABCC8, KCNJ11, and GCK), and in 47% (56 of 118) of diazoxide-responsive probands (ABCC8, KCNJ11, GLUD1, HADH, UCP2, HNF4A, and HNF1A). In diazoxide-unresponsive diffuse probands, 89% (109 of 122) carried KATP mutations; 2% (2 of 122) had GCK mutations. In mutation-positive diazoxide-responsive probands, 42% were GLUD1, 41% were dominant KATP mutations, and 16% were in rare genes (HADH, UCP2, HNF4A, and HNF1A). Of the 183 unique KATP mutations, 70% were novel at the time of identification. Focal HI accounted for 53% (149 of 282) of diazoxide-unresponsive probands; monoallelic recessive KATP mutations were detectable in 97% (145 of 149) of these cases (maternal transmission excluded in all cases tested). The presence of a monoallelic recessive KATP mutation predicted focal HI with 97% sensitivity and 90% specificity.Conclusions:Genotype to phenotype correlations were most successful in children with GLUD1, GCK, and recessive KATP mutations. Correlations were complicated by the high frequency of novel missense KATP mutations that were uncharacterized, because such defects might be either recessive or dominant and, if dominant, be either responsive or unresponsive to diazoxide. Accurate and timely prediction of phenotype based on genotype is critical to limit exposure to persistent hypoglycemia in infants and children with congenital HI.
    The Journal of Clinical Endocrinology and Metabolism 12/2012; · 6.31 Impact Factor
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    ABSTRACT: Paracrine signaling between pancreatic islet beta-cells and alpha-cells has been proposed to play a role in regulating glucagon responses to elevated glucose and hypoglycemia. To examine this possibility in human islets, we employed a metabolomic approach to trace the responses of amino acids and other potential neurotransmitters to stimulation with [U-13C]glucose in both normals and type 2 diabetics. Islets from type 2 diabetics uniformly showed decreased glucose stimulation of insulin secretion and respiratory rate, but demonstrated two different patterns of glucagon responses to glucose: one group responded normally to suppression of glucagon by glucose, but the second group was non-responsive. The non-responsive group showed evidence of suppressed islet GABA levels and of GABA shunt activity. In further studies with normal human islets, we found that gamma-hydroxybutyrate (GHB), a potent inhibitory neurotransmitter, is generated in beta-cells by an extension of the GABA shunt during glucose stimulation and interacts with alpha-cell GHB receptors, thus, mediating the suppressive effect of glucose on glucagon release. We also identified glycine, acting via alpha-cell glycine receptors, as the predominant amino acid stimulator of glucagon release. The results suggest that glycine and GHB provide a counterbalancing receptor-based mechanism for controlling alpha-cell secretory responses to metabolic fuels.
    Journal of Biological Chemistry 12/2012; · 4.65 Impact Factor
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    ABSTRACT: Congenital hyperinsulinism (CHI) occurs as a consequence of unregulated insulin secretion from the pancreatic beta-cells. Severe recessive mutations and milder dominant mutations have been described in the ABCC8 and KCNJ11 genes encoding SUR1 and Kir6.2 subunits of the beta-cell ATP-sensitive K(+) channel. Here we report two patients with CHI unresponsive to medical therapy with diazoxide. Sequencing analysis identified a compound heterozygous mutation in ABCC8 in both patients. The first one, is a carrier for the known mild dominant mutation p.Glu1506Lys jointly with the novel mutation p.Glu1323Lys. The second carries the p.Glu1323Lys mutation and a second novel mutation, p.Met1394Arg. Functional studies of both novel alleles showed reduced or null cell surface expression, typical of recessive mutations. Compound heterozygous mutations in congenital hyperinsulinism result in complex interactions. The studying of these mechanisms can improve the knowledge of this disease and modify its therapy.
    Gene 12/2012; · 2.20 Impact Factor
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    ABSTRACT: The primary accumulating metabolites in fatty acid oxidation defects are intramitochondrial acyl-CoAs. Typically, secondary metabolites such as acylcarnitines, acylglycines and dicarboxylic acids are measured to study these disorders. Methods have not been adapted for tissue acyl-CoA measurement in defects with primarily acyl-CoA accumulation. Our objective was to develop a method to measure fatty acyl-CoA species that are present in tissues of mice with fatty acid oxidation defects using flow-injection tandem mass spectrometry. Following the addition of internal standards of [(13)C(2)] acetyl-CoA, [(13)C(8)] octanoyl-CoA, and [C(17)] heptadecanoic CoA, acyl-CoA's are extracted from tissue samples and are injected directly into the mass spectrometer. Data is acquired using a 506.9 neutral loss scan and multiple reaction-monitoring (MRM). This method can identify all long, medium and short-chain acyl-CoA species in wild type mouse liver including predicted 3-hydroxyacyl-CoA species. We validated the method using liver of the short-chain-acyl-CoA dehydrogenase (SCAD) knock-out mice. As expected, there is a significant increase in [C(4)] butyryl-CoA species in the SCAD -/- mouse liver compared to wild type. We then tested the assay in liver from the short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficient mice to determine the profile of acyl-CoA accumulation in this less predictable model. There was more modest accumulation of medium chain species including 3-hydroxyacyl-CoA's consistent with the known chain-length specificity of the SCHAD enzyme.
    Molecular Genetics and Metabolism 10/2012; · 2.83 Impact Factor
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    ABSTRACT: Infants with congenital hyperinsulinism owing to inactivating mutations in the K(ATP) channel (K(ATP)HI) who are unresponsive to medical therapy will require pancreatectomy to control the hypoglycemia. In preclinical studies, we showed that the GLP-1 receptor antagonist exendin-(9-39) suppresses insulin secretion and corrects fasting hypoglycemia in SUR-1(-/-) mice. The aim of this study was to examine the effects of exendin-(9-39) on fasting blood glucose in subjects with K(ATP)HI. This was a randomized, open-label, two-period crossover pilot clinical study. Nine subjects with K(ATP)HI received either exendin-(9-39) or vehicle on two different days. The primary outcome was blood glucose; secondary outcomes were insulin, glucagon, and GLP-1. In all subjects, mean nadir blood glucose and glucose area under the curve were significantly increased by exendin-(9-39). Insulin-to-glucose ratios were significantly lower during exendin-(9-39) infusion compared with vehicle. Fasting glucagon and intact GLP-1 were not affected by treatment. In addition, exendin-(9-39) significantly inhibited amino acid-stimulated insulin secretion in pancreatic islets isolated from neonates with K(ATP)HI. Our findings have two important implications: 1) GLP-1 and its receptor play a role in the regulation of fasting glycemia in K(ATP)HI; and 2) the GLP-1 receptor may be a therapeutic target for the treatment of children with K(ATP)HI.
    Diabetes 08/2012; 61(10):2585-91. · 7.90 Impact Factor
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    ABSTRACT: Context: Inactivating mutations in HNF1A and HNF4A cause the maturity-onset diabetes of youth (MODY)-3 and MODY1 forms of monogenic diabetes, respectively. Children carrying HNF4A (MODY1) mutations can present in early infancy with macrosomia and diazoxide-responsive hyperinsulinism. Objective: Our objective was to describe three novel cases of hyperinsulinism associated with MODY1 and MODY3 mutations. Research Design and Methods: Clinical data were obtained from chart review. Gene sequencing was performed on genomic DNA. Results: Case 1 was diagnosed at 20 months with persistent hyperinsulinemic hypoglycemia and was found to have a novel MODY3 HNF1A mutation, carried by her father who had diabetes. Case 2 was diagnosed with diazoxide-responsive hyperinsulinism at 3 months of age and had complete resolution of hyperinsulinism by 4 yr. She was found to have a novel MODY3 HNF1A missense mutation, also carried by her father. Case 3 presented as a newborn with diazoxide-responsive hyperinsulinism and later developed renal Fanconi syndrome, hypophosphatemic rickets, and hepatic glycogenosis. Although the latter's features suggested Fanconi-Bickel syndrome, sequencing of the SLC2A2 gene was normal. The patient was found to have a known MODY1 mutation in HNF4A. In all cases, the hyperinsulinism improved with age. Conclusions: The first two cases demonstrate that mutations in HNF1A (MODY3) can cause hyperinsulinism early in life and diabetes later, similar to the phenotype recently reported for HNF4A (MODY1) mutations. Case 3 indicates that the effects of HNF4A mutations in infancy may extend beyond pancreatic β-cells to produce a disorder similar to glucose transporter 2 deficiency involving both liver glycogen metabolism and renal tubular transport.
    The Journal of Clinical Endocrinology and Metabolism 07/2012; 97(10):E2026-30. · 6.31 Impact Factor
  • Diva D De León, Charles Stanley
    Frontiers in Diabetes: Monogenic Hyperinsulinemic Hypoglycemia Disorders, Edited by Stanley, De León DD, 02/2012; Karger.
  • Samir Sayed, Franz Matschinsky, Charles A. Stanley
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    ABSTRACT: Glucokinase (GK) initiates glucose oxidation in pancreatic beta-cells and is a critical determinant of the glucose threshold for insulin secretion. Activating mutations of glucokinase were the second form of genetic hyperinsulinism (HI) to be discovered. GK-HI is inherited in an autosomal dominant fashion, but increasing numbers of de novo cases have been detected through genetic mutation analysis. The disease phenotype may include severe neonatal onset HI, but the disorder can go unrecognized until later in life. Patients manifest fasting hypoglycemia, but are not protein- or leucine-sensitive. Most disease-causing missense mutations cluster in the allosteric region of glucokinase near binding sites for GK activators and the inhibitory GK regulatory protein. Mutation expression studies show strong genotype-phenotype relationships; however, in vitro enzyme kinetics correlate poorly with glucose thresholds observed clinically, suggesting that additional factors are involved in controlling glucose levels. This important form of monogenic HI provides a model for the development of GK activating drugs for antidiabetic therapy.
    Monogenic Hyperinsulinemic Hypoglycemia Disorders, Vol. 21 edited by Stanley CA, De León DD, 02/2012: chapter Hyperinsulinism due to activating mutations of glucokinase: pages 146-157; Karger., ISBN: 3805599439, 978-3805599436

Publication Stats

5k Citations
1,182.70 Total Impact Points

Institutions

  • 1984–2014
    • The Children's Hospital of Philadelphia
      • • Department of Pediatrics
      • • Division of Endocrinology and Diabetes
      • • Center for Applied Genomics
      • • Center for Fetal Diagnosis and Treatment
      Philadelphia, Pennsylvania, United States
  • 2002–2013
    • Donald Danforth Plant Science Center
      San Luis, Missouri, United States
    • University of California, Los Angeles
      • Division of Adult Psychiatry
      Los Angeles, CA, United States
  • 1989–2013
    • University of Pennsylvania
      • • Department of Medicine
      • • Department of Pediatrics
      • • Division of Geriatric Medicine
      Philadelphia, Pennsylvania, United States
  • 2006–2010
    • Oregon Health and Science University
      • Center for Research on Occupational and Environmental Toxicology (CROET)
      Portland, OR, United States
    • University of Bergen
      • Department of Clinical Medicine
      Bergen, Hordaland Fylke, Norway
  • 2009
    • New Jersey Institute of Technology
      Newark, New Jersey, United States
  • 1993–2008
    • Hospital of the University of Pennsylvania
      • • Department of Genetics
      • • Department of Pediatrics
      Philadelphia, Pennsylvania, United States
    • University of Chicago
      • Department of Pediatrics
      Chicago, Illinois, United States
    • University of Illinois at Chicago
      • Department of Pediatrics (Chicago)
      Chicago, IL, United States
  • 2005
    • University of Oxford
      • Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM)
      Oxford, ENG, United Kingdom
  • 2004
    • University College London
      • Institute of Child Health
      London, ENG, United Kingdom
  • 2001
    • Purdue University
      • Department of Biological Sciences
      West Lafayette, IN, United States
  • 1999
    • Hadassah Medical Center
      • Department of Endocrinology and Metabolism
      Yerushalayim, Jerusalem District, Israel
    • Hebrew University of Jerusalem
      • Hadassah Medical School
      Jerusalem, Jerusalem District, Israel
  • 1997
    • Murdoch Childrens Research Institute
      Melbourne, Victoria, Australia
  • 1986–1997
    • University of Washington Seattle
      • • Division of Metabolism, Endocrinology and Nutrition
      • • Division of General Internal Medicine
      • • Department of Pediatrics
      Seattle, WA, United States
  • 1988–1989
    • Hartford Hospital
      • Department of Pediatrics
      Hartford, Connecticut, United States
    • University of Massachusetts Medical School
      Worcester, Massachusetts, United States