RESUMO
Congenital hyperinsulinism (HI), a beta cell disorder most commonly caused by inactivating mutations of beta cell KATP channels, results in dysregulated insulin secretion and persistent hypoglycemia. Children with KATP-HI are unresponsive to diazoxide, the only FDA-approved drug for HI, and utility of octreotide, the second-line therapy, is limited because of poor efficacy, desensitization, and somatostatin receptor type 2 (SST2)-mediated side effects. Selective targeting of SST5, an SST receptor associated with potent insulin secretion suppression, presents a new avenue for HI therapy. Here, we determined that CRN02481, a highly selective nonpeptide SST5 agonist, significantly decreased basal and amino acid-stimulated insulin secretion in both Sur1-/- (a model for KATP-HI) and wild-type mouse islets. Oral administration of CRN02481 significantly increased fasting glucose and prevented fasting hypoglycemia compared to vehicle in Sur1-/- mice. During a glucose tolerance test, CRN02481 significantly increased glucose excursion in both WT and Sur1-/- mice compared to the control. CRN02481 also reduced glucose- and tolbutamide-stimulated insulin secretion from healthy, control human islets similar to the effects observed with SS14 and peptide somatostatin analogs. Moreover, CRN02481 significantly decreased glucose- and amino acid-stimulated insulin secretion in islets from two infants with KATP-HI and one with Beckwith-Weideman Syndrome-HI. Taken together, these data demonstrate that a potent and selective SST5 agonist effectively prevents fasting hypoglycemia and suppresses insulin secretion not only in a KATP-HI mouse model but also in healthy human islets and islets from HI patients.
Assuntos
Hiperinsulinismo , Receptores de Somatomedina , Animais , Criança , Humanos , Lactente , Camundongos , Trifosfato de Adenosina/metabolismo , Aminoácidos/metabolismo , Glucose/metabolismo , Hiperinsulinismo/tratamento farmacológico , Hipoglicemia/metabolismo , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Receptores de Somatomedina/agonistasRESUMO
PURPOSE OF REVIEW: To highlight advances in congenital hyperinsulinism (HI), including newly described molecular mechanisms of disease, novel therapeutic interventions, and improved understanding of long-term outcomes. RECENT FINDINGS: Important advances have been made elucidating the molecular mechanisms responsible for HI. Non-coding variants in HK1 have been found to cause aberrant hexokinase expression. Inactivating mutations in SLC25A36 have been identified in children with features of the hyperinsulinism hyperammonemia syndrome. Low-level mosaic mutations in known HI genes have been detected in cases of 'genetic testing negative' HI. Identification and localization of focal HI lesions remains a priority, since focal HI can be cured with surgery. Use of 68 Ga-NODAGA-exendin-4 PET has been proposed to localize focal lesions. Additional studies are needed before this technique replaces 18 F-DOPA PET as standard of care. Treatment options for children with diffuse HI remain limited. The long-acting somatostatin analog, lanreotide, was shown to significantly improve glycemic control in a large series of children with HI. New therapies are under development, with promising preliminary results. Long-term quality of life and neurodevelopmental outcomes remain suboptimal. SUMMARY: Advanced genetic and epigenomic analytic techniques have uncovered novel molecular mechanisms of HI. Development of new drugs holds promise to improve long-term outcomes for individuals with HI.
Assuntos
Hiperinsulinismo Congênito , Qualidade de Vida , Criança , Humanos , Lactente , Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/terapia , Mutação , Testes GenéticosRESUMO
BACKGROUND: Fasting hypoglycemia is a recognized occurrence among pediatric patients with acute lymphoblastic leukemia (ALL) during maintenance therapy. Existing publications describing this finding are limited to small studies and case reports. Our objective was to determine the incidence of hypoglycemia during maintenance chemotherapy and to investigate the association of age, as well as other potential risk factors, with this outcome in pediatric patients with ALL. PROCEDURE: This retrospective cohort study included individuals 1 to 21 years of age with ALL treated with antimetabolite-containing maintenance chemotherapy at a large children's hospital between January 2011 and December 2014. The primary endpoint was time to first documented episode of hypoglycemia during maintenance therapy, defined as single measurement of plasma glucose <60 mg/dL. Cox regression was used to evaluate the association with age and identify other potential risk factors. RESULTS: We identified 126 eligible patients, of whom 63% were documented as White, non-Hispanic, 28% as non-White, non-Hispanic, and 9% as Hispanic. Twenty-eight children (22%) had documented hypoglycemia during maintenance therapy. Younger age at the start of maintenance and hepatotoxicity documented during chemotherapy prior to maintenance initiation were associated with hypoglycemia (adjusted HR age = 0.88; 95% CI, 0.78-0.99; adjusted HR prior hepatotoxicity = 3.50; 95% CI, 1.47-8.36). CONCLUSIONS: Nearly one quarter of children in our cohort had hypoglycemia documented during maintenance chemotherapy. Younger age at maintenance initiation and hepatotoxicity during chemotherapy prior to maintenance initiation emerged as risk factors. These findings highlight the importance of counseling about the risk of, and monitoring for, hypoglycemia, particularly in young children.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Hipoglicemia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Criança , Pré-Escolar , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Incidência , Lactente , Quimioterapia de Manutenção/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Estudos Retrospectivos , Fatores de RiscoRESUMO
Hyperinsulinemic hypoglycemia of infancy, also known as congenital hyperinsulinism, is a group of disorders characterized by dysregulated insulin release. Neonates with severe, persistent hyperinsulinemic hypoglycemia who are unresponsive to medical therapy require pancreatectomy to prevent brain damage from hypoglycemia. To date, multiple genetic mutations and syndromes and several unique histopathological entities have been identified in children with hyperinsulinism. Histopathology is characterized as diffuse, focal or atypical. Surgical resection of a focal lesion results in a cure in up to 97% of these children. Imaging with 6-fluoro-(18F)-L-3,4-dihydroxyphenylalanine (18F-FDOPA) positron emission tomography (PET) is the test of choice for identifying and localizing a focal lesion and has proved to be an invaluable guide for surgical resection. Genetic evaluation is essential for determining who will benefit from PET imaging. This article provides an approach to determine who should be imaged, how to set up a protocol and how to interpret the imaging findings. The diagnosis and management of this disorder require a multidisciplinary approach to prevent brain damage from hypoglycemia.
Assuntos
Hiperinsulinismo Congênito , Criança , Hiperinsulinismo Congênito/diagnóstico por imagem , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/cirurgia , Di-Hidroxifenilalanina/genética , Humanos , Lactente , Recém-Nascido , Mutação , Tomografia por Emissão de Pósitrons/métodosRESUMO
Idiopathic ketotic hypoglycemia (IKH) is a diagnosis of exclusion with glycogen storage diseases (GSDs) as a differential diagnosis. GSD IXa presents with ketotic hypoglycemia (KH), hepatomegaly, and growth retardation due to PHKA2 variants. In our multicenter study, 12 children from eight families were diagnosed or suspected of IKH. Whole-exome sequencing or targeted next-generation sequencing panels were performed. We identified two known and three novel (likely) pathogenic PHKA2 variants, such as p.(Pro869Arg), p.(Pro498Leu), p.(Arg2Gly), p.(Arg860Trp), and p.(Val135Leu), respectively. Erythrocyte phosphorylase kinase activity in three patients with the novel variants p.(Arg2Gly) and p.(Arg860Trp) were 15%-20% of mean normal. One patient had short stature and intermittent mildly elevated aspartate aminotransferase, but no hepatomegaly. Family testing identified two asymptomatic children and 18 adult family members with one of the PHKA2 variants, of which 10 had KH symptoms in childhood and 8 had mild symptoms in adulthood. Our study expands the classical GSD IXa phenotype of PHKA2 missense variants to a continuum from seemingly asymptomatic carriers, over KH-only with phosphorylase B kinase deficiency, to more or less complete classical GSD IXa. In contrast to typical IKH, which is confined to young children, KH may persist into adulthood in the KH-only phenotype of PHKA2.
Assuntos
Doença de Depósito de Glicogênio/genética , Hepatomegalia/genética , Hipoglicemia/genética , Fosforilase Quinase/genética , Acidemia Propiônica/genética , Adolescente , Adulto , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/patologia , Hepatomegalia/diagnóstico , Hepatomegalia/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hipoglicemia/diagnóstico , Hipoglicemia/patologia , Masculino , Mutação de Sentido Incorreto/genética , Linhagem , Fenótipo , Acidemia Propiônica/diagnóstico , Acidemia Propiônica/epidemiologia , Acidemia Propiônica/patologia , Sequenciamento do Exoma , Adulto JovemRESUMO
Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant genetic syndrome characterized by distinct facial features, broad thumbs, growth restriction, microcephaly, intellectual disability, and developmental delay. Pathogenic variants in both CREBBP and EP300 have been associated with RSTS. Here we present a case of a female with hyperinsulinism and features consistent with RSTS, found to have a pathogenic variant in EP300. While there have been a few rare case reports of hyperinsulinism in RSTS, we suggest that hyperinsulinism might be a more prominent feature in EP300 variant RSTS than previously recognized.
Assuntos
Proteína p300 Associada a E1A/genética , Predisposição Genética para Doença , Hiperinsulinismo/genética , Síndrome de Rubinstein-Taybi/genética , Feminino , Variação Genética/genética , Genótipo , Humanos , Hiperinsulinismo/patologia , Lactente , Recém-Nascido , Mutação/genética , Fenótipo , Síndrome de Rubinstein-Taybi/patologia , Deleção de Sequência/genéticaRESUMO
Heterozygous pathogenic variants in HNF4A cause hyperinsulinism, maturity onset diabetes of the young type 1, and more rarely Fanconi renotubular syndrome. Specifically, the recurrent missense pathogenic variant c.253C>T (p.Arg85Trp) has been associated with a syndromic form of hyperinsulinism with additional features of macrosomia, renal tubular nephropathy, hypophosphatemic rickets, and liver involvement. We present an affected mother, who had been previously diagnosed clinically with the autosomal recessive Fanconi Bickel Syndrome, and her affected son. The son's presentation expands the clinical phenotype to include multiple congenital anomalies, including penile chordee with hypospadias and coloboma. This specific pathogenic variant should be considered in the differential diagnosis of Fanconi Bickel Syndrome when genetics are negative or the family history is suggestive of autosomal dominant inheritance. The inclusion of hyperinsulinism and maturity onset of the diabetes of the young changes the management of this syndrome and the recurrence risk is distinct. Additionally, this family also emphasizes the importance of genetic confirmation of clinical diagnoses, especially in adults who grew up in the premolecular era that are now coming to childbearing age. Finally, the expansion of the phenotype to include multiple congenital anomalies suggests that the full spectrum of HNF4A is likely unknown.
Assuntos
Coloboma/genética , Diabetes Mellitus/genética , Síndrome de Fanconi/genética , Predisposição Genética para Doença , Fator 4 Nuclear de Hepatócito/genética , Idade de Início , Coloboma/complicações , Coloboma/diagnóstico , Diabetes Mellitus/diagnóstico , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Raquitismo Hipofosfatêmico Familiar/genética , Raquitismo Hipofosfatêmico Familiar/patologia , Síndrome de Fanconi/complicações , Síndrome de Fanconi/diagnóstico , Feminino , Macrossomia Fetal/complicações , Macrossomia Fetal/diagnóstico , Macrossomia Fetal/genética , Macrossomia Fetal/patologia , Heterozigoto , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Linhagem , GravidezRESUMO
RATIONALE: Diabetes is associated with worse cystic fibrosis (CF) outcomes. The CFTR potentiator ivacaftor is suggested to improve glucose homeostasis in individuals with CF. OBJECTIVES: To test the hypothesis that clinically indicated ivacaftor would be associated with improvements in glucose tolerance and insulin and incretin secretion. METHODS: Oral glucose tolerance tests, mixed-meal tolerance tests, and glucose-potentiated arginine tests were compared preivacaftor initiation and 16 weeks postivacaftor initiation in CF participants with at least one CFTR gating or conductance mutation. Meal-related 30-minute (early phase) and 180-minute incremental area under the curves were calculated as responses for glucose, insulin, C-peptide, and incretin hormones; glucagon-like peptide-1; and glucose-dependent insulinotropic polypeptide. First-phase insulin secretion, glucose potentiation of arginine-induced insulin secretion, and disposition index were characterized by glucose-potentiated arginine stimulation tests. MEASUREMENTS AND MAIN RESULTS: Twelve subjects completed the study: six male/six female; seven normal/five abnormal glucose tolerance (oral glucose tolerance test 1-h glucose ≥155 and 2-h glucose <200 mg/dl); of median (minimum-maximum) age (13.8 yr [6.0-42.0]), body mass index-Z of 0.66 (-2.4 to 1.9), and FEV1% predicted of 102 (39-122). Glucose tolerance normalized in one abnormal glucose tolerance subject. Ivacaftor treatment did not alter meal responses except for an increase in early phase C-peptide (P = 0.04). First-phase (P = 0.001) and glucose potentiation of arginine-induced (P = 0.027) insulin secretion assessed by acute C-peptide responses improved after ivacaftor treatment. Consistent with an effect on ß-cell function, the disposition index relating the amount of insulin secreted for insulin sensitivity also improved (P = 0.04). CONCLUSIONS: Insulin secretion improved following 4 months of clinically indicated ivacaftor therapy in this relatively young group of patients with CF with normal to mildly impaired glucose tolerance, whereas incretin secretion remained unchanged.
Assuntos
Aminofenóis/uso terapêutico , Glicemia/efeitos dos fármacos , Fibrose Cística/sangue , Fibrose Cística/tratamento farmacológico , Incretinas/sangue , Quinolonas/uso terapêutico , Adolescente , Adulto , Aminofenóis/sangue , Peptídeo C/sangue , Peptídeo C/efeitos dos fármacos , Criança , Feminino , Seguimentos , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Masculino , Quinolonas/sangue , Adulto JovemRESUMO
Hypoglycemia remains a significant cause of morbidity in infants and children. Up to 50% of children with hypoglycemic disorders suffer from neurodevelopmental deficits, as a consequence of delays in the diagnosis and inadequate treatment. Recent advances in the field have resulted in new therapies and improved outcomes. To review these advances and have a dialogue regarding controversies in the field, the Fourth International Hyperinsulinism Symposium, sponsored by the Children's Hospital of Philadelphia was held in Philadelphia, Pennsylvania on September 5-6, 2019. The symposium faculty, leaders in the field of hyperinsulinism and hypoglycemia, presented 25 plenary lectures on all aspects of these disorders. Additionally, a mini-symposium on neonatal hypoglycemia closed out the conference. Objectives of the symposium were to: 1. Describe the clinical manifestations, genetics and natural history of congenital hyperinsulinism 2. Review recent advances in the medical and surgical management of hyperinsulinism 3. Discuss current controversies and management options of neonatal hypoglycemia.
Assuntos
Hiperinsulinismo Congênito , Humanos , Recém-NascidoRESUMO
Congenital hyperinsulinism (HI) is the most frequent cause of persistent hypoglycemia in infants and children. Delays in diagnosis and initiation of appropriate treatment contribute to a high risk of neurocognitive impairment. HI represents a heterogeneous group of disorders characterized by dysregulated insulin secretion by the pancreatic beta cells, which in utero, may result in somatic overgrowth. There are at least nine known monogenic forms of HI as well as several syndromic forms. Molecular diagnosis allows for prediction of responsiveness to medical treatment and likelihood of surgically-curable focal hyperinsulinism. Timely genetic mutation analysis has thus become standard of care. However, despite significant advances in our understanding of the molecular basis of this disorder, the number of patients without an identified genetic diagnosis remains high, suggesting that there are likely additional genetic loci that have yet to be discovered.
Assuntos
Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/fisiopatologia , Criança , Hiperinsulinismo Congênito/metabolismo , Epigênese Genética , Testes Genéticos , Humanos , Lactente , Mutação , Philadelphia , SíndromeRESUMO
PURPOSE: Beckwith-Wiedemann syndrome (BWS) is a human genomic imprinting disorder characterized by lateralized overgrowth, macroglossia, abdominal wall defects, congenital hyperinsulinism, and predisposition to embryonal tumors. One of the molecular etiologies underlying BWS is paternal uniparental isodisomy of chromosome 11p15.5 (pUPD11). About 8% of pUPD11 cases are due to genome-wide paternal uniparental isodisomy (GWpUPD). About 30 cases of live-born patients with GWpUPD have been described, most of whom were mosaic and female. We present male patients with BWS due to GWpUPD, elucidate the underlying mechanism, and make recommendations for management. METHODS: Three male patients with GWpUPD underwent clinical and molecular evaluation by single-nucleotide polymorphism (SNP) microarrays in different tissues. Previously published cases of GWpUPD were reviewed. RESULTS: SNP microarray demonstrated a GWpUPD cell population with sex chromosomes XX and biparental cell population with sex chromosomes XY, consistent with dispermic androgenetic chimerism. CONCLUSION: SNP microarray is necessary to distinguish GWpUPD cases and the underlying mechanisms. The percentage of GWpUPD cell population within a specific tissue type correlated with the amount of tissue dysplasia. Males with BWS due to GWpUPD are important to distinguish from other molecular etiologies because the mechanism indicates risk for germ cell tumors and autosomal recessive diseases in addition to other BWS features.
Assuntos
Síndrome de Beckwith-Wiedemann/etiologia , Dissomia Uniparental/genética , Quimerismo , Cromossomos Humanos Par 11/genética , Metilação de DNA/genética , Impressão Genômica/genética , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Mosaicismo , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Dissomia Uniparental/diagnóstico , Dissomia Uniparental/fisiopatologiaRESUMO
The author Diva D. De Leon was incorrectly listed as instead of Diva D. De Leó-Critchlow in the original version of this paper.
RESUMO
Inactivating mutations in the genes encoding the two subunits of the pancreatic beta-cell KATP channel, ABCC8 and KCNJ11, are the most common finding in children with congenital hyperinsulinism (HI). Interpreting novel missense variants in these genes is problematic, because they can be either dominant or recessive mutations, benign polymorphisms, or diabetes mutations. This report describes six novel missense variants in ABCC8 and KCNJ11 that were identified in 11 probands with congenital HI. One of the three ABCC8 mutations (p.Ala1458Thr) and all three KCNJ11 mutations were associated with responsiveness to diazoxide. Sixteen family members carried the ABCC8 or KCNJ11 mutations; only two had hypoglycemia detected at birth and four others reported symptoms of hypoglycemia. Phenotype testing of seven adult mutation carriers revealed abnormal protein-induced hypoglycemia in all; fasting hypoketotic hypoglycemia was demonstrated in four of the seven. All of six mutations were confirmed to cause dominant pathogenic defects based on in vitro expression studies in COSm6 cells demonstrating normal trafficking, but reduced responses to MgADP and diazoxide. These results indicate a combination of in vitro and in vivo phenotype tests can be used to differentiate dominant from recessive KATP channel HI mutations and personalize management of children with congenital HI.
Assuntos
Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Canais KATP/genética , Mutação , Alelos , Análise Mutacional de DNA , Feminino , Frequência do Gene , Genótipo , Humanos , Lactente , Canais KATP/química , Masculino , Linhagem , Fenótipo , Relação Estrutura-AtividadeRESUMO
Sotos syndrome is an overgrowth syndrome characterized by distinctive facial features and intellectual disability caused by haploinsufficiency of the NSD1 gene. Genotype-phenotype correlations have been observed, with major anomalies seen more frequently in patients with 5q35 deletions than those with point mutations in NSD1. Though endocrine features have rarely been described, transient hyperinsulinemic hypoglycemia (HI) of the neonatal period has been reported as an uncommon presentation of Sotos syndrome. Eight cases of 5q35 deletions and one patient with an intragenic NSD1 mutation with transient HI have been reported. Here, we describe seven individuals with HI caused by NSD1 gene mutations with three having persistent hyperinsulinemic hypoglycemia. These patients with persistent HI and Sotos syndrome caused by NSD1 mutations, further dispel the hypothesis that HI is due to the deletion of other genes in the deleted 5q35 region. These patients emphasize that NSD1 haploinsufficiency is sufficient to cause HI, and suggest that Sotos syndrome should be considered in patients presenting with neonatal HI. Lastly, these patients help extend the phenotypic spectrum of Sotos syndrome to include HI as a significant feature.
Assuntos
Hiperinsulinismo Congênito/patologia , Deficiências do Desenvolvimento/patologia , Transtornos do Crescimento/patologia , Histona-Lisina N-Metiltransferase/genética , Mutação , Síndrome de Sotos/patologia , Adulto , Hiperinsulinismo Congênito/genética , Deficiências do Desenvolvimento/genética , Feminino , Transtornos do Crescimento/genética , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Prognóstico , Síndrome de Sotos/genéticaRESUMO
PURPOSE OF REVIEW: New more stable formulations of glucagon have recently become available, and these provide an opportunity to expand the clinical roles of this hormone in the prevention and management of insulin-induced hypoglycemia. This is applicable in type 1 diabetes, hyperinsulinism, and alimentary hypoglycemia. The aim of this review is to describe these new formulations of glucagon and to provide an overview of current and future therapeutic opportunities that these may provide. RECENT FINDINGS: Four main categories of glucagon formulation have been studied: intranasal glucagon, biochaperone glucagon, dasiglucagon, and non-aqueous soluble glucagon. All four have demonstrated similar glycemic responses to standard glucagon formulations when administered during hypoglycemia. In addition, potential roles of these formulations in the management of congenital hyperinsulinism, alimentary hypoglycemia, and exercise-induced hypoglycemia in type 1 diabetes have been described. As our experience with newer glucagon preparations increases, the role of glucagon is likely to expand beyond the emergency use that this medication has been limited to in the past. The innovations described in this review likely represent early examples of a pending large repertoire of indications for stable glucagon.
Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Glucagon/administração & dosagem , Hormônios/administração & dosagem , Hipoglicemia/metabolismo , Hipoglicemia/prevenção & controle , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 1/terapia , Exercício Físico , Homeostase , Humanos , Hipoglicemia/sangue , Hipoglicemia/tratamento farmacológicoRESUMO
AIMS: Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycaemia in infants and children. Exendin-(9-39), an inverse glucagon-like peptide 1 (GLP-1) agonist, is a novel therapeutic agent for HI that has demonstrated glucose-raising effect. We report the first population pharmacokinetic (PopPK) model of the exendin-(9-39) in patients with HI and propose the optimal dosing regimen for future clinical trials in neonates with HI. METHODS: A total of 182 pharmacokinetic (PK) observations from 26 subjects in three clinical studies were included for constructing the PopPK model using first order conditional estimation (FOCE) with interaction method in nonlinear mixed-effects modelling (NONMEM). Exposure metrics (area under the curve [AUC] and maximum plasma concentration [Cmax ]) at no observed adverse effect levels (NOAELs) in rats and dogs were determined in toxicology studies. RESULTS: Observed concentration-time profiles of exendin-(9-39) were described by a linear two-compartmental PK model. Following allometric scaling of PK parameters, age and creatinine clearance did not significantly affect clearance. The calculated clearance and elimination half-life for adult subjects with median weight of 69 kg were 11.8 l h-1 and 1.81 h, respectively. The maximum recommended starting dose determined from modelling and simulation based on the AUC0-last at the NOAEL and predicted AUC0-inf using the PopPK model was 27 mg kg-1 day-1 intravenously. CONCLUSIONS: This is the first study to investigate the PopPK of exendin-(9-39) in humans. The final PopPK model was successfully used with preclinical toxicology findings to propose the optimal dosing regimen of exendin-(9-39) for clinical studies in neonates with HI, allowing for a more targeted dosing approach to achieve desired glycaemic response.
Assuntos
Hiperinsulinismo Congênito/tratamento farmacológico , Modelos Biológicos , Fragmentos de Peptídeos/administração & dosagem , Adolescente , Adulto , Fatores Etários , Animais , Área Sob a Curva , Criança , Pré-Escolar , Estudos Cross-Over , Cães , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Nível de Efeito Adverso não Observado , Dinâmica não Linear , Fragmentos de Peptídeos/efeitos adversos , Fragmentos de Peptídeos/farmacocinética , Projetos Piloto , Ratos , Ratos Sprague-Dawley , Adulto JovemRESUMO
PURPOSE OF REVIEW: Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in infants and children. Early and appropriate recognition and treatment of hypoglycemia is vital to minimize neurocognitive impairment. RECENT FINDINGS: There are at least 11 known monogenic forms of hyperinsulinism and several associated syndromes. Molecular diagnosis allows for prediction of the effectiveness of diazoxide and the likelihood of focal hyperinsulinism. Inactivating mutations in the genes encoding the ATP-sensitive potassium channel (KATP hyperinsulinism) account for 60% of all identifiable mutations, including 85% of diazoxide-unresponsive cases. Syndromes or disorders associated with hyperinsulinism include Beckwith-Wiedemann syndrome, Kabuki syndrome, Turner syndrome, and congenital disorders of glycosylation. Although focal hyperinsulinism can be cured by resection of the lesion, therapeutic options for nonfocal hyperinsulinism remain limited and include diazoxide, octreotide, long-acting somatostatin analogs, and near-total pancreatectomy. Although sirolimus has been reported to improve glycemic control in infants with diazoxide-unresponsive hyperinsulinism, the extent of improvement has been limited, and significant adverse events have been reported. SUMMARY: Identification of the cause of congenital hyperinsulinism helps guide management decisions. Use of therapies with limited benefit and significant potential risks should be avoided.
Assuntos
Hiperinsulinismo Congênito/genética , Criança , Hiperinsulinismo Congênito/complicações , Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/terapia , Marcadores Genéticos , Testes Genéticos , Humanos , Lactente , SíndromeRESUMO
BACKGROUND: Dominant inactivating mutations in HNF1A and HNF4A have been described to cause hyperinsulinism (HI) before evolving to diabetes. However, information available in the literature regarding the clinical phenotype is limited. OBJECTIVE: To report the prevalence of HNF1A and HNF4A mutations in a large cohort of children with HI, and to describe their genotypes and phenotypes. DESIGN: Retrospective descriptive study. METHODS: Medical records were reviewed to extract clinical information. Mutation analysis was carried out for 8 genes associated with HI (ABCC8, KCNJ11, GLUD1, GCK, HADH, HNF4A, HNF1A, and UCP2). RESULTS: HNF1A and HNF4A mutations were identified in 5.9% (12 out of 204; HNF1A = 7, HNF4A = 5) of diazoxide-responsive HI probands. The clinical phenotypes were extremely variable. Two children showed evidence of ketone production during hypoglycemia, a biochemical profile atypical for hyperinsulinism. At the time of analysis, diazoxide was discontinued in 5 children at a median age of 6.8 years. None had developed diabetes mellitus at a median age of 7.0 years. CONCLUSIONS: Given the heterogeneous clinical phenotypes of HNF1A- and HNF4A-HI, all children with transient, diazoxide-responsive HI without clear history of perinatal stress, should be screened for HNF1A and HNF4A mutations as it predicts the clinical course and affects the subsequent management plan.
Assuntos
Fator 1-alfa Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/genética , Hiperinsulinismo/genética , Criança , Diazóxido/uso terapêutico , Feminino , Humanos , Hiperinsulinismo/tratamento farmacológico , Masculino , Mutação , Estudos RetrospectivosRESUMO
OBJECTIVE: To determine the incidence of and risk factors for development of celiac disease (CD) in individuals with type 1 diabetes. METHODS: Cohort study using The Health Improvement Network (THIN), a UK primary care database of >13 million people. Individuals with incident type 1 diabetes diagnosed at 1 to 35 years of age between 1995 and 2015 with no previous diagnosis of CD were included. Cox regression was used to identify risk factors for CD, including age at diabetes diagnosis and sex, while adjusting for year of diagnosis to control for potential rising incidence in CD over time. RESULTS: Subjects (n = 9180; 43% female) had a median observation time of 5.1 years (interquartile range 2.0-10.1). CD was diagnosed in 196 (2%) during follow up. Median time to diagnosis was 2.1 years, but 25% were diagnosed more than 5 years after diabetes diagnosis. Incidence (per 10 000 person-years) was greater in females (43.0 [95% confidence interval [CI] 35.2-52.0]) vs males (26.8 [95% CI 21.5-32.9]). In multivariable Cox regression stratified by childhood- vs young adult-onset diabetes, younger age at diabetes diagnosis within childhood (hazard ratio [HR] 0.91 [95% CI 0.88-0.94]) and female sex among the adult-onset diabetes group (HR 3.19 [95% CI 1.39-7.34]) were associated with greater risk of CD. CONCLUSIONS: As expected, incidence of CD was higher in individuals with childhood-onset diabetes vs those with adult-onset diabetes. However, individuals with diabetes are at risk of developing CD throughout childhood and adulthood, and prolonged screening after diagnosis may be warranted. Prospective studies are needed in order to guide risk-stratified approaches to screening.