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1.
Clin Endocrinol (Oxf) ; 92(5): 387-395, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31917867

RESUMO

Congenital Hyperinsulinism (CHI) is a rare disease of hypoglycaemia but is the most common form of recurrent and severe hypoglycaemia causing brain injury and neurodisability in children. The management of CHI is complex due to the limited choice of medications, all with a limited therapeutic window, often lacking efficacy and associated with serious side effects. The therapeutic strategy in CHI is to recognize and treat hypoglycaemia promptly, thereby optimizing long-term neurological outcomes; this should be achieved through individualized treatment plans that deliver glycaemic stability while minimizing side effects. Further, such a strategy should consider the likelihood of reduction in disease severity over time, with dose adjustments and medication withdrawal as indicated to optimize both safety and tolerability. The option for pancreatic surgery should also be considered in specific circumstances as appropriate for the patient's best long-term interests.


Assuntos
Hiperinsulinismo Congênito , Hiperinsulinismo , Glicemia , Criança , Hiperinsulinismo Congênito/tratamento farmacológico , Humanos
2.
J Pediatr ; 166(1): 191-4, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25444530

RESUMO

Congenital hyperinsulinism causes profound hypoglycemia, which may persist or resolve spontaneously. Among 13 children with congenital hyperinsulinism, elevated incretin hormone concentrations were detected in 2 with atypical, persistent disease. We suggest that incretin biomarkers may identify these patients, and that elevated hormone levels may contribute to their pathophysiology.


Assuntos
Biomarcadores/sangue , Hiperinsulinismo Congênito/sangue , Incretinas/sangue , Canais KATP/genética , Pré-Escolar , Hiperinsulinismo Congênito/genética , Humanos , Lactente , Recém-Nascido , Mutação , Reino Unido
3.
Artigo em Inglês | MEDLINE | ID: mdl-35675953

RESUMO

INTRODUCTION: Hypoglycemia is often recurrent and severe in patients with congenital hyperinsulinism (CHI). However, there is little information regarding frequency or patterns of episodes to inform clinical management and future trial design. RESEARCH DESIGN AND METHODS: We aimed to describe frequency and patterns of hypoglycemia by varying thresholds through a large continuous glucose monitoring (CGM) dataset. Through the UK CHI centers of excellence, data were analyzed from patients with CHI over a 5-year period. Hypoglycemia thresholds of 3.0 (H3.0), 3.5 (H3.5) and 3.9 (H3.9) mmol/L were used to test threshold change on hypoglycemia frequencies. RESULTS: From 63 patients, 3.4 million data points, representing 32 years of monitoring, were analyzed. By UK consensus threshold H3.5, patients experienced a mean 1.3 hypoglycemic episodes per day. Per cent time hypoglycemic increased from 1.2% to 3.3% to 6.9% when threshold changed from H3.0 to H3.5 and H3.9. Merged data showed periodicity of hypoglycemia risk in 24-hour periods in all patients. CONCLUSIONS: We have evaluated a large dataset to provide a comprehensive picture of the frequency and patterns of hypoglycemia for patients with CHI in the UK. These data establish a baseline risk of hypoglycemia by CGM and provide a framework for clinical management and clinical trial design.


Assuntos
Hiperinsulinismo Congênito , Diabetes Mellitus Tipo 1 , Glicemia , Automonitorização da Glicemia , Hiperinsulinismo Congênito/induzido quimicamente , Hiperinsulinismo Congênito/epidemiologia , Diabetes Mellitus Tipo 1/induzido quimicamente , Humanos , Hipoglicemiantes/efeitos adversos , Reino Unido/epidemiologia
4.
Orphanet J Rare Dis ; 15(1): 162, 2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32580746

RESUMO

BACKGROUND: Hypoglycaemia due to hyperinsulinism (HI) is the commonest cause of severe, recurrent hypoglycaemia in childhood. Cohort outcomes of HI remain to be described and whilst previous follow up studies have focused on neurodevelopmental outcomes, there is no information available on feeding and auxology. AIM: We aimed to describe HI outcomes for auxology, medications, feeding and neurodevelopmental in a cohort up to age 5 years. METHOD: We reviewed medical records for all patients with confirmed HI over a three-year period in a single centre to derive a longitudinal dataset. RESULTS: Seventy patients were recruited to the study. Mean weight at birth was - 1.0 standard deviation scores (SDS) for age and sex, while mean height at 3 months was - 1.5 SDS. Both weight and height trended to the population median over the follow up period. Feeding difficulties were noted in 17% of patients at 3 months and this reduced to 3% by 5 years. At age 5 years, 11 patients (15%) had neurodevelopmental delay and of these only one was severe. Resolution of disease was predicted by lower maximum early diazoxide dose (p = 0.007) and being born SGA (p = 0.009). CONCLUSION: In a three-year cohort of HI patients followed up for 5 years, in spite of feeding difficulties and carbohydrate loading in early life, auxology parameters are normal in follow up. A lower than expected rate of neurodevelopmental delay could be attributed to prompt early treatment.


Assuntos
Hiperinsulinismo Congênito , Criança , Pré-Escolar , Biologia do Desenvolvimento , Diazóxido , Seguimentos , Humanos , Recém-Nascido
5.
PLoS One ; 14(9): e0222350, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31525223

RESUMO

Congenital hyperinsulinism (CHI) is characterised by inappropriate insulin secretion causing profound hypoglycaemia and brain damage if inadequately controlled. Pancreatic tissue isolated from patients with diffuse CHI shows abnormal proliferation rates, the mechanisms of which are not fully resolved. Understanding cell proliferation in CHI may lead to new therapeutic options, alongside opportunities to manipulate ß-cell mass in patients with diabetes. We aimed to generate cell-lines from CHI pancreatic tissue to provide in vitro model systems for research. Three pancreatic mesenchymal stem cell-lines (CHIpMSC1-3) were derived from patients with CHI disease variants: focal, atypical and diffuse. All CHIpMSC lines demonstrated increased proliferation compared with control adult-derived pMSCs. Cell cycle alterations including increased CDK1 levels and decreased p27Kip1 nuclear localisation were observed in CHIpMSCs when compared to control pMSCs. In conclusion, CHIpMSCs are a useful in vitro model to further understand the cell cycle alterations leading to increased islet cell proliferation in CHI.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30386300

RESUMO

Background: Congenital Hyperinsulinism (CHI) is an important cause of severe and persistent hypoglycaemia in infancy and childhood. The focal form (CHI-F) of CHI can be potentially cured by pancreatic lesionectomy. While diagnostic characteristics of CHI-F pancreatic histopathology are well-recognized, correlation with clinical phenotype has not been established. Aims: We aimed to correlate the diversity in clinical profiles of patients with islet cell organization in CHI-F pancreatic tissue. Methods: Clinical datasets were obtained from 25 patients with CHI-F due to ABCC8/KCNJ11 mutations. 18F-DOPA PET-CT was used to localize focal lesions prior to surgery. Immunohistochemistry was used to support protein expression studies. Results: In 28% (n = 7) of patient tissues focal lesions were amorphous and projected into adjoining normal pancreatic tissue without clear delineation from normal tissue. In these cases, severe hypoglycaemia was detected within, on average, 2.8 ± 0.8 (range 1-7) days following birth. By contrast, in 72% (n = 18) of tissues focal lesions were encapsulated within a defined matrix capsule. In this group, the onset of severe hypoglycaemia was generally delayed; on average 46.6 ± 14.3 (range 1-180) days following birth. For patients with encapsulated lesions and later-onset hypoglycaemia, we found that surgical procedures were curative and less complex. Conclusion: CHI-F is associated with heterogeneity in the organization of focal lesions, which correlates well with clinical presentation and surgical outcomes.

8.
Orphanet J Rare Dis ; 12(1): 96, 2017 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-28532504

RESUMO

BACKGROUND: Congenital Hyperinsulinism (CHI) is a disease of severe hypoglycaemia caused by excess insulin secretion and associated with adverse neurodevelopment in a third of children. The Vineland Adaptive Behavior Scales Second Edition (VABS-II) is a parent report measure of adaptive functioning that could be used as a developmental screening tool in patients with CHI. We have investigated the performance of VABS-II as a screening tool to identify developmental delay in a relatively large cohort of children with CHI. VABS-II questionnaires testing communication, daily living skills, social skills, motor skills and behaviour domains were completed by parents of 64 children with CHI, presenting both in the early neonatal period (Early-CHI, n = 48) and later in infancy (Late-CHI, n = 16). Individual and adaptive composite (Total) domain scores were converted to standard deviation scores (SDS). VABS-II scores were tested for correlation with objective developmental assessment reported separately by developmental paediatricians, clinical and educational psychologists. VABS-II scores were also investigated for correlation with the timing of hypoglycaemia, gender and phenotype of CHI. RESULTS: Median (range) total VABS-II SDS was low in CHI [-0.48 (-3.60, 4.00)] with scores < -2.0 SDS in 9 (12%) children. VABS-II Total scores correctly identified developmental delay diagnosed by objective assessment in the majority [odds ratio (OR) (95% confidence intervals, CI) 0.52 (0.38, 0.73), p < 0.001] with 95% specificity [area under curve (CI) 0.80 (0.68, 0.90), p < 0.001] for cut-off < -2.0 SDS, although with low sensitivity (26%). VABS-II Total scores were inversely correlated (adjusted R2 = 0.19, p = 0.001) with age at presentation (p = 0.024) and male gender (p = 0.036), males having lower scores than females in those with Late-CHI [-1.40 (-3.60, 0.87) v 0.20 (-1.07, 1.27), p = 0.014]. The presence of a genetic mutation representing severe CHI also predicted lower scores (R2 = 0.19, p = 0.039). CONCLUSIONS: The parent report VABS-II is a reliable and specific tool to identify developmental delay in CHI patients. Male gender, later age at presentation and severity of disease are independent risk factors for lower VABS-II scores.


Assuntos
Adaptação Psicológica , Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/psicologia , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/psicologia , Inquéritos e Questionários/normas , Adolescente , Fatores Etários , Criança , Pré-Escolar , Estudos de Coortes , Hiperinsulinismo Congênito/epidemiologia , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/psicologia , Feminino , Humanos , Masculino , Transtornos do Neurodesenvolvimento/epidemiologia , Fatores Sexuais
9.
J Clin Endocrinol Metab ; 102(9): 3261-3267, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28605545

RESUMO

Objectives: We aimed to characterize mosaic populations of pancreatic islet cells from patients with atypical congenital hyperinsulinism in infancy (CHI-A) and the expression profile of NKX2.2, a key transcription factor expressed in ß-cells but suppressed in δ-cells in the mature pancreas. Patients/Methods: Tissue was isolated from three patients with CHI-A following subtotal pancreatectomy. CHI-A was diagnosed on the basis of islet mosaicism and the absence of histopathological hallmarks of focal and diffuse CHI (CHI-D). Immunohistochemistry was used to identify and quantify the proportions of insulin-secreting ß-cells and somatostatin-secreting δ-cells in atypical islets, and results were compared with CHI-D (n = 3) and age-matched control tissues (n = 3). Results: In CHI-A tissue, islets had a heterogeneous profile. In resting/quiescent islets, identified by a condensed cytoplasm and nuclear crowding, ß-cells were reduced to <50% of the total cell numbers in n = 65/70 islets, whereas δ-cell numbers were increased with 85% of islets (n = 49/57) containing >20% δ-cells. In comparison, all islets in control tissue (n = 72) and 99% of CHI-D islets (n = 72) were composed of >50% ß-cells, and >20% δ-cells were found only in 12% of CHI-D (n = 8/66) and 5% of control islets (n = 3/60). Active islets in CHI-A tissue contained proportions of ß-cells and δ-cells similar to those of control and CHI-D islets. Finally, when compared with active islets, quiescent islets had a twofold higher prevalence of somatostatin/NKX2.2+ coexpressed cells. Conclusions: Marked increases in NKX2.2 expression combined with increased numbers of δ-cells strongly imply that an immature δ-cell profile contributed to the pathobiology of CHI-A.


Assuntos
Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/patologia , Predisposição Genética para Doença , Ilhotas Pancreáticas/patologia , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Biópsia por Agulha , Pré-Escolar , Estudos de Coortes , Hiperinsulinismo Congênito/cirurgia , Feminino , Proteína Homeobox Nkx-2.2 , Proteínas de Homeodomínio , Humanos , Imuno-Histoquímica , Lactente , Ilhotas Pancreáticas/metabolismo , Masculino , Mosaicismo , Pancreatectomia/métodos , Prognóstico , Valores de Referência , Índice de Gravidade de Doença , Fator Nuclear 1 de Tireoide
10.
Diabetes ; 66(7): 1901-1913, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28442472

RESUMO

Loss-of-function mutations of ß-cell KATP channels cause the most severe form of congenital hyperinsulinism (KATPHI). KATPHI is characterized by fasting and protein-induced hypoglycemia that is unresponsive to medical therapy. For a better understanding of the pathophysiology of KATPHI, we examined cytosolic calcium ([Ca2+] i ), insulin secretion, oxygen consumption, and [U-13C]glucose metabolism in islets isolated from the pancreases of children with KATPHI who required pancreatectomy. Basal [Ca2+] i and insulin secretion were higher in KATPHI islets compared with controls. Unlike controls, insulin secretion in KATPHI islets increased in response to amino acids but not to glucose. KATPHI islets have an increased basal rate of oxygen consumption and mitochondrial mass. [U-13C]glucose metabolism showed a twofold increase in alanine levels and sixfold increase in 13C enrichment of alanine in KATPHI islets, suggesting increased rates of glycolysis. KATPHI islets also exhibited increased serine/glycine and glutamine biosynthesis. In contrast, KATPHI islets had low γ-aminobutyric acid (GABA) levels and lacked 13C incorporation into GABA in response to glucose stimulation. The expression of key genes involved in these metabolic pathways was significantly different in KATPHI ß-cells compared with control, providing a mechanism for the observed changes. These findings demonstrate that the pathophysiology of KATPHI is complex, and they provide a framework for the identification of new potential therapeutic targets for this devastating condition.


Assuntos
Cálcio/metabolismo , Hiperinsulinismo Congênito/metabolismo , Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Consumo de Oxigênio , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Receptores de Sulfonilureias/metabolismo , Alanina/metabolismo , Isótopos de Carbono , Estudos de Casos e Controles , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/cirurgia , Feminino , Citometria de Fluxo , Expressão Gênica , Glutamina/biossíntese , Glicina/biossíntese , Glicólise/genética , Humanos , Imuno-Histoquímica , Lactente , Recém-Nascido , Secreção de Insulina , Células Secretoras de Insulina/ultraestrutura , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/ultraestrutura , Canais KATP/genética , Canais KATP/metabolismo , Masculino , Metabolômica , Microscopia Eletrônica de Transmissão , Mutação , Pancreatectomia , Canais de Potássio Corretores do Fluxo de Internalização/genética , RNA Mensageiro/metabolismo , Análise de Sequência de RNA , Serina/biossíntese , Receptores de Sulfonilureias/genética , Ácido gama-Aminobutírico/metabolismo
11.
Orphanet J Rare Dis ; 11(1): 163, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27908292

RESUMO

BACKGROUND: Patients with Congenital Hyperinsulinism (CHI) due to mutations in K-ATP channel genes (K-ATP CHI) are increasingly treated by conservative medical therapy without pancreatic surgery. However, the natural history of medically treated K-ATP CHI has not been described; it is unclear if the severity of recessively and dominantly inherited K-ATP CHI reduces over time. We aimed to review variation in severity and outcomes in patients with K-ATP CHI treated by medical therapy. METHODS: Twenty-one consecutively presenting patients with K-ATP CHI with dominantly and recessively inherited mutations in ABCC8/KCNJ11 were selected in a specialised CHI treatment centre to review treatment outcomes. Medical treatment included diazoxide and somatostatin receptor agonists (SSRA), octreotide and somatuline autogel. CHI severity was assessed by glucose infusion rate (GIR), medication dosage and tendency to resolution. CHI outcome was assessed by glycaemic profile, fasting tolerance and neurodevelopment. RESULTS: CHI presenting at median (range) age 1 (1, 240) days resolved in 15 (71%) patients at age 3.1(0.2, 13.0) years. Resolution was achieved both in patients responsive to diazoxide (n = 8, 57%) and patients responsive to SSRA (n = 7, 100%) with earlier resolution in the former [1.6 (0.2, 13.0) v 5.9 (1.6, 9.0) years, p = 0.08]. In 6 patients remaining on treatment, diazoxide dose was reduced in follow up [10.0 (8.5, 15.0) to 5.4 (0.5, 10.8) mg/kg/day, p = 0.003]. GIR at presentation did not correlate with resolved or persistent CHI [14.9 (10.0, 18.5) v 16.5 (13.0, 20.0) mg/kg/min, p = 0.6]. The type of gene mutation did not predict persistence; resolution could be achieved in recessively-inherited CHI with homozygous (n = 3), compound heterozygous (n = 2) and paternal mutations causing focal CHI (n = 2). Mild developmental delay was present in 8 (38%) patients; adaptive functioning assessed by Vineland Adaptive Behavior Scales questionnaire showed a trend towards higher standard deviation scores (SDS) in resolved than persistent CHI [-0.1 (-1.2, 1.6) v -1.2 (-1.7, 0.03), p = 0.1]. CONCLUSIONS: In K-ATP CHI patients managed by medical treatment only, severity is reduced over time in the majority, including those with compound heterozygous and homozygous mutations in ABCC8/KCNJ11. Severity and treatment requirement should be assessed periodically in all children with K-ATP CHI on medical therapy.


Assuntos
Hiperinsulinismo Congênito/tratamento farmacológico , Hiperinsulinismo Congênito/genética , Transportadores de Cassetes de Ligação de ATP/genética , Pré-Escolar , Hiperinsulinismo Congênito/metabolismo , Diazóxido/uso terapêutico , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mutação/genética , Octreotida/uso terapêutico
12.
Am J Clin Pathol ; 145(6): 757-68, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27334808

RESUMO

OBJECTIVES: To quantify islet cell nucleomegaly in controls and tissues obtained from patients with congenital hyperinsulinism in infancy (CHI) and to examine the association of nucleomegaly with proliferation. METHODS: High-content analysis of histologic sections and serial block-face scanning electron microscopy were used to quantify nucleomegaly. RESULTS: Enlarged islet cell nuclear areas were 4.3-fold larger than unaffected nuclei, and the mean nuclear volume increased to approximately threefold. Nucleomegaly was a normal feature of pediatric islets and detected in the normal regions of the pancreas from patients with focal CHI. The incidence of nucleomegaly was highest in diffuse CHI (CHI-D), with more than 45% of islets containing two or more affected cells. While in CHI-D nucleomegaly was negatively correlated with cell proliferation, in all other cases, there was a positive correlation. CONCLUSIONS: Increased incidence of nucleomegaly is pathognomonic for CHI-D, but these cells are nonproliferative, suggesting a novel role in the pathobiology of this condition.


Assuntos
Núcleo Celular/patologia , Hiperinsulinismo Congênito/patologia , Ilhotas Pancreáticas/patologia , Núcleo Celular/ultraestrutura , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Ilhotas Pancreáticas/ultraestrutura , Masculino , Microscopia Eletrônica
13.
Artigo em Inglês | MEDLINE | ID: mdl-26903946

RESUMO

BACKGROUND: Congenital hyperinsulinism (CHI) is a rare but severe disorder of hypoglycemia in children, often complicated by brain injury. In CHI, the long-term prevention of hypoglycemia is dependent on reliable enteral intake of glucose. However, feeding problems (FPs) often impede oral glucose delivery, thereby complicating the management of hypoglycemia. FPs have not been systematically characterized in follow-up in a cohort with CHI. AIMS: We aimed to determine the prevalence, types, and persistence of FPs in a cohort of children with CHI and investigate potential causal factors. METHODS: FPs were defined as difficulty with sucking, swallowing, vomiting, and food refusal (or a combination) in an observational study in 83 children in a specialized CHI treatment center. The prevalence of FPs at diagnosis, 6, and 12 months after diagnosis were noted. Genetic mutation status and markers of severity of CHI were tested for association with FPs. RESULTS: A third of children with CHI had FPs (n = 28), of whom 93% required antireflux medication and 75% required nasogastric and gastrostomy tube feeding. Sucking and swallowing problems were present at diagnosis but absent later. Vomiting was present in 54% at 6 months, while food refusal was present in 68% at 6 months and 52% at 12 months. The age at commencing and stopping nasogastric tube feeding did not correlate with FPs frequency at 6 and 12 months. Children with FPs had severe hypoglycemia at diagnosis and required glucagon infusion more often [odds ratio (OR) (95% confidence intervals) (95% CI) 28.13 (2.6-300.1), p = 0.006] to normalize glucose levels. FPs were more frequent in those with diffuse CHI undergoing subtotal pancreatectomy [n (%) = 10 (35%) vs. 0 (0%), p < 0.001], in contrast to those with spontaneous resolution [6 (22%) vs. 32 (58%), p = 0.002]. Those undergoing focal lesionectomy also had reduced FPs at 6 months after diagnosis [OR (95% CI) 0.01 (0.0-0.2), R (2) = 0.42, p = 0.004]. These observations suggest that persistence of hyperinsulinism was associated with FPs. CONCLUSION: FPs occur in a significant proportion of children with CHI. Severe hyperinsulinism, rather than nasogastric tube feeding or medications, is the main factor associated with FPs.

14.
Diabetes ; 64(9): 3182-8, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25931474

RESUMO

Diffuse congenital hyperinsulinism in infancy (CHI-D) arises from mutations inactivating the KATP channel; however, the phenotype is difficult to explain from electrophysiology alone. Here we studied wider abnormalities in the ß-cell and other pancreatic lineages. Islets were disorganized in CHI-D compared with controls. PAX4 and ARX expression was decreased. A tendency toward increased NKX2.2 expression was consistent with its detection in two-thirds of CHI-D δ-cell nuclei, similar to the fetal pancreas, and implied immature δ-cell function. CHI-D δ-cells also comprised 10% of cells displaying nucleomegaly. In CHI-D, increased proliferation was most elevated in duct (5- to 11-fold) and acinar (7- to 47-fold) lineages. Increased ß-cell proliferation observed in some cases was offset by an increase in apoptosis; this is in keeping with no difference in INSULIN expression or surface area stained for insulin between CHI-D and control pancreas. However, nuclear localization of CDK6 and P27 was markedly enhanced in CHI-D ß-cells compared with cytoplasmic localization in control cells. These combined data support normal ß-cell mass in CHI-D, but with G1/S molecules positioned in favor of cell cycle progression. New molecular abnormalities in δ-cells and marked proliferative increases in other pancreatic lineages indicate CHI-D is not solely a ß-cell disorder.


Assuntos
Hiperinsulinismo Congênito/genética , Células Secretoras de Glucagon/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Somatostatina/metabolismo , Estudos de Casos e Controles , Linhagem da Célula , Proliferação de Células , Criança , Pré-Escolar , Hiperinsulinismo Congênito/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Feto/citologia , Células Secretoras de Glucagon/citologia , Proteína Homeobox Nkx-2.2 , Proteínas de Homeodomínio/metabolismo , Humanos , Lactente , Recém-Nascido , Insulina/metabolismo , Células Secretoras de Insulina/citologia , Mutação , Proteínas Nucleares , Fatores de Transcrição Box Pareados/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/genética , Células Secretoras de Somatostatina/citologia , Receptores de Sulfonilureias/genética , Fatores de Transcrição/metabolismo , Proteínas de Peixe-Zebra
15.
J Clin Endocrinol Metab ; 89(12): 6224-34, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15579781

RESUMO

Hyperinsulinism of infancy is a genetically heterogeneous disease characterized by dysregulation of insulin secretion resulting in severe hypoglycemia. To date, mutations in five different genes, the sulfonylurea receptor (SUR1, ABCC8), the inward rectifying potassium channel (K(IR)6.2, KCNJ11), glucokinase (GCK), glutamate dehydrogenase (GLUD1), and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), have been implicated. Previous reports suggest that, in 40% of patients, no mutation can be identified in any of these genes, suggesting additional locus heterogeneity. However, previous studies did not screen all five genes using direct sequencing, the most sensitive technique available for mutation detection. We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11. If no mutation was identified, the coding sequence and intron/exon boundaries of GCK, GLUD1, and SCHAD were sequenced. Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened. Functional studies on beta-cells from six patients showed abnormal ATP-sensitive K+ channel function in five of the patients; the sixth had normal channel activity, and no mutations were found. Photolabeling studies using a reconstituted system showed that all missense mutations altered intracellular trafficking. Each of the promoter mutations decreased expression of a reporter gene by about 60% in a heterologous expression system. In four patients (27%), no mutations were identified. Thus, further genetic heterogeneity is suggested in this disorder. These patients represent a cohort that can be used for searching for mutations in other candidate genes.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Mapeamento Cromossômico , Heterogeneidade Genética , Hiperinsulinismo/genética , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio/genética , Receptores de Droga/genética , Adenina , Estudos de Coortes , Eletrofisiologia , Guanina , Humanos , Hiperinsulinismo/fisiopatologia , Recém-Nascido , Ilhotas Pancreáticas/fisiopatologia , Mutação de Sentido Incorreto , Linhagem , Regiões Promotoras Genéticas/genética , Receptores de Sulfonilureias
16.
J Clin Endocrinol Metab ; 87(11): 4860-8, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12414839

RESUMO

A novel ATP-sensitive potassium channel (K(ATP)) channel agonist, BPDZ 154 (6,7-dichloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide), was synthesized, and its effects on insulin-secreting cells were evaluated using electrophysiology, (86)Rb(+) and (45)Ca(2+) efflux, and RIA determinations of insulin secretion. BPDZ 154, an analog of diazoxide, inhibited both glucose-induced insulin secretion from isolated perifused islets and the secretion of insulin induced by glucose and tolbutamide. These effects were mediated by the activation of ATP-sensitive potassium channels because BPDZ 154 induced a concentration-dependent increase in channel activity that was inhibited by the sulfonylurea tolbutamide and the imidazoline efaroxan. In beta-cells isolated from patients with either nontypical hyperinsulinism (preserved K(ATP) channel function) or from the control areas of the pancreas of patients with focal hyperinsulinism, BPDZ 154 activated K(ATP) channels and was found to be more effective and less readily reversible than diazoxide. By contrast, it was not possible to activate K(ATP) channels by either diazoxide or BPDZ 154 in beta-cells from patients with hyperinsulinism as a consequence of defects in K(ATP) channel function. In beta-cells isolated from a patient with pancreatic insulinoma, K(ATP) channels were readily recorded and modulated by BPDZ 154. These data suggest that BPDZ 154 or BPDZ 154-like compounds may have therapeutic potential in the treatment of certain forms of hyperinsulinism.


Assuntos
Trifosfato de Adenosina/farmacologia , Benzotiadiazinas/farmacologia , Óxidos S-Cíclicos/farmacologia , Hiperinsulinismo/fisiopatologia , Insulina/metabolismo , Ilhotas Pancreáticas/fisiopatologia , Canais de Potássio/efeitos dos fármacos , Adolescente , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Benzofuranos/farmacologia , Radioisótopos de Cálcio/metabolismo , Linhagem Celular , Pré-Escolar , Feminino , Glucose/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Imidazóis/farmacologia , Lactente , Secreção de Insulina , Insulinoma/fisiopatologia , Masculino , Neoplasias Pancreáticas/fisiopatologia , Canais de Potássio/fisiologia , Ratos , Ratos Wistar , Radioisótopos de Rubídio/metabolismo , Tolbutamida/farmacologia
17.
Eur J Pharmacol ; 486(2): 133-9, 2004 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-14975702

RESUMO

The effect of Y-26763 [(-)-(3S,4R)-4-(N-acetyl-N-hydroxyamino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol], a novel ATP-sensitive K(+) (K(ATP)) channel activator, was tested on insulin secretion from human pancreatic islets in vitro. Y-26763 was able to inhibit both glucose- and tolbutamide-induced insulin secretion from islets as assessed by radioimmunoassay. The mechanism for inhibition of insulin secretion was characterised using patch clamp electrophysiology on dispersed human pancreatic beta-cells which express K(ATP) channels comprised of Kir6.2 and SUR1, and the NES2Y human beta-cell line, transfected with Kir6.2DeltaC26. Y-26763 activated K(ATP) channels in a reversible manner with a similar activity to diazoxide. This required the presence of hydrolysable nucleotides and appeared to be mediated by interaction of Y-26763 with SUR1 since: (a) tolbutamide was able to reverse the actions of Y-26763 and (b) Y-26763 failed to activate Kir6.2DeltaC26 in the absence of SUR1. We conclude that Y-26763-induced inhibition of insulin release is dependent upon the activation of K(ATP) channels in human beta-cells.


Assuntos
Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/fisiologia , Benzopiranos/farmacologia , Antagonistas da Insulina/farmacologia , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Canais de Potássio/fisiologia , Transportadores de Cassetes de Ligação de ATP , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Células Cultivadas , Humanos , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Técnicas de Patch-Clamp , Canais de Potássio/agonistas , Canais de Potássio Corretores do Fluxo de Internalização , Radioimunoensaio , Receptores de Droga , Receptores de Sulfonilureias , Transfecção
18.
J Pediatr Endocrinol Metab ; 17(12): 1613-21, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15645695

RESUMO

We describe the clinical features of a new syndrome causing hyperinsulinism in infancy (HI), severe enteropathy, profound sensorineural deafness, and renal tubulopathy in three children born to two pairs of consanguineous parents. This combination of clinical features is explained by a 122-kb contiguous gene deletion on the short arm of chromosome 11. It deletes 22 of the 39 exons of the gene coding for the SUR1 component of the KATP channel on the pancreatic beta-cell thereby causing severe HI. It also deletes all but two of the 28 exons of the USH1C gene, which causes Usher syndrome and is important for the normal development and function of the ear and the eye, the gastrointestinal tract, and the kidney, thereby accounting for the symptoms of deafness, vestibular dysfunction and retinal dystrophy seen in type 1 Usher syndrome, diarrhoea, malabsorption, and tubulopathy. This contiguous gene deletion provides important insights into the normal development of several body organ systems.


Assuntos
Cromossomos Humanos Par 11 , Surdez/complicações , Deleção de Genes , Hiperinsulinismo/complicações , Enteropatias/complicações , Túbulos Renais/patologia , Pré-Escolar , Surdez/genética , Humanos , Hiperinsulinismo/genética , Lactente , Enteropatias/genética , Síndrome
19.
Artigo em Inglês | MEDLINE | ID: mdl-24659984

RESUMO

OBJECTIVE: Congenital hyperinsulinism (CHI) is a rare condition of hypoglycemia where therapeutic options are limited and often complicated by side-effects. Omega-3-polyunsaturated fatty acids (PUFA), which can suppress cardiac myocyte electrical activity, may also reduce ion channel activity in insulin-secreting cells. PUFA supplements in combination with standard medical treatment may improve glucose profile and may reduce glycemic variability in diazoxide-responsive CHI. DESIGN: Open label pilot trial with MaxEPA(R) liquid (eicosapentaenoic and docosahexaenoic acid) PUFA (3 ml/day for 21 days) in diazoxide-responsive CHI patients (https://eudract.ema.europa.eu/, EudraCT number 201100363333). METHODS: Glucose levels were monitored pre-treatment, end of treatment, and at follow-up by subcutaneous continuous glucose monitoring systems (CGMS) in 13 patients (7 girls) who received PUFA. Outcome measures were an improved glucose profile, reduced glycemic variability quantified by a reduction in the frequency of glucose levels <4 and >10 mmol/l, and safety of PUFA. All children were analyzed either as intention to treat (n = 13) or as per protocol (n = 7). RESULTS: Mean (%) CGMS glucose levels increased by 0.1 mmol/l (2%) in intention to treat and by 0.4 mmol/l (8%) in per protocol analysis (n = 7). The frequency of CGMS <4 mmol/l was significantly less at the end of treatment than in the pre-treatment period [556 (7%) vs. 749 (10%)]. Similarly, the frequency of CGMS >10 mmol/l, was also less at the end of treatment [27 (0.3%) vs. 49 (0.7%)]. Except for one child with increased LDL cholesterol, all safety parameters were normal. CONCLUSION: MaxEPA(R) was safe and reduced glycemic variability, but did not increase glucose profiles significantly in diazoxide-responsive CHI. The supplemental value of PUFA should be evaluated in a comprehensive clinical trial.

20.
Orphanet J Rare Dis ; 8: 21, 2013 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-23394473

RESUMO

Congenital Hyperinsulinism is a condition with a number of genetic causes, but for the majority of patients, the underlying aetiology is unknown. We present here a rational argument for the use of computational biology as a valuable resource for identifying new candidate genes which may cause disease and for understanding the complex mechanisms which define the pathophysiology of this rare disease.


Assuntos
Biologia Computacional/métodos , Hiperinsulinismo Congênito/etiologia , Hiperinsulinismo Congênito/genética , Proteínas/genética , Hiperinsulinismo Congênito/fisiopatologia , Predisposição Genética para Doença , Humanos , Mutação , Proteínas/metabolismo
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