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1.
N Engl J Med ; 382(9): 835-844, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32101665

RESUMO

Mutations in VHL, which encodes von Hippel-Lindau tumor suppressor (VHL), are associated with divergent diseases. We describe a patient with marked erythrocytosis and prominent mitochondrial alterations associated with a severe germline VHL deficiency due to homozygosity for a novel synonymous mutation (c.222C→A, p.V74V). The condition is characterized by early systemic onset and differs from Chuvash polycythemia (c.598C→T) in that it is associated with a strongly reduced growth rate, persistent hypoglycemia, and limited exercise capacity. We report changes in gene expression that reprogram carbohydrate and lipid metabolism, impair muscle mitochondrial respiratory function, and uncouple oxygen consumption from ATP production. Moreover, we identified unusual intermitochondrial connecting ducts. Our findings add unexpected information on the importance of the VHL-hypoxia-inducible factor (HIF) axis to human phenotypes. (Funded by Associazione Italiana Ricerca sul Cancro and others.).


Assuntos
Mutação em Linhagem Germinativa , Transtornos do Crescimento/genética , Hipoglicemia/genética , Fator 1 Induzível por Hipóxia/deficiência , Mitocôndrias/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Expressão Gênica , Crescimento/genética , Humanos , Masculino , Metaboloma/genética , Metaboloma/fisiologia , Síndrome , Adulto Jovem
2.
BMJ Case Rep ; 12(11)2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31791989

RESUMO

Neonatal conjugated hyperbilirubinemia is a diagnostic challenge. A full term, small for gestational age boy presented with cholestasis, hypoglycemia, hyperferritinemia and severe bilateral deafness. Diagnostic work-up revealed two hereditary diseases: alpha-1-antitrypsin deficiency (PI*ZZ genotype) and autosomal recessive deafness type 3 (compound heterozygous MYO15A gene mutation). In addition, we found late hypoglycemia on full enteral feeding which complicated this case. Hyperferritinemia is an uncommon finding in newborn cholestasis without liver failure.


Assuntos
Colestase/diagnóstico , Perda Auditiva Neurossensorial/diagnóstico , Hipoglicemia/diagnóstico , Distúrbios do Metabolismo do Ferro/diagnóstico , Deficiência de alfa 1-Antitripsina/diagnóstico , Colestase/genética , Diagnóstico Diferencial , Ferritinas/sangue , Perda Auditiva Neurossensorial/genética , Humanos , Hipoglicemia/genética , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Distúrbios do Metabolismo do Ferro/genética , Miosinas/genética , Deficiência de alfa 1-Antitripsina/genética
3.
Hum Gene Ther ; 30(10): 1263-1273, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31319709

RESUMO

Glycogen storage diseases (GSDs) type I (GSDI) and type III (GSDIII), the most frequent hepatic GSDs, are due to defects in glycogen metabolism, mainly in the liver. In addition to hypoglycemia and liver pathology, renal, myeloid, or muscle complications affect GSDI and GSDIII patients. Currently, patient management is based on dietary treatment preventing severe hypoglycemia and increasing the lifespan of patients. However, most of the patients develop long-term pathologies. In the past years, gene therapy for GSDI has generated proof of concept for hepatic GSDs. This resulted in a recent clinical trial of adeno-associated virus (AAV)-based gene replacement for GSDIa. However, the current limitations of AAV-mediated gene transfer still represent a challenge for successful gene therapy in GSDI and GSDIII. Indeed, transgene loss over time was observed in GSDI liver, possibly due to the degeneration of hepatocytes underlying the physiopathology of both GSDI and GSDIII and leading to hepatic tumor development. Moreover, multitissue targeting requires high vector doses to target nonpermissive tissues such as muscle and kidney. Interestingly, recent pharmacological interventions or dietary regimen aiming at the amelioration of the hepatocyte abnormalities before the administration of gene therapy demonstrated improved efficacy in GSDs. In this review, we describe the advances in gene therapy and the limitations to be overcome to achieve efficient and safe gene transfer in GSDs.


Assuntos
Dependovirus/genética , Terapia Genética/métodos , Glucose-6-Fosfatase/genética , Doença de Depósito de Glicogênio Tipo III/terapia , Doença de Depósito de Glicogênio Tipo I/terapia , Hipoglicemia/terapia , Animais , Ensaios Clínicos como Assunto , Dependovirus/metabolismo , Modelos Animais de Doenças , Técnicas de Transferência de Genes , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Glucose-6-Fosfatase/metabolismo , Glicogênio/biossíntese , Doença de Depósito de Glicogênio Tipo I/enzimologia , Doença de Depósito de Glicogênio Tipo I/genética , Doença de Depósito de Glicogênio Tipo I/patologia , Doença de Depósito de Glicogênio Tipo III/enzimologia , Doença de Depósito de Glicogênio Tipo III/genética , Doença de Depósito de Glicogênio Tipo III/patologia , Hepatócitos/enzimologia , Hepatócitos/patologia , Humanos , Hipoglicemia/enzimologia , Hipoglicemia/genética , Hipoglicemia/patologia , Fígado/enzimologia , Fígado/patologia , Transgenes
4.
J Diabetes Investig ; 10(6): 1454-1462, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31094068

RESUMO

AIMS/INTRODUCTION: The principal aim of this study was to investigate the clinical, genetic and functional characteristics of two cases of congenital hyperinsulinism (CHI) caused by glucokinase (GCK) mutations in young patients. MATERIALS AND METHODS: Novel mutations were detected by CHI next-generation sequencing, and the kinetic parameters and thermal stability of recombinant wild-type and mutant glucokinase were determined in vitro. In addition, 18 naturally occurring GCK-CHI mutations reported previously were also summarized. RESULTS: A de novo mutation (M197V) was found in a 17-year-old male with an epilepsy history, whereas an autosomal dominant mutation (K90R) was found in a 20-year-old female with inherited asymptomatic hypoglycemia. Kinetic analysis showed increased enzyme activity for both mutants (RAI 4.7 for M197V and 1.6 for K90R) and enhanced thermal stability for the M197V mutant. However, of all the GCK-CHI mutants, the increase in enzyme activity (RAI between 1.6 and 130) did not correlate strongly with the severity of hypoglycemia. The de novo group (7/19) showed distinctive phenotypes from the autosomal dominant group (12/19), such as a higher proportion of diazoxide unresponsiveness (28.6% vs 0%), a higher incidence of macrosomia (85.7% vs 40%) and a rarer incidence of adulthood onset (0% vs 25%). CONCLUSIONS: The clinical phenotypes of GCK-CHIs were highly heterogeneous. We have identified two novel GCK-CHI mutations in young patients and investigated their pathogenicity by enzyme kinetic analysis, which expanded the spectrum of this rare disease.


Assuntos
Hiperinsulinismo Congênito/patologia , Quinases do Centro Germinativo/genética , Quinases do Centro Germinativo/metabolismo , Hipoglicemia/patologia , Mutação , Adolescente , Adulto , Hiperinsulinismo Congênito/complicações , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/metabolismo , Feminino , Humanos , Hipoglicemia/complicações , Hipoglicemia/genética , Hipoglicemia/metabolismo , Masculino , Linhagem , Fenótipo , Prognóstico , Adulto Jovem
5.
Med Hypotheses ; 127: 150-153, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31088640

RESUMO

The high prevalence of deleterious polygenic type 2 diabetes (T2D) is a paradox requiring explanation beyond food excess, inactivity and the obesity resulting from positive energy balance. Historically, hunting-foraging and later agrarian communities often manifested a converse negative energy balance due to nutritional deficit and/or high physical energy demand - both potentially resulting in hypoglycaemia. Since hypoglycaemia impairs both reproductive fitness and cognitive function, it is proposed that that by expressing resistance to hypoglycaemia, T2D phenotypes were subject to positive selection. The insulin resistance present in often-associated atherosclerotic cardiovascular disease, metabolic syndrome and polycystic ovarian disease may also explain their frequent coexistence and current prevalence.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/genética , Hipoglicemia/genética , Resistência à Insulina/genética , Seleção Genética , Animais , Evolução Biológica , Metabolismo Energético , Genótipo , Glucose/metabolismo , Humanos , Insulina , Síndrome Metabólica/complicações , Obesidade/complicações
6.
Proc Natl Acad Sci U S A ; 116(15): 7449-7454, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30910968

RESUMO

When mice are subjected to 60% calorie restriction for several days, they lose nearly all of their body fat. Although the animals lack energy stores, their livers produce enough glucose to maintain blood glucose at viable levels even after a 23-hour fast. This adaptation is mediated by a marked increase in plasma growth hormone (GH), which is elicited by an increase in plasma ghrelin, a GH secretagogue. In the absence of ghrelin, calorie-restricted mice develop hypoglycemia, owing to diminished glucose production. To determine the site of GH action, in the current study we used CRISPR/Cas9 and Cre recombinase technology to produce mice that lack GH receptors selectively in liver (L-Ghr -/- mice) or in adipose tissue (Fat-Ghr-/- mice). When subjected to calorie restriction and then fasted for 23 hours, the L-Ghr -/- mice, but not the Fat-Ghr-/- mice, developed hypoglycemia. The fall in blood glucose in L-Ghr-/- mice was correlated with a profound drop in hepatic triglycerides. Hypoglycemia was prevented by injection of lactate or octanoate, two sources of energy to support gluconeogenesis. Electron microscopy revealed extensive autophagy in livers of calorie-restricted control mice but not in L-Ghr -/- mice. We conclude that GH acts through its receptor in the liver to activate autophagy, preserve triglycerides, enhance gluconeogenesis, and prevent hypoglycemia in calorie-restricted mice, a model of famine.


Assuntos
Autofagia , Glicemia/metabolismo , Restrição Calórica , Hormônio do Crescimento/sangue , Hipoglicemia/sangue , Fígado/metabolismo , Inanição/sangue , Animais , Glicemia/genética , Doença Crônica , Modelos Animais de Doenças , Hormônio do Crescimento/genética , Hipoglicemia/genética , Fígado/patologia , Camundongos , Camundongos Knockout , Inanição/genética , Inanição/patologia
7.
BMC Med Genet ; 20(1): 56, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30925902

RESUMO

BACKGROUND: PHKA2 gene mutations can cause liver phosphorylase kinase (PhK) deficiency, resulting in glycogen storage disease type IXa (GSD IXa). Elevated liver transaminase levels and liver enlargement are the most frequent phenotypes of GSD IXa. However, whether the phenotypes are applicable to Chinese patients remains unclear. CASE REPORT: A boy aged 2 years and 8 months with a history of episodic fatigue and weakness since he was 2 years old was referred to our endocrinology clinic. Apart from symptomatic ketotic hypoglycemic episodes (palpitation, hand shaking, sweating, etc.), no abnormalities of liver transaminase levels or liver size were found. To identify the aetiology of his clinically diagnosed hypoglycaemia, the proband and his parents were screened for PHKA2 gene mutations by next-generation sequencing. A heterozygous mutation (c.2972C > G, p.G991A) in PHKA2 was found in the proband and his mother. Twenty-one Chinese cases with GSD IXa have been reported in the literature to date, and elevated liver transaminase levels (95%) and liver enlargement (91%) are the most frequent phenotypes of GSD IXa in Chinese patients. Hypoglycaemia may be one of the early onset symptoms in infants with GSD IXa. CONCLUSIONS: This study enriches our knowledge of the PHKA2 gene mutation spectrum and provides further information about the phenotypic characteristics of Chinese GSD IXa patients.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Doença de Depósito de Glicogênio/genética , Hipoglicemia/complicações , Fosforilase Quinase/genética , Mutação Puntual , Pré-Escolar , Doença de Depósito de Glicogênio/etiologia , Doença de Depósito de Glicogênio/metabolismo , Doença de Depósito de Glicogênio/patologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Hipoglicemia/genética , Fígado/enzimologia , Fígado/patologia , Masculino , Linhagem , Fenótipo , Análise de Sequência de DNA , Transaminases/metabolismo
8.
Gene ; 699: 102-109, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30858132

RESUMO

INTRODUCTION: Fructose-1,6-bisphosphatase deficiency (FBPase deficiency) is a rare inborn error of metabolism that affects gluconeogenesis. Ketotic hypoglycemia is the main symptom and can occur at any age, usually after long periods of fasting or during illness. The diagnosis may be achieved by measurement of the enzyme activity in a liver sample, but FBP1 analysis has become the most common approach. AIM: To characterize the genotype of Southern Brazilian FBPase-deficient patients. METHODOLOGY: The FBP1 gene of six unrelated patients (one had consanguineous parents) with previous diagnoses of FBPase deficiency (enzymatic, pts A, B, D, E; genetic through Next-Generation Sequencing-NGS, pt F; enzymatic and Sanger sequencing, pt C) was first analyzed through NGS. Pathogenic variants found in NGS were confirmed by Sanger sequencing. The pathogenicity of novel missense variants was evaluated through in silico analysis. RESULTS: Five patients (pt A, B, D, E, F) had their genotype identified by NGS, all of them being homozygous. In Pt C, NGS detected only one pathogenic variant. Among the 11 alleles analyzed, only three variants were found, two being novel: c.958G > A and c.986T > C. In silico analysis indicated the pathogenicity of both variants. Interestingly, the three variants seem to be linked to specific haplotypes, indicating that an endogamy effect may be acting on these alleles in the population of Southern Brazil. CONCLUSIONS: Our data suggest that NGS is a good tool for the diagnosis of FBPase deficiency. Variants c.958G > A and c.986T > C are the most prevalent variants in the country.


Assuntos
Deficiência de Frutose-1,6-Difosfatase/genética , Frutose-Bifosfatase/genética , Adulto , Alelos , Brasil , Criança , Pré-Escolar , Consanguinidade , Feminino , Testes Genéticos/métodos , Variação Genética/genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Homozigoto , Humanos , Hipoglicemia/genética , Masculino , Linhagem
9.
Hormones (Athens) ; 18(2): 229-236, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30747411

RESUMO

BACKGROUND: Biallelic mutations in the TBX19 gene cause severe early-onset adrenal failure due to isolated ACTH deficiency (IAD). This rare disease is characterized by low plasma ACTH and cortisol levels, with normal secretion of other pituitary hormones. Herein, we report a patient with IAD due to a novel TBX19 gene mutation, who is also of tall stature. CASE REPORT: A 48/12-year-old girl was presented with loss of consciousness due to hypoglycemia. The patient was born at term with a birth weight of 3800 g. Her parents were first-degree cousins. She had a history of several hospitalizations for recurrent seizures, abdominal pain, and vomiting. At presentation, her weight and height were + 1.8 and + 2.2 SDS, respectively. Serum glucose was 25 mg/dl (1.4 mmol/L), with normal sodium, potassium, and insulin concentrations. The child was hypocortisolemic (0.1 µg/dl), and ACTH levels were extremely low (< 5.0 pg/ml). A diagnosis of IAD was made and hydrocortisone treatment was started. Hypoglycemic episodes, seizures, and recurrent gastrointestinal complaints disappeared after hydrocortisone replacement. Magnetic resonance imaging of the pituitary was normal. Whole exome sequencing revealed a novel homozygous c.302G > A (W101*) mutation in the TBX19 gene. CONCLUSION: We report a new mutation in the TBX19 gene in a patient with isolated ACTH deficiency. While overgrowth is a known feature of some types of adrenal insufficiencies, including MC2R gene defects and POMC deficiency, it may be a novel feature for TPIT deficiency, as in our patient.


Assuntos
Hormônio Adrenocorticotrópico/deficiência , Desenvolvimento Infantil , Doenças do Sistema Endócrino/diagnóstico , Doenças do Sistema Endócrino/genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Proteínas de Homeodomínio/genética , Hipoglicemia/diagnóstico , Hipoglicemia/genética , Puberdade/fisiologia , Proteínas com Domínio T/genética , Hormônio Adrenocorticotrópico/genética , Pré-Escolar , Doenças do Sistema Endócrino/complicações , Feminino , Doenças Genéticas Inatas/complicações , Predisposição Genética para Doença , Humanos , Hipoglicemia/complicações , Hipoglicemia/etiologia , Linhagem , Puberdade/genética , Maturidade Sexual/genética
10.
Genet Med ; 21(4): 772-789, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30659246

RESUMO

PURPOSE: Glycogen storage disease (GSD) types VI and IX are rare diseases of variable clinical severity affecting primarily the liver. GSD VI is caused by deficient activity of hepatic glycogen phosphorylase, an enzyme encoded by the PYGL gene. GSD IX is caused by deficient activity of phosphorylase kinase (PhK), the enzyme subunits of which are encoded by various genes: ɑ (PHKA1, PHKA2), ß (PHKB), É£ (PHKG1, PHKG2), and δ (CALM1, CALM2, CALM3). Glycogen storage disease types VI and IX have a wide spectrum of clinical manifestations and often cannot be distinguished from each other, or from other liver GSDs, on clinical presentation alone. Individuals with GSDs VI and IX can present with hepatomegaly with elevated serum transaminases, ketotic hypoglycemia, hyperlipidemia, and poor growth. This guideline for the management of GSDs VI and IX was developed as an educational resource for health-care providers to facilitate prompt and accurate diagnosis and appropriate management of patients. METHODS: A national group of experts in various aspects of GSDs VI and IX met to review the limited evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management. Evidence bases for these rare disorders are largely based on expert opinion, particularly when targeted therapeutics that have to clear the US Food and Drug Administration (FDA) remain unavailable. RESULTS: This management guideline specifically addresses evaluation and diagnosis across multiple organ systems involved in GSDs VI and IX. Conditions to consider in a differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, and prenatal diagnosis are addressed. CONCLUSION: A guideline that will facilitate the accurate diagnosis and optimal management of patients with GSDs VI and IX was developed. This guideline will help health-care providers recognize patients with GSDs VI and IX, expedite diagnosis, and minimize adverse sequelae from delayed diagnosis and inappropriate management. It will also help identify gaps in scientific knowledge that exist today and suggest future studies.


Assuntos
Genômica , Doença de Depósito de Glicogênio/genética , Hipoglicemia/genética , Fosforilase Quinase/genética , Gerenciamento Clínico , Genética Médica/tendências , Glicogênio/genética , Glicogênio/metabolismo , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/epidemiologia , Doença de Depósito de Glicogênio/terapia , Guias como Assunto , Humanos , Hipoglicemia/metabolismo , Hipoglicemia/terapia , Fígado/metabolismo , Fígado/patologia , Mutação , Fosforilase Quinase/química , Estados Unidos/epidemiologia
12.
Exp Clin Endocrinol Diabetes ; 127(4): 226-233, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29396966

RESUMO

Sulfonylureas are insulin secretagogues which act in pancreatic ß cells by blocking the KATP channels encoded by KCNJ11 and ABCC8 genes. In the present study, a pharmacoepigenetic approach was applied for the first time, investigating the correlation of KCNJ11 and ABCC8 gene promoter methylation with sulfonylureas-induced mild hypoglycemic events as well as the KCNJ11 E23K genotype. Sodium bisulfite-treated genomic DNA of 171 sulfonylureas treated T2DM patients previously genotyped for KCNJ11 E23K, including 88 that had experienced drug-associated hypoglycemia and 83 that had never experienced hypoglycemia, were analyzed for DNA methylation of KCNJ11 and ABCC8 gene promoters via quantitative Methylation-Specific PCR. KCNJ11 methylation was detected in 19/88 (21.6%) of hypoglycemic and in 23/83 (27.7%) of non-hypoglycemic patients (p=0.353), while ABCC8 methylation in 6/83 (7.2%) of non-hypoglycemic and none (0/88) of the hypoglycemic patients (p=0.012). Methylation in at least one promoter (KCNJ11 or ABCC8) was significantly associated with non-hypoglycemic patients who are carriers of KCNJ11 EK allele (p=0.030). Our data suggest that ABCC8 but not KCNJ11 methylation is associated to hypoglycemic events in sulfonylureas-treated T2DM patients. Furthermore, it is demonstrated that the KCNJ11 E23K polymorphism in association to either of the two genes' DNA methylation may have protective role against sulfonylurea-induced hypoglycemia.


Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemia , Hipoglicemiantes/farmacologia , Farmacogenética , Canais de Potássio Corretores do Fluxo de Internalização , Compostos de Sulfonilureia/farmacologia , Receptores Sulfonilureia , Idoso , Metilação de DNA/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética/genética , Feminino , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/genética , Hipoglicemia/metabolismo , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Compostos de Sulfonilureia/efeitos adversos , Receptores Sulfonilureia/genética , Receptores Sulfonilureia/metabolismo
13.
Proteins ; 87(1): 41-50, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30367518

RESUMO

Mammalian glutamate dehydrogenase (GDH) has complex allosteric regulation and the loss of GTP inhibition causes the hyperinsulinism/hyperammonemia syndrome (HHS) where insulin is hypersecreted upon consumption of protein. The archetypical HHS lesion is H454Y and lies in the GTP binding pocket. To better understand the mechanism of HHS, we determined the crystal structure of H454Y. When the bovine GDH crystal structures were minimized to prepare for further computational analysis, unusually large deviations were found at the allosteric NADH binding site due to chemical sequence errors. Notably, 387 lies in an allosteric where several activators and inhibitors bind and should be lysine rather than asparagine. All structures were re-refined and the consequence of this sequence error on NADH binding was calculated using free energy perturbation. The binding free energy penalty going from the correct to incorrect sequence found is +5 kcal/mol per site and therefore has a significant impact on drug development. BROADER AUDIENCE ABSTRACT: Glutamate dehydrogenase is a key enzyme involved in amino acid catabolism. As such, it is heavily regulated in animals by a wide array of metabolites. The importance of this regulation is most apparent in a genetic disorder called hyperinsulinism/hyperammonemia (HHS) where patients hypersecrete insulin upon the consumption of protein. We determined the atomic structure of one of these HHS mutants to better understand the disease and also analyzed an allosteric regulatory site.


Assuntos
Glutamato Desidrogenase/química , Guanosina Trifosfato/metabolismo , Hiperinsulinismo/genética , Hipoglicemia/genética , Proteínas Mutantes/química , Mutação , Regulação Alostérica , Glutamato Desidrogenase/genética , Glutamato Desidrogenase/metabolismo , Humanos , Hiperinsulinismo/enzimologia , Hipoglicemia/enzimologia , Modelos Moleculares , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Conformação Proteica
14.
Horm Res Paediatr ; 92(6): 395-403, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32344415

RESUMO

INTRODUCTION: Isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is a rare cause of adrenal insufficiency and T-box pituitary restricted transcription factor (TBX19) mutations are responsible for two-thirds of the neonatal onset form of the disease. IAD presents with hypoglycemia and prolonged jaundice in the neonatal period. TBX19 is important for both pro-opiomelanocortin (POMC) gene transcription and differentiation of POMC-expressing cells. We describe 2 patients, 1 with a reported and 1 with a novel TBX19 mutation, and present information about the long-term follow-up of these patients. CASE PRESENTATION: Both patients had critical illnesses, recurrent hypoglycemia, convulsions, and neonatal hyperbilirubinemia. They also had low cortisol and ACTH levels, while other pituitary hormones were within the normal range. Pituitary imaging was normal. After hydrocortisone treatment, there was resolution of the hypoglycemia and the convulsions were controlled. Genetic studies of the patients revealed both had inherited a homozygous mutation of the TBX19 gene. The first patient had an alteration of NM_005149.3:c.856C>T (p.R286*) and the second patient had a novel NM_005149.3:c.584C>T (p.T195I) mutation, analyzed by next-generation sequencing. The noteworthy findings of the patients at follow-up were: short stature, microcephaly, and decreased pubic hair in the first, and dysmorphic features, Chiari type 1 malformation, tall stature, and low bone mineral density (BMD) in the second. CONCLUSION: Congenital IAD can be life-threatening if it is not recognized and treated early. TBX19 mutations should be considered in the differential diagnosis of IAD. Further cases or functional analyses are needed for genotype-phenotype correlations. Low BMD, dysmorphic features, Chiari type 1 malformation, and sparse pubic hair are some of the important features in these patients.


Assuntos
Hormônio Adrenocorticotrópico/deficiência , Doenças do Sistema Endócrino/genética , Doenças Genéticas Inatas/genética , Proteínas de Homeodomínio/genética , Hipoglicemia/genética , Proteínas com Domínio T/genética , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/genética , Pré-Escolar , Doenças do Sistema Endócrino/sangue , Doenças do Sistema Endócrino/patologia , Feminino , Seguimentos , Doenças Genéticas Inatas/sangue , Doenças Genéticas Inatas/patologia , Proteínas de Homeodomínio/metabolismo , Humanos , Hipoglicemia/sangue , Hipoglicemia/patologia , Lactente , Proteínas com Domínio T/metabolismo
15.
Biomed Res Int ; 2019: 2682657, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31950036

RESUMO

Aim. To compare the effects of once-weekly Dulaglutide with once-daily glargine in poorly oral-antidiabetic controlled patients with type 2 diabetes mellitus (T2DM). Method. A total of 25 patients with T2DM admitted into Department of Endocrinology from December 2012 to August 2013 were randomly assigned into two groups: Dulaglutide group (n = 16) and glargine group (n = 9). All patients received either Dulaglutide or glargine treatments for 52 weeks. Continuous glucose monitoring systems (CGMS) were applied to them for two 72 h periods at before and after the treatment each. Patient general clinical data were collected and analyzed. Result. Fast blood glucose (FBG) of the glargine group declined more significantly than the Dulaglutide group after treatment (p < 0.05). The mean blood glucose (MBG), standard deviation of blood glucose (SDBG), mean amplitude of glycemic excursion (MAGE) within a day, the largest amplitude of glycemic excursion (LAGE), M-value, absolute means of daily difference (MODD) of glycemic excursion, the percentage of time (≤2.8 mmol/L, ≤3.9 mmol/L, ≥10.0 mmol/L, ≥13.9 mmol/L, 3.9-7.8 mmol/L, and 9-10.0 mmol/L), maximum glycemic value, and minimum glycemic value were similar between the two groups (p > 0.05). The incidence of hypoglycemia was also similar between the two groups (p > 0.05). Though serum levels of TNF-α, IL-6, and 8-PGF2α all decreased, significant reduction was found in TNF-α and 8-PGF2α. TNF-α was only significantly reduced in the Dulaglutide group, while 8-PGF2α was seen in both groups. Conclusion. For T2DM patients with poorly controlled oral antidiabetic drugs, once-weekly Dulaglutide not only has the same effect on glucose fluctuation as once-daily glargine but also significantly reduced TNF-α and 8-PGF2α after a 52 week treatment protocol. This trial is registered with ClinicalTrials.gov NCT01648582.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemia/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Insulina Glargina/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Idoso , Glicemia/efeitos dos fármacos , Automonitorização da Glicemia/métodos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Dinoprosta/genética , Quimioterapia Combinada/efeitos adversos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Glucose/metabolismo , Hemoglobina A Glicada/genética , Humanos , Hipoglicemia/genética , Hipoglicemia/patologia , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Insulina Glargina/efeitos adversos , Interleucina-6/genética , Masculino , Metformina/administração & dosagem , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversos , Fator de Necrose Tumoral alfa/genética
16.
Lipids Health Dis ; 17(1): 245, 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30376839

RESUMO

BACKGROUND: Dracocephalum kotschyi, as a wild-growing flowering plant (from Lamiaceae family), is locally prescribed for its various health-promoting properties including hypolipidemic and hypoglycemic effects. To evaluate the scientific basis of the traditional use of Dracocephalum kotschyi extract (DKE), we aimed to disclose its mode of action with main focus on white adipose tissue of diabetic rats. METHODS: Streptozotocin-induced diabetic rats were exposed to different doses of DKE for 28 days followed by the determination of the sera biochemical factors. The oxidative stress status of the diabetic versus nondiabetic rats' adipose tissue under the influence of DKE were also evaluated in terms of malondialdehyde (MDA) and some of antioxidant enzymes (superoxide dismutase, SOD, and catalase). Furthermore, we exposed 3T3-L1 cells to DKE and then evaluated both the extent of cells differentiation to adipocytes and measured the expression levels of some of the key signaling elements involved in adipogenesis and lipogenesis with main focus on PPARγ. RESULTS: Our results indicated that DKE administration attenuated the levels of TG (triglycerides), TC (total cholesterol), LDL and blood glucose by 54, 40, 54 and 25%, respectively and enhanced the levels of HDL, catalase and SOD by 45, 74 and 56%, respectively. In addition to profound adipogenic and lipogenic effects on 3T3-L1 cells, DKE significantly enhanced p-AKT, p-FOXO1, PPARγ and SREBP-1 expressions while that of p-JNK was quenched parallel to effect of pioglitazone, an antidiabetic agent, used in our investigation as the positive control drug. CONCLUSIONS: Besides of confirming the hypolipidemic action of the plant, our results provided documents on at least one mode of action of DKE with profound effect on lipid metabolism in adipose tissue. Regarding our results, further investigation on DKE, as a new potential hypolipidemic alternative drug is warranted.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemia/tratamento farmacológico , Proteínas do Tecido Nervoso/genética , PPAR gama/genética , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Colesterol/sangue , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipoglicemia/genética , Hipoglicemia/patologia , Hipolipemiantes/administração & dosagem , Hipolipemiantes/química , Lamiaceae/química , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Ratos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Triglicerídeos/sangue
18.
Food Chem Toxicol ; 121: 495-503, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30248482

RESUMO

Binge alcohol drinking is an important health concern and well-known risk factor for the development of numerous disorders. Oxidative stress plays a critical role in the pathogenesis of acute alcoholism. Nuclear factor erythroid 2 like 2 (NRF2) is a master regulator of cellular adaptive response to oxidative insults. However, the role of NRF2 in acute alcoholism and associated pathologies remains unclear. We found that Nrf2-knockout (Nrf2-KO) mice had exaggerated hypoglycemia and hypothermia and increased mortality compared to wildtype mice after binge ethanol exposure. This phenotype was partially rescued by providing warm environment and/or glucose administration. Acute high dose of alcohol exposure resulted in substantially worsened liver and pancreatic injuries in Nrf2-KO mice. Importantly, deficiency of Nrf2 allowed severe pancreatitis and pancreatic ß-cell injury with increased insulin secretion and/or leaking during binge ethanol exposure, which contributed to hypoglycemia. In contrast, a clinically used NRF2 activator dimethyl fumarate (DMF) protected against hypoglycemia and lethality induced by acute ethanol exposure. Furthermore, Nrf2-KO mice likely had defective hepatic acetaldehyde metabolism. Taken together, NRF2 plays an important protective role against acute binge alcohol-induced hepatic and pancreatic damage, which may be partially attributable to its primary regulating role in antioxidant response and impact on ethanol metabolism.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Etanol/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Pancreatopatias/induzido quimicamente , Doença Aguda , Animais , Fumarato de Dimetilo/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/farmacologia , Temperatura Alta , Hiperinsulinismo/induzido quimicamente , Hipoglicemia/induzido quimicamente , Hipoglicemia/genética , Hipotermia/induzido quimicamente , Hipotermia/genética , Camundongos , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Pancreatopatias/metabolismo
19.
J Pediatr ; 202: 272-278.e4, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30193751

RESUMO

OBJECTIVES: To evaluate the role of next generation sequencing in genetic diagnosis of pediatric patients with persistent hypoglycemia. STUDY DESIGN: Sixty-four patients investigated through an extensive workup were divided in 3 diagnostic classes based on the likelihood of a genetic diagnosis: (1) single candidate gene (9/64); (2) multiple candidate genes (43/64); and (3) no candidate gene (12/64). Subsequently, patients were tested through a custom gene panel of 65 targeted genes, which included 5 disease categories: (1) hyperinsulinemic hypoglycemia, (2) fatty acid-oxidation defects and ketogenesis defects, (3) ketolysis defects, (4) glycogen storage diseases and other disorders of carbohydrate metabolism, and (5) mitochondrial disorders. Molecular data were compared with clinical and biochemical data. RESULTS: A proven diagnosis was obtained in 78% of patients with suspicion for a single candidate gene, in 49% with multiple candidate genes, and in 33% with no candidate gene. The diagnostic yield was 48% for hyperinsulinemic hypoglycemia, 66% per fatty acid-oxidation and ketogenesis defects, 59% for glycogen storage diseases and other carbohydrate disorders, and 67% for mitochondrial disorders. CONCLUSIONS: This approach provided a diagnosis in ~50% of patients in whom clinical and laboratory evaluation did not allow identification of a single candidate gene and a diagnosis was established in 33% of patients belonging to the no candidate gene class. Next generation sequencing technique is cost-effective compared with Sanger sequencing of multiple genes and represents a powerful tool for the diagnosis of inborn errors of metabolism presenting with persistent hypoglycemia.


Assuntos
Erros Inatos do Metabolismo dos Carboidratos/diagnóstico , Erros Inatos do Metabolismo dos Carboidratos/genética , Genômica/métodos , Hipoglicemia/diagnóstico , Hipoglicemia/genética , Adolescente , Criança , Pré-Escolar , Doença Crônica , Estudos de Coortes , Análise Mutacional de DNA/métodos , Predisposição Genética para Doença/epidemiologia , Gluconeogênese/fisiologia , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Lactente , Recém-Nascido , Itália , Masculino , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Estudos Retrospectivos , Sensibilidade e Especificidade
20.
J Inherit Metab Dis ; 41(6): 965-976, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30043186

RESUMO

BACKGROUND: Glycogen storage disease type Ia (GSD Ia) in dogs closely resembles human GSD Ia. Untreated patients with GSD Ia develop complications associated with glucose-6-phosphatase (G6Pase) deficiency. Survival of human patients on intensive nutritional management has improved; however, long-term complications persist including renal failure, nephrolithiasis, hepatocellular adenomas (HCA), and a high risk for hepatocellular carcinoma (HCC). Affected dogs fail to thrive with dietary therapy alone. Treatment with gene replacement therapy using adeno-associated viral vectors (AAV) expressing G6Pase has greatly prolonged life and prevented hypoglycemia in affected dogs. However, long-term complications have not been described to date. METHODS: Five GSD Ia-affected dogs treated with AAV-G6Pase were evaluated. Dogs were euthanized due to reaching humane endpoints related to liver and/or kidney involvement, at 4 to 8 years of life. Necropsies were performed and tissues were analyzed. RESULTS: Four dogs had liver tumors consistent with HCA and HCC. Three dogs developed renal failure, but all dogs exhibited progressive kidney disease histologically. Urolithiasis was detected in two dogs; uroliths were composed of calcium oxalate and calcium phosphate. One affected and one carrier dog had polycystic ovarian disease. Bone mineral density was not significantly affected. CONCLUSIONS: Here, we show that the canine GSD Ia model demonstrates similar long-term complications as GSD Ia patients in spite of gene replacement therapy. Further development of gene therapy is needed to develop a more effective treatment to prevent long-term complications of GSD Ia.


Assuntos
Carcinoma Hepatocelular/etiologia , Terapia Genética , Doença de Depósito de Glicogênio Tipo I/complicações , Doença de Depósito de Glicogênio Tipo I/terapia , Neoplasias Hepáticas/etiologia , Animais , Dependovirus/genética , Modelos Animais de Doenças , Cães , Feminino , Vetores Genéticos , Glucose-6-Fosfatase/genética , Glucose-6-Fosfatase/metabolismo , Hipoglicemia/genética , Hipoglicemia/metabolismo , Fígado/patologia , Masculino
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