RESUMO
AIMS/HYPOTHESIS: Monogenic diabetes (MD) might be misdiagnosed as type 1 diabetes. The prevalence of MD among children with apparent type 1 diabetes has not been established. Our aim was to estimate the prevalence of common forms of MD in childhood diabetes. METHODS: We investigated 2,756 children aged 0-14 years with newly diagnosed diabetes who had been recruited to the nationwide population-based Norwegian Childhood Diabetes Registry (NCDR), from July 2002 to March 2012. Completeness of ascertainment was 91%. Children diagnosed with diabetes who were under12 months of age were screened for mutations in KCNJ11, ABCC8 and INS. Children without GAD and protein tyrosine phosphatase-like protein antibodies were screened in two ways. Those who had a parent with diabetes were screened for mutations in HNF1A, HNF4A, INS and MT-TL1. Children with HbA1c <7.5% (<58 mmol/mol) and no insulin requirement were screened for mutations in GCK. Finally, we searched the Norwegian MODY Registry for children with genetically verified MD. RESULTS: We identified 15 children harbouring a mutation in HNF1A, nine with one in GCK, four with one in KCNJ11, one child with a mutation in INS and none with a mutation in MT-TL1. The minimum prevalence of MD in the NCDR was therefore 1.1%. By searching the Norwegian MODY Registry, we found 24 children with glucokinase-MODY, 15 of whom were not present in the NCDR. We estimated the minimum prevalence of MD among Norwegian children to be 3.1/100,000. CONCLUSIONS/INTERPRETATION: This is the first prevalence study of the common forms of MD in a nationwide, population-based registry of childhood diabetes. We found that 1.1% of patients in the Norwegian Childhood Diabetes Registry had MD.
Assuntos
Diabetes Mellitus Tipo 1/genética , Adolescente , Criança , Pré-Escolar , Feminino , Glucoquinase/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/genética , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Sistema de Registros , Receptores de Sulfonilureias/genéticaRESUMO
Heritable deficiency of phosphorylase kinase (Phk), a regulatory enzyme of glycogen metabolism, is responsible for 25% of all cases of glycogen storage disease and occurs with a frequency of -1 in 100,000 births. It is genetically and clinically heterogeneous, occurring in X-linked and autosomal-recessive forms and exhibiting various patterns of principally affected tissues (liver only, muscle only, liver and muscle, liver and kidney, heart only). This heterogeneity is thought to reflect the enzyme's structural complexity [subunit composition, (alpha beta gamma delta)4] and isoform diversity. Two isoforms encoded by separate genes are known for the subunits alpha (muscle [alpha M] and liver [alpha L isoforms) and gamma (muscle [gamma M] and testis [gamma T] isoforms), whereas only one gene appears to exist for the subunit beta. The subunit delta is calmodulin; identical calmodulins are expressed from three different human genes. Additional isoform diversity arises by differential mRNA splicing of the alpha M, alpha L and beta subunits. Mutations responsible for the various forms of Phk deficiency are sought in those subunit/isoform genes with a matching chromosomal location and tissue-specificity of expression. We report here that autosomal liver-specific Phk deficiency is associated with mutations in the gene encoding the testis/liver isoform of the catalytic gamma subunit (PHKG2). We found homozygous PHKG2 mutations in three human patients of consanguineous parentage and in the gsd (glycogen storage disease) rat strain, which is thus identified as an animal model for the human disorder. One human mutation is a single base-pair insertion in codon 89 that causes a frameshift and premature chain termination. The three other mutations result in non-conservative replacements of amino acid residues (V106E, G189E, D215N) that are highly conserved within the catalytic core regions of all protein kinases. These are the first mutations to be reported for an autosomal form of Phk deficiency. The findings suggest that the PHKG2 gene product is the predominant isoform of the catalytic gamma subunit of Phk not only in testis but also in liver, erythrocytes and, possibly, other non-muscle tissues.
Assuntos
Doença de Depósito de Glicogênio/genética , Fígado/enzimologia , Mutação , Fosforilase Quinase/genética , Testículo/enzimologia , Adolescente , Animais , Pré-Escolar , Elementos de DNA Transponíveis , Feminino , Homozigoto , Humanos , Lactente , Glicogênio Hepático/metabolismo , Masculino , Fosforilase Quinase/deficiência , Fosforilase Quinase/metabolismo , Ratos , Ratos Endogâmicos , Análise de Sequência de DNARESUMO
AIMS: To analyse, in a population-based study, the association between parental fear of hypoglycaemia and (i) the prevalence of hypoglycaemia and diabetes treatment factors in children with Type 1 diabetes and (ii) emotional distress in mothers and fathers. METHODS: Mothers (n = 103) and fathers (n = 97) of 115 children with Type 1 diabetes (1-15 years old) participated in the study. In addition to demographic and disease-specific data, the participants completed the Hypoglycaemia Fear Survey-Parent version (HFS-P) (worry and behaviour subscales) and the Hopkins Symptom Checklist-25 items (HSCL-25) to measure emotional distress. RESULTS: A higher HFS-P worry score was associated with higher glycated haemoglobin (HbA(1c)), a higher frequency (>or= 7) of what parents experienced as problematic hypoglycaemic events during the past year and co-morbid disease in the child. A higher HFS-P behaviour score was associated with children receiving insulin injections compared with using an insulin pump and a higher frequency (>or= 7 per day) of blood glucose measurements. The mothers had higher scores than the fathers in both the worry and behaviour subscales. The mothers' and the fathers' HFS-P worry scores correlated significantly with their HSCL-25 scores. CONCLUSIONS: The association between a higher level of hypoglycaemic-related fear and parental emotional distress and poorer glycaemic control in the child emphasizes the need for programmes to support and guide parents. The results suggest that future interventions should target both the parents' fear and appropriate ways to prevent hypoglycaemia in children with Type 1 diabetes.
Assuntos
Diabetes Mellitus Tipo 1/psicologia , Medo/psicologia , Hipoglicemia/psicologia , Insulina/uso terapêutico , Pais/psicologia , Adolescente , Atitude Frente a Saúde , Lista de Checagem , Criança , Pré-Escolar , Estudos Transversais , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Humanos , Hipoglicemia/epidemiologia , Hipoglicemia/etiologia , Lactente , Recém-Nascido , Sistemas de Infusão de Insulina , MasculinoRESUMO
Potassium channels in the plasma membrane of the pancreatic beta cells are critical in maintaining glucose homeostasis by responding to ATP and coupling metabolic changes to insulin secretion. These channels consist of subunits denoted the sulfonylurea receptor SUR1 and the inwardly rectifying ion channel KIR6.2, which are encoded by the genes ABCC8 and KCNJ11, respectively. Activating mutations in the subunit genes can result in monogenic diabetes, whereas inactivating mutations are the most common cause of congenital hyperinsulinism of infancy (CHI). Twenty-six Norwegian probands with CHI were analyzed for alterations in ABCC8 and KCNJ11. Fifteen probands (58%) had mutations in the ABCC8 gene. Nine patients were homozygous or compound heterozygous for the mutations, indicating diffuse pancreatic disease. In five patients, heterozygous and paternally inherited mutations were found, suggesting focal disease. One patient had a de novo mutation likely to cause a milder, dominant form of CHI. Altogether, 16 different ABCC8 mutations (including the novel alterations W231R, C267X, IVS6-3C>G, I462V, Q917X and T1531A) were identified. The mutations IVS10+1G>T, R1493W and V21D occurred in five, three and two families, respectively. KCNJ11 mutations were not found in any patients. Based on our mutation screening, we estimate the minimum birth prevalence of ABCC8-CHI in Norway to 1:70,000 during the past decade. Our results considerably extend the knowledge of the molecular genetics behind CHI in Scandinavia.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Hiperinsulinismo Congênito/genética , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Receptores de Droga/genética , Estudos de Coortes , Feminino , Testes Genéticos , Humanos , Recém-Nascido , Masculino , Noruega , Linhagem , Receptores de SulfonilureiasRESUMO
AIMS: Hepatocyte nuclear factor 1B (HNF1B) gene mutation carriers have a systemic disease characterized by congenital malformations in the urogenital tract, diabetes mellitus of maturity-onset diabetes of the young type and dysfunction of the liver and exocrine pancreas. We aimed to investigate pancreatic structure and exocrine function in carriers of HNF1B mutations. METHODS: We studied five subjects from two families with the previously reported mutation R137_K161del and the novel mutation F148L in HNF1B. All patients underwent computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP). We measured faecal elastase and serum vitamins D and E. RESULTS: One of the mutation carriers reported abdominal symptoms. All five subjects had faecal elastase deficiency, three had vitamin D deficiency and two had vitamin E deficiency. Neither CT nor MRCP depicted tissue corresponding to the pancreatic body and tail in the five mutation carriers, indicating agenesis of the dorsal pancreas. The head of the pancreas was slightly atrophic but had normal X-ray attenuation at CT in all patients. CONCLUSIONS: Agenesis of the pancreatic body and tail and pancreatic exocrine dysfunction are parts of the phenotype in HNF1B mutation carriers. This strengthens the evidence for a critical role of HNF1B in development and differentiation of at least the dorsal pancreas.
Assuntos
Diabetes Mellitus Tipo 2/genética , Fator 1-beta Nuclear de Hepatócito/genética , Mutação/genética , Pâncreas/anormalidades , Adolescente , Adulto , Criança , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas Exócrino/patologia , LinhagemRESUMO
AIMS: Previous reports have indicated that maturity-onset diabetes of the young (MODY) caused by hepatocyte nuclear factor 1A (HNF1A) mutations (MODY3) is the most common MODY subtype in Northern Europe, but population-based prevalence estimates are lacking. We sought to determine the prevalence of HNF1A-MODY in diabetic subjects of a defined Norwegian population (the HUNT2 Study). METHODS: Of the 1972 diabetic HUNT2 subjects, we identified a subgroup of 43 suspected MODY cases based on information on family history, disease onset and anti-glutamic acid decarboxylase autoantibody status. These cases were considered a discovery group for HNF1A mutations and underwent full DNA sequencing. Subsequently, the entire cohort of diabetic HUNT2 subjects was screened for three selected HNF1A mutations. Possible founder effects were examined using the Norwegian MODY Registry. RESULTS: Three subjects from the discovery group harboured HNF1A mutations. Two subjects had the previously described R229Q mutation, one had a novel S6N alteration, whereas the HNF1A hot-spot mutation P291fsinsC was not identified. Genotyping the cohort of diabetic HUNT2 subjects identified five additional R229Q-positive subjects. Microsatellite analysis performed for all R229Q-positive probands of the Norwegian MODY Registry and those found in the HUNT2 population revealed that 17 of 18 (94%) had genotypes consistent with a common haplotype. CONCLUSIONS: Clinical MODY criteria were fulfilled in 2.2% of diabetic HUNT2 subjects. The minimum prevalence of HNF1A-MODY among diabetic HUNT2 subjects was 0.4%. Because of founder effects, registry-based prevalence studies probably need to be very large and they should also include prospectively collected phenotypes and extensive mutation screening to establish the true prevalence of MODY.
Assuntos
Diabetes Mellitus Tipo 2/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Mutagênese/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/epidemiologia , Métodos Epidemiológicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologiaRESUMO
Wolcott-Rallison syndrome (WRS) (OMIM 226980) is a rare, autosomal recessive disorder with infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, osteopenia, mental retardation or developmental delay, and hepatic and renal dysfunction as main clinical findings. Patients with WRS have mutations in the EIF2AK3 gene, which encodes the pancreatic eukaryotic translation initiation factor 2-alpha kinase 3. We report a female patient who developed insulin-requiring diabetes at 2.5 months of age. Multiple epiphyseal dysplasia was diagnosed at age 2 years. At age 5.5 years she developed a Reye-like syndrome with hypoketotic hypoglycaemia and renal and hepatic insufficiency and died. A partial autopsy showed fat infiltration in the liver and kidneys. Examination of urine by gas chromatography and mass spectrometry showed large amounts of C(6)-dicarboxylic acid (adipic acid), 3-hydroxy-C(8)-dicarboxylic acid, 3-hydroxy-C(10)-dicarboxylic acid, and 3-hydroxydecenedioic acid. Acetoacetate and 3-hydroxybutyrate were absent. The findings suggested a metabolic block in mitochondrial fatty acid oxidation, but lack of material precluded enzyme analyses. The clinical diagnosis of WRS was suggested in retrospect, and confirmed by sequencing of DNA extracted from stored autopsy material. The patient was compound heterozygous for the novel EIF2AK3 mutations c.1694_1695delAT (Y565X) and c.3044T > C (F1015S). Our data suggest that disruption of the EIF2AK3 gene may lead to defective mitochondrial fatty acid oxidation and hypoglycaemia, thus adding to the heterogeneous phenotype of WRS.
Assuntos
Diabetes Mellitus Tipo 1/diagnóstico , Ácidos Dicarboxílicos/urina , Hidroxiácidos/urina , Erros Inatos do Metabolismo Lipídico/etiologia , Osteocondrodisplasias/diagnóstico , Adipatos/urina , Biomarcadores/urina , Pré-Escolar , Análise Mutacional de DNA , Diabetes Mellitus/etiologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/urina , Progressão da Doença , Epífises/anormalidades , Epífises/enzimologia , Evolução Fatal , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Insuficiência Hepática/etiologia , Humanos , Lactente , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/urina , Mutação , Osteocondrodisplasias/complicações , Osteocondrodisplasias/enzimologia , Osteocondrodisplasias/etiologia , Osteocondrodisplasias/genética , Osteocondrodisplasias/urina , Insuficiência Renal/etiologia , eIF-2 Quinase/genéticaRESUMO
AIMS: Heterozygous mutations in hepatocyte nuclear factor-1A (HNF1A) cause maturity-onset diabetes of the young type 3 (MODY3). Our aim was to compare two families with suspected dominantly inherited diabetes and a new HNF1A variant of unknown clinical significance. METHODS: The HNF1A gene was sequenced in two independently recruited families from the Norwegian MODY Registry. Both familes were phenotyped clinically and biochemically. Microsatellite markers around and within the HNF1A locus were used for haplotyping. Chromosomal linkage analysis was performed in one family, and whole-exome sequencing was undertaken in two affected family members from each family. Transactivation activity, DNA binding and nuclear localization of wild type and mutant HNF-1A were assessed. RESULTS: The novel HNF1A variant c.539C>T (p.Ala180Val) was found in both families. The variant fully co-segregated with diabetes in one family. In the other family, two subjects with diabetes mellitus and one with normal glucose levels were homozygous variant carriers. Chromosomal linkage of diabetes to the HNF1A locus or to other genomic regions could not be established. The protein functional studies did not reveal significant differences between wild type and variant HNF-1A. In each family, whole-exome sequencing failed to identify any other variant that could explain the disease. CONCLUSIONS: The HNF1A variant p.Ala180Val does not seem to cause MODY3, although it may confer risk for type 2 diabetes mellitus. Our data demonstrate challenges in causality evaluation of rare variants detected in known diabetes genes.
Assuntos
Diabetes Mellitus Tipo 2/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Adolescente , Adulto , Idade de Início , Sequência de Aminoácidos , Sequência de Bases , Feminino , Estudos de Associação Genética , Ligação Genética , Predisposição Genética para Doença , Células HeLa , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Noruega , Linhagem , Fenótipo , Adulto JovemRESUMO
Recent studies have shown that the risk conferred by the high-risk DQA1*03-DQB1*0302 (DQ8) haplotype is modified by the DRB1*04 allele that is also carried by this haplotype. However, many of these studies suffer from lack of sufficient numbers of DQ-matched control subjects, which are necessary because there is a strong linkage disequilibrium between genes in the HLA complex. In the present study, using a large material of IDDM patients and DQ-matched control subjects, we have addressed the contribution of DR4 subtypes to IDDM susceptibility. Our data, together with recent data from others, clearly demonstrate that some DR4-DQ8 haplotypes are associated with disease susceptibility, while others are associated with protection, depending on the DRB1*04 allele carried by the same haplotype. In particular, our data demonstrate that DRB1*0401 confers a higher risk than DRB1*0404. Based on combined available data on the genetic susceptibility encoded by various DR4-DQ8 haplotypes and the amino acid composition of the involved DRbeta*04 chains as well as the ligand motifs for these DR4 subtypes, we have developed a unifying hypothesis explaining the different risks associated with different DR4-DQ8 haplotypes. We suggest that disease susceptibility is mainly conferred by DQ8 while DR4 subtypes confer different degrees of protection. Some DR4 subtypes (i.e., DRB1*0405, 0402, and 0401) confer little or no protection, while others (i.e., DRB1*0404, 0403, and 0406) cause an increasing degree of protection, possibly by binding a common protective peptide. Features of a protective peptide that fit such a model are briefly discussed.
Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Antígeno HLA-DR4/genética , Adolescente , Criança , Diabetes Mellitus Tipo 1/epidemiologia , Suscetibilidade a Doenças , Genótipo , Cadeias alfa de HLA-DQ , Cadeias HLA-DRB1 , Haplótipos , Humanos , Valores de Referência , Medição de Risco , Fatores de RiscoRESUMO
Results from a recent study suggested that polymorphisms within the HLA class II genes LMP2 and LMP7 were associated with the susceptibility for developing IDDM, and that this association could not be explained by linkage disequilibrium to HLA-DR or -DQ genes. We typed 285 IDDM patients and 337 HLA-DRB1-DQA1-DQB1 genotypically matched control subjects from an ethnically homogeneous population for both the G/T polymorphism in intron 6 of the LMP7 gene and the Arg-His polymorphism in the LMP2 gene. In addition, we typed IDDM families in which at least one parent was homozygous for a DRB1-DQA1-DQB1 haplotype and performed a transmission/disequilibrium test of these LMP polymorphisms. Our data suggest that none of these LMP2 or LMP7 polymorphisms are independently associated with IDDM susceptibility, in contrast to what has been previously reported by others. Further, our results suggest that one partial explanation for the previously reported independent association between IDDM and these LMP polymorphisms may have been that patients and control subjects were not matched for DRB1*04 subtypes. Our results emphasize the need for a complete matching for DRB1, DQA1, and DQB1 alleles between patients and control subjects when attempting to detect independent effects of other polymorphisms in the HLA complex on IDDM susceptibility or protection.
Assuntos
Cisteína Endopeptidases , Diabetes Mellitus Tipo 1/genética , Genes MHC da Classe II , Complexos Multienzimáticos , Proteínas/genética , Proteínas da Matriz Viral/genética , Ligação Genética , Genótipo , Antígenos HLA-DR/genética , Humanos , Noruega , Polimorfismo Genético , Complexo de Endopeptidases do ProteassomaRESUMO
The so-called dead-in-bed syndrome refers to sudden death in young diabetic patients without any history of long-term complications. Autopsy is typically negative. The present report summarizes frequency data on this condition from studies in the U.K. and the Scandinavian countries. It appears that such deaths occur in 6% of all deaths in diabetic patients below age 40 years. The frequency may also be expressed as 2-6 events per 10,000 [corrected] patient-years. The causes are by definition unknown, but a plausible theory is a death in hypoglycemia, since a history of nocturnal hypoglycemia is noted in most cases. While waiting for the clarification of the underlying pathophysiology, one should attempt to identify patients who are at particular risk of hypoglycemia and advocate caution in efforts to normalize blood glucose and HbAlc in these cases.
Assuntos
Morte Súbita/etiologia , Diabetes Mellitus Tipo 1/mortalidade , Adolescente , Adulto , Glicemia/análise , Ritmo Circadiano , Morte Súbita/prevenção & controle , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemia/mortalidade , Fatores de TempoRESUMO
OBJECTIVE: It is unclear whether the demands of good metabolic control or the consequences of poor control have a greater influence on quality of life (QOL) for adolescents with diabetes. This study aimed to assess these relations in a large international cohort of adolescents with diabetes and their families. RESEARCH DESIGN AND METHODS: The study involved 2,101 adolescents, aged 10-18 years, from 21 centers in 17 countries in Europe, Japan, and North America. Clinical and demographic data were collected from March through August 1998. HbA(1c) was analyzed centrally (normal range 4.4-6.3%; mean 5.4%). Adolescent QOL was assessed by a previously developed Diabetes Quality of Life (DQOL) questionnaire for adolescents, measuring the impact of diabetes, worries about diabetes, satisfaction with life, and health perception. Parents and health professionals assessed family burden using newly constructed questionnaires. RESULTS: Mean HbA(1c) was 8.7% (range 4.8-17.4). Lower HbA(1c) was associated with lower impact (P < 0.0001), fewer worries (P < 0.05), greater satisfaction (P < 0.0001), and better health perception (P < 0.0001) for adolescents. Girls showed increased worries (P < 0.01), less satisfaction, and poorer health perception (P < 0.01) earlier than boys. Parent and health professional perceptions of burden decreased with age of adolescent (P < 0.0001). Patients from ethnic minorities had poorer scores for impact (P < 0.0001), worries (P < 0.05), and health perception (P < 0.01). There was no correlation between adolescent and parent or between adolescent and professional scores. CONCLUSIONS: In a multiple regression model, lower HbA(1c) was significantly associated with better adolescent-rated QOL on all four subscales and with lower perceived family burden as assessed by parents and health professionals.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 1/psicologia , Hemoglobinas Glicadas/metabolismo , Qualidade de Vida , Adolescente , Biomarcadores , Criança , Comparação Transcultural , Diabetes Mellitus Tipo 1/sangue , Europa (Continente) , Feminino , Nível de Saúde , Humanos , Japão , Masculino , Distribuição Normal , América do Norte , Valores de Referência , Análise de Regressão , Fatores Sexuais , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Twenty-one international pediatric diabetes centers from 17 countries investigated the effect of simple feedback about the grand mean HbA(1c) level of all centers and the average value of each center on changes in metabolic control, rate of severe hypoglycemia, and insulin therapy over a 3-year period. RESEARCH DESIGN AND METHODS: Clinical data collection and determination of HbA(1c) levels were conducted at a central location in 1995 (n = 2,780, age 0-18 years) and 1998 (n = 2,101, age 11-18 years). RESULTS: Striking differences in average HbA(1c) concentrations were found among centers; these differences remained after adjustment for the significant confounders of sex, age, and diabetes duration. They were apparent even in patients with short diabetes duration and remained stable 3 years later (mean adjusted HbA(1c) level: 8.62 +/- 0.03 vs. 8.67 +/- 0.04 [1995 vs. 1998, respectively]). Three centers had improved significantly, four centers had deteriorated significantly in their overall adjusted HbA(1c) levels, and 14 centers had not changed in glycemic control. During the observation period, there were increases in the adjusted insulin dose by 0.076 U/kg, the adjusted number of injections by 0.23 injections per day, and the adjusted BMI by 0.95 kg/m(2). The 1995 versus 1998 difference in glycemic control for the seven centers could not be explained by prevailing insulin regimens or rates of hypoglycemia. CONCLUSIONS: This study reveals significant outcome differences among large international pediatric diabetes centers. Feedback and comparison of HbA(1c) levels led to an intensification of insulin therapy in most centers, but improved glycemic control in only a few.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Hemoglobinas Glicadas/análise , Hipoglicemia/epidemiologia , Hipoglicemia/prevenção & controle , Adolescente , Biomarcadores/sangue , Criança , Estudos Transversais , Diabetes Mellitus Tipo 1/tratamento farmacológico , Europa (Continente) , Feminino , Humanos , Incidência , Insulina/efeitos adversos , Insulina/uso terapêutico , Japão , Masculino , América do Norte , Reprodutibilidade dos TestesRESUMO
We developed a coupled NaH14CO3 fixation assay to detect 3-oxothiolase deficiency in extracts of cultured human fibroblasts. Cell extracts were incubated with tiglyl-CoA, NAD, CoASH, ATP and NaH14CO3. The enzymatic activities of tiglyl-CoA (enoyl-CoA) hydratase, 2-methyl-3-hydroxybutyryl-CoA dehydrogenase and 2-methylacetoacetyl-CoA thiolase (3-oxothiolase) were coupled to produce propionyl-CoA. Propionyl-CoA produced in the assay was estimated by fixation of NaH14CO3 into [14C]methylmalonyl-CoA employing endogenous propionyl-CoA carboxylase. The control activity was 32 +/- 23 pmol/min per mg protein (+/- 1 S.D., range 7-94; 28 cell lines). Five known cases of 3-oxothiolase deficiency had a mean activity of 2% of the control; a sixth case of 3-oxothiolase deficiency was significantly higher at 27% of the mean control value. Coupled assay activity was also low (3% of control) in the cells from a patient with propionyl-CoA carboxylase deficiency.
Assuntos
Acetil-CoA C-Acetiltransferase/deficiência , Enoil-CoA Hidratase/metabolismo , Fibroblastos/enzimologia , Isoleucina/metabolismo , Acil Coenzima A/metabolismo , Trifosfato de Adenosina/farmacologia , Bicarbonatos/metabolismo , Bicarbonatos/farmacologia , Radioisótopos de Carbono , Células Cultivadas , Humanos , Cloreto de Magnésio/farmacologia , NAD/metabolismo , Sódio/metabolismo , Sódio/farmacologia , Bicarbonato de SódioRESUMO
Insulin binding was studied in subpopulations of bovine chromaffin cells enriched in adrenalin-producing cells (A-cells) or noradrenalin-producing cells (NA-cells). Binding of 125I-insulin was carried out at 15 degrees C for 3 hrs in the absence or presence of excess unlabelled hormone. Four fractions of cells were obtained by centrifugation on a stepwise bovine serum albumin gradient. The four fractions were all shown to bind insulin in a specific manner and the highest binding was measured in the cell layers of higher densities, containing mainly A-cells. The difference in binding of insulin to the four subpopulations of chromaffin cells seemed to be related to differences in numbers of receptors as opposed to receptor affinities. We conclude that bovine chromaffin cells possess high affinity binding sites for insulin and that these binding sites are mainly confined to A-cells.
Assuntos
Medula Suprarrenal/metabolismo , Grânulos Cromafim/metabolismo , Sistema Cromafim/metabolismo , Insulina/metabolismo , Medula Suprarrenal/citologia , Animais , Bovinos , Separação Celular , Epinefrina/metabolismo , Norepinefrina/metabolismoRESUMO
A boy with delayed psychomotor development, attention deficit disorder, and therapy-resistant epilepsy was treated with valproate. The patient died of liver failure after 4 months of valproate treatment. Postmortem investigation of cultured fibroblasts suggested medium chain acyl-CoA dehydrogenase deficiency, an unexpected finding since the boy had not presented typical manifestations of this disease. Because medium chain acyl-CoA dehydrogenase is an important enzyme in the beta-oxidation of fatty acids, our patient probably had a genetically reduced tolerance to valproate. This drug should be omitted in the treatment of seizures in patients with possible medium chain acyl-CoA dehydrogenase deficiency.
Assuntos
Acil-CoA Desidrogenases/deficiência , Anticonvulsivantes/efeitos adversos , Epilepsia Tônico-Clônica/tratamento farmacológico , Falência Hepática/induzido quimicamente , Ácido Valproico/efeitos adversos , Acil-CoA Desidrogenase , Células Cultivadas , Criança , Epilepsia Tônico-Clônica/enzimologia , Evolução Fatal , Fibroblastos/enzimologia , Humanos , Falência Hepática/enzimologia , Masculino , Pele/citologia , Pele/enzimologiaRESUMO
Two well-characterized patients with congenital, generalized lipodystrophy have been studied by the euglycaemic hyperinsulinaemic clamp technique in combination with indirect calorimetry. Furthermore, glycogen synthase in muscle biopsies was studied in one patient with regard to enzyme activity, immunoreactive protein and mRNA levels. The patients had fasting hyperinsulinaemia, and the rate of total glucose disposal was severely impaired, primarily due to a decreased non-oxidative glucose metabolism. In the patient studied with muscle biopsy, the expected activation of glycogen synthase by insulin did not occur. In both patients there was severely increased hepatic glucose output in the basal state, suggesting a failure of insulin to suppress hepatic gluconeogenesis. During insulin infusion a substantially elevated rate of lipid oxidation remained in the patients, in contrast to the almost completely suppressed lipid oxidation in the controls. It is concluded that patients with congenital generalized lipodystrophy may present severe insulin resistance with regard to hepatic glucose production as well as muscle glycogen synthesis and lipid oxidation. The results suggest a postreceptor defect in the action of insulin in congenital generalized lipodystrophy. The further localization of such a defect is hampered by the still incomplete understanding of the pathways that link insulin-stimulated tyrosine phosphorylation to the ultimate action of insulin upon target cells.
Assuntos
Resistência à Insulina , Lipodistrofia/congênito , Lipodistrofia/fisiopatologia , Calorimetria Indireta , Feminino , Glucose/metabolismo , Técnica Clamp de Glucose , Glicogênio Sintase/metabolismo , Humanos , Hiperinsulinismo/fisiopatologia , Metabolismo dos Lipídeos , Lipodistrofia/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To estimate the associations of maternal and paternal age at delivery and of birth order with the risk of childhood onset type 1 diabetes. DESIGN: Cohort study by record linkage of the medical birth registry and the national childhood diabetes registry in Norway. SETTING: Norway. SUBJECTS: All live births in Norway between 1974 and 1998 (1.4 million people) were followed for a maximum of 15 years, contributing 8.2 million person years of observation during 1989-98. 1824 cases of type 1 diabetes diagnosed between 1989 and 1998 were identified. MAIN OUTCOME MEASURES: Incidence of type 1 diabetes. RESULTS: There was no association between maternal age at delivery and type 1 diabetes among firstborn children, but among fourth born children there was a 43.2% increase in incidence of diabetes for each five year increase in maternal age (95% confidence interval 6.4% to 92.6%). Each increase in birth order was associated with a 17.9% reduction in incidence (3.2% to 30.4%) when maternal age was 20-24 years, but the association was weaker when maternal age was 30 years or more. Paternal age was not associated with type 1 diabetes after maternal age was adjusted for. CONCLUSIONS: Intrauterine factors and early life environment may influence the risk of type 1 diabetes. The relation of maternal age and birth order to risk of type 1 diabetes is complex.
Assuntos
Ordem de Nascimento , Diabetes Mellitus Tipo 1/epidemiologia , Idade Materna , Idade Paterna , Adulto , Idade de Início , Estudos de Coortes , Diabetes Mellitus Tipo 1/etiologia , Feminino , Humanos , Incidência , Recém-Nascido , Masculino , Noruega/epidemiologia , RiscoRESUMO
OBJECTIVE: To assess the associations between birth weight or gestational age and risk of type 1 diabetes. DESIGN: Population based cohort study by record linkage of the medical birth registry and the National Childhood Diabetes Registry. SETTING: Two national registries in Norway. PARTICIPANTS: All live births in Norway between 1974 and 1998 (1 382 602 individuals) contributed a maximum of 15 years of observation, a total of 8 184 994 person years of observation in the period 1989 to 1998. 1824 children with type 1 diabetes were diagnosed between 1989 and 1998. MAIN OUTCOME MEASURES: Estimates of rate ratios with 95% confidence intervals for type 1 diabetes from Poisson regression analyses. RESULTS: The incidence rate of type 1 diabetes increased almost linearly with birth weight. The rate ratio for children with birth weights 4500 g or more compared with those with birth weights less than 2000 g was 2.21 (95% confidence interval 1.24 to 3.94), test for trend P=0.0001. There was no significant association between gestational age and type 1 diabetes. The results persisted after adjustment for maternal diabetes and other potential confounders. CONCLUSION: There is a relatively weak but significant association between birth weight and increased risk of type 1 diabetes consistent over a wide range of birth weights.