RESUMO
WFS1 mutations are responsible for Wolfram syndrome (WS) characterized by juvenile-onset diabetes mellitus and optic atrophy, and for low-frequency sensorineural hearing loss (LFSNHL). Our aim was to analyze the French cohort of 96 patients with WFS1-related disorders in order (i) to update clinical and molecular data with 37 novel affected individuals, (ii) to describe uncommon phenotypes and, (iii) to precise the frequency of large-scale rearrangements in WFS1. We performed quantitative polymerase chain reaction (PCR) in 13 patients, carrying only one heterozygous variant, to identify large-scale rearrangements in WFS1. Among the 37 novel patients, 15 carried 15 novel deleterious putative mutations, including one large deletion of 17,444 base pairs. The analysis of the cohort revealed unexpected phenotypes including (i) late-onset symptoms in 13.8% of patients with a probable autosomal recessive transmission; (ii) two siblings with recessive optic atrophy without diabetes mellitus and, (iii) six patients from four families with dominantly-inherited deafness and optic atrophy. We highlight the expanding spectrum of WFS1-related disorders and we show that, even if large deletions are rare events, they have to be searched in patients with classical WS carrying only one WFS1 mutation after sequencing.
Assuntos
Estudos de Associação Genética , Proteínas de Membrana/genética , Mutação , Fenótipo , Síndrome de Wolfram/diagnóstico , Síndrome de Wolfram/genética , Adolescente , Adulto , Substituição de Aminoácidos , Criança , Estudos de Coortes , Família , Feminino , França , Genes Dominantes , Genes Recessivos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Autoimmune hypoglycaemia, based on the presence of autoantibodies directed against endogenous insulin (insulin autoimmune syndrome or Hirata's disease), is a rare cause of hypoglycaemia. Treatment of the disease is not standardized and various therapeutic options have been proposed. We wondered whether using a continuous glucose-monitoring system could help quantify precisely glucose excursions and allow evaluation of treatment efficacy. CASE REPORT: A 44-year-old Caucasian patient with insulin autoimmune syndrome was studied for 7 days using a continuous glucose monitoring system under various treatment regimens, i.e. diet modification, high-dose corticosteroids, alpha-glucosidase inhibitors, and plasmapheresis. CONCLUSION: Continuous glucose monitoring system data confirmed that insulin autoimmune syndrome alternated between periods of prandial hyperglycaemia and interprandial hypoglycaemia. Alpha glucosidase inhibitors and plasmapheresis were more potent in limiting glucose excursions than corticosteroid or diet-only treatments. The continuous glucose monitoring system appears to be a useful tool in the management of insulin autoimmune syndrome.
Assuntos
Doenças Autoimunes/diagnóstico , Automonitorização da Glicemia , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Hiperglicemia/sangue , Hipoglicemia/prevenção & controle , Anticorpos Anti-Insulina/sangue , Plasmaferese , Corticosteroides/uso terapêutico , Adulto , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Dieta com Restrição de Carboidratos , Humanos , Hiperglicemia/terapia , Hipoglicemiantes/uso terapêutico , Masculino , Síndrome , Resultado do TratamentoRESUMO
BACKGROUND: Genus and species level analysis is the best way to characterize alterations in the human gut microbiota that are associated with obesity, because the clustering of obese and lean microbiotas increases with the taxonomic depth of the analysis. Bifidobacterium genus members have been associated with a lean status, whereas different Lactobacillus species are associated both with a lean and an obese status. OBJECTIVES AND METHODS: We analyzed the fecal concentrations of Bacteroidetes, Firmicutes, Methanobrevibacter smithii, the genus Lactobacillus, five other Lactobacillus species previously linked with lean or obese populations, Escherichia coli and Bifidobacterium animalis in 263 individuals, including 134 obese, 38 overweight, 76 lean and 15 anorexic subjects to test for the correlation between bacterial concentration and body mass index (BMI). Of these subjects, 137 were used in our previous study. FINDINGS: Firmicutes were found in >98.5%, Bacteroidetes in 67%, M. smithii in 64%, E. coli in 51%, Lactobacillus species between 17 and 25% and B. animalis in 11% of individuals. The fecal concentration of Lactobacillus reuteri was positively correlated with BMI (coefficient=0.85; 95% confidence interval (CI) 0.12-0.58; P=0.02) in agreement with what was reported for Lactobacillus sakei. As reported, B. animalis (coefficient=-0.84; 95% CI -1.61 to -0.07; P=0.03) and M. smithii (coefficient=-0.43, 95% CI -0.90 to 0.05; P=0.08) were negatively associated with the BMI. Unexpectedly, E. coli was found here for the first time to negatively correlate with the BMI (coefficient=-1.05; 95% CI -1.60 to -0.50; P<0.001). CONCLUSION: Our findings confirm the specificity of the obese microbiota and emphasize the correlation between the concentration of certain Lactobacillus species and obesity.
Assuntos
Bifidobacterium/isolamento & purificação , Índice de Massa Corporal , Escherichia coli/isolamento & purificação , Fezes/microbiologia , Trato Gastrointestinal/microbiologia , Limosilactobacillus reuteri/isolamento & purificação , Methanobrevibacter/isolamento & purificação , Adulto , Anorexia Nervosa/microbiologia , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/microbiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Inquéritos e Questionários , Magreza/microbiologiaRESUMO
The rebirth of bacterial culture has been highlighted successively by environmental microbiologists, the design of axenic culture for intracellular bacteria in clinical microbiology, and, more recently, by human gut microbiota studies. Indeed, microbial culturomics (large scale of culture conditions with the identification of colonies by MALDI-TOF or 16S rRNA) allowed to culture 32 new bacterial species from only four stool samples studied. We performed culturomics in comparison with pyrosequencing 16S rRNA targeting the V6 region on an anorexia nervosa stool sample because this clinical condition has never been explored before by culture, while its composition has been observed to be atypical by metagenomics. We tested 88 culture conditions generating 12,700 different colonies identifying 133 bacterial species, with 19 bacterial species never isolated from the human gut before, including 11 new bacterial species for which the genome has been sequenced. These 11 new bacterial species isolated from a single stool sample allow to extend more significantly the repertoire in comparison to the bacterial species validated by the rest of the world during the last 2 years. Pyrosequencing indicated a dramatic discrepancy with the culturomics results, with only 23 OTUs assigned to the species level overlapping (17 % of the culturomics results). Most of the sequences assigned to bacteria detected only by pyrosequencing belonged to Ruminococcaceae, Lachnospiraceae, and Erysipelotrichaceae constituted by strictly anaerobic species, indicating the future route for culturomics. This study revealed new bacterial species participating significantly to the extension of the gut microbiota repertoire, which is the first step before being able to connect the bacterial composition with the geographic or clinical status.
Assuntos
Anorexia Nervosa/microbiologia , Bactérias/classificação , Bactérias/isolamento & purificação , Técnicas Bacteriológicas/métodos , Biodiversidade , Fezes/microbiologia , Bactérias/genética , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Feminino , Humanos , Dados de Sequência Molecular , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Adulto JovemRESUMO
Essential hypertension is a common multifactorial trait. The molecular basis of a number of rare diseases that after blood pressure in humans has been established, identifying pathways that may be involved in more common forms of hypertension. Pseudohypoaldosteronism type II (PHAII, also known as familial hyperkalaemia and hypertension or Gordon's syndrome; OMIM #145260), is characterized by hyperkalaemia despite normal renal glomerular filtration, hypertension and correction of physiologic abnormalities by thiazide diuretics. Mild hyperchloremia, metabolic acidosis and suppressed plasma renin activity are variable associated findings. The pathogenesis of PHAII is unknown, although clinical studies indicate an abnormality in renal ion transport. As thiazide diuretics are among the most efficacious agents in the treatment of essential hypertension, understanding the pathogenesis of PHAII may be of relevance to more common forms of hypertension. Analysis of linkage in eight PHAII families showing autosomal dominant transmission demonstrates locus heterogeneity of this trait, with a multilocus lod score of 8.1 for linkage of PHAII to chromosomes 1q31-q42 and 17p11-q21. Interestingly, the chromosome-17 locus overlaps a syntenic interval in rat that contains a blood pressure quantitative trait locus (QTL). Our findings provide a first step toward identification of the molecular basis of PHAII.
Assuntos
Cromossomos Humanos Par 17 , Cromossomos Humanos Par 1 , Ligação Genética , Hiperpotassemia/genética , Hipertensão/genética , Pseudo-Hipoaldosteronismo/genética , Animais , Mapeamento Cromossômico , Feminino , Humanos , Hiperpotassemia/complicações , Hipertensão/complicações , Masculino , Linhagem , Pseudo-Hipoaldosteronismo/complicações , RatosRESUMO
BACKGROUND: Obesity is associated with increased health risk and has been associated with alterations in bacterial gut microbiota, with mainly a reduction in Bacteroidetes, but few data exist at the genus and species level. It has been reported that the Lactobacillus and Bifidobacterium genus representatives may have a critical role in weight regulation as an anti-obesity effect in experimental models and humans, or as a growth-promoter effect in agriculture depending on the strains. OBJECTIVES AND METHODS: To confirm reported gut alterations and test whether Lactobacillus or Bifidobacterium species found in the human gut are associated with obesity or lean status, we analyzed the stools of 68 obese and 47 controls targeting Firmicutes, Bacteroidetes, Methanobrevibacter smithii, Lactococcus lactis, Bifidobacterium animalis and seven species of Lactobacillus by quantitative PCR (qPCR) and culture on a Lactobacillus-selective medium. FINDINGS: In qPCR, B. animalis (odds ratio (OR)=0.63; 95% confidence interval (CI) 0.39-1.01; P=0.056) and M. smithii (OR=0.76; 95% CI 0.59-0.97; P=0.03) were associated with normal weight whereas Lactobacillus reuteri (OR=1.79; 95% CI 1.03-3.10; P=0.04) was associated with obesity. CONCLUSION: The gut microbiota associated with human obesity is depleted in M. smithii. Some Bifidobacterium or Lactobacillus species were associated with normal weight (B. animalis) while others (L. reuteri) were associated with obesity. Therefore, gut microbiota composition at the species level is related to body weight and obesity, which might be of relevance for further studies and the management of obesity. These results must be considered cautiously because it is the first study to date that links specific species of Lactobacillus with obesity in humans.
Assuntos
Bifidobacterium/isolamento & purificação , Trato Gastrointestinal/microbiologia , Inflamação/microbiologia , Inflamação/fisiopatologia , Limosilactobacillus reuteri/isolamento & purificação , Methanobrevibacter/isolamento & purificação , Obesidade/microbiologia , Adulto , Células Cultivadas , Feminino , França , Trato Gastrointestinal/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Inquéritos e QuestionáriosRESUMO
AIMS: To determine plasma levels of apoprotein (apo) C-II and apoprotein C-III in Type 2 diabetic patients and to examine the clinical and biological factors that are associated with elevated apoC concentrations. METHODS: We measured apoC-II and apoC-III in total plasma and in non-high-density lipoprotein fractions by an immunoturbidimetric assay in 88 Caucasian Type 2 diabetic patients and in 138 healthy control subjects. RESULTS: Plasma levels of both apoC-II and apoC-III were increased in Type 2 diabetic patients. The clinical conditions associated with an increase of plasma apoC-II and apoC-III were abdominal obesity, body mass index, poor glycaemic control and lack of insulin treatment. However, when multivariate analysis was used, plasma apoCs levels correlated with triglyceride levels only. The apoC-III/apoC-II ratio was similar in the Type 2 diabetic and control subjects. CONCLUSIONS: Our study shows the parallel increase of apoC-II and C-III in Type 2 diabetic patients. This parallel increase is related to hypertriglyceridaemia only.
Assuntos
Apolipoproteínas C/sangue , Diabetes Mellitus Tipo 2/sangue , Hipertrigliceridemia/sangue , Idoso , Índice de Massa Corporal , Estudos de Casos e Controles , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Diabetes Mellitus Tipo 2/terapia , Feminino , Humanos , Lipase Lipoproteica/metabolismo , Masculino , Pessoa de Meia-Idade , ObesidadeRESUMO
Low circulating VVH7-like immunoreactivity (VVH7 i.r) level was amazingly observed in human diabetic sera. Here, we examined the impact of diabetes type, clinico-biological features and metabolic control on circulating VVH7 i.r level in this disease. ELISA test was used to measure VVH7 i.r in sera of 120 diabetic patients (type 1 diabetes in 64, type 2 diabetes in 56). Three enzymatic tests were also applied to determine serum cathepsin D (CD), dipeptidyl peptidase IV (DPP-IV) and angiotensin-converting enzyme (ACE) activities. A subgroup of 24 type 1 diabetic patients negative for microalbuminuria and hypertension were submitted to an ambulatory blood pressure monitoring to evaluate the relationship between VVH7 i.r level and blood pressure parameters. The mean serum concentration of VVH7 i.r was drastically reduced in diabetic patients (0.91+/-0.93 micromol/l versus 5.63+/-1.11 micromol/l in controls) (p<0.001). A negative correlation between VVH7 i.r level and daytime diastolic blood pressure existed in type 1 diabetic patients. There was no association of low VVH7 i.r with either type of diabetes or HbA1c level. An increase of cathepsin D activity was found in serum of diabetic patients compared to controls (0.47 U/ml versus 0.15 U/ml, respectively) whereas DPPIV activity was significantly decreased in diabetic sera (50.81 U/ml versus 282.10 U/l respectively). Diminution of VVH7 i.r in sera of diabetic patients was confirmed but still remained unexplained. Relationships between higher systolic blood pressure and decrease of VVH7 i.r reinforce the need to investigate this pathway in this disease to elucidate its role in macro- and micro-angiopathy.
Assuntos
Catepsina D/metabolismo , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 2/enzimologia , Dipeptidil Peptidase 4/metabolismo , Fragmentos de Peptídeos/sangue , Peptidil Dipeptidase A/metabolismo , Adulto , Idoso , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Hemoglobinas/imunologia , Hemoglobinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/imunologiaRESUMO
The 2007 international consensus about the standardization of HbA(1c) determination and expression of results is progressively implemented in most countries. In France, a common working group of the Société française de biologie clinique (SFBC) and the Société francophone de diabétologie (SFD) has expressed the following recommendations. HbA(1c) results are expressed in percentage of total hemoglobin and in mmol HbA(1c)/mol Hb, but are not converted into estimated average glucose. A table indicating the correspondence between HbA(1c) and estimated average glucose may be given with the results, subject to precautions of interpretation at the individual level.
Assuntos
Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Hemoglobinas Glicadas/análise , Europa (Continente) , França , Humanos , Cooperação Internacional , Padrões de Referência , Estados UnidosRESUMO
AIMS: Mutations of the WFS1 gene have been implicated in autosomal dominant diseases, such as low-frequency sensorineural hearing impairment (LFSNHI) and/or diabetes mellitus and/or optic atrophy. The aim was to investigate WFS1 gene sequences in a family with diabetes mellitus and hearing impairment. METHODS: Three members of a family with a maternally inherited combination of diabetes mellitus and hearing impairment, but no specific mutations in its mitochondrial genome, were investigated for mutations in the WFS1 gene. RESULTS: This pedigree, in which the proband had non-insulin-dependent diabetes mellitus and congenital hearing impairment and his mother a triple combination of diabetes mellitus, hearing impairment and optic atrophy, was found to be associated with autosomal dominant transmission of the E864K mutation of the WFS1 gene. CONCLUSIONS: In the light of this confirmatory study, we recommend the systematic analysis of WFS1 gene sequences in patients with parentally inherited diabetes mellitus and deafness (+/- optic atrophy), in particular when diabetogenic mtDNA mutations have been excluded.
Assuntos
Diabetes Mellitus/genética , Perda Auditiva/genética , Proteínas de Membrana/genética , Mutação de Sentido Incorreto/genética , Adulto , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
AIM: Sporadic malignant insulinoma (SMI) is a rare disease, and the consequent paucity of data in the literature and the development of aggressive treatments for liver metastases have led us to retrospectively analyze a series of 12 cases of SMI. METHODS: Every patient presenting with SMI, according to the WHO 2004 histopathology criteria, between 1970 and June 2005 in Marseille was included in the study. Patients with multiple endocrine neoplasia type 1 (MEN-1) and tumours of uncertain malignant potential were excluded. RESULTS: The ratio of male/female was 4/8, and mean age at diagnosis was 52.5 years. A 48-h fasting test in 10 patients was conclusive in nine, after a mean duration of 12 h 45 min. SMI size ranged from 7-120 mm (mean 30.3mm). Six patients had liver metastases and one had isolated lymph-node invasion. Surgery was performed in 12 patients. Five persisting diseases (mean follow-up of 1.8 years) required other treatments (chemoembolization, radiofrequency thermoablation [RFTA], liver transplantation); one patient relapsed 8.5 years after surgery; six were still in complete remission (mean follow-up of 5.8 years), and one patient had died by the time of the 24-month follow-up. CONCLUSION: Aggressive sequential multimodal therapy can prolong the survival of patients with SMI even in the presence of liver metastases.
Assuntos
Insulinoma/terapia , Neoplasias Pancreáticas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada/mortalidade , Feminino , Seguimentos , Humanos , Insulinoma/mortalidade , Insulinoma/secundário , Insulinoma/cirurgia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/cirurgia , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
OBJECTIVE: To establish the equivalence in efficacy (HbA(1c)) of insulin glargine injected at dinner versus bedtime in a large number of patients with type 1 diabetes using a fast-acting analogue (FAA) or regular human insulin (RHI) as prandial insulin in an insulin glargine-bolus regimen. RESEARCH DESIGN AND METHODS: In a 26-week trial, 1178 patients with type 1 diabetes and treated with different basal-bolus regimens were randomized to receive insulin glargine once daily at dinner (n=589) or at bedtime (n=589) while continuing their previous prandial insulin (FAA: 75%; RHI: 25% of patients). The primary objective was to demonstrate equivalence in terms of HbA(1c) levels at endpoint. RESULTS: Baseline characteristics were similar in the two groups. At endpoint, HbA(1c) (mean+/-standard deviation [S.D.]) had decreased by 0.25+/-0.66% to 7.77+/-0.96% in the dinnertime group (P<0.0001), and by 0.24+/-0.76% to 7.83+/-1.07% in the bedtime group (P<0.0001). The HbA(1c) difference between dinner and bedtime was -0.022% (two-sided 90% confidence interval [CI] -0.09; 0.05), demonstrating statistical equivalence of HbA(1c) at endpoint between the two groups. Equivalence was also demonstrated within prandial groups: HbA(1c) difference between dinner and bedtime was -0.03% (two-sided 90% CI: -0.11; 0.06) for FAAs and -0.04% (two-sided 90% CI: -0.19; 0.11) for RHIs. The incidence of severe hypoglycaemia did not differ between the treatment groups. CONCLUSION: These data confirm that insulin glargine in combination with either FAA or RHI is equally effective and safe, whether it is administered at dinner or bedtime.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobinas Glicadas/metabolismo , Insulina/análogos & derivados , Adulto , Idoso , Albuminúria/epidemiologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Índice de Massa Corporal , Intervalos de Confiança , Doença das Coronárias/epidemiologia , Angiopatias Diabéticas/epidemiologia , Neuropatias Diabéticas/epidemiologia , Retinopatia Diabética/epidemiologia , Esquema de Medicação , Feminino , Hemoglobinas Glicadas/efeitos dos fármacos , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Insulina Glargina , Insulina de Ação Prolongada , Masculino , Pessoa de Meia-Idade , Neurite (Inflamação)/epidemiologiaRESUMO
Intentional insulin overdose in diabetic patients is a rather rare critical situation. We report the case of a patient suffering from type 1 diabetes who was found comatose with a plasma glucose close to zero after having injected herself massive doses of both aspart and glargine insulin analogues. The prevention of hypoglycaemic episodes in this patient required a long-term glucose infusion (i.e., 59 hours) which significantly exceeds the usual time-effect profile of glargine. This observation emphasizes again that clinicians should be aware of the extremely prolonged action of long acting insulin analogue glargine after intentional massive injection in order to avoid a too early interruption of glucose infusion and a subsequent risk of relapse of severe hypoglycaemic episodes.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Overdose de Drogas , Hipoglicemiantes/intoxicação , Insulina/análogos & derivados , Adulto , Glicemia/efeitos dos fármacos , Feminino , Glucose/administração & dosagem , Glucose/uso terapêutico , Humanos , Infusões Intravenosas , Insulina/administração & dosagem , Insulina/intoxicação , Insulina/uso terapêutico , Insulina Aspart , Insulina Glargina , Insulina de Ação ProlongadaRESUMO
Anorexic patients are prone to refuse treatment despite life-threatening complications. The therapist's ethical code can be torn between duty to protect life, and law that demands respect of the patient's autonomy. The age of these girls introduces a third participant in this ethical conflict with three characters: "the girl, her family and the physician". Even if her decision to refuse treatment can appear unreasonable, the patient suffering from anorexia nervosa remains "competent" to receive information concerning her state of health and to make up her own mind about what to do next. French law only recognises for the therapist a real duty to make efforts to convince the patient of the absolute necessity of treatment. However it appears important to confront these legal obligations with different situations created by the disease in order to help pave the way to finding medical solutions capable of conciliating the objective of the best treatment, the own ethical code of the physician and the respect of current legislation.
Assuntos
Anorexia Nervosa/psicologia , Conflito Psicológico , Ética Médica , Autonomia Pessoal , Recusa do Paciente ao Tratamento , Feminino , Humanos , Fatores de RiscoRESUMO
Scleredema of Buschke or scleredema diabetorum is a skin complication of diabetes with deposits of collagen and aminoglycans in the dermis. This disease characterized by thickening and hardening of the skin, is usually localized in nape, back and shoulder areas. Consequences could be a decrease in motility of the shoulders and an impairment of respiratory function. Other possible complications are sleep apnoea syndrome and monoclonal gammapathy. Type 1 or type 2 diabetes may be associated with scleredema of Buschke in more than 50% of cases. Diabetes-related risk factors are long duration of the disease, presence of microangiopathy, overweight and need of insulin. Various specific treatments proposed in the literature are poorly validated. In most severe cases, radiation therapy may be useful.
Assuntos
Complicações do Diabetes/epidemiologia , Escleredema do Adulto/epidemiologia , Dermatopatias/epidemiologia , Adulto , Complicações do Diabetes/patologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Humanos , Masculino , Escleredema do Adulto/patologia , Dermatopatias/patologiaRESUMO
A heteroplasmic T to C transition at nucleotide position 14709 in the mitochondrial tRNA glutamic acid (tRNA(Glu)) gene has previously been associated with maternally inherited diabetes and deafness (MIDD). To investigate the pathogenic mechanism of the T14709C mutation, we have constructed transmitochondrial cell lines by transferring fibroblasts mitochondria from a patient with the mutation into human cells lacking mitochondrial DNA (mtDNA) (rho degrees cells). Clonal cybrid cell lines were obtained containing various levels of the heteroplasmic mutation, or exclusively mutated or wild-type mtDNA. Measurement of respiratory chain enzymatic activities failed to detect a difference between the homoplasmic mutant and homoplasmic wild-type cybrid cell lines. However, a subtle decrease in the steady-state levels of tRNA(Glu) transcripts in some mutant clones. Our studies suggest that the T14709C mutation is insufficient to lead impairment of mitochondrial function in homoplasmic osteosarcoma cybrid clones, and that we cannot exclude that the T14709C mutation affects mitochondrial function by a yet unidentified mechanism.
Assuntos
DNA Mitocondrial/genética , Surdez/genética , Diabetes Mellitus/genética , Sequência de Bases , Northern Blotting , Fusão Celular , Células Clonais , Surdez/complicações , Complicações do Diabetes , Complexo I de Transporte de Elétrons , Complexo II de Transporte de Elétrons , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Fibroblastos/metabolismo , Genótipo , Humanos , Complexos Multienzimáticos/metabolismo , NADH NADPH Oxirredutases/metabolismo , Oxirredutases/metabolismo , Mutação Puntual , RNA de Transferência de Ácido Glutâmico/análise , Succinato Desidrogenase/metabolismoRESUMO
Plasma levels of pancreatic polypeptide (PP) were studied in a group of 22 normal and 22 obese subjects after an overnight fast. In a second group of 10 normal and 13 obese adults, PP secretion was stimulated by a protein-rich meal. The results indicate lower fasting PP values in the obese subjects and a decreased response during the second phase of the meal-induced secretion. This could suggest a possible role of PP in obesity.
Assuntos
Obesidade/sangue , Polipeptídeo Pancreático/sangue , Adulto , Glicemia , Dieta , Jejum , Feminino , Humanos , MasculinoRESUMO
The reg gene has previously been shown to be associated with regeneration of pancreatic islets. Strategies for influencing the replication and the growth of the beta-cell mass may be important for prevention and/or treatment of type I diabetes. In this study, we have examined the level of reg gene expression at various degrees of diabetogenesis in the pancreas of the NOD mouse (male, female, and cyclophosphamide-treated male) using both human reg cDNA as the probe and dot blot analysis. The expression of the reg gene was found to be significantly increased in female mice compared with male mice, and in both cases, the expression level was not influenced by age. Nondiabetic female mice have a significantly higher expression of the gene than diabetic female mice, and there was a positive correlation between the age of diabetes onset and the reg mRNA level. In addition, overexpression of the reg gene was found in male mice treated by cyclophosphamide, an agent known to be a potent inducer of diabetes in male NOD mice. None of these results were found in the diabetes-resistant control OF1 mice, in which pancreatic reg gene expression did not differ between female and male mice treated or untreated with cyclophosphamide. All of these data suggest that there is a strong correlation between reg gene expression in the pancreas of the NOD mouse and the likelihood of developing diabetes.