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1.
Nat Genet ; 9(3): 299-304, 1995 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-7773293

RESUMO

Non-insulin-dependent diabetes mellitus (NIDDM) affects about 5% of the world population. The disease presents a polygenic mode of inheritance, but mechanisms and genes involved in late-onset NIDDM are largely unknown. We report the association of a single heterozygous Gly to Ser missense mutation in the glucagon receptor gene with late-onset NIDDM. This mutation was highly associated with NIDDM in a pooled set of French and Sardinian patients (chi 2 = 14.4, P = 0.0001) and showed some evidence for linkage to diabetes in 18 sibships from 9 French pedigrees (chi 2 = 6.63, P < 0.01). Receptor binding studies using cultured cells expressing the Gly40Ser mutation demonstrate that this mutation results in a receptor which binds glucagon with a three-fold lower affinity compared to the wild type receptor.


Assuntos
Diabetes Mellitus Tipo 2/genética , Mutação Puntual , Receptores de Glucagon/genética , Primers do DNA/genética , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Ligação Genética , Glucagon/metabolismo , Heterozigoto , Humanos , Masculino , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Receptores de Glucagon/metabolismo
2.
Nat Genet ; 24(3): 291-5, 2000 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10700186

RESUMO

Type 2 diabetes is a polygenic and genetically heterogeneous disease . The age of onset of the disease is usually late and environmental factors may be required to induce the complete diabetic phenotype. Susceptibility genes for diabetes have not yet been identified. Islet-brain-1 (IB1, encoded by MAPK8IP1), a novel DNA-binding transactivator of the glucose transporter GLUT2 (encoded by SLC2A2), is the homologue of the c-Jun amino-terminal kinase-interacting protein-1 (JIP-1; refs 2-5). We evaluated the role of IBi in beta-cells by expression of a MAPK8IP1 antisense RNA in a stable insulinoma beta-cell line. A 38% decrease in IB1 protein content resulted in a 49% and a 41% reduction in SLC2A2 and INS (encoding insulin) mRNA expression, respectively. In addition, we detected MAPK8IP1 transcripts and IBi protein in human pancreatic islets. These data establish MAPK8IP1 as a candidate gene for human diabetes. Sibpair analyses performed on i49 multiplex French families with type 2 diabetes excluded MAPK8IP1 as a major diabetogenic locus. We did, however, identify in one family a missense mutation located in the coding region of MAPK8IP1 (559N) that segregated with diabetes. In vitro, this mutation was associated with an inability of IB1 to prevent apoptosis induced by MAPK/ERK kinase kinase 1 (MEKK1) and a reduced ability to counteract the inhibitory action of the activated c-JUN amino-terminal kinase (JNK) pathway on INS transcriptional activity. Identification of this novel non-maturity onset diabetes of the young (MODY) form of diabetes demonstrates that IB1 is a key regulator of 3-cell function.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Diabetes Mellitus Tipo 2/genética , Ilhotas Pancreáticas/metabolismo , Proteínas Nucleares/genética , Transativadores/genética , Idade de Início , Apoptose/genética , Ensaio de Unidades Formadoras de Colônias , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Efeito Fundador , França/epidemiologia , Predisposição Genética para Doença , Genótipo , Transportador de Glucose Tipo 2 , Humanos , Insulina/metabolismo , Secreção de Insulina , Insulinoma/genética , Insulinoma/metabolismo , Insulinoma/patologia , Proteínas Quinases JNK Ativadas por Mitógeno , Escore Lod , Sistema de Sinalização das MAP Quinases , Masculino , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Proteínas de Transporte de Monossacarídeos/metabolismo , Proteínas Nucleares/fisiologia , Obesidade/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Linhagem , Transativadores/fisiologia , Transcrição Gênica , Células Tumorais Cultivadas/metabolismo
3.
Diabetologia ; 53(12): 2562-8, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20711718

RESUMO

AIMS/HYPOTHESIS: Homozygosity for a five leucine repeat (5L-5L) in the carnosinase gene (CNDP1) has been found to be cross-sectionally associated with a low frequency of diabetic nephropathy (DN), mainly in type 2 diabetes. We prospectively investigated in patients with type 1 diabetes whether: (1) 5L-5L is associated with mortality; (2) there is an interaction of 5L-5L with DN or sex for prediction of mortality; and (3) 5L-5L is associated with progression to end-stage renal disease (ESRD). METHODS: In this prospective study in white European patients with type 1 diabetes, individuals with DN were defined by persistent albuminuria ≥ 300 mg/24 h. Controls without nephropathy were defined by persistent (>15 years) normoalbuminuria < 30 mg/24 h. Leucine repeats were assessed with a fluorescent DNA analysis system. Onset of ESRD was defined by need to start chronic dialysis or kidney transplantation. RESULTS: The study involved 916 patients with DN and 1,170 controls. During follow-up for 8.8 years, 107 patients (14%) with 5L-5L died compared with 182 patients (13.8%) with other genotypes (p = 0.99). There was no significant interaction of 5L-5L with DN for prediction of mortality (p = 0.57), but a trend towards interaction with sex (p = 0.08). In patients with DN, HR for ESRD in 5L-5L vs other genotypes was not constant over time, with increased risk for 5L-5L beyond 8 years of follow-up (p = 0.03). CONCLUSIONS/INTERPRETATION: CNDP1 polymorphism was not associated with mortality, and nor was there an interaction of this polymorphism with DN for prediction of mortality in patients with type 1 diabetes. CNDP1 polymorphism predicts progression to ESRD in patients with DN, but only late after baseline measurements.


Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/mortalidade , Nefropatias Diabéticas/genética , Dipeptidases/genética , Falência Renal Crônica/genética , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/diagnóstico , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/mortalidade , Progressão da Doença , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/etiologia , Falência Renal Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/fisiologia , Prognóstico , Análise de Sobrevida , População Branca/genética
4.
Obes Surg ; 30(4): 1332-1338, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31754925

RESUMO

PURPOSE: Roux en Y gastric bypass surgery (RYGB) is an effective therapy for patients with severe obesity. It induces both significant weight loss and rapid improvements of metabolic complications. This study was undertaken to better define the direct role of weight loss in the metabolic improvements. METHODS: A retrospective, case-control study of a cohort of 649 patients with obesity who underwent RYGB, comparing higher and lower responders at 2 years after surgery (n = 100 pairs). Pairs of patients were matched for age, gender, and initial BMI. The rates of remission of diabetes, hypertension, dyslipidemia, and hyperuricemia were compared using a mixed effects logistic regression analysis. RESULTS: Diabetes before surgery was present in 12/100 lower responders and 17/100 higher responders. Remission at 2 years was observed in 4/12 (33%) of lower responders, compared to 15/17 (88%) of higher responders. Thus, the odds of diabetes remission was significantly smaller in lower responders (OR = 0.067, 95% CI 0.01-0.447). A mixed model regression analysis of all the parameters for each patient showed that the odds of achieving remission of any comorbidity was significantly lower in lower responders (OR = 0.62, 95% CI = 0.39-0.97). CONCLUSION: We could demonstrate that weight loss is a significant determinant of the remission of diabetes 2 years after RYGB. These data underline the importance of weight loss in the benefits of this procedure.


Assuntos
Cirurgia Bariátrica , Diabetes Mellitus Tipo 2 , Diabetes Mellitus , Derivação Gástrica , Obesidade Mórbida , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/cirurgia , Humanos , Obesidade Mórbida/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Redução de Peso
5.
Diabetologia ; 52(12): 2590-3, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19834686

RESUMO

AIMS/HYPOTHESIS: Hyperglycaemia increases oxidative stress and may thereby increase the risk of diabetic complications, including diabetic nephropathy. Cells are protected from oxidative damage by, for example, the manganese superoxide dismutase enzyme (MnSOD), but the functional polymorphism V16A affects the localisation of MnSOD and therefore its ability to scavenge superoxide radicals. In a Danish cohort of type 1 diabetes patients, we sought to confirm previous findings of association between the V allele and the risk of diabetic nephropathy and to investigate the influence of this polymorphism on the development of cardiovascular disease. METHODS: Type 1 diabetes patients attending the Steno Diabetes Center, Gentofte, Denmark, between 1993 and 2001 were enrolled in this study. A total of 441 cases with diabetic nephropathy (albumin excretion > or =300 mg/24 h) and 314 controls with persistent normoalbuminuria (<30 mg/24 h), despite diabetes of duration > or =20 years, were identified. The median duration of diabetes was 35 years (range 12-73 years). RESULTS: We confirmed the significant association between carrier status of the V allele and diabetic nephropathy. The association was independent of age at diabetes onset, HbA(1c), sex, smoking and diabetes duration (OR 1.7, 95% CI 1.2-2.4). The VV and AV genotypes considered together also predicted the risk of cardiovascular disease, independently of age at follow-up, HbA(1c), sex, smoking, systolic blood pressure, cholesterol and nephropathy status. The hazard ratio was 1.6 (95% CI 1.0-2.5). CONCLUSIONS/INTERPRETATION: The MnSOD V16A polymorphism is involved in the development of nephropathy caused by type 1 diabetes and seems to predict cardiovascular disease during follow-up.


Assuntos
Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 1/genética , Angiopatias Diabéticas/genética , Nefropatias Diabéticas/genética , Polimorfismo de Nucleotídeo Único , Superóxido Dismutase/genética , Adulto , Albuminúria/sangue , Pressão Sanguínea , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/epidemiologia , Ponte de Artéria Coronária/estatística & dados numéricos , Complicações do Diabetes/enzimologia , Complicações do Diabetes/genética , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/enzimologia , Angiopatias Diabéticas/enzimologia , Angiopatias Diabéticas/epidemiologia , Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/epidemiologia , Seguimentos , Hemoglobinas Glicadas/metabolismo , Humanos , Falência Renal Crônica/enzimologia , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/genética , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/genética , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética
6.
J Clin Invest ; 93(3): 1120-30, 1994 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8132752

RESUMO

Pancreatic beta-cell function was studied in six subjects with mutations in the enzyme glucokinase (GCK) who were found to have elevated fasting and postprandial glucose levels in comparison to six normoglycemic controls. Insulin secretion rates (ISRs) were estimated by deconvolution of peripheral C-peptide values using a two-compartment model and individual C-peptide kinetics obtained after bolus intravenous injections of biosynthetic human C-peptide. First-phase insulin secretory responses to intravenous glucose and insulin secretion rates over a 24-h period on a weight maintenance diet were not different in subjects with GCK mutations and controls. However, the dose-response curve relating glucose and ISR obtained during graded intravenous glucose infusions was shifted to the right in the subjects with GCK mutations and average ISRs over a glucose range between 5 and 9 mM were 61% lower than those in controls. In the controls, the beta cell was most sensitive to an increase in glucose at concentrations between 5.5 and 6.0 mM, whereas in the patients with GCK mutations the point of maximal responsiveness was increased to between 6.5 and 7.5 mM. Even mutations that resulted in mild impairment of in vitro enzyme activity were associated with a > 50% reduction in ISR. The responsiveness of the beta cell to glucose was increased by 45% in the subjects with mutations after a 42-h intravenous glucose infusion at a rate of 4-6 mg/kg per min. During oscillatory glucose infusion with a period of 144 min, profiles from the subjects with mutations revealed reduced spectral power at 144 min for glucose and ISR compared with controls, indicating decreased ability to entrain the beta cell with exogenous glucose. In conclusion, subjects with mutations in GCK demonstrate decreased responsiveness of the beta cell to glucose manifest by a shift in the glucose ISR dose-response curve to the right and reduced ability to entrain the ultradian oscillations of insulin secretion with exogenous glucose. These results support a key role for the enzyme GCK in determining the in vivo glucose/ISR dose-response relationships and define the alterations in beta-cell responsiveness that occur in subjects with GCK mutations.


Assuntos
Glucoquinase/genética , Hiperglicemia/metabolismo , Insulina/metabolismo , Mutação , Adolescente , Adulto , Peptídeo C/metabolismo , Feminino , Glucose/farmacologia , Teste de Tolerância a Glucose , Humanos , Secreção de Insulina , Masculino , Pessoa de Meia-Idade
7.
J Clin Invest ; 101(3): 521-6, 1998 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-9449683

RESUMO

Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous disorder characterized by hyperglycemia resulting from defects in insulin secretion and action. Recent studies have found mutations in the hepatocyte nuclear factor-4 alpha gene (HNF-4alpha) in families with maturity-onset diabetes of the young (MODY), an autosomal dominant form of diabetes characterized by early age at onset and a defect in glucose-stimulated insulin secretion. During the course of our search for susceptibility genes contributing to the more common late-onset NIDDM forms, we observed nominal evidence for linkage between NIDDM and markers in the region of the HNF-4alpha/MODY1 locus in a subset of French families with NIDDM diagnosed before 45 yr of age. Thus, we screened these families for mutations in the HNF-4alpha gene. We found a missense mutation, resulting in a valine-to-isoleucine substitution at codon 393 in a single family. This mutation cosegregated with diabetes and impaired insulin secretion, and was not present in 119 control subjects. Expression studies showed that this conservative substitution is associated with a marked reduction of transactivation activity, a result consistent with this mutation contributing to the insulin secretory defect observed in this family.


Assuntos
Proteínas de Ligação a DNA , Diabetes Mellitus Tipo 2/genética , Proteínas Nucleares , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Mutação Puntual , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ativação Transcricional , Idade de Início , Animais , Apolipoproteína C-III , Apolipoproteínas C/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Células COS , Feminino , Teste de Tolerância a Glucose , Fator 1 Nuclear de Hepatócito , Fator 1-alfa Nuclear de Hepatócito , Fator 1-beta Nuclear de Hepatócito , Fator 4 Nuclear de Hepatócito , Humanos , Insulina/metabolismo , Secreção de Insulina , Isoleucina/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Timidina Quinase/genética , Distribuição Tecidual , Valina/genética
8.
Diabetes ; 42(6): 930-2, 1993 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8495815

RESUMO

We have identified a simple tandem repeat DNA polymorphism in the human glycogen synthase gene of the form (TG)n. This DNA polymorphism has 10 alleles and a heterozygosity of 0.82 and can be easily typed using the polymerase chain reaction. It has been localized within the framework genetic map of chromosome 19 and is located in the region of the apolipoprotein C-II and histidine-rich calcium-binding protein genes. This DNA polymorphism will facilitate genetic studies of the role of the glycogen synthase gene in the development of insulin resistance and NIDDM.


Assuntos
Cromossomos Humanos Par 19 , DNA/genética , Glicogênio Sintase/genética , Polimorfismo Genético/genética , Sequências Repetitivas de Ácido Nucleico/genética , Sequência de Bases , Mapeamento Cromossômico , DNA/isolamento & purificação , Ligação Genética , Marcadores Genéticos , Humanos , Masculino , Dados de Sequência Molecular
9.
Diabetes ; 44(10): 1202-8, 1995 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-7556958

RESUMO

Glucose-dependent insulinotropic polypeptide (GIP) is a hormone secreted by the endocrine K-cells from the duodenum that stimulates glucose-induced insulin secretion. Here, we present the molecular characterization of the human pancreatic islet GIP receptor. cDNA clones for the GIP receptor were isolated from a human pancreatic islet cDNA library. They encoded two different forms of the receptor, which differed by a 27-amino acid insertion in the COOH-terminal cytoplasmic tail. The receptor protein sequence was 81% identical to that of the rat GIP receptor. When expressed in Chinese hamster lung fibroblasts, both forms of the receptor displayed high-affinity binding for GIP (180 and 600 pmol/l). GIP binding was displaced by < 20% by 1 mumol/l glucagon, glucagon-like peptide (GLP-I)(7-36) amide, vasoactive intestinal peptide, and secretin. However exendin-4 and exendin-(9-39) at 1 mumol/l displaced binding by approximately 70 and approximately 100% at 10 mumol/l. GIP binding to both forms of the receptor induced a dose-dependent increase in intracellular cAMP levels (EC50 values of 0.6-0.8 nmol/l) but no elevation of cytoplasmic calcium concentrations. Interestingly, both exendin-4 and exendin-(9-39) were antagonists of the receptor, inhibiting GIP-induced cAMP formation by up to 60% when present at a concentration of 10 mumol/l. Finally, the physical and genetic chromosomal localization of the receptor gene was determined to be on 19q13.3, close to the ApoC2 gene. These data will help study the physiology and pathophysiology of the human GIP receptor.


Assuntos
Cromossomos Humanos Par 19 , Ilhotas Pancreáticas/metabolismo , Polimorfismo de Fragmento de Restrição , Receptores dos Hormônios Gastrointestinais/biossíntese , Receptores dos Hormônios Gastrointestinais/genética , Sequência de Aminoácidos , Animais , Apolipoproteína C-II , Apolipoproteínas C/genética , Cálcio/metabolismo , Mapeamento Cromossômico , Clonagem Molecular , AMP Cíclico/metabolismo , Desoxirribonucleases de Sítio Específico do Tipo II , Polipeptídeo Inibidor Gástrico/metabolismo , Expressão Gênica , Biblioteca Gênica , Ligação Genética , Glucose/farmacologia , Humanos , Hibridização in Situ Fluorescente , Cinética , Dados de Sequência Molecular , Ratos , Receptores dos Hormônios Gastrointestinais/efeitos dos fármacos , Mapeamento por Restrição , Homologia de Sequência de Aminoácidos
10.
Diabetes ; 50(5): 1214-8, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11334430

RESUMO

Advanced glycation end-products (AGEs) may play an important role in the pathogenesis and progression of cardiovascular and renal complications of diabetes. Four putative AGE receptors (RAGEs), AGE-R1, AGE-R2, and AGE-R3 have been described. In this study, we scanned the sequence of the genes encoding these AGE receptors in 48 patients with type 1 diabetes and investigated the identified polymorphisms (n = 19) in 199 type 1 diabetic patients with nephropathy and 193 type 1 diabetic patients without nephropathy. Overall, none of the polymorphisms was strongly associated with nephropathy. The minor allele of a polymorphism located in the promoter region of the RAGE gene (C-1152A) conferred a weak protective effect (P < 0.05) and was associated with a longer duration of nephropathy-free diabetes (P = 0.08).


Assuntos
Diabetes Mellitus Tipo 1/genética , Nefropatias Diabéticas/genética , Polimorfismo Genético , Receptores Imunológicos/genética , Regiões 5' não Traduzidas/genética , Adolescente , Adulto , Idade de Início , Mapeamento Cromossômico , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 6 , Diabetes Mellitus Tipo 1/fisiopatologia , Testes Genéticos , Produtos Finais de Glicação Avançada/metabolismo , Homozigoto , Humanos , Mutação Puntual , Regiões Promotoras Genéticas , Isoformas de Proteínas/genética , Receptor para Produtos Finais de Glicação Avançada
11.
Diabetes ; 44(10): 1243-7, 1995 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-7556965

RESUMO

Non-insulin-dependent diabetes mellitus (NIDDM) is a clinically and genetically heterogeneous disorder. Maturity-onset diabetes of the young (MODY), an autosomal dominant form of NIDDM, has been used as a model for genetic studies of NIDDM. We recently reported linkage between markers on chromosome 12q and diabetes in 25% of our French MODY families. To evaluate if this gene is also implicated in late-onset NIDDM, we performed linkage studies between two markers of the MODY region and diabetes in 172 families with late-onset NIDDM. Both parametric and nonparametric methods were used in a total of 600 affected sib-pairs. Linkage was rejected in this population by all methods, implying that the MODY gene on chromosome 12q is not a major gene for late-onset NIDDM in this population. However, we cannot exclude a modifying role in a polygenic disorder or an important role in some families.


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 12 , Diabetes Mellitus Tipo 2/genética , Ligação Genética , Adulto , Fatores Etários , Idade de Início , Sequência de Bases , Primers do DNA , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Genes Dominantes , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Pais , Reação em Cadeia da Polimerase , Caracteres Sexuais
12.
Diabetes ; 43(3): 389-95, 1994 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-7508874

RESUMO

Maturity-onset diabetes of the young (MODY) is a model for genetic studies of non-insulin-dependent diabetes mellitus. We have identified 15 MODY families in which diabetes is not the result of mutations in the glucokinase gene. This cohort of families will be useful for identifying other diabetes-susceptibility genes. Nine other candidate genes potentially implicated in insulin secretion or insulin action have been tested for linkage with MODY in these families, including glucokinase regulatory protein, hexokinase II, insulin receptor substrate 1, fatty acid-binding protein 2, glucagon-like peptide-1 receptor, apolipoprotein C-II, glycogen synthase, adenosine deaminase (a marker for the MODY gene on chromosome 20), and phosphoenolpyruvate carboxykinase. None of these loci showed evidence for linkage with MODY, implying that mutations in these genes do not make a major genetic contribution to the development of MODY. In addition to these linkage analyses, one or two affected subjects from each family were screened for the presence of the A to G mutation at nucleotide 3,243 of the mitochondrial tRNA(Leu(UUR)) gene. This mutation was not found in any of these subjects. Finally, we report the localization of the gene encoding the regulatory protein of glucokinase to chromosome 2, band p22.3 and the identification of a restriction fragment length polymorphism at this locus.


Assuntos
Diabetes Mellitus Tipo 2/genética , Adolescente , Adulto , Fatores Etários , Idoso , Sequência de Bases , Criança , Pré-Escolar , Mapeamento Cromossômico , Cromossomos Humanos Par 2 , Feminino , Ligação Genética , Glucoquinase/antagonistas & inibidores , Glucoquinase/genética , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Linhagem , Polimorfismo de Fragmento de Restrição , Proteínas/genética , RNA/genética , RNA Mitocondrial , RNA de Transferência de Leucina/genética
13.
Diabetes ; 42(9): 1238-45, 1993 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-8349034

RESUMO

Mutations in the glucokinase gene are a major cause of maturity-onset diabetes of the young. To evaluate the contribution of this gene to the development of late-onset NIDDM, linkage analyses between DNA polymorphisms at the glucokinase locus and NIDDM were performed in 79 multigenerational French families. In addition, all exons and the islet promoter region of glucokinase gene from 1 affected member from each family as well as from 17 unrelated women with previous gestational diabetes were amplified by polymerase chain reaction and screened for mutations by single-strand conformational polymorphism and DNA sequencing. Linkage of glucokinase and NIDDM was significantly rejected under all models tested. However, in 1 family, the lod score was 2.30, and we found a nucleotide substitution at the position -30 in the islet promoter region that cosegregated with diabetes. The proband of this family was a gestational diabetic individual. No other mutation in glucokinase was found in the 79 NIDDM families. We identified a missense mutation (TGG257-->CGG257) in exon 7 of glucokinase gene from 1 of 17 women with gestational diabetes, which was present in all diabetic members of her family. This family is likely to be a cryptic maturity-onset diabetes of the young, as 4 younger members, carrying this mutation, were subsequently found to be hyperglycemic. In conclusion, no evidence was obtained to incriminate glucokinase as a major gene for late age of onset NIDDM. Diabetic families with mutations in glucokinase must be carefully investigated, to differentiate cryptic maturity-onset diabetes of the young from late-onset NIDDM. Furthermore, pregnancy reveals diabetes in women carrying a glucokinase defect.


Assuntos
Diabetes Mellitus Tipo 2/genética , Ligação Genética , Glucoquinase/genética , Mutação , Adolescente , Adulto , Idoso , Sequência de Bases , Criança , DNA de Cadeia Simples/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Genético , Gravidez , Gravidez em Diabéticas/genética
14.
Diabetes ; 42(6): 937-40, 1993 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8495817

RESUMO

Recent studies have shown that mutations in the glucokinase gene on chromosome 7 can cause an autosomal dominant form of NIDDM with a variable clinical phenotype and onset during childhood. The variable clinical phenotype includes mild fasting hyperglycemia (i.e., a plasma glucose value of > 110 mg/dl, a value that is at least 2-3 SDs above normal), impaired glucose tolerance, gestational diabetes mellitus, as well as overt NIDDM as defined using National Diabetes Data Group or World Health Organization criteria. Because gestational diabetes mellitus was a clinical feature associated with glucokinase mutations, we have screened a group of women with gestational diabetes who also had a first-degree relative with diabetes mellitus for the presence of mutations in this gene. Among 40 subjects, we identified two mutations, suggesting a prevalence of approximately 5% in this group. Extrapolating from this result, the prevalence of glucokinase-deficient NIDDM among Americans may be approximately 1 in 2500.


Assuntos
Diabetes Gestacional/enzimologia , Glucoquinase/genética , Mutação Puntual , Sequência de Aminoácidos , Sequência de Bases , Diabetes Gestacional/genética , Feminino , Humanos , Dados de Sequência Molecular , Gravidez
15.
Diabetes ; 46(6): 1062-8, 1997 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9166680

RESUMO

As part of an ongoing search for susceptibility loci for NIDDM, we tested 19 genes whose products are implicated in insulin secretion or action for linkage with NIDDM. Loci included the G-protein-coupled inwardly rectifying potassium channels expressed in beta-cells (KCNJ3 and KCNJ7), glucagon (GCG), glucokinase regulatory protein (GCKR), glucagon-like peptide I receptor (GLP1R), LIM/homeodomain islet-1 (ISL1), caudal-type homeodomain 3 (CDX3), proprotein convertase 2 (PCSK2), cholecystokinin B receptor (CCKBR), hexokinase 1 (HK1), hexokinase 2 (HK2), mitochondrial FAD-glycerophosphate dehydrogenase (GPD2), liver and muscle forms of pyruvate kinase (PKL, PKM), fatty acid-binding protein 2 (FABP2), hepatic phosphofructokinase (PFKL), protein serine/threonine phosphatase 1 beta (PPP1CB), and low-density lipoprotein receptor (LDLR). Additionally, we tested the histidine-rich calcium locus (HRC) on chromosome 19q. All regions were tested for linkage with microsatellite markers in 751 individuals from 172 families with at least two patients with overt NIDDM (according to World Health Organization criteria) in the sibship, using nonparametric methods. These 172 families comprise 352 possible affected sib pairs with overt NIDDM or 621 possible affected sib pairs defined as having a fasting plasma glucose value of >6.1 mmol/l or a glucose value of >7.8 mmol/l 2 h after oral glucose load. No evidence for linkage was found with any of the 19 candidate genes and NIDDM in our population by nonparametric methods, suggesting that those genes are not major contributors to the pathogenesis of NIDDM. However, some evidence for suggestive linkage was found between a more severe form of NIDDM, defined as overt NIDDM diagnosed before 45 years of age, and the CCKBR locus (11p15.4; P = 0.004). Analyses of six additional markers spanning 27 cM on chromosome 11p confirmed the suggestive linkage in this region. Whether an NIDDM susceptibility gene lies on chromosome 11p in our population must be determined by further analyses.


Assuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 2/genética , Diabetes Mellitus Tipo 2/genética , Fatores Etários , Alelos , Sequência de Bases , Índice de Massa Corporal , Estudos de Coortes , Primers do DNA/química , Família , França , Ligação Genética , Marcadores Genéticos/genética , Humanos , Modelos Genéticos , Modelos Estatísticos , Dados de Sequência Molecular , Polimorfismo Genético , Sequências Repetitivas de Ácido Nucleico
16.
Diabetes ; 46(4): 688-94, 1997 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9075812

RESUMO

The sulfonylurea receptor (SUR) is a key component in glucose-stimulated insulin secretion. Obesity and NIDDM are frequently associated and share some metabolic abnormalities, suggesting that they might also share some susceptibility genes. Thus, the SUR encoding gene is a plausible candidate for a primary pancreatic beta-cell defect and thus for hyperglycemia and weight gain. Through association and linkage studies, we have investigated the potential role of the SUR gene in families with NIDDM and in two independent sets of morbidly obese families. The exon 22 T-allele at codon 761 was more common in patients with NIDDM (7.7%) and morbid obesity (7.8%) than in control subjects (1.8%, P = 0.030 and P = 0.023, respectively). This variant was associated with morbid obesity (odds ratio 3.71, P = 0.017) and NIDDM (odds ratio 2.20, P = 0.04; association dependent on BMI). Although the frequencies for intron 24 variant were similar in all groups, morbidly obese patients homozygous for the c-allele had a more deleterious form of obesity. Sib-pair linkage studies with NIDDM in French Caucasian families gave no evidence for linkage to the SUR locus. However, in one set of the obese families, we found an indication for linkage with a SUR-linked microsatellite marker (D11S419, P = 0.0032). We conclude that in Caucasians, the SUR locus may contribute to the genetic susceptibility to NIDDM and obesity.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Cromossomos Humanos Par 11/genética , Diabetes Mellitus Tipo 2/genética , Obesidade Mórbida/genética , Canais de Potássio Corretores do Fluxo de Internalização , Canais de Potássio/genética , Receptores de Droga/genética , População Branca/genética , Adulto , Mapeamento Cromossômico , Estudos de Coortes , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , França/epidemiologia , Frequência do Gene , Genótipo , Humanos , Modelos Logísticos , Masculino , Obesidade Mórbida/etnologia , Obesidade Mórbida/fisiopatologia , Receptores de Sulfonilureias
17.
Diabetes ; 45(4): 478-87, 1996 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-8603770

RESUMO

An A-to-G transition in the mitochondrial tRNALeu(UUR) gene at base pair 3243 has been shown to be associated with the maternally transmitted clinical phenotype of NIDDM and sensorineural hearing loss in white and Japanese pedigrees. We have detected this mutation in 25 of 50 tested members of five white French pedigrees. Affected (mutation-positive) family members presented variable clinical features, ranging from normal glucose tolerance (NGT) to insulin-requiring diabetes. The present report describes the clinical phenotypes of affected members and detailed evaluations of insulin secretion and insulin sensitivity in seven mutation-positive individuals who have a range of glucose tolerance from normal (n = 3) to impaired (n = 1) to NIDDM (n = 3). Insulin secretion was evaluated during two experimental protocols: the first involved the measurement of insulin secretory responses during intravenous glucose tolerance test, hyperglycemic clamp, and intravenous injection of arginine. The second consisted of the administration of graded and oscillatory infusions of glucose and studies to define C-peptide kinetics. This protocol was aimed at assessing two sensitive measures of beta-cell dysfunction: the priming effect of glucose on the glucose-insulin secretion rate (ISR) dose-response curve and the ability of oscillatory glucose infusion to entrain insulin secretory oscillations. Insulin sensitivity was assessed by euglycemic-hyperinsulinemic clamp. Evaluation of insulin secretion demonstrated a large degree of between- and within-subject variability. However, all subjects, including those with NGT, demonstrated abnormal insulin secretion on at least one of the tests. In the four subjects with normal or impaired glucose tolerance, glucose failed to prime the ISR response, entrainment of ultradian insulin secretory oscillations was abnormal, or both defects were present. The response to arginine was always preserved, including in subjects with NIDDM. Insulin resistance was observed only in the subjects with overt diabetes. In conclusion, the pathophysiological mechanisms responsible for the development of NIDDM and insulin-requiring diabetes in this syndrome are complex and might include defects in insulin production, glucose toxicity, and insulin resistance. However, our data suggest that a defect of glucose-regulated insulin secretion is an early possible primary abnormality in carriers of the mutation. This defect might result from the progressive reduction of oxidative phosphorylation and implicate the glucose-sensing mechanism of beta-cells.


Assuntos
Surdez/genética , Diabetes Mellitus Tipo 2/genética , Insulina/metabolismo , Mutação Puntual , RNA de Transferência de Leucina/genética , Adenina , Adolescente , Adulto , Idoso , Arginina , Glicemia/metabolismo , Índice de Massa Corporal , Peptídeo C/sangue , Criança , Pré-Escolar , Surdez/sangue , Surdez/fisiopatologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Impressão Genômica , Teste de Tolerância a Glucose , Hemoglobinas Glicadas/análise , Guanina , Humanos , Insulina/sangue , Insulina/farmacologia , Secreção de Insulina , Masculino , Pessoa de Meia-Idade , Linhagem , Periodicidade , Fenótipo , Valores de Referência , Caracteres Sexuais
18.
Trends Endocrinol Metab ; 4(3): 86-90, 1993 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18407139

RESUMO

The enzyme glucokinase catalyzes the phosphorylation of glucose and plays a key role in the regulation o f insulin secretion by pancreatic beta cells and glucose disposal in hepatocytes. Recent studies have shown that mutations in the gene encoding this key regulatory enzyme of glycolysis are a common cause of an autosomal dominant form of non-insulin-dependent (type 2) diabetes mellitus that has an onset often during childhood. The association of mutations in the glucokinase gene with impaired pancreatic cell function underscores the importance of glycolysis in the regulation of insulin secretion and suggests that mutations in other genes expressed in the beta-cell that also control rate-limiting steps in glucose metabolism may lead to diabetes.

19.
J Hypertens ; 15(6): 601-6, 1997 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9218178

RESUMO

OBJECTIVE: To determine whether angiotensinogen (AGT) and angiotensin II type 1 (AT1) receptor genes contribute to the development of arterial hypertension in members of French Caucasian families and in subjects with hypertension associated with non-insulin-dependent diabetes mellitus (NIDDM). METHODS: Sibpair linkage analyses were performed with microsatellites near the AGT and AT1 receptor genes in 179 hypertensive sibpairs from 69 NIDDM kindreds. In addition, population/association studies were performed with the M235T and T174M polymorphisms of the AGT gene, and the A1166C polymorphism of the AT1 receptor gene. RESULTS: No evidence for linkage between the AGT and AT1 receptor loci and hypertension was observed. In addition, the distributions of genotypes of AGT and AT1 receptor gene polymorphisms did not differ significantly among a group of unrelated individuals with both hypertension and NIDDM (n = 188) and three groups of unrelated control subjects with NIDDM (n = 117), hypertension (n = 75) or none of these conditions (n = 125). CONCLUSIONS: These results suggest that the AGT and AT1 receptor genes are not major genetic determinants of hypertension associated with NIDDM in this population, although we can not exclude the possibility that these loci make a minor contribution in a polygenic context.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Hipertensão/complicações , Hipertensão/genética , Sistema Renina-Angiotensina/genética , Idoso , Angiotensinogênio/genética , Angiotensinogênio/fisiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Ligação Genética , Genótipo , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , Receptores de Angiotensina/genética , Receptores de Angiotensina/fisiologia , Sistema Renina-Angiotensina/fisiologia
20.
Diabetes Metab ; 22(6): 451-4, 1996 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8985654

RESUMO

There is strong evidence that non-insulin-dependent-diabetes mellitus (NIDDM) has a polygenic mode of inheritance. Nevertheless, major gene effects may be involved in its pathogenesis, especially in forms with an early age of onset. We performed linkage analyses between 4 candidate genes for insulin resistance and NIDDM in a set of 55 multigenerational French Caucasian families, using the affected sib-pair approach. No significant results were obtained with glycogen synthase (GSY), insulin receptor substrate-1 (IRS-1) and apolipoprotein C-II (APOC-II) genes. However, a significant trend towards linkage was found between NIDDM and the phosphoenolpyruvate carboxykinase gene (PCK1) located on chromosome 20q (p = 0.005 for the mean estimated proportion of alleles shared identically by descent, mean IBD = 0.55), particularly among sib-pairs with diabetes diagnosed before the age of 46 years (p = 0.0003, mean IBD = 0.66). These results suggest that the PCK1 gene or a nearby locus contributes to the development of NIDDM in the French population.


Assuntos
Cromossomos Humanos Par 20 , Diabetes Mellitus Tipo 2/genética , Ligação Genética , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Alelos , Apolipoproteína C-II , Apolipoproteínas C/genética , Mapeamento Cromossômico , Diabetes Mellitus Tipo 2/enzimologia , Feminino , França , Glicogênio Sintase/genética , Humanos , Proteínas Substratos do Receptor de Insulina , Resistência à Insulina/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Fosfoproteínas/genética , População Branca
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