RESUMEN

Defective function of antigen-presenting cells has been postulated to be one of the non-HLA-linked susceptibility factors for type 1 diabetes mellitus, though the underlying genetic factors remain unclear. SLC11A1 (formerly NRAMP1), a divalent cation transporter, plays a crucial role in macrophage activation. We performed a case-control study in 224 healthy and 95 type 1 diabetic Japanese subjects, examining the length polymorphisms in the promoter region (-377 to -222) of SLC11A1, which may influence transcriptional activity. Alleles designated 2, 3, and 7 have been identified in Japanese subjects. The frequency of allele 7 was significantly higher in subjects with type 1 diabetes (9.47%) than in the healthy controls (4.46%). The difference is more marked in the subpopulation of Japanese subjects with type 1 diabetes; diabetic subjects with at least one protective HLA class II allele and those without any susceptibility HLA class II haplotypes, DR4-DQ4 or DR9-DQ9, had a much higher allele 7 frequency than controls. These findings suggest that the novel promoter polymorphism of SLC11A1 influences the susceptibility to type 1 diabetes in Japanese subjects.

Asunto(s)

Proteínas de Transporte de Catión/genética , Diabetes Mellitus Tipo 1/genética , Predisposición Genética a la Enfermedad , Polimorfismo Genético , Regiones Promotoras Genéticas/genética , Adolescente , Adulto , Alelos , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Genotipo , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Haplotipos/genética , Humanos , Lactante , Japón , Masculino

RESUMEN

AIM/HYPOTHESIS: Urotensin II is a potent vasoactive hormone and the urotensin II gene (UTS2) is localized to 1p36-p32, one of the regions reported to show possible linkage with Type 2 diabetes in Japanese subjects. The aim of this study is to investigate a possible contribution of SNPs in the UTS2 gene to the development of Type 2 diabetes. METHODS: We surveyed SNPs in the UTS2 gene in 152 Japanese subjects with Type 2 diabetes mellitus and two control Japanese cohorts: one consisting of 122 elderly subjects who met stringent criteria for being non-diabetic, including being older than 60 years of age with no evidence of diabetes (HbA(1c)<5.6%), and another 268 subjects with normal glucose tolerance. RESULTS: We identified two SNPs with amino acid substitutions, designated T21M and S89N. The allele frequency of 89N was higher in Type 2 diabetic patients than in both elderly normal subjects (p=0.0018) and subjects with normal glucose tolerance (p=0.0011), whereas the allele frequency of T21M was essentially identical in these three groups. Furthermore, in the subjects with normal glucose tolerance, 89N was associated with higher insulin concentrations on oral glucose tolerance test, suggesting reduced insulin sensitivity in subjects with 89N. CONCLUSION/INTERPRETATION: These results strongly suggest that the S89N polymorphism in the UTS2 gene is associated with the development of Type 2 diabetes, via insulin sensitivity, in Japanese subjects.

Asunto(s)

Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad/genética , Intolerancia a la Glucosa/genética , Polimorfismo de Nucleótido Simple , Urotensinas/genética , Anciano , Empalme Alternativo , Pueblo Asiatico/genética , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Amplificación de Genes , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/sangre , Resistencia a la Insulina/genética , Japón , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción

RESUMEN

AIMS/HYPOTHESIS: The increased oxidative stress in diabetes is known to contribute to the progression of diabetes and its complications. We have reported a significant relation between the content of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a product of oxidative DNA damage in urine or leukocytes and the severity of diabetic nephropathy and retinopathy [1]. We investigated whether 8-oxodG in urine or leukocytes is associated with the progression of diabetic nephropathy. METHODS: We measured urinary 8-oxodG contents at entry and carried out a prospective longitudinal study to assess the progression of nephropathy over 5 years. RESULTS: There was a significant progression of diabetic nephropathy in the patients with higher excretion of 8-oxodG in urine compared with the patients with moderate or lower excretion of 8-oxodG. There was no significant association between the leukocyte 8-oxodG contents and the development of nephropathy. The multivariate logistic regression analysis suggests that the urinary 8-oxodG was the strongest predictor of nephropathy among several known risk factors. CONCLUSION/INTERPRETATION: This study provides evidence that increased oxidative stress has a primary role in the pathogenesis of diabetic nephropathy. A local enhancement of oxidative stress in diabetic kidney might explain the possible linkage between the increased urinary excretion of 8-oxodG and the development of nephropathy. 8-oxodG in urine is a useful clinical marker to predict the development of diabetic nephropathy in diabetic patients.

Asunto(s)

Biomarcadores/orina , Desoxiadenosinas/orina , Diabetes Mellitus Tipo 2/orina , Nefropatías Diabéticas/diagnóstico , Edad de Inicio , Nefropatías Diabéticas/orina , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Valores de Referencia , Factores de Tiempo

RESUMEN

A high association between type 2 diabetes mellitus and depressive illness has been reported. Insulin resistance during depressive illness might contribute to the linkage between depression and type 2 diabetes. To determine whether the genetic polymorphisms of the tyrosine hydroxylase ([TH] HUMTH01) and insulin (INS-VNTR) genes contribute to insulin resistance in depressive illness, we analyzed the association between the polymorphisms and insulin resistance in 41 Japanese patients with depressive disorder, 204 normal control subjects, 161 cohort subjects with normal glucose tolerance (NGT) and without depressive symptomatology, and 59 NGT subjects with depressive symptomatology. The depressive patients had a significantly lower insulin sensitivity index (SI) than the control subjects (P= .016). Depressive NGT subjects had a significantly higher homeostasis model assessment (HOMA) insulin resistance index [HOMA(R)] than the nondepressive NGT subjects (P < .0001). The depressive patients and NGT subjects had more HUMTH01 allele 7 (TH7) than the controls and nondepressive NGT subjects. SI was significantly lower in patients with the TH7/7 homozygote versus patients with the other genotypes and the controls. TH7 was associated with higher HOMA(R) as compared with the other alleles in the NGT subjects. Insulin resistance was associated with depressive disorders. The HUMTH01 and INS-VNTR were associated with insulin resistance and depressive symptoms.

Asunto(s)

Trastorno Depresivo/genética , Resistencia a la Insulina/genética , Repeticiones de Microsatélite , Polimorfismo Genético , Tirosina 3-Monooxigenasa/genética , Adulto , Alelos , Estudios de Cohortes , Diabetes Mellitus Tipo 2/genética , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/genética , Masculino , Persona de Mediana Edad , Repeticiones de Minisatélite

RESUMEN

Type 2 or non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes worldwide, affecting approximately 4% of the world's adult population. It is multifactorial in origin with both genetic and environmental factors contributing to its development. A genome-wide screen for type 2 diabetes genes carried out in Mexican Americans localized a susceptibility gene, designated NIDDM1, to chromosome 2. Here we describe the positional cloning of a gene located in the NIDDM1 region that shows association with type 2 diabetes in Mexican Americans and a Northern European population from the Botnia region of Finland. This putative diabetes-susceptibility gene encodes a ubiquitously expressed member of the calpain-like cysteine protease family, calpain-10 (CAPN10). This finding suggests a novel pathway that may contribute to the development of type 2 diabetes.

Asunto(s)

Calpaína/genética , Cromosomas Humanos Par 2 , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Variación Genética , Polimorfismo Genético , Adulto , Secuencia de Aminoácidos , Calpaína/química , Mapeo Cromosómico , Diabetes Mellitus Tipo 2/enzimología , Diabetes Mellitus Tipo 2/epidemiología , Finlandia , Frecuencia de los Genes , Marcadores Genéticos , Genoma Humano , Haplotipos , Humanos , Americanos Mexicanos/genética , Datos de Secuencia Molecular , Medición de Riesgo , Estados Unidos , Población Blanca/genética

RESUMEN

OBJECTIVE: Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous subtype of type 2 diabetes characterized by an early age at onset and autosomal dominant inheritance. MODY can result from heterozygous mutations in at least five genes. The purpose of this study was to determine whether alterations in known MODY genes and two MODY candidate genes contribute to the development of early-onset type 2 diabetes in Pima Indians. RESEARCH DESIGN AND METHODS: The coding regions of the known MODY genes hepatocyte nuclear factor (HNF)-1alpha, HNF-4alpha, HNF-1beta, and insulin promoter factor 1 and the coding regions of two MODY candidate genes, HNF-3beta and the dimerization cofactor of HNF-1, were sequenced in genomic DNA from Pima Indians. The primary "affected" study population consisted of 46 Pima Indians whose age at onset of type 2 diabetes was < or =20 years. DNA sequence variants identified in the affected group were then analyzed in a group of 80 "unaffected" Pima Indians who were at least 40 years old and had normal glucose tolerance. RESULTS: A total of 11 polymorphisms were detected in these genes. However, none of the polymorphisms differed in frequency among Pima Indians with an early age at onset of diabetes compared with older Pima Indians with normal glucose tolerance. CONCLUSIONS: Mutations in these known MODY or MODY candidate genes are not a common cause of early-onset diabetes in Pima Indians.

Asunto(s)

Proteínas de Unión al ADN/genética , Diabetes Mellitus Tipo 2/genética , Etnicidad/genética , Proteínas de Homeodominio , Indígenas Norteamericanos/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , Polimorfismo Genético , Transactivadores/genética , Factores de Transcripción/genética , Adolescente , Adulto , Edad de Inicio , Arizona , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Codón , Dimerización , Exones , Factor Nuclear 1 del Hepatocito , Factor Nuclear 1-alfa del Hepatocito , Factor Nuclear 1-beta del Hepatocito , Factor Nuclear 3-beta del Hepatocito , Factor Nuclear 4 del Hepatocito , Humanos , Mutación , Factores de Transcripción/química

RESUMEN

Mutations in the transcription factors hepatocyte nuclear factor (HNF)-4alpha and -1alpha, insulin promoter factor-1, and HNF-1beta are the causes of four forms of maturity-onset diabetes of the young (MODY1 and 3-5, respectively). The winged-helix transcription factor HNF-3beta has been implicated in the regulation of expression of each of these MODY genes, suggesting that mutations in the HNF-3beta gene (HNF3B) may also cause MODY. We have tested this hypothesis by screening a panel of 57 unrelated Japanese subjects with a clinical diagnosis of MODY for mutations in HNF3B. This analysis revealed four frequent polymorphisms that were not associated with MODY, including one in the promoter region (-213A/G), two silent mutations in the codons for Ala 97 (291C/T) and Gly 279 (837A/G), and one in the 3'-untranslated region (1424C/T). Two rare substitutions in the 5'-untranslated region, -156C/T and -67A/C, were found in a heterozygous state in two subjects, and two subjects were heterozygous for putative missense mutations, S109N (326G > A) and A328V (983C>T). The two missense mutations were not found in 106 normal chromosomes from nondiabetic subjects. It was not possible to test for co-segregation of these mutations with diabetes and thus, it is unclear whether or not these mutations can cause MODY. The results of our study suggest that mutations in HNF3B are not a common cause of MODY in Japanese subjects.

Asunto(s)

Proteínas de Unión al ADN/genética , Diabetes Mellitus Tipo 2/genética , Islotes Pancreáticos/metabolismo , Proteínas Nucleares/genética , Factores de Transcripción/genética , Adulto , Pueblo Asiatico/genética , Factor Nuclear 3-beta del Hepatocito , Humanos , Japón , Masculino , Mutación/genética , Mutación Missense/genética

RESUMEN

Mutations in genes encoding hepatocyte nuclear factor (HNF) are responsible for three of the five subtypes of maturity-onset diabetes of the young (MODY). This observation and molecular studies indicate that the HNF network is required for normal function of pancreatic beta-cells. This suggests that transcription factors involved in this complex network are candidates for genetic defects in MODY. Because the HNF-3beta gene is implicated in this network, we screened it for mutations in 21 probands of French ancestry with clinical diagnosis of MODY and early-onset type 2 diabetes. All of the five known MODY genes, HNF-4alpha, glucokinase, HNF-1alpha, HNF-1beta, and IPF1, were previously excluded as being the cause of diabetes in these families. By direct sequencing, we identified two transitions, an A-to-G at position -213 and a C-to-T at position -63 in the promoter and exon 1, respectively, of the HNF-3beta gene. A G-to-C transversion at position +32 in the intron 1 and three transitions, C-to-T at position 291, A-to-G at position 837, and G-to-A at position 1188 in the exon 3, resulting in noncoding mutations Ala97Ala, Gly279Gly, and Gln396Gln, respectively, were also identified. The allele frequencies were not significantly different between a control group and MODY probands. Familial segregation studies and linkage analysis showed that genetic variation in the HNF-3beta gene is unlikely to be the cause of early-onset type 2 diabetes in these Caucasian families.

Asunto(s)

Proteínas de Unión al ADN/genética , Diabetes Mellitus Tipo 2/genética , Variación Genética/genética , Proteínas Nucleares/genética , Factores de Transcripción , Población Blanca/genética , Adulto , Edad de Inicio , Secuencia de Bases/genética , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Francia , Ligamiento Genético , Factor Nuclear 3-beta del Hepatocito , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

The locus of the vitamin D-binding protein (DBP; also known as group-specific component protein or Gc) gene, chromosome 4q12, has been reported to be associated with glucose metabolism in several ethnic groups, including Pima Indians. We have recently reported the association of the DBP genotype with type 2 diabetes mellitus in Japan. The aim of this study was to investigate whether genetic variations of DBP have any influence on glucose metabolism without secondary effects of hyperglycemia or diabetes mellitus using 82 Japanese with normal glucose tolerance. The variations of the DBP gene (Gc 1F, 1S, and 2) were determined by PCR-restriction fragment length polymorphism. Fasting plasma insulin concentration and homeostasis model assessment, an index of insulin resistance, were significantly different based on the DBP genotype (P < 0.01 and P < 0.05, respectively). The people with Gc 1S-2 (5.73 +/- 2.57 microU/mL) and 1S-1S (5.30 +/- 3.46 microU/mL) had significantly higher fasting plasma concentrations than those with 1F-1F (2.84 +/- 1.67 microU/mL) (P < 0.01 and P < 0.03, respectively). There was no significant difference in plasma glucose concentration, body mass index, total cholesterol, triglyceride, and blood pressure. In conclusion, genetic variations of DBP are associated with insulin resistance in Japanese with normal glucose tolerance, which might contribute to the development of type 2 diabetes.

Asunto(s)

Glucemia/metabolismo , Variación Genética , Insulina/sangre , Proteína de Unión a Vitamina D/genética , Pueblo Asiatico , Presión Sanguínea , Índice de Masa Corporal , Colesterol/sangre , HDL-Colesterol/sangre , Femenino , Genotipo , Prueba de Tolerancia a la Glucosa , Homeostasis , Humanos , Resistencia a la Insulina , Japón , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Triglicéridos/sangre

RESUMEN

Increased oxidative stress induced by hyperglycemia may contribute to the pathogenesis of diabetic complications. Oxidative stress is known to increase the conversion of deoxyguanosine (dG) to 8-hydroxydeoxyguanosine (8-OHdG) in DNA, which is linked to increased mitochondrial DNA (mtDNA) deletions. We investigated mtDNA deletions and 8-OHdG in the muscle DNA of non-insulin-dependent diabetes mellitus (NIDDM) patients. mtDNA deletion of 4977 bp (delta mtDNA4977) and the content of 8-OHdG in the muscle DNA of the NIDDM patients were much higher than those of the control subjects. There was a significant correlation between delta mtDNA4977 and the 8-OHdG content (P < 0.0001). Both delta mtDNA4977 and the 8-OHdG content were also correlated with the duration of diabetes. Delta mtDNA4977 and the 8-OHdG content in muscle DNA increased in proportion to the severity of diabetic nephropathy and retinopathy. This is the first report that an increase in delta mtDNA4977 and 8-OHdG is proportional to the severity of diabetic complications. Oxidative mtDNA damage is speculated to contribute to the pathogenesis of diabetic complications though a defect in mitochondrial oxidative phosphorylation or other mechanisms. 8-OHdG and delta mtDNA4977 are useful markers to evaluate oxidative mtDNA damage in the diabetic patients.

Asunto(s)

Daño del ADN , ADN Mitocondrial/genética , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , 8-Hidroxi-2'-Desoxicoguanosina , ADN Mitocondrial/química , ADN Mitocondrial/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/análisis , Diabetes Mellitus Tipo 2/fisiopatología , Humanos , Músculo Esquelético/metabolismo , Reacción en Cadena de la Polimerasa , Valores de Referencia , Análisis de Regresión , Eliminación de Secuencia

RESUMEN

AIMS/HYPOTHESIS: Augmented oxidative stress induced by hyperglycaemia possibly contributes to the pathogenesis of diabetic complications. Oxidative stress is known to increase the conversion of deoxyguanosine to 8-oxo, 2'-deoxyguanosine in DNA. To investigate the possible contribution of oxidative DNA damage to the pathogenesis of diabetic complications, we measured the content of 8-oxo, 2'-deoxyguanosine in the urine and the blood mononuclear cells of Type II (non-insulin-dependent) diabetic patients. METHODS: We studied 53 Type II diabetic patients and 39 age-matched healthy control subjects. We assayed 8-oxo, 2'-deoxyguanosine by HPLC-electrochemical detection method. RESULTS: The content of 8-oxo, 2'-deoxyguanosine in the urine and the mononuclear cells of the Type II diabetic patients was much higher than that of the control subjects. Urinary 8-oxo, 2'-deoxyguanosine excretion and the 8-oxo, 2'-deoxyguanosine content in the mononuclear cells from the diabetic patients with complications were higher than those from the diabetic patients without complications. Urinary excretion of 8-oxo, 2'-deoxyguanosine was significantly correlated with the 8-oxo, 2'-deoxyguanosine content in the mononuclear cells. The 8-oxo, 2'-deoxyguanosine content in the urine and mononuclear cells was correlated with the haemoglobin A1c value. CONCLUSIONS/INTERPRETATION: This is the first report of a direct association between oxidative DNA damage and the complications of diabetes. The augmented oxidative DNA damage in diabetes is speculated to contribute to the pathogenesis of diabetic complications.

Asunto(s)

Daño del ADN , Desoxiguanosina/análogos & derivados , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Nefropatías Diabéticas/fisiopatología , Retinopatía Diabética/fisiopatología , Estrés Oxidativo , 8-Hidroxi-2'-Desoxicoguanosina , Análisis de Varianza , Biomarcadores/análisis , Desoxiguanosina/análisis , Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/genética , Retinopatía Diabética/genética , Femenino , Hemoglobina Glucada/análisis , Humanos , Masculino , Persona de Mediana Edad , Valores de Referencia , Fumar

Asunto(s)

Diabetes Mellitus Tipo 2/genética , Proteína de Unión a Vitamina D/genética , Alelos , Diabetes Mellitus Tipo 2/epidemiología , Frecuencia de los Genes , Genotipo , Humanos , Japón/epidemiología , Polimorfismo Genético

RESUMEN

The characteristic clinical features of diabetes mellitus with mitochondrial DNA (mtDNA) 3243(A-G) mutation are progressive insulin secretory defect, neurosensory deafness and maternal inheritance, referred to as maternally inherited diabetes mellitus and deafness (MIDD). A treatment for MIDD to improve insulin secretory defects and reduce deafness has not been established. The effects of coenzyme Q10 (CoQ10) treatment on insulin secretory response, hearing capacity and clinical symptoms of MIDD were investigated. 28 MIDD patients (CoQ10-DM), 7 mutant subjects with impaired glucose tolerance (IGT), and 15 mutant subjects with normal glucose tolerance (NGT) were treated daily with oral administration of 150 mg of CoQ10 for 3 years. Insulin secretory response, blood lactate after exercise, hearing capacity and other laboratory examinations were investigated every year. In the same way we evaluated 16 MIDD patients (control-DM), 5 mutant IGT and 5 mutant NGT subjects in yearly examinations. The insulin secretory response assessed by glucagon-induced C-peptide secretion and 24 h urinary C-peptide excretion after 3 years in the CoQ10-DM group was significantly higher than that in the control-DM group. CoQ10 therapy prevented progressive hearing loss and improved blood lactate after exercise in the MIDD patients. CoQ10 treatment did not affect the diabetic complications or other clinical symptoms of MIDD patients. CoQ10 treatment did not affect the insulin secretory capacity of the mutant IGT and NGT subjects. There were no side effects during therapy. This is the first report demonstrating the therapeutic usefulness of CoQ10 on MIDD.

Asunto(s)

ADN Mitocondrial/genética , Sordera/tratamiento farmacológico , Diabetes Mellitus/tratamiento farmacológico , Ubiquinona/análogos & derivados , Adulto , Péptido C/sangre , Péptido C/efectos de los fármacos , Péptido C/orina , Coenzimas , Sordera/complicaciones , Sordera/genética , Complicaciones de la Diabetes , Diabetes Mellitus/genética , Nefropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/tratamiento farmacológico , Retinopatía Diabética/tratamiento farmacológico , Salud de la Familia , Femenino , Glucagón/sangre , Glucagón/efectos de los fármacos , Intolerancia a la Glucosa/tratamiento farmacológico , Prueba de Tolerancia a la Glucosa , Audición/efectos de los fármacos , Humanos , Ácido Láctico/sangre , Masculino , Persona de Mediana Edad , Madres , Mutación Puntual/genética , Factores de Tiempo , Resultado del Tratamiento , Ubiquinona/sangre , Ubiquinona/uso terapéutico

RESUMEN

Accumulating reports indicate a relationship between mitochondrial DNA mutation and impaired glucose-induced insulin secretion leading to a subtype of noninsulin-dependent diabetes mellitus. DNA from a 45-yr-old Japanese woman with noninsulin-dependent diabetes mellitus and muscle atrophy was isolated and studied for mitochondrial DNA mutations. We identified a mitochondrial DNA C-T heteroplasmic mutation at nucleotide position 3256. The mutation was located in the transfer ribonucleic acidLeu in a region conserved in evolution. Eight other members of her family were examined for the mutation. Six of them had the same mutation together with noninsulin-dependent diabetes mellitus, and one teenage boy had the mutation and impaired glucose tolerance. The other family member who did not have this mutation had normal glucose tolerance. The enzyme activity of the mitochondrial oxidative phosphorylation pathway in the muscle of the proband was measured. The enzyme activity was decreased in the proband, especially in complex I. This mutation might be responsible for the abnormal glucose metabolism.

Asunto(s)

ADN Mitocondrial/genética , Diabetes Mellitus Tipo 2/genética , Mutación/genética , Adolescente , Adulto , Secuencia de Bases , Células Sanguíneas/metabolismo , Mejilla/patología , Mejilla/fisiología , ADN Mitocondrial/sangre , ADN Mitocondrial/metabolismo , Densitometría , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Femenino , Cabello/metabolismo , Humanos , Japón/etnología , Masculino , Persona de Mediana Edad , Mitocondrias Musculares/metabolismo , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción

Asunto(s)

Proteínas de Unión al ADN , Diabetes Mellitus Tipo 2/genética , Mutación , Factores de Transcripción/genética , Adulto , Femenino , Factor Nuclear 1 del Hepatocito , Factor Nuclear 1-alfa del Hepatocito , Factor Nuclear 1-beta del Hepatocito , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Proteínas Nucleares/genética , Linaje

RESUMEN

Hepatocyte nuclear factor-4 alpha (HNF-4 alpha) is a member of the nuclear receptor superfamily, a class of ligand-activated transcription factors. A nonsense mutation in the gene encoding this transcription factor was recently found in a white family with one form of maturity-onset diabetes of the young, MODY1. Here, we report the exon-intron organization and partial sequence of the human HNF-4 alpha gene. In addition, we have screened the 12 exons, flanking introns and minimal promoter region for mutations in a group of 57 unrelated Japanese subjects with early-onset NIDDM/MODY of unknown cause. Eight nucleotide substitutions were noted, of which one resulted in the mutation of a conserved arginine residue, Arg127 (CGG)-->Trp (TGG) (designated R127W), located in the T-box, a region of the protein that may play a role in HNF-4 alpha dimerization and DNA binding. This mutation was not found in 214 unrelated nondiabetic subjects (53 Japanese, 53 Chinese, 51 white, and 57 African-American). The R127W mutation was only present in three of five diabetic members in this family, indicating that it is not the only cause of diabetes in this family. The remaining seven nucleotide substitutions were located in the proximal promoter region and introns. They are not predicted to affect the transcription of the gene or mRNA processing and represent polymorphisms and rare variants. The results suggest that mutations in the HNF-4 alpha gene may cause early-onset NIDDM/MODY in Japanese but they are less common than mutations in the HNF-1 alpha/MODY3 gene. The information on the sequence of the HNF-4 alpha gene and its promoter region will facilitate the search for mutations in other populations and studies of the role of this gene in determining normal pancreatic beta-cell function.

Asunto(s)

Proteínas de Unión al ADN , ADN/química , Mutación , Fosfoproteínas/genética , Factores de Transcripción/genética , Empalme Alternativo , Animales , Secuencia de Bases , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Femenino , Factor Nuclear 4 del Hepatocito , Humanos , Islotes Pancreáticos/química , Japón , Masculino , Ratones , Datos de Secuencia Molecular , Linaje , Polimorfismo de Longitud del Fragmento de Restricción , Regiones Promotoras Genéticas , ARN Mensajero/análisis , ARN Mensajero/genética , Homología de Secuencia

RESUMEN

Recent studies have shown that mutations in the hepatocyte nuclear factor (HNF)-1alpha gene are the cause of maturity-onset diabetes of the young type 3 (MODY3). We have screened 193 unrelated Japanese subjects with NIDDM for mutations in this gene: 83 with early-onset NIDDM (diagnosis at <30 years of age) and 110 with late-onset NIDDM (diagnosis > or = 30 years of age). All of the members of the latter group also had at least one sibling with NIDDM. The 10 exons, flanking introns, and promoter region were amplified using polymerase chain reaction and were sequenced directly. Mutations were found in 7 of the 83 (8%) unrelated subjects with early-onset NIDDM. The mutations were each different and included four missense mutations (L12H, R131Q, K205Q, and R263C) and three frameshift mutations (P379fsdelCT, T392fsdelA, and L584S585fsinsTC). One of the 110 subjects with late-onset NIDDM was heterozygous for the missense mutation G191D. This subject, who was diagnosed with NIDDM at 64 years of age, also had a brother with NIDDM (age at diagnosis, 54 years) who carried the same mutation, suggesting that this mutation contributed to the development of NIDDM in these two siblings. None of these mutations were present in 50 unrelated subjects with normal glucose tolerance (100 normal chromosomes). Mutations in the HNF-1alpha gene occur in Japanese subjects with NIDDM and appear to be an important cause of early-onset NIDDM in this population. In addition, they are present in about 1% of subjects with late-onset NIDDM.

Asunto(s)

Proteínas de Unión al ADN , Diabetes Mellitus Tipo 2/genética , Proteínas Nucleares , Factores de Transcripción/genética , Factores de Edad , Femenino , Factor Nuclear 1 del Hepatocito , Factor Nuclear 1-alfa del Hepatocito , Factor Nuclear 1-beta del Hepatocito , Humanos , Japón/etnología , Masculino , Linaje , Mutación Puntual , Polimorfismo de Longitud del Fragmento de Restricción , Eliminación de Secuencia

RESUMEN

OBJECTIVE: To present a novel mitochondrial DNA mutation in a diabetic family RESEARCH DESIGN AND METHODS: The proband was a 64-year-old man. In the family, diabetes was maternally inherited. He had diabetes, cerebellar ataxia, cervical lipoma, hearing loss, olfactory dysfunction, ophthalmoplegia, and facial nerve bilateral palsy. On examination, early insulin secretion was blunted, and the M value on glucose clamp test was low. In muscle, ragged red fibers were not found. T-to-C mutation at position 3264 was detected in the proband (0.5% mutant DNAs in leukocyte and 30% in muscle), but was not detected in 201 normal individuals. RESULTS: Heteroplasmy of mutation, maternal inheritance of diabetes, and symptoms related to mitochondrial dysfunction suggest the pathogenecity of this 3264 mutation. As for diabetes etiology, both impaired insulin secretion and decreased insulin sensitivity seem to be important. In phenotypic characteristics, the combination of cerebellar ataxia and lipoma is a symptom sometimes found in myoclonic epilepsy and ragged red fibers (MERRFs). Ophthamoplegia is a symptom of chronic progressive external ophthalmoplegia (CPEO). These suggest that our proband had phenotypic overlap with MERRF and CPEO. Conversely, facial nerve bilateral palsy is a rare finding. The pictures that focused on his cranial nerves were thus unique, suggesting the heterogeneity of mitochondrial DNA (mtDNA)-related diabetes. CONCLUSIONS: A novel 3264 mitochondrial DNA mutation in diabetes gives new insight to the etiology of mitochondrial diabetes. Its pathogenecity supports the belief that the tRNA(Leu)(UUR) gene is an etiological hot spot of mitochondrial diseases.

Asunto(s)

ADN Mitocondrial/genética , Diabetes Mellitus Tipo 2/genética , Mutación Puntual/genética , ARN de Transferencia de Leucina/genética , ADN Mitocondrial/análisis , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/fisiopatología , Humanos , Leucocitos/química , Masculino , Persona de Mediana Edad , Músculos/química , Linaje , Reacción en Cadena de la Polimerasa

RESUMEN

The open trial was designed to evaluate the effects of long-term antihypertensive treatment with the calcium-channel blocker, manidipine and the angiotensin converting enzyme (ACE) inhibitor, delapril on insulin sensitivity in Japanese non-insulin dependent diabetes mellitus (NIDDM) patients with essential hypertension. We measured the insulin sensitivity index (SI) and the glucose-effectiveness (SG) by the use of Bergman's minimal model method in 18 hypertensive NIDDM patients before and after administration of manidipine (group A) or delapril (group B) for 3 months. Manidipine treatment for 3 months significantly improved SI in group A from 3.35 +/- 0.61 (x 10(-4) min-1 microU-1 ml-1) to 4.70 +/- 1.34 (P < 0.05). Delapril treatment for 3 months also significantly improved SI in group B from 3.56 +/- 1.04 to 5.00 +/- 0.87 (P < 0.05). Manidipine significantly improved SG in group A from 1.60 +/- 0.64 (x 10(-2) min) to 2.19 +/- 0.38 (P < 0.05). Delapril treatment also significantly improved SG in the group B from 1.41 +/- 0.56 to 1.91 +/- 0.35 (P < 0.05). Manidipine and delapril did not affect urinary C-peptide excretion for 24 h in the hypertensive NIDDM patients. Treatment with manidipine or delapril significantly reduced systolic and diastolic blood pressures in the hypertensive NIDDM patients. There were no differences between plasma glucose, serum total triglycerides, and cholesterol or lipoprotein cholesterol fractions, heart rate and body weight after 3 months on manidipine or delapril. This study confirmed the improving effects on SI and SG by long-term treatment with manidipine or delapril in the hypertensive NIDDM patients.

Asunto(s)

Antihipertensivos/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/tratamiento farmacológico , Dihidropiridinas/uso terapéutico , Hipertensión/tratamiento farmacológico , Indanos/uso terapéutico , Resistencia a la Insulina , Glucemia/análisis , Femenino , Hemoglobina Glucada/análisis , Humanos , Masculino , Persona de Mediana Edad , Nitrobencenos , Piperazinas

RESUMEN

Mitochondrial DNA (mtDNA) mutation is associated with a subtype of non-insulin-dependent diabetes mellitus (NIDDM). We identified two homoplasmic mtDNA mutations at the positions of 3394 (T-C) and 3423 (G-T) in a NIDDM patient with clinical features of mitochondrial encephalopathy. The mtDNA 3394T-C mutation changed a conserved tyrosine to a histidine in NADH dehydrogenase subunit 1. The frequency of mtDNA 3994 T-C mutation was determined with Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) in general NIDDM patients and nondiabetic control subjects. The mutation was seen in 4.9% of NIDDM patients and 1.3% of nondiabetic controls. It is indicated that the mtDNA 3394 T-C mutation is associated with NIDDM in Japan.

Asunto(s)

ADN Mitocondrial/genética , Diabetes Mellitus Tipo 2/enzimología , Diabetes Mellitus Tipo 2/genética , Encefalomiopatías Mitocondriales/genética , NADH Deshidrogenasa/genética , Mutación Puntual , Secuencia de Bases , Cartilla de ADN , Femenino , Humanos , Sustancias Macromoleculares , Masculino , Encefalomiopatías Mitocondriales/enzimología , Datos de Secuencia Molecular , NADH Deshidrogenasa/química , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo Conformacional Retorcido-Simple , ARN de Transferencia de Leucina/genética