Assuntos
Insuficiência Adrenal/complicações , Síndrome POEMS/complicações , Adulto , Humanos , MasculinoRESUMO
Adenomatous polyposis coli (APC) is a multifunctional protein as well as a tumor suppressor. To determine the functions of the C-terminal domain of Apc, we have investigated Apc ( 1638T/1638T ) mice, which express a truncated Apc that lacks the C-terminal domain. Apc ( 1638T/1638T ) mice are tumor free and exhibit growth retardation. In the present study, we analyzed the morphology and functions of the thyroid gland in Apc ( 1638T/1638T ) mice. There was no significant difference in the basal concentration of serum thyroid hormones between Apc ( 1638T/1638T ) and Apc (+/+) mice. Thyroid follicle size was significantly larger in Apc ( 1638T/1638T ) mice than in Apc (+/+) mice. The extent of serum T4 elevation following exogenous thyroid-stimulating hormone (TSH) injection was lower in Apc ( 1638T/1638T ) mice than in Apc (+/+) mice. TSH also induced a greater reduction in thyroid follicle size in Apc ( 1638T/1638T ) mice than in Apc (+/+) mice. Analyses using immunohistochemistry and electron microscopy indicated that follicular epithelial cells in Apc ( 1638T/1638T ) mice had an enlarged rough endoplasmic reticulum of irregular shape. These results suggest that the C-terminal domain of Apc is involved in thyroid morphology and function.
Assuntos
Proteína da Polipose Adenomatosa do Colo/química , Morfogênese , Fragmentos de Peptídeos/química , Glândula Tireoide/crescimento & desenvolvimento , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Animais , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Estrutura Terciária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Deleção de Sequência , Glândula Tireoide/metabolismo , Glândula Tireoide/ultraestrutura , Tireotropina/farmacologia , Tireotropina/fisiologia , Tiroxina/sangue , Tri-Iodotironina/sangueRESUMO
Genetic analysis of the KLF11 gene revealed two rare variants, A347S and T220M, segregating in families with early-onset type 2 diabetes, and one frequent polymorphic Q62R variant significantly associated with type 2 diabetes in Northern Europeans. Furthermore, it has been reported that over-expression of KLF11 has a deleterious effect on insulin promoter activity. Thus, an altered expression level of KLF11 may contribute to the occurrence of type 2 diabetes. To investigate the contribution of KLF11 to type 2 diabetes in Japanese, we surveyed the 5' flanking region of KLF11 by reporter assay and identified the minimal promoter region of the gene. The promoter region from -250 to +162 bp including five Sp1 binding sites showed basal promoter activity both in MIN6-m9 and HepG2 cells. We also examined the entire region of KLF11 to detect genetic variants. A total of 19 polymorphisms, six of which are novel, were identified, but none of them showed association with the occurrence of type 2 diabetes. Two of the identified polymorphisms, R29Q and S124F, are novel coding variants. Functional analyses of these variants were performed, and similarly reduced effects on transcriptional activities of insulin, catalase1, and the Smad7 gene were found. We conclude that variants of KLF11 are not a major factor in the occurrence of type 2 diabetes in Japanese. The promoter region of KLF11 identified in the present study should be useful in further elucidation of the transcriptional regulation mechanism of the gene and genetic analyses of type 2 diabetes.
Assuntos
Proteínas de Ciclo Celular/genética , Diabetes Mellitus Tipo 2/genética , Regiões Promotoras Genéticas , Proteínas Repressoras/genética , Adolescente , Idoso , Sequência de Aminoácidos , Proteínas Reguladoras de Apoptose , Povo Asiático/genética , Sequência de Bases , Criança , Feminino , Frequência do Gene , Variação Genética , Haplótipos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Telomerase (TA) activity is known to be present in malignant tumor cells, but not in most somatic differentiated cells. TA shows relatively high activity in thyroid cancer cells, but reports vary. This fact prompted us to elucidate whether cell component inhibitors of TA in the thyroid follicles can modulate its activity. The activity of TA extracted from Hela cells was inhibited by mixing with the supernatant fraction of human thyroid tissue extract. To examine the effect of iodine, thyroid hormones (l-T3 and l-T4) and human thyroglobulin (hTg) contained in the thyroid follicles, l-T3, l-T4 and hTg were added to the TRAP assay system in vitro, using TA from Hela cells. Iodine, l-T3 and l-T4 did not affect TA activity, but hTg inhibited the TA activity in a dose-dependent manner (IC(50) of hTg: ca 0.45 microM: inhibiting concentration of hTg was from 0.15 microM to 3.0 microM). The hTg inhibition was not evident in the RT-PCR system, suggesting no effect of hTg on Taq DNA polymerase activity. The hTg inhibition of TA activity was attenuated by dNTP but not significantly by TS primer. These data suggest that hTg contained in thyroid follicular cells of various thyroid diseases may affect the TA activity measured in biopsied thyroid specimens, and that the reduction of the TA activity by hTg may induce slow progression and growth, and low grade malignancy of thyroid cancer, particularly differentiated carcinoma.
Assuntos
Telomerase/metabolismo , Tireoglobulina/farmacologia , Glândula Tireoide/enzimologia , Carcinoma Papilar, Variante Folicular/enzimologia , Carcinoma Papilar, Variante Folicular/metabolismo , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/enzimologia , Neoplasias da Glândula Tireoide/metabolismo , Fatores de TempoRESUMO
Mutations in the small heterodimer partner gene (NR0B2; alias SHP) are associated with high birth weight and mild obesity in Japanese children. SHP mutations may also be associated with later obesity and insulin resistance syndrome that induces diabetes. To investigate this possibility, the prevalence of SHP mutations in Japanese with and without type 2 diabetes mellitus and the functional properties of the mutant proteins were evaluated. Direct sequencing of two exons and flanking sequences of SHP in 805 diabetic patients and 752 non-diabetic controls identified 15 different mutations in 44 subjects, including 6 novel mutations. Functional analyses of the mutant proteins revealed significantly reduced activity of nine of the mutations. Mutations with reduced activity were found in 19 patients (2.4%) in the diabetic group and in 6 subjects (0.8%) in the control group. The frequency difference between DM and control subjects adjusted for sex and age was statistically significant (P=0.029, odds ratio 2.67, 95% CI 1.05-6.81, 1-beta=0.91). We conclude that SHP mutations associated with mild obesity in childhood increase susceptibility to type 2 diabetes in later life in Japanese.
Assuntos
Diabetes Mellitus Tipo 2/genética , Mutação , Obesidade/genética , Receptores Citoplasmáticos e Nucleares/genética , Adulto , Idoso , Povo Asiático/genética , Análise Mutacional de DNA , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/epidemiologia , Fatores de RiscoRESUMO
CONTEXT AND OBJECTIVE: Arterial stimulation and venous sampling (ASVS) is an important technique for localizing insulinoma. The principle behind ASVS is that insulin secretion is promoted from insulinoma cells by the injection of calcium into the insulinoma-feeding artery. However, the mechanism for ASVS-induced insulin secretion remains unclear. Both insulinoma and familial hypocalciuric hypercalcemia (FHH) are rare diseases. This study reports on a case in which both of these diseases occur concurrently. DESIGN AND PATIENT: The patient with FHH also suffered from insulinoma. We reasoned that insulin secretion for ASVS is dependent on the calcium-sensing receptor (CaSR). ASVS was performed on this patient. The expression of the CaSR protein and corresponding mRNA were confirmed. RESULTS: No significant changes in the plasma levels of insulin and C-peptide were observed during ASVS. The patient was clinically diagnosed as having FHH. We confirmed that a mutation in the CaSR gene was present in the genomic DNA of this patient and that there were no mutations in the multiple endocrine neoplasia type 1 gene. In addition, expression of both CaSR mRNA and CaSR protein was confirmed in the insulinoma samples. CONCLUSION: These results suggest that the CaSR gene is involved in ASVS-induced insulin secretion.
Assuntos
Hipercalcemia/patologia , Insulinoma/patologia , Receptores de Detecção de Cálcio/fisiologia , Western Blotting , Feminino , Humanos , Hipercalcemia/diagnóstico por imagem , Hipercalcemia/genética , Hipercalcemia/metabolismo , Imuno-Histoquímica , Insulina/metabolismo , Insulinoma/genética , Insulinoma/metabolismo , Fígado/diagnóstico por imagem , Fígado/metabolismo , Fígado/patologia , Pessoa de Meia-Idade , Pâncreas/diagnóstico por imagem , Pâncreas/metabolismo , Pâncreas/patologia , Cintilografia , Receptores de Detecção de Cálcio/genética , Receptores de Detecção de Cálcio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tomografia Computadorizada por Raios XRESUMO
The level of leptin increases with obesity, whereas that of adiponectin decreases with obesity. It is reported that the ratio of leptin to adiponectin (L/A) is associated with insulin resistance. It is difficult to evaluate insulin resistance in diabetic patients who have a dysfunction of insulin secretion. The aim of this study was to examine whether the L/A ratio is a useful marker for insulin resistance in diabetic patients. We examined L/A in the serum of a total of 139 Japanese patients with type 2 diabetes mellitus (66 women and 73 men) and 7 healthy individuals recruited in our hospital. Changes in the levels of leptin and adiponectin were observed using the oral glucose tolerance test and a hyper- and euglycemic clamp test. Twenty-one patients with type 2 diabetes mellitus were observed for more than 6 months after treatment with pioglitazone, and 31 patients with type 2 diabetes mellitus were observed for more than 6 months after the treatment with metformin. The mean value of L/A in 139 Japanese patients with type 2 diabetes mellitus was 1.22 +/- 1.41 (1.68 +/- 1.76 in women, 0.81 +/- 0.80 in men; P = .0002). In the clamp tests, L/A correlated with glucose infusion rate (GIR) (r(2) = 0.26, P = .0034). The correlation of L/A and GIR indicated a stronger correlation than either leptin (r(2) = 0.144, P = .03) or adiponectin alone (r(2) = 0.023, P = .41), or the homeostasis model assessment of insulin resistance (r(2) = 0.103, P = .08). The average hemoglobin A(1c) (HbA(1c)) improved from 10.2% +/- 1.2% to 9.2% +/- 1.6% (P = .0037) in 6 months after treatment with pioglitazone. Our results indicate pioglitazone to be effective for HbA(1c) improvement in subjects with high L/A and low L/A. The average HbA(1c) improved from 9.2% +/- 0.9% to 8.0% +/- 1.2% (P = .0002) in 6 months after treatment with metformin. Our results indicate metformin to be effective for HbA(1c) improvement in subjects with a low L/A. In conclusion, we demonstrate that L/A is different between male and female subjects. The correlation of L/A and GIR by the euglycemic hyperinsulinemic clamp test suggests that L/A is a useful indicator for the choice of drug to treat diabetes mellitus.
Assuntos
Adiponectina/sangue , Diabetes Mellitus Tipo 2/sangue , Hipoglicemiantes/uso terapêutico , Resistência à Insulina/fisiologia , Leptina/sangue , Glicemia/metabolismo , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Pioglitazona , Tiazolidinedionas/uso terapêuticoRESUMO
Recent findings suggest that thyroid stimulating hormone (TSH) is a negative regulator of skeletal remodeling by reducing both differentiation of osteoblasts and formation of osteoclasts. In addition, increased fracture risk in untreated hypothyroid patients has been reported to begin up to 8 years before diagnosis. The aim of the present study was to evaluate the effect of subclinical hypothyroidism on bone structure by using the heel QUS. Subjects were outpatients without any past or present history of thyroid disease. Among 210 postmenopausal women, 22 of 33 patients (Hypo), who had elevated serum TSH concentration (TSH>or=4 microU/ml) with normal serum free thyroxine (FT4) concentration, agreed to join to this study. We also randomly selected 24 control subjects (Cont) from 176 postmenopausal women with normal thyroid status. Calcaneus osteo sono assessment indices (OSI) of right feet were measured using the ultrasound bone densitometry AOS-100. Serum TSH concentrations in Hypo patients (5.31 +/- 1.3 microU/ml) were higher than those in Cont patients (2.05 +/- 1.1 microU/ml), and there was significant difference of FT(4) concentrations (Cont 1.33 +/- 0.15 ng/dl; Hypo 1.19 +/- 0.17 ng/dl). OSI and its Z-score in Hypo subjects (OSI, 2.138 +/- 0.152; Z-Score -0.322 +/- 0.504 SD, Mean SD) were significantly lower than those in Cont subjects (OSI, 2.347 +/- 0.243; Z-Score 0.322 +/- 0.91 SD, Mean +/- SD). Simple regression statistical analysis showed that OSI decreased according to the increase of serum TSH concentration (n = 47, P<0.037). In addition, multiple regression analysis showed that the elevation of serum TSH concentration was associated with the decrease of OSI. These results suggest that the elevation of serum TSH concentration in subclinical hypothyroidism affects not bone turnover but bone structure as assessed by QUS.
Assuntos
Calcâneo/diagnóstico por imagem , Hipotireoidismo/complicações , Hipotireoidismo/diagnóstico por imagem , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/diagnóstico por imagem , Idoso , Densidade Óssea , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Tireotropina/sangue , Tiroxina/sangue , UltrassonografiaRESUMO
The prevalence of hypovitaminosis D has been recently reevaluated, and diabetes is considered as a risk factor for osteoporosis. We studied the association of the prevalence of hypovitaminosis D with the clinical features of diabetes. We conducted the observational study in 581 Japanese patients with type 2 diabetes mellitus and 51 normal subjects, and analyzed the relationship between serum 25-hydroxyvitamin D (25-OHD) concentration and the clinical features associated with type 2 diabetes. Mean serum 25-OHD concentration in type 2 diabetes patients was 17.0 +/- 7.1 ng/ml (Mean +/- SD) in winter, and was not statistically different from normal population (17.5 +/- 3.6 ng/ml). The prevalence of hypovitaminosis D (<20 ng/ml) was 70.6%. Serum concentrations of 25-OHD were associated with HbA1c (P = 0.013), age (P = 0.070) and serum albumin (P < 0.001), but were not related to BMI or the duration of diabetes. The levels of 25-OHD were significantly lower in the population with apparent microvascular complications, although serum creatinine levels were below 2.0 mg/dl. Serum 25-OHD concentrations in the group treated with insulin (15.4 +/- 6.5 ng/ml) was lower than those in the patients treated with diet alone (20.8 +/- 7.6 ng/ml) and with oral hypoglycemic agents (17.3 +/- 7.0 ng/ml). Furthermore, the highest incidence of osteoporotic fracture and/or back deformity was observed in insulin-treated patients with hypovitaminosis D. In conclusion, these results suggest that microvascular complications and insulin treatment in type 2 diabetes patients are associated with the co-existence of hypovitaminosis D, and that hypovitaminosis D in insulin-treated patients is possibly related to the risk of osteoporotic fracture.
Assuntos
Complicações do Diabetes/sangue , Diabetes Mellitus Tipo 2/complicações , Deficiência de Vitamina D/complicações , Vitamina D/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Creatinina/sangue , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/terapia , Feminino , Fraturas Ósseas , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Vitamina D/sangue , Deficiência de Vitamina D/sangueAssuntos
Acantose Nigricans/terapia , Hipoglicemiantes/administração & dosagem , Resistência à Insulina , Metformina/administração & dosagem , Acantose Nigricans/diagnóstico , Acantose Nigricans/etiologia , Adulto , Povo Asiático , Dieta para Diabéticos , Feminino , Humanos , Obesidade/etiologia , Obesidade/terapia , Resultado do TratamentoRESUMO
CONTEXT AND OBJECTIVE: Vascular endothelial growth factor plays a critical role both in neovascularization of proliferative diabetic retinopathy and in angiogenesis of islets in the pancreatic developmental stage in determining beta-cell mass and properties. Vascular endothelial growth factor mRNA levels increase as a result of increased transcriptional activation, mediated predominantly by hypoxia-inducible factor-1 alpha (HIF-1alpha) in response to hypoxia. DESIGN AND PATIENTS: In this study, we examined all regions of the HIF-1alpha to detect single-nucleotide polymorphisms (SNPs), evaluated the pattern of linkage disequilibrium to analyze haplotypes, and performed association studies in Japanese type 2 diabetes patients with or without retinopathy. RESULTS: A total of 35 SNPs were found in the gene, 27 of which were reported previously and eight of which were novel. Three of the 35 SNPs were located in coding regions, one in exon 2 (S28Y), and the others in exon 12 (P582S, A588T). The P582S HIF-1alpha mutation was associated with type 2 diabetes (P = 0.0028) by a consistently higher level of transcriptional activity than wild type, especially under hypoxic condition (P = 0.012), but no association with retinopathy was detected. CONCLUSION: This is the first report that HIF-1alpha is associated with the occurrence of type 2 diabetes and suggests that the P582S HIF-1alpha mutation should be assessed in larger studies as a risk factor for type 2 diabetes.
Assuntos
Proteínas de Ligação a DNA/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Variação Genética/fisiologia , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Alelos , Clonagem Molecular , Análise Mutacional de DNA , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/genética , Éxons/genética , Feminino , Frequência do Gene , Haplótipos , Humanos , Fator 1 Induzível por Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Japão/epidemiologia , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Variation in the gene encoding the cysteine protease calpain-10 has been linked and associated with risk of type 2 diabetes. We have examined the effect of three polymorphisms in the calpain-10 gene (SNP-43, Indel-19, and SNP-63) on the development of type 2 diabetes in the Japanese population in a pooled analysis of 927 patients and 929 controls. We observed that SNP-43, Indel-19, and SNP-63 either individually or as a haplotype were not associated with altered risk of type 2 diabetes with the exception of the rare 111/221 haplogenotype (odds ratio (OR) =3.53, P=0.02). However, stratification based on the median age-at-diagnosis in the pooled study population (<50 and > or =50 years) revealed that allele 2 of Indel-19 and the 121 haplotype were associated with reduced risk in patients with later age-at-diagnosis (age-at-diagnosis > or =50 years OR=0.82 and 0.80, respectively; P=0.04 and 0.02). Thus, variation in the calpain-10 gene may affect risk of type 2 diabetes in Japanese, especially in older individuals.
Assuntos
Calpaína/genética , Diabetes Mellitus Tipo 2/genética , Polimorfismo Genético , Adulto , Idade de Início , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
An accelerated polyol pathway in diabetes contributes to the development of diabetic complications. To elucidate diabetic nephropathy involving also renal tubular damage, we measured urinary sorbitol concentration concomitantly with urinary N-acetyl-D-glucosaminidase (NAG) excretion in WBN-kob diabetic rats.Twenty-four-hour urinary sorbitol concentrations increased in the diabetic rats in parallel with whole blood sorbitol concentrations. An increase in 24-h urinary NAG excretion coincided with the elevated urinary sorbitol levels in the diabetic rats. The administration of epalrestat, an aldose reductase inhibitor, reduced the increased whole blood and urinary sorbitol concentrations and urinary NAG excretion concomitantly with renal aldose reductase inhibition in the diabetic rats. These results indicate that diabetic nephropathy involves distorted cell function of renal tubules, and that treatment with epalrestat may prevent at least the progress of the nephropathy.
Assuntos
Nefropatias Diabéticas/urina , Rodanina/análogos & derivados , Rodanina/uso terapêutico , Sorbitol/urina , Acetilglucosaminidase/urina , Aldeído Redutase/análise , Aldeído Redutase/antagonistas & inibidores , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Rim/metabolismo , Masculino , Modelos Animais , Ratos , Ratos Wistar , TiazolidinasRESUMO
Understanding the causes of diabetic vascular complications has become an increasingly important issue because of the rapidly rising prevalence of diabetes. Recently discovered vasoconstrictors and angiogenesis regulators, such as endothelin (ET) and vascular endothelial growth factor (VEGF), have been intensely studied for possible pathogenic roles in diabetic vascular complications. The present study was undertaken to clarify the effect of glycemic control on serum VEGF and plasma ET-1 concentrations in diabetic patients, and to identify other factors that may cause fluctuations of these substances. Plasma VEGF and ET-1 concentrations of 45 hospitalized diabetic patients and 54 control subjects were measured by enzyme immunoassay (EIA) and radioimmunoassay (RIA), respectively. Plasma VEGF was elevated in poorly controlled diabetic patients compared with healthy subjects and plasma VEGF concentrations declined after hospitalized treatment with either insulin or oral hypoglycemic agents in combination with diet. There was a significant correlation between plasma VEGF concentration and both fasting plasma glucose (FPG) and hemoglobin A(1c) (HbA(1c)). Plasma ET-1 in poorly controlled diabetic patients was higher than in healthy controls, but improved glycemic control did not affect plasma ET-1 concentrations. Thus, poor glycemic control causes increased levels of plasma VEGF, which may result in hypertension and vascular complications in diabetes. Short-term treatment resulting in good glycemic control can improve levels of VEGF and may provide beneficial effects on diabetic vascular complications.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus/sangue , Endotelina-1/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Índice de Massa Corporal , Estudos de Casos e Controles , Complicações do Diabetes , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Neuropatias Diabéticas/sangue , Retinopatia Diabética/sangue , Jejum/sangue , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Proteinúria/sangue , Análise de RegressãoRESUMO
The 112/121 haplotype combination defined by the UCSNP-43, -19, and -63 alleles in the calpain-10 gene is associated with type 2 diabetes in Mexican Americans. To determine whether this genetic variation constitutes risk of type 2 diabetes in Japanese, we investigated its frequency in 177 patients with type 2 diabetes and 172 controls. Though this variation occurs in Japanese more frequently than in Mexican Americans, there is no significant difference in frequency between diabetic (29.9%) and control (31.9%) subjects. We also screened all exons and the putative promoter of the calpain-10 gene for mutations in 96 of the genotyped patients, resulting in the identification of 7 coding variants, including 3 missense mutations and 5 nucleotide alterations in the promoter. However, their frequencies all are similar in patients and controls, suggesting that these genetic variations are not a major factor in the occurrence of type 2 diabetes in Japanese, although they could yet be associated with various phenotypes of the disease.