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Kentaro Ohtoshi

Publications and source records attributed to Kentaro Ohtoshi.

9 recordsLinked to original sources
PubMed2005

Beneficial effects of nateglinide on insulin resistance in type 2 diabetes.

Nateglinide, a rapid insulin secretagogue, is known to facilitate the early phase of insulin secretion and has been used for the treatment of type 2 diabetic patients with postprandial hyperglycemia. The aim of this study is to evaluate the effect of nateglinide on insulin resistance as well as insulin secretory defects in type 2 diabetic patients. Insulin secretion ability was evaluated by the hyperglycemic clamp test, and insulin sensitivity was evaluated by the euglycemic hyperinsulinemic clamp test, using an artificial pancreas. The hyperglycemic clamp test showed that a 7-day treatment with nateglinide significantly increased insulin secretion in response to high glucose. Interestingly, although nateglinide is known to facilitate insulin secretion, daily urinary C-peptide excretion was decreased after nateglinide treatment. Moreover, in the euglycemic hyperinsulinemic clamp test, glucose infusion rate was significantly increased by nateglinide treatment, indicating that nateglinide functions to decrease insulin resistance. Nateglinide ameliorates insulin resistance as well as insulin secretory defects in type 2 diabetic patients.

Blood Glucose↗
PubMed2005

Association of soluble epoxide hydrolase gene polymorphism with insulin resistance in type 2 diabetic patients.

The insulin resistance found in diabetes is influenced by vascular tone and local blood flow. Endothelial-derived hyperpolarizing factor (EDHF) functions as a potent vasodilator to regulate vascular tone, and its production is regulated by soluble epoxide hydrolase (sEH). In this study, we examined the genotype distribution and allele frequency of sEH gene G860A (Arg287Gln) polymorphism in Japanese subjects (n=499) (non-diabetic subjects, n=205; type 2 diabetic patients, n=294). Also, to accurately evaluate insulin resistance, we performed the euglycemic hyperinsulinemic clamp test for each type 2 diabetic patient (n=86) from whom agreement was obtained, and then examined a possible association of sEH gene G860A polymorphism with insulin resistance status. There was no significant difference in genotype distribution and allele frequency between non-diabetic subjects and type 2 diabetic patients. Interestingly, however, there was close association of sEH gene G860A (Arg287Gln) polymorphism with insulin resistance in type 2 diabetic patients, which was not observed in non-diabetic subjects. These results suggest that sEH and EDHF play some important role in the pathogenesis of insulin resistance found in type 2 diabetes.

Adult↗
PubMed2005

Decreased endogenous secretory advanced glycation end product receptor in type 1 diabetic patients: its possible association with diabetic vascular complications.

OBJECTIVE: The binding of advanced glycation end products (AGEs) to their receptor (RAGE) plays an important role in the development of diabetic vascular complications. In the present study, we examined circulating endogenous secretory RAGE (esRAGE) levels in subjects with type 1 diabetes and explored the possible association between esRAGE levels and the severity of diabetic vascular complications. RESEARCH DESIGN AND METHODS: Circulating esRAGE levels in serum were examined in 67 Japanese type 1 diabetic patients (22 men and 45 women, age 24.0 +/- 4.4 years [means +/- SD]) and 23 age-matched healthy nondiabetic subjects (10 men and 13 women aged 24.9 +/- 1.4 years). Daily urinary albumin excretion, the presence of retinopathy, and intima-media thickness (IMT) of the carotid artery were also evaluated. We further explored the association between esRAGE levels and severity of diabetic vascular complications. RESULTS: Circulating esRAGE levels were significantly lower in subjects with type 1 diabetes than in nondiabetic subjects (0.266 +/- 0.089 vs. 0.436 +/- 0.121 ng/ml, respectively, P < 0.0001) and was inversely correlated with HbA(1c) (A1C) levels (r = -0.614, P < 0.0001). In addition, multivariate regression analysis demonstrated that A1C was an independent risk factor for a low esRAGE value. Furthermore, circulating esRAGE levels were inversely correlated with carotid IMT (r = -0.325, P = 0.0017) and was one of the independent risk factors for IMT thickening. Furthermore, there was a significant difference (P = 0.0124) in esRAGE levels between patients without retinopathy (0.286 +/- 0.092 ng/ml) and those with retinopathy (0.230 +/- 0.074 ng/ml). CONCLUSIONS: Circulating esRAGE levels were significantly lower in type 1 diabetic patients than in nondiabetic subjects and were inversely associated with the severity of some diabetic vascular complications.

Adult↗
PubMed2004

Possible novel index determined by the glucose clamp test for selection of a suitable therapy for each type 2 diabetic patient.

The hallmark of type 2 diabetes is insulin resistance and insufficient insulin secretion, and appropriate therapy should be selected for each patient. In this study, to establish some index to select suitable therapy for each patient, we evaluated insulin sensitivity and insulin secretion with euglycemic hyperinsulinemic clamp and hyperglycemic clamp tests, respectively, and found that specific GIR index (GIRxIRI (90)) could be a useful marker to select suitable therapy for each type 2 diabetic patient (GIR: glucose infusion rate in euglycemic hyperinsulinemic clamp test; IRI (90): plasma insulin level 90 min after starting the hyperglycemic clamp test).

Blood Glucose↗
PubMed2003

Association of NAD(P)H oxidase p22 phox gene variation with advanced carotid atherosclerosis in Japanese type 2 diabetes.

OBJECTIVE: To evaluate the association between the C242T polymorphism of the p22 phox gene, an essential component of NAD(P)H oxidase in the vasculature, with intima-media thickness (IMT) of the carotid artery and risk factors for atherosclerosis in type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: C242T polymorphism of the p22 phox gene was detected by polymerase chain reaction-restriction fragment-length polymorphism in 200 Japanese type 2 diabetic subjects and 215 nondiabetic subjects. We examined the association with this mutation and carotid atherosclerosis as well as the patients' clinical characteristics and the level of 8-hydroxy-2'deoxyguanosine (8-OHdG) as an index of oxidative DNA damage. RESULTS: The diabetic subjects with the TC+TT genotypes displayed a significantly lower average IMT (1.13 +/- 0.31 vs. 1.31 +/- 0.34 mm; P = 0.0099) and a not significantly lower serum 8-OHdG level than those with the CC genotype, despite no difference in the risk factors. Stepwise multiple regression analysis showed that the risk factors for increased IMT in the diabetic subjects were systolic blood pressure (P = 0.0042) and p22 phox CC genotype (P = 0.0151). In nondiabetic subjects, the average IMT of the TC+TT group was not different from that of the CC group (0.85 +/- 0.14 vs. 0.94 +/- 0.30 mm, P = 0.417). Fasting plasma insulin concentration (41.4 +/- 15.6 vs. 64.2 +/- 59.4 pmol/l, P = 0.0098) and insulin resistance index of homeostasis model assessment (HOMA-R) (1.58 +/- 0.66 vs. 2.60 +/- 2.56, P = 0.0066) were significantly lower in the TC+TT group than in the CC group. CONCLUSIONS: These results show that the C242T mutation in the p22 phox gene is associated with progression of asymptomatic atherosclerosis in the subjects with type 2 diabetes and is also associated with insulin resistance in nondiabetic subjects.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2002

Protein kinase C-dependent, CCAAT/enhancer-binding protein beta-mediated expression of insulin-like growth factor I gene.

The possible involvement of the protein kinase C (PKC) pathway in transcriptional regulation of the human insulin-like growth factor-I (IGF-I) gene has been suggested. In this study, we sought to determine whether a PKC-dependent pathway is implicated in the transcriptional control, and if it is, how this occurs. Treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) caused an increase in the activity of the human IGF-I gene major promoter in HepG2 cells. A CCAAT/enhancer-binding protein (C/EBP) binding site located at +22 to +30 was bound by C/EBP beta in a TPA-dependent manner and was solely responsible for the TPA responsiveness. This increase in C/EBP beta activity occurs through transcriptional and posttranslational regulation, and the latter is mediated by activation of p90 ribosomal S6 kinase (RSK): co-expression of dominant negative RSK abolished the TPA-responsive and C/EBP beta-dependent transactivation. Also, TPA-responsive activation of GAL4-C/EBP beta chimera required the Ser residue known as the RSK target. In SK-N-MC cells, which display constitutive, high expression of IGF-I on use of the major promoter, a large amount of C/EBP beta binding was observed with the C/EBP site in the basal state. Treatment with PKC inhibitors substantially reduced the promoter activity and mRNA amounts of IGF-I, with the binding of C/EBP beta to the C/EBP site also being reduced. When the C/EBP site was disrupted, the basal promoter activity was reduced, but the reduction by the PKC inhibitor was no longer observed. These observations suggest that the increase of C/EBP beta binding to the C/EBP site, which is in part mediated via activation of RSK, can primarily explain the TPA responsiveness of the IGF-I gene promoter. The intrinsic PKC activity in SK-N-MC cells should play a major role in the constitutive, high expression of IGF-I and may therefore contribute in part to the maintenance of the tumor phenotype of the cells.

Base Sequence↗
PubMed2002

Elevated C-reactive protein associates with early-stage carotid atherosclerosis in young subjects with type 1 diabetes.

OBJECTIVE: To evaluate whether low-grade inflammation contributes to early-stage advanced carotid atherosclerosis in young subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: The mean and maximum (max) intima-media thicknesses (IMT) of the carotid artery were assessed using ultrasound B-mode imaging in 55 patients with type 1 diabetes (22 men and 33 women, aged 22.1 +/- 3.6 years (+/- SD), duration of diabetes 14.2 +/- 5.7 years) and 75 age-matched healthy nondiabetic subjects (28 men and 47 women). High-sensitive C-reactive protein (hs-CRP) levels were measured with a latex-enhanced immunonephelometer. RESULTS: The patients with type 1 diabetes had significantly higher hs-CRP levels (median 0.35, range 0.05-1.47 mg/l vs. median 0.14, range 0.05-1.44 mg/l; P = 0.001) as well as significantly higher mean IMT and max IMT than the nondiabetic subjects (mean IMT 0.76 +/- 0.09 vs. 0.72 +/- 0.04 mm, P = 0.003; max IMT 0.84 +/- 0.11 vs. 0.77 +/- 0.06 mm, P < 0.0001). Hs-CRP levels were significantly correlated with the mean and max IMT of patients with type 1 diabetes and with the max IMT of nondiabetic patients. Multivariate regression analyses for both diabetic and nondiabetic subjects as a single group showed that hs-CRP levels are independently correlated with the mean IMT and max IMT levels (P = 0.002 and P = 0.023, respectively) as well as with diastolic blood pressure, sex, and duration of diabetes. CONCLUSIONS: Our data indicate that hs-CRP levels are elevated in young patients with type 1 diabetes, possibly corresponding with early-stage advanced carotid atherosclerosis.

Adult↗
PubMed2002

NAD (P) H oxidase p22 phox C242T polymorphism affects LDL particle size and insulin resistance in Japanese subjects.

Elevated cardiovascular risk is associated with an increased number of small, dense low-density lipoprotein (LDL) particles, which exhibit increased susceptibility to lipid oxidation, however, the mechanism determining LDL particle size has never been fully elucidated. We have examined the association between the C242T polymorphism of the p22 phox gene, which is a small subunit of vascular NAD(P)H oxidase, and both LDL particle size and clinical characteristics in 260 healthy subjects. Peak LDL particle diameter (LDL-PPD) was measured by continuous disk polyacrylamide gel electrophoresis. Twenty-one of the 217 subjects with the CC genotype showed pattern B (median LDL-PPD under 25.5 nm), whereas, none of the 43 subjects with TC + TT genotypes showed pattern B. The pattern B fraction was significantly larger in the CC group than in the TC + TT group (p = 0.030). The subjects with the CC genotype also showed a significantly higher fasting glucose level, plasma insulin level, and insulin resistance index of homeostasis model assessment (HOMA-R) than those with the TC + TT genotype. Our data demonstrate that variation in the small NAD(P)H oxidase subunit p22 phox gene substantially influences LDL particle size and may also reflect differences in the insulin sensitivity of non-diabetic subjects.

Adult↗