PubMed Health⌕ Search

Biomedical subjects

Yoshimitsu Yamasaki

Publications and source records attributed to Yoshimitsu Yamasaki.

At least 19 recordsLinked to original sources
PubMed2007

Involvement of oxidative stress in the pathogenesis of diabetes.

Pancreatic beta-cell failure is the common characteristic of type 1 and type 2 diabetes. Type 1 diabetes is induced by pancreatic beta-cell destruction, which is mediated by an autoimmune mechanism and consequent inflammatory process. Various inflammatory cytokines and oxidative stress produced by islet-infiltrating immune cells have been proposed to play an important role in mediating the destruction of beta cells. The JNK pathway is also activated by such cytokines and oxidative stress and is involved in beta-cell destruction. Type 2 diabetes is the most prevalent and serious metabolic disease affecting people all over the world. Pancreatic beta-cell dysfunction and insulin resistance are the hallmark of type 2 diabetes. Once hyperglycemia becomes apparent, beta-cell function gradually deteriorates, and insulin resistance is aggravated. This process is called "glucose toxicity." Under such conditions, oxidative stress is provoked, and the JNK pathway is activated, which is likely involved in pancreatic beta-cell dysfunction and insulin resistance. In addition, oxidative stress and activation of the JNK pathway are involved in the progression of atherosclerosis, which is often observed under diabetic conditions. Taken together, it is likely that oxidative stress and subsequent activation of the JNK pathway are involved in the pathogenesis of type 1 and type 2 diabetes.

Atherosclerosis↗
PubMed2006

A novel index of insulin resistance determined from the homeostasis model assessment index and adiponectin levels in Japanese subjects.

Insulin resistance is the principal cause of glucose intolerance and type 2 diabetes and induces progression of severe atherosclerosis in these patients. Adiponectin, the adipose-specific proteins, is known to correlate negatively with insulin resistance in patients with obesity and type 2 diabetes. The purpose of this study was to evaluate the potential of using serum adiponectin levels as a marker of insulin resistance in various states of insulin resistance. Furthermore, we attempted to establish a modified index of the homeostasis model assessment index (HOMA-IR), calculated from the product of serum insulin and plasma glucose levels divided by serum adiponectin levels (HOMA-AD). We recruited 117 Japanese subjects with various degrees of glucose tolerance and determined serum adiponectin levels and insulin sensitivity (M-value) by using the euglycemic hyperinsulinemic clamp technique. M-value, the gold standard index of insulin resistance, correlates significantly and independently with fasting insulin (r=-0.313, P<0.001), glucose (r=-0.319, P<0.001), and adiponectin (r=0.241, P<0.002) levels. M-values were more significantly correlated with HOMA-AD (r=-0.643, P<0.001) than HOMA-IR values (r=-0.591, P<0.001). In subjects with moderate hyperglycemia (fasting glucose levels>8.0mmol/L, n=30), HOMA-AD showed a more significant correlation with the M-value than HOMA-IR (r=-0.535, P=0.005 versus r=-0.461, P=0.010). We would therefore like to propose a novel index, HOMA-AD, as a simple and adequate index for determining insulin resistance even in diabetic patients with overt hyperglycemia.

Adiponectin↗
PubMed2006

Marked increase of insulin gene transcription by suppression of the Rho/Rho-kinase pathway.

The hallmarks of type 2 diabetes are pancreatic beta-cell dysfunction and insulin resistance. It has been suggested that Rho/Rho-kinase is a mediator of insulin signaling, and thereby involved in the development of insulin resistance, regulation of insulin action, and glucose homeostasis, but the role of Rho/Rho-kinase in beta-cells remained unknown. The aim of this study was to examine the possible role of Rho/Rho-kinase in beta-cell function. Immunostaining showed that RhoA was expressed in mature beta-cells, with higher expression observed in beta-cells of diabetic C57BL/KsJ-db/db mice compared to non-diabetic mice. In addition, to examine the functional role of Rho/Rho-kinase in beta-cells, we evaluated the effect of Rho-kinase inhibitors on insulin biosynthesis. Northern blot analysis showed that insulin mRNA levels were markedly increased by Rho-kinase inhibitors, Y-27632 and fasudil, in beta-cell-derived HIT-T15 cells. Furthermore, using the luciferase reporter gene assay, insulin promoter activity was also dramatically increased by Y-27632, which was associated with an increase in the insulin mRNA level. These results suggest that suppression of Rho/Rho-kinase increases insulin promoter activity, which leads to an increase in insulin mRNA level. Taken together, Rho/Rho-kinase is activated in beta-cells under diabetic conditions and suppression of the Rho/Rho-kinase pathway increases insulin gene transcription. These results imply that Rho/Rho-kinase activation is involved in the suppression of insulin expression found in diabetes and that suppression of the Rho/Rho-kinase pathway could be a useful tool to augment insulin gene transcription.

Animals↗
PubMed2006

Rationale and protocol of a trial for prevention of diabetic atherosclerosis by using antiplatelet drugs: study of Diabetic Atherosclerosis Prevention by Cilostazol (DAPC study).

BACKGROUND: Secondary treatment of arteriosclerosis may be applicable for the primary prevention of atherosclerosis in diabetic patients. This prospective, 2-year follow-up study was designed to determine the efficacy and safety of antiplatelet therapy in the prevention of atherosclerosis of diabetic subjects. METHODS: Patients with type 2 diabetes and arteriosclerosis obliterans from the Eastern Asian countries were registered online and randomly assigned either to the aspirin group (81-100 mg/day) or the cilostazol group (100-200 mg/day) in this international, 2-year, prospective follow-up interventional study. RESULTS: The primary study endpoint was changes in right and left maximum intima-media thickness of the common carotid artery. Secondary endpoints include changes in right and left maximum intima-media thickness of the internal carotid artery; semiquantitative evaluation of cerebral infarction by magnetic resonance imaging; cardiovascular events including sudden death, stroke, transient cerebral ischemic attacks, acute myocardial infarction, angina, and progression of arteriosclerosis obliterans; overall death; withdrawal; and change in ankle-brachial pressure index. CONCLUSION: This is the first study to use an online system that was developed in Asian countries for pooling data from an international clinical trial. These findings are expected to help in the prevention of diabetic atherosclerosis and subsequent cardiovascular and cerebrovascular disease.

Atherosclerosis↗
PubMed2006

Recent advances of intervention to inhibit progression of carotid intima-media thickness in patients with type 2 diabetes mellitus.

BACKGROUND AND PURPOSE: Type 2 diabetes is associated with a high cardiovascular morbidity and mortality. Recent advances of intervention studies in type 2 diabetes with use of carotid intima-media thickness (CIMT) measurement as a surrogate end point may allow for better understanding of the undetermined process of atherosclerosis, the effect of interventions, and the usefulness of CIMT to inhibit events of cardiovascular disease. SUMMARY OF REVIEW: Data were available from 11 studies (n=1578) in subjects with type 2 diabetes (including impaired glucose tolerance, n=132) that evaluated the effect of interventions on change in CIMT. The overall weighed rate of change in mean CIMT based on data among control groups (ie, type 2 diabetes without interventions) was 0.034 mm/y (95% CI, 0.029 to 0.039; median SD, 0.054), in which mean HbA(1c) was 7.86% (95% CI, 7.72 to 8.00; median SD, 1.5). A significant close correlation of HbA(1c) with rate of CIMT change was found (R(2)=0.35, P=0.01). Agents for lowering of blood glucose, platelet activation, or blood pressure significantly reduced the CIMT increase, independent of blood glucose control. This implies that other mechanisms of such agents to diminish CIMT increase should be explored. CONCLUSIONS: CIMT measurement may contribute to elucidating the short- and/or long-term effect of interventions on the rate of change in CIMT in relation to the levels of various risk factors. Although the method needs further standardization, pharmacological interventions are likely to inhibit progression of CIMT, leading to a reduction of cardiovascular events.

Carotid Arteries↗
PubMed2006

Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation.

The transcription factor pancreatic and duodenal homeobox factor 1 (PDX-1) is expressed in pancreatic progenitor cells. In exocrine pancreas, PDX-1 is down-regulated during late development, while re-up-regulation of PDX-1 has been reported in pancreatic cancer and pancreatitis. To determine whether sustained expression of PDX-1 could affect pancreas development, PDX-1 was constitutively expressed in all pancreatic lineages by transgenic approaches. The transgenic pancreas was markedly small with the replacement of acinar cells by duct-like structures, accompanied by activated Stat3. Genetic ablation of Stat3 in the transgenic pancreas profoundly suppressed the metaplastic phenotype. These results provide a mechanism of pancreatic metaplasia by which persistent PDX-1 expression cell-autonomously induces acinar-to-ductal transition through Stat3 activation.

Animals↗
PubMed2006

Role of oxidative stress, endoplasmic reticulum stress, and c-Jun N-terminal kinase in pancreatic beta-cell dysfunction and insulin resistance.

Type 2 diabetes is the most prevalent and serious metabolic disease affecting people all over the world. Pancreatic beta-cell dysfunction and insulin resistance are the hallmark of type 2 diabetes. Normal beta-cells can compensate for insulin resistance by increasing insulin secretion and/or beta-cell mass, but insufficient compensation leads to the onset of glucose intolerance. Once hyperglycemia becomes apparent, beta-cell function gradually deteriorates and insulin resistance aggravates. Under diabetic conditions, oxidative stress and endoplasmic reticulum stress are induced in various tissues, leading to activation of the c-Jun N-terminal kinase pathway. The activation of c-Jun N-terminal kinase suppresses insulin biosynthesis and interferes with insulin action. Indeed, suppression of c-Jun N-terminal kinase in diabetic mice improves insulin resistance and ameliorates glucose tolerance. Thus, the c-Jun N-terminal kinase pathway plays a central role in pathogenesis of type 2 diabetes and could be a potential target for diabetes therapy.

Animals↗
PubMed2006

Combination of multiple genetic risk factors is synergistically associated with carotid atherosclerosis in Japanese subjects with type 2 diabetes.

OBJECTIVE: Several genetic risk factors, such as single nucleotide polymorphisms (SNPs), in candidate genes have been reported to be responsible for intima-media thickness (IMT), which is one of the surrogate end points of cardiovascular events. However, the synergistic effects of SNPs have not been evaluated in detail. RESEARCH DESIGN AND METHODS: We measured the average IMT of the common and internal carotid artery in Japanese type 2 diabetic patients (n = 690) (>50 years old) using ultrasonography. We also determined their genotypes regarding 106 SNPs in candidate genes responsible for cardiovascular diseases. Among the 106 SNPs, we selected 40 common (frequency of minor allele >/=10%) SNPs. We compared the average IMT of subjects with and without any pairs of four genotypes selected from the 40 common SNPs. RESULTS: The combination of methylen-tetrahydrofolate reductase 677 TT genotype and lymphotoxin-alpha (LTA) 252 GG genotype and that of ACE DD genotype and LTA 252 GG genotype were evaluated as responsible for a statistically significant (P = 2.7 x 10(-9) and 3.5 x 10(-6), respectively) increase in average IMT (mean [+/-SD] 1.54 +/- 0.60 and 1.43 +/- 0.58 mm, respectively) compared with those of the subjects without these combinations (1.04 +/- 0.34 and 1.04 +/- 0.34 mm, respectively). No single genotype was shown to be responsible for the statistically significant difference in average IMT after Bonferroni's multiple comparison procedure. CONCLUSIONS: The present analysis demonstrates an approach to evaluate combinations of multiple genetic risk factors that are synergistically associated with carotid atherosclerosis.

Aged↗
PubMed2006

[Strategy for order-made treatment of diabetic macroangiopathy].

Several genetic risk factors such as single nucleotide polymorphisms(SNPs) in candidate genes have been reported to be responsible for diabetic macroangiopathy. We determined their genotypes regarding more than 100 SNPs in candidate genes responsible for average IMT of Japanese type 2 diabetic patients. We depicted some SNPs which were found to be significantly (p<0.05) responsible to the increase in AveIMT. Then, two combinations of double SNPs were evaluated as responsible for significant increases in AveIMT. Also, these two combinations were probably responsible for a high frequency of history of old myocardial infarction. The present analysis may provide one approach to evaluate combination of multiple genetic risk factors, which is synergistically associated with carotid atherosclerosis and myocardial infarction.

Carotid Artery Diseases↗
PubMed2005

The forkhead transcription factor Foxo1 bridges the JNK pathway and the transcription factor PDX-1 through its intracellular translocation.

It has been shown that oxidative stress and activation of the c-Jun N-terminal kinase (JNK) pathway induce the nucleocytoplasmic translocation of the pancreatic transcription factor PDX-1, which leads to pancreatic beta-cell dysfunction. In this study, we have shown that the forkhead transcription factor Foxo1/FKHR plays a role as a mediator between the JNK pathway and PDX-1. Under oxidative stress conditions, Foxo1 changed its intracellular localization from the cytoplasm to the nucleus in the pancreatic beta-cell line HIT-T15. The overexpression of JNK also induced the nuclear localization of Foxo1, but in contrast, suppression of JNK reduced the oxidative stress-induced nuclear localization of Foxo1, suggesting the involvement of the JNK pathway in Foxo1 translocation. In addition, oxidative stress or activation of the JNK pathway decreased the activity of Akt in HIT cells, leading to the decreased phosphorylation of Foxo1 following nuclear localization. Furthermore, adenovirus-mediated Foxo1 overexpression reduced the nuclear expression of PDX-1, whereas repression of Foxo1 by Foxo1-specific small interfering RNA retained the nuclear expression of PDX-1 under oxidative stress conditions. Taken together, Foxo1 is involved in the nucleocytoplasmic translocation of PDX-1 by oxidative stress and the JNK pathway.

Active Transport, Cell Nucleus↗
PubMed2005

Post-prandial hyperglycemia is an important predictor of the incidence of diabetic microangiopathy in Japanese type 2 diabetic patients.

Diabetic microangiopathy is often observed in diabetic patients, but there is little evidence regarding the relationship between post-prandial glycemia or insulinemia and the incidence of diabetic microangiopathy. In this study, to elucidate the relationship between post-prandial glycemia (or insulinemia) and diabetic microangiopathy, we performed a cross-sectional study of 232 subjects with type 2 diabetes mellitus who were not being treated with insulin injections. A multiple regression analysis showed that post-prandial hyperglycemia independently correlated with the incidence of diabetic retinopathy and neuropathy. Post-prandial hyperglycemia also correlated, although not independently, with the incidence of diabetic nephropathy. In addition, interestingly, post-prandial hypoinsulinemia independently correlated with the incidence of diabetic retinopathy, although not correlated with diabetic neuropathy or nephropathy. In conclusion, post-prandial hyperglycemia, rather than fasting glycemia or hemoglobin A1c levels, is an important predictor of the incidence of diabetic microangiopathy in Japanese type 2 diabetic patients.

Aged↗
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↗