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Biomedical subjects

Hideyuki Sasaki

Publications and source records attributed to Hideyuki Sasaki.

At least 19 recordsLinked to original sources
PubMed2006

IA-2beta, but not IA-2, is induced by ghrelin and inhibits glucose-stimulated insulin secretion.

Ghrelin is a newly discovered peptide and an endogenous ligand for growth hormone (GH) secretagogue (GHS) receptor. It has been shown to possess various central and peripheral effects, including GH secretion, food intake, and gastric and cardiac effects. Ghrelin and the GHS receptor are expressed also in pancreatic islets. We have identified several ghrelin-induced genes by PCR-select subtraction methods, among which is a beta-cell autoantigen for type 1 diabetes, IA-2beta. Administration of ghrelin increased IA-2beta mRNA in mouse brain, pancreas, and insulinoma cell lines (MIN6 and betaTC3). However, the expression of IA-2, another structurally related beta-cell autoantigen, was not induced by ghrelin. Administration of ghrelin or overexpression of IA-2beta, but not overexpression of IA-2, inhibited glucose-stimulated insulin secretion in MIN6 insulinoma cells and, moreover, inhibition of IA-2beta expression by the RNA interference technique ameliorated ghrelin's inhibitory effects on glucose-stimulated insulin secretion. These findings strongly suggest that inhibitory effects of ghrelin on glucose-stimulated insulin secretion are at least partly due to increased expression of IA-2beta induced by ghrelin. Our data demonstrate the link among ghrelin, IA-2beta, and glucose-stimulated insulin secretion.

Animals↗
PubMed2006

Living-related intestinal transplantation for a patient with hypoganglionosis.

A 14-yr-old boy with total parenteral nutrition-dependent short-bowel syndrome associated with hypoganglionosis underwent the LR-IT by using a 150 cm segment of distal ileum taken from a healthy donor. The graft vessels were connected to infrarenal aorta and inferior vena cava. The immunosuppressive regimen consisted of daclizumab, tacrolimus, and steroid. The graft surveillance for ACR was accomplished using zoom endoscopy and mucosal biopsy. The blood trough level of tacrolimus was maintained between 20 and 25 ng/mL for the first 2 months, followed by 15-20 ng/mL thereafter. The 50 mg of daclizumab was administered on the day of operation, and same dosage was repeated at 2-wk intervals. The first ACR occurred on POD-9 and was progressive, and required a 14-day course of OKT-3 injection. After the treatment with OKT-3, the graft recovered from the ACR, and began to function well enough to discontinue the intravenous nutrition on POD-55. No infectious complication has occurred. The patient was discharged in POD-112, and currently tolerates full oral intake without requiring intravenous nutritional or fluid supplementation. The donor was discharged without any complications. The LR-IT could successfully be performed with minimal risk to the donor, and it can be a treatment of choice for patients with short-gut syndrome associated with hypoganglionosis.

Adolescent↗
PubMed2006

Uncoupling protein 2 promoter polymorphism -866G/A affects peripheral nerve dysfunction in Japanese type 2 diabetic patients.

OBJECTIVE: To determine genetic predispositions for diabetic polyneuropathy, we investigated the relationship between the -866G/A polymorphism of uncoupling protein (UCP) 2 and neurological manifestations in 197 type 2 diabetic patients. RESEARCH DESIGN AND METHODS: We first examined whether UCP2 mRNA had been expressed in the dorsal root ganglion (DRG) in four Long-Evans Tokushima Otsuka rats using RT-PCR and electrophoresis. Genotyping of UCP2 promoter polymorphism -866G/A was then performed in 197 unrelated Japanese type 2 diabetic patients, who were subjected to nerve conduction, quantitative vibratory perception, head-up tilt, and heart rate variability tests, by PCR restriction fragment-length polymorphism. The relationships between UCP2 genotype and various nerve functions were analyzed by uni- and multivariable analysis. RESULTS: Expression of UCP2 mRNA was confirmed in rat DRG. Multiple regression analysis clarified the hypothesis that the G/A + A/A genotype was significantly related to decreased motor nerve conduction velocity and impaired blood pressure maintenance on the head-up tilt test. Multiple logistic regression analysis revealed that the G/A + A/A genotypes are a significant risk factor for sensory nerve conduction slowing and orthostatic hypotension. CONCLUSIONS: UCP2 promoter gene polymorphism -866 G/A was significantly associated with nerve conduction slowing and vasomotor sympathetic functions. These findings suggest that the higher UCP2 activity related to the A allele has an energy-depleting effect on peripheral nerve function in type 2 diabetic patients.

Alleles↗
PubMed2005

A role of the adrenal gland in stress-induced up-regulation of cytokines in plasma.

To reveal a pathway by which psychological/physical stresses influence host defense capability, responses to immobilization stress in mice were investigated, focusing on a multifunctional cytokine, interleukin-18 (IL-18). Immobilization stress induced interleukin-18 accumulation in plasma and in the adrenal gland. Inhibition on ACTH resulted in suppressed levels of IL-18 both in plasma and the adrenal gland. In hemi-adrenalectomized mice, plasma IL-18 levels after stress were lower than in sham-operated mice. This, together with the observation in stressed hemi-adrenalectomized mice that IL-6 levels in plasma were suppressed but up-regulated by recombinant IL-18, showed that the adrenal gland plays a crucial role in stress-related elevation of IL-6 in plasma via IL-18. Adrenal gland is highlighted as an organ connecting the psychological, endocrine, and immune systems. Controlling the secretion of IL-18 from the adrenal gland may serve as a possible preventative means against a stress-related disruption of host defenses.

Adrenal Glands↗
PubMed2005

Peripheral nerve functions may deteriorate parallel to the progression of microangiopathy in diabetic patients.

Our aim was to obtain information to help in the early detection of impaired nerve function and to assess the severity of diabetic symmetric polyneuropathy (DPN). Various somatic and autonomic nerve functions in 40 diabetics and 20 age-matched healthy volunteers were evaluated using six objective examinations: nerve conduction study, quantitative vibratory perception threshold, heart rate variability, Valsalva test, head-up tilt and quantitative sudomotor axonal reflex test (QSART). The diabetics were divided into three groups according to the severity of their microangiopathy. The nerve function data and level of impairment were compared between a healthy control and three diabetic groups. The relationships between nerve function data and clinical background were also examined using multivariate analysis. Results were as follows: (1) all nerve dysfunctions seemed to develop parallel to the progression of microangiopathy, (2) reduced nerve conduction velocity and elevated vibratory perception thresholds in the feet might be early detectable signs of DPN, (3) vasomotor and sudomotor sympathetic functions and cardiovagal functions seemed to deteriorate with the appearance of microangiopathy, (4) lowered compound muscle action potential seemed to appear at the advanced microangiopathic condition, (5) hypohydrosis was closely related to diabetic foot ulcers. In conclusion, nerve dysfunction in diabetics might generally progress with microangiopathy from somatic sensory nerve dysfunction to autonomic nerve dysfunction and then to somatic motor nerve dysfunction. Sympathetic sudomotor dysfunction might be a sensitive predictor of diabetic foot ulcer.

Adult↗
PubMed2005

Extracellular superoxide dismutase gene polymorphism is associated with insulin resistance and the susceptibility to type 2 diabetes.

Oxidative stress has been implicated in pancreatic beta-cell damage, insulin resistance and vascular function in diabetic patients and the dysfunction of antioxidant enzymes may be associated with the pathogenesis of diabetes. Extracellular superoxide dismutase (EC-SOD) is found in the extracellular matrix of tissues and the major scavenger of superoxide radical. To investigate the role of genetic variability for the pathogenesis of type 2 diabetes, we scanned the protein coding exon and flanking introns of EC-SOD gene for mutation in Japanese type 2 diabetic patients. We identified two missense mutations, Ala40Thr (GCG-->ACG) and Arg213Gly (CGG-->GGG), and a silent mutation, Leu53Leu (CTG-->TTG). For one of these variants, the Ala40Thr polymorphism, the frequency of Thr allele and the number of subjects with Thr allele (Ala/Thr+Thr/Thr) were higher in type 2 diabetic patients (n=205) than those in non-diabetic subjects (n=220) (33.2% versus 24.1%, p=0.003 and 55.6% versus 42.7%, p=0.008, respectively). The patients with Thr allele also showed earlier age at diagnosis of diabetes (42.2+/-7.8 years versus 44.4+/-6.9 years, p=0.037) and higher prevalence of hypertension (53.5% versus 38.5%, p=0.032) than those without the allele. Insulin sensitivity, furthermore, was evaluated in 71 type 2 diabetic patients with short insulin tolerance test (SITT). The patients with Thr allele showed lower insulin sensitivity (Kitt value of SITT) than those without the allele (1.78+/-0.78%/min versus 2.33+/-1.02%/min, p=0.012), although no significant differences in other clinical and biochemical characteristics were observed between two groups. These results suggest that the genetic variant of EC-SOD gene is associated with insulin resistance and the susceptibility to type 2 diabetes.

Amino Acid Substitution↗
PubMed2005

Prevalence and risk factors for erectile dysfunction in Japanese diabetics.

We evaluated the prevalence and risk factors for erectile dysfunction (ED) and interest in ED treatment among Japanese men being treated for type 2 diabetes mellitus. Patients (40-79 years; n=1118) completed the 5-item version of the International Index of Erectile Function (IIEF-5), and questions related to interest in ED pharmacotherapy, subjective symptoms of diabetes, and general quality of life. A separate survey completed by physicians examined the relationships between age, diabetic treatments (insulin or oral), symptoms of diabetes (poor glycemic control, microangiopathy), complications of diabetes (hypertension, ischemic heart disease, cerebrovascular disease), and ED. The prevalence of ED in patients with diabetes was 90%, a rate double that of non-diabetic individuals. Multivariate analyses revealed that age, insulin therapy, microangiopathy, hypertension, history of cerebrovascular or cardiovascular disease, leg dysesthesia, dysuria, insomnia, and anorexia all represented significant risk factors for ED. Half of all respondents were interested (29%) or would consider pharmacotherapy for ED (21%). These findings suggest that ED is a significant problem in Japanese men with diabetes, and that specific risk factors increase the prevalence of ED. Furthermore, the survey results expose national attitudes toward treatment of ED.

Adult↗
PubMed2005

Increased gene expression of antioxidant enzymes in KKAy diabetic mice but not in STZ diabetic mice.

Oxidative stress and the gene expression at the transcriptional level of antioxidant enzymes were investigated in two models of diabetes in mice. We used KKAy mice as a model of obese insulin-resistant diabetes, and streptozotocin-induced diabetic mice (STZ mice) as a model of insulin-deficient diabetes. C57BL mice and saline-injected ICR mice were used as the respective non-diabetic controls. To assess oxidative damage, plasma malonedialdehyde (MDA), urine 8-isoprostane and 8-hydroxy deoxyguanosine (8-OHdG) were measured. The mRNA expression of antioxidant enzymes, superoxide dismutase 1 (SOD-1) and glutathione peroxidase 1 (GPx-1) in the kidney and heart were quantified using a real-time polymerase chain reaction. The KKAy mice demonstrated moderate hyperglycemia and hyperlipidemia, and the STZ mice showed severe hyperglycemia and hypolipidemia. The KKAy mice, but not the STZ mice, showed elevated plasma MDA relative to the non-diabetic controls. Urine 8-isoprostane and 8-OHdG in both diabetic mouse groups increased significantly. The urine oxidative stress markers in the severely hyperglycemic STZ mice were higher than those in the moderately hyperglycemic KKAy mice. Although GPx-1 and SOD-1 showed elevated mRNA expression in the KKAy mice in the kidney and heart, in the STZ mice they did not increase compared to the controls. The compensatory up-regulation of the mRNA expression of antioxidant enzymes may be impaired in the insulin-deficient severely hyperglycemic state.

Animals↗
PubMed2005

A functional variant in the human betacellulin gene promoter is associated with type 2 diabetes.

Betacellulin (BTC) plays an important role in differentiation, growth, and antiapoptosis of pancreatic beta-cells. We characterized about 2.3 kb of the 5'-flanking region of human BTC gene and identified six polymorphisms (-2159A>G, -1449G>A, -1388C>T, -279C>A, -233G>C, and -226A>G). The G allele in the -226A>G polymorphism was more frequent in type 2 diabetic patients (n = 250) than in nondiabetic subjects (n = 254) (35.6% vs. 27.8%, P = 0.007), and the -2159G, -1449A, and -1388T alleles were in complete linkage disequilibrium with the -226G allele. The frequencies of the -279A and -233C alleles were low (7.0 and 2.0% in diabetic patients), and no significant differences were observed. In the diabetic group, insulin secretion ability, assessed by the serum C-peptide response to intravenous glucagon stimulation, was lower in patients with the -226G allele (G/G, 2.96 +/- 0.16 ng/ml; G/A, 3.65 +/- 0.18 ng/ml; A/A, 3.99 +/- 0.16 ng/ml at 5 min after stimulation; P = 0.008). Furthermore, in vitro functional analyses indicated that both the -226G and the -233C alleles caused an approximately 50% decrease in the promoter activity, but no effects of the -2159A>G, -1449G>A, -1388C>T, and -279C>A polymorphisms were observed. These results suggest that the -226A/G polymorphism of the BTC gene may contribute to the development of diabetes.

5' Untranslated Regions↗
PubMed2004

Molecular scanning of the betacellulin gene for mutations in type 2 diabetic patients.

Betacellulin (BTC), a member of the epidermal growth factor (EGF) family, is an important factor in the growth and/or differentiation of pancreatic beta cells. In this point of view, we determined the transcriptional start site of the human BTC gene and screened the protein-coding region for mutations. The transcriptional start site was located 347 bp upstream from the translational initiation codon. After screening the protein coding exons (exons 1-5), we identified two novel missense mutations, Cys (TGC) to Gly (GGC) at codon 7 (C7G) and Leu (TTG) to Met (ATG) at codon 124 (L124M), and a single nucleotide substitution (-31c/t) in the intron 2. The C7G was located in the signal peptide and the L124M in the transmembrane domain and this Leu at codon 124 was conserved among human, bovine, rat, and mouse. The frequencies of these variants, however, were similar between type 2 diabetic patients (n = 228) and non-diabetic control subjects (n = 170). These data suggest that genetic variations in the protein-coding region of the human BTC gene are unlikely to be a major contributor to development of type 2 diabetes.

Aged↗
PubMed2004

Prevalence and risk factors of erectile dysfunction in Japanese men with type 2 diabetes.

This study aimed to elucidate the prevalence and clinical risk factors of erectile dysfunction (ED) in Japanese male diabetics. Questionnaires were administered to 82 male diabetics and 25 male non-diabetics (controls), to determine the international index of erectile function (IIEF). This index consists of five parts, with questions related to erectile function (EF), intercourse satisfaction (IS), orgasmic function (OF), sexual desire (SD), and overall satisfaction (OS). IIEF scores were compared between diabetics and controls, and were also analyzed in relation to clinical factors. Although EF, IS, and OF scores (physical factors) in diabetic men were significantly lower than those of age-matched controls, no significant differences were apparent in SD and OS scores (psychological factors). All patients with EF score > or = 18 reported being able to achieve sexual intercourse, we determined the criterion for ED as EF < 18. The prevalence of ED in diabetics and age-matched controls was 60% and 20%, respectively. EF score decreased with duration of diabetes and progression of retinopathy, proteinuria, ischemic heart disease, delayed nerve conduction, orthostatic intolerance, and attenuated heart rate variability. ED was found to be common in Japanese male diabetics. Possible influences of both microangiopathy and macroangiopathy on ED are suggested.

Diabetes Mellitus, Type 2↗
PubMed2004

History of obesity as a risk factor for both carotid atherosclerosis and microangiopathy.

As a westernized lifestyle becomes widespread in Japan, the number of individuals with obesity, as well as type 2 diabetes, is rapidly increasing. In this investigation, we studied the prevalence of obesity and its association with the development of diabetic macroangiopathy and microangiopathy. The clinical records of 634 patients in our hospital with type 2 diabetes were surveyed. The relationship between obesity and diabetic retinopathy and nephropathy and macroangiopathy (carotid artery intima-media thickness, IMT) was examined using univariate and multivariate analysis. A body mass index (BMI) > or = 25 kg/m2 was used as the diagnostic criterion for obesity. The prevalence of obesity at the time of the survey was 35% and a history of obesity was reported in 70% of the survey population. Multiple regression analysis revealed that the maximum BMI was significantly correlated with IMT thickening. The prevalence of nephropathy in previously obese patients was significantly higher than in non-obese patients. The maximum BMI was significantly associated with the development of retinopathy and nephropathy, as shown by logistic regression analysis. This suggests that a history of obesity may be an important risk factor for the development of micro- and macroangiopathy in Japanese with type 2 diabetes.

Carotid Artery Diseases↗
PubMed2004

Rice bran extract prevents the elevation of plasma peroxylipid in KKAy diabetic mice.

Oxidative stress is now considered to be a key factor in the development of diabetes and its complications. In this study, we examined the anti-oxidative effects of a crude lipophilic rice bran extract, Ricetrienol, which contains alpha-tocopherol, tocotrienol and phytosterol, in obese diabetic KKAy mice. We used KKAy mice fed a normal diet (DM group) or a diet including 0.1% Ricetrienol (RT group), and non-diabetic C57BL mice (C group). After 6 weeks, body weight, HbA1c, plasma glucose, lipids, peroxylipid (malonedialdehyde, MDA), alpha-tocopherol and glutathione peroxidase 1 (GPx) mRNA expression in the kidney were measured. At 1 week and at the end of the experimental period, urine 8-isoprostane and 8-hydroxy deoxyguanosine (8-OHdG) were also measured. Ricetrienol administration did not affect hyperglycemia, body weight or hyperlipidemia. Plasma MDA, urine 8-isoprostane and 8-OHdG in the DM group were significantly increased compared with the C group and the elevation of plasma MDA was significantly suppressed by 0.1% Ricetrienol. GPx mRNA expression was significantly increased in the RT group when compared with the C group. Plasma alpha-tocopherol in the RT group was significantly higher than that in the DM group. These findings suggest that Ricetrienol exerts a protective effect against oxidative damage in diabetes mellitus.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2004

Cholangitis as a late complication in long-term survivors after surgery for biliary atresia.

BACKGROUND/PURPOSE: A retrospective review was performed to assess the utility of diagnostic imaging (DI), efficacy of treatment, and outcome of late cholangitis in long-term survivors after surgery for biliary atresia. METHODS: Sixty-one patients surviving without liver transplantation (LTx) for more than 20 years were divided into 2 groups depending on whether cholangitis developed after age 20. Clinical factors including the type of obstruction, the age at the initial operation, and the early complication with cholangitis were compared between the 2 groups. DI such as computed tomography scan and magnetic resonance imaging, clinical courses after treatment of cholangitis, and current status of the patients were also evaluated. RESULTS: Thirteen patients had cholangitis after age 20. There was no statistical difference in the clinical factors studied between the 2 groups. Abnormal DI findings including dilatation of intrahepatic bile ducts and hepatic fibrosis were seen in 10 patients with late cholangitis. One patient died, and 2 ultimately underwent LTx. The remaining 10 patients including 4 with normal or near-normal liver function have survived without LTx. CONCLUSIONS: Although the majority of the patients had potential predisposing factors for cholangitis such as dilatation of intrahepatic bile ducts, a few patients unexpectedly had cholangitis without such abnormal findings after an excellent, long-term postoperative course.

Adult↗
PubMed2004

Extensive but hemiallelic methylation of the hMLH1 promoter region in early-onset sporadic colon cancers with microsatellite instability.

BACKGROUND AND AIMS: Methylation of the hMLH1 promoter region is frequently observed in microsatellite instability (MSI)-positive sporadic colorectal carcinomas. We studied hMLH1 promoter methylation in peripheral blood lymphocytes of 87 index patients representing 29 cases of hereditary nonpolyposis colorectal cancers (HNPCCs), 28 cases of atypical HNPCCs, and 30 sporadic cases of the development of early-onset colorectal carcinomas or multiple primary cancers. METHODS: Methylation of the hMLH1 promoter region was analyzed by Na-bisulfite polymerase chain reaction/single-strand conformation polymorphism analysis or methylation-specific polymerase chain reaction. MSI, allelic status of the hMLH1 locus, and loss of hMLH1 protein expression were examined in cases for which tumor tissues were available. RESULTS: Extensive methylation of the hMLH1 promoter was detected in peripheral blood lymphocytes of 4 of 30 patients with sporadic early-onset colon cancer, among whom multiple primary cancers (1 colon and 1 endometrial cancer) developed in 2 cases. This methylation was not detected in analyses of HNPCC or atypical HNPCC groups or healthy control subjects. MSI was positive, and extensive methylation was detected in both cancers (colon and endometrial cancer) and normal tissues (colon, gastric mucosa, endometrium, and bone marrow) in all of the examined cases (3 of 3). Analysis of a polymorphic site in the hMLH1 promoter in 2 informative cases showed that methylation was hemiallelic. In 1 case, the unmethylated allele was lost in the colon cancer but not in the metachronous endometrial cancer. CONCLUSIONS: Constitutive, hemiallelic methylation of the hMLH1 promoter region was shown to be associated with carcinogenesis in sporadic, early-onset MSI-positive colon cancers.

Adaptor Proteins, Signal Transducing↗