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Biomedical subjects

Yuichiro Yamada

Publications and source records attributed to Yuichiro Yamada.

At least 19 recordsLinked to original sources
PubMed2007

Tumor necrosis factor-alpha and its inducer inhibit morphine-induced rewarding effects and sensitization.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is emerging as an important modulator of the function of the central nervous system (CNS). We have demonstrated that TNF-alpha or Leu-Ile, a TNF-alpha inducer, inhibits methamphetamine-induced rewarding effects and sensitization. In this study, we investigated the effects of TNF-alpha or Leu-Ile on morphine (MOR)-induced rewarding effects and sensitization. METHODS: Levels of TNF-alpha messenger RNA (mRNA) and protein were determined by real-time reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Effects of TNF-alpha or Leu-Ile on MOR-induced rewarding effects and sensitization were investigated by conditioned place preference and locomotor activity tests. Extracellular dopamine levels were examined using in vivo microdialysis. Effects of TNF-alpha or Leu-Ile on MOR-induced antinociceptive effect and withdrawal symptoms were examined by hot plate test and naloxone-precipitated withdrawal. RESULTS: Morphine induced TNF-alpha mRNA expression via dopamine and opioid receptors. Posttreatment with TNF-alpha or Leu-Ile attenuated the MOR-induced place preference and sensitization even after their development, as well as pretreatment with TNF-alpha or Leu-Ile blocked them. An inhibitory effect of Leu-Ile on MOR-induced place preference was not observed in TNF-alpha knockout mice. Tumor necrosis factor-alpha or Leu-Ile inhibited the increase in extracellular dopamine levels in the nucleus accumbens induced by repeated MOR treatment. CONCLUSIONS: These results suggest that TNF-alpha inhibits MOR-induced rewarding effect and sensitization by regulating extracellular dopamine levels, and Leu-Ile inhibits them via the induction of TNF-alpha.

Animals↗
PubMed2006

Follow-up study of the first successful living donor islet transplantation.

BACKGROUND: Islet transplantation has become an option for the treatment of insulin-dependent diabetes mellitus and is usually performed using brain-dead heartbeating donors. However, we have very limited number of such donors in Japan; therefore, it is not allowed to perform islet transplantation with brain-dead donors. In order to perform islet transplantation in Japan, we need to seek new donor resources. METHODS: We performed the first successful living-donor islet transplantation. In this case, the recipient had brittle diabetes with hypoglycemic unawareness. The donor was deemed qualified after undergoing both metabolic and preoperative assessments. Distal pancreatectomy was performed using open laparotomy and more than 400,000 islets were isolated and transplanted immediately. RESULTS: The recipient has been insulin independent posttransplant with positive C-peptide for more than one year. She no longer suffers from hypoglycemic unawareness and displayed a substantial improvement in hemoglobulin (Hb) A1C. The donor's clinical course was uneventful, which allowed her to return to her job within one month. She maintained normal fasting C-peptide and HbA1C levels during follow-up period. CONCLUSION: In our first case of living donor islet transplantation, both the donor and the recipient have been maintaining excellent glycemic control with no untreatable complications for more than one year.

Adolescent↗
PubMed2006

Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure.

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) control glucose homeostasis through well-defined actions on the islet beta cell via stimulation of insulin secretion and preservation and expansion of beta cell mass. We examined the importance of endogenous incretin receptors for control of glucose homeostasis through analysis of Glp1r(-/-), Gipr(-/-), and double incretin receptor knockout (DIRKO) mice fed a high-fat (HF) diet. DIRKO mice failed to upregulate levels of plasma insulin, pancreatic insulin mRNA transcripts, and insulin content following several months of HF feeding. Both single incretin receptor knockout and DIRKO mice exhibited resistance to diet-induced obesity, preservation of insulin sensitivity, and increased energy expenditure associated with increased locomotor activity. Moreover, plasma levels of plasminogen activator inhibitor-1 and resistin failed to increase significantly in DIRKO mice after HF feeding, and the GIP receptor agonist [D-Ala(2)]GIP, but not the GLP-1 receptor agonist exendin-4, increased the levels of plasma resistin in studies of both acute and chronic administration. These findings extend our understanding of how endogenous incretin circuits regulate glucose homeostasis independent of the beta cell via control of adipokine secretion and energy expenditure.

Animals↗
PubMed2006

Adult pancreatic islets require differential pax6 gene dosage.

Pax6, a paired homeodomain transcription factor, plays crucial roles in morphogenesis of eye, central nervous system, and pancreatic islets. Recently, heterozygosity for pax6 mutation has been reported in some individuals with glucose intolerance and aniridia. To investigate the role of pax6 for pancreatic islet function, we examined the pancreatic phenotype of small eye rat strain (rSey(2)) with a point mutation in the pax6 locus resulting in truncated PAX6 proteins. Analyses of the insulin secretory profile of heterozygous rSey(2)/+ revealed that insulin secretion is significantly increased in response to membrane-depolarizing stimuli such as arginine, tolbutamide, and KCl. The processes of insulin granule exocytosis were suggested to be enhanced in rSey(2)/+. On the other hand, pancreatic insulin and glucagon content and islet architecture in rSey(2)/+ showed no significant differences compared to wild-type. These findings indicate differential requirements for pax6 gene dosage in displaying function and maintaining architecture of adult pancreatic islets.

Aging↗
PubMed2006

An inducer for glial cell line-derived neurotrophic factor and tumor necrosis factor-alpha protects against methamphetamine-induced rewarding effects and sensitization.

BACKGROUND: There are few efficacious medications for drug dependence. We investigated the potential of Leu-Ile, which induces the expression of glial cell line-derived neurotrophic factor (GDNF) and tumor necrosis factor-alpha (TNF-alpha), as a novel therapeutic agent for methamphetamine (METH)-induced dependence. METHODS: The levels of GDNF and TNF-alpha messenger RNA (mRNA) were determined by real-time reverse transcription polymerase chain reaction. Enzyme immunoassays and immunohistochemistry were employed to determine levels of these proteins. Effects of Leu-Ile on METH-induced rewarding effects and sensitization were investigated with conditioned place preference and locomotor activity tests. Extracellular dopamine (DA) levels and DA uptake into synaptosomes were examined with an in vivo microdialysis and trititated thymidine ([(3)H]) DA uptake assay. RESULTS: Leu-Ile induced the expression of not only GDNF but also TNF-alpha. Pretreatment with Leu-Ile blocked the acquisition of METH-induced place preference and sensitization. Interestingly, post-treatment with Leu-Ile attenuated them even after their development. An inhibitory effect of Leu-Ile on METH-induced place preference was observed in neither GDNF heterozygous nor TNF-alpha knockout mice. Leu-Ile inhibited DA release in the nucleus accumbens and the decrease in synaptosomal DA uptake in the midbrain induced by repeated METH treatment. CONCLUSIONS: These results suggest that Leu-Ile inhibits METH-induced rewarding effects and sensitization by regulating extracellular DA levels via the induction of GDNF and TNF-alpha expression.

Analysis of Variance↗
PubMed2006

Gatifloxacin acutely stimulates insulin secretion and chronically suppresses insulin biosynthesis.

Gatifloxacin can cause both hypoglycemia and hyperglycemia in both diabetic and non-diabetic patients. Gatifloxacin recently has been reported to stimulate insulin secretion by inhibition of ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells. Gatifloxacin-induced hypoglycemia is associated with concomitant use of sulfonylureas, and usually occurs immediately after administration of the drug. We find that gatifloxacin acutely stimulates insulin secretion from mouse pancreatic islets and that glibenclamide has additive effects on gatifloxacin-induced insulin secretion. On the other hand, gatifloxacin-induced hyperglycemia often takes several days to develop. We also demonstrate that chronic gatifloxacin treatment decreases islet insulin content by inhibiting insulin biosynthesis, which process may be associated with gatifloxacin-induced hyperglycemia. Moreover, discontinuation of gatifloxacin results in improved insulin secretory response. These data clarify the differing mechanisms of gatifloxacin-induced hyper- and hypoglycemia, and suggest that blood glucose levels should be carefully monitored during gatifloxacin administration, especially in elderly patients with renal insufficiency, unrecognized diabetes, or other metabolic disorders. Because the risk of potentially life-threatening dysglycemia is increased during gatifloxacin therapy, these findings have important implications for clinical practice.

Animals↗
PubMed2006

The spontaneously diabetic Torii rat with gastroenteropathy.

The spontaneously diabetic Torii (SDT) rat was recently recognized as a new animal model of non-obese type 2 diabetes. As the severe diabetic ocular complications seen in SDT rats already have been investigated, we examined another common diabetic complication, gastroenteropathy. Male SDT rats developed diabetes at 20 weeks and diarrhea at 28 weeks of age. Gastrointestinal motility was evaluated at 28 weeks by measuring the distance of small intestinal transit by oral administration of the non-absorbed marker, arabic gum. SDT rats exhibited greater intestinal transit distance than control SD rats (54.1+/-2.6% versus 43.0+/-1.2%). Insulin treatment of SDT rats begun at 20 weeks of age produced improved stool and reduced intestinal transit distance (41.4+/-0.3%). Morphologically, the SDT rats exhibited longer villi and heavier weight of intestine compared to control SD rats. These results suggest that the SDT rat may be a useful animal model for studies of diabetic gastroenteropathy.

Animals↗
PubMed2006

Successful islet transplantation from nonheartbeating donor pancreata using modified Ricordi islet isolation method.

BACKGROUND: Current success of islet transplantation has led to donor shortage and the need for marginal donor utilization to alleviate this shortage. The goal of this study was to improve the efficacy of islet transplantation using nonheartbeating donors (NHBDs). METHODS: First, we used porcine pancreata for the implementation of several strategies and applied to human pancreata. These strategies included ductal injection with trypsin inhibitor for protection of pancreatic ducts, ET-Kyoto solution for pancreas preservation, and Iodixanol for islet purification. RESULTS: These strategies significantly improved both porcine and human islet isolation efficacy. Average 399,469+/-36,411 IE human islets were obtained from NHBDs (n=13). All islet preparations met transplantation criteria and 11 out of 13 cases (85%) were transplanted into six type 1 diabetic patients for the first time in Japan. All islets started to secrete insulin and all patients showed better blood glucose control without hypoglycemic loss of consciousness. The average HbA1c levels of the six recipients significantly improved from 7.5+/-0.4% at transplant to 5.1+/-0.2% currently (P<0.0003). The average insulin amounts of the six recipients significantly reduced from 49.2+/-3.3 units at transplant to 11+/-4.4 units (P<0.0005) and five out of six patients reduced to less than half dose. The first patient is now insulin free, the first such case in Japan. CONCLUSION: This demonstrates that our current protocol makes it feasible to use NHBDs for islet transplant into type 1 diabetic patients efficiently.

Adult↗
PubMed2006

SUIT, secretory units of islets in transplantation: An index for therapeutic management of islet transplanted patients and its application to type 2 diabetes.

Evaluation of a patient's pancreatic beta-cell function is important in both diagnosis and treatment of diabetes. We sought to determine beta-cell function with a single sampling of blood. Examination of fasting blood glucose (F-BG, mM) and C-peptide (F-CPR, nM) levels in seven post-islet-transplanted states of four patients revealed a linear relationship between F-BG and F-CPR. Assuming that normal subjects aged <40 years have 100% pancreatic beta-cell function, we developed the secretory units of islets in transplantation (SUIT) as an index of beta-cell function by the formula: 250 x F-CPR/(F-BG-3.43). The SUIT index was correlated with the stimulated C-peptide levels not only in islet-transplanted patients (R2 = 0.68, P < 0.05) but also in type 2 patients (R2 = 0.34, P < 0.001). Since the SUIT index can be calculated from data obtained at a single fasting blood sampling and predict the pancreatic beta-cell function, the formula may be a useful tool in clinical management of diabetes.

Blood Glucose↗
PubMed2006

A single transplantation of the islets can produce glycemic stability and reduction of basal insulin requirement.

We investigated glycemic stability and insulin requirement 1 month after a single transplantation of the islets from non-heart-beating donors or a living donor. Overall blood glucose levels decreased immediately after transplantation. The M-value and mean amplitude of glycemic excursions (MAGE) decreased significantly from 53.0 (range, 8.9-91.0) to 4.2 (0.6-8.8, P<0.05) and from 8.5 mM (4.8-11.7) to 3.3 mM (2.0-4.5, P<0.05), respectively. The values after transplantation were lower than the first quartile of 102 type 2 diabetic control patients. The estimated HbA1c level decreased significantly from 7.9% (5.7-10.9) to 5.4% (4.7-5.9, P<0.05). The supplement of basal insulin decreased 43% from 0.31 units/kg/day (0.16-0.37) to 0.18 units/kg/day (0-0.22, P<0.05), while that of stimulated insulin did not decrease significantly, from 0.28 units/kg/day (0.13-0.51) to 0.21 units/kg/day (0-0.41). Thus, only one islet transplantation can be sufficient to attain metabolic stability, probably by effective supply of basal insulin secretion, sufficient to avoid life-threatening severe hypoglycemia and prevent or delay the progress of secondary complications of diabetes by decreasing the HbA1c level.

Adult↗
PubMed2006

Diphenylhydantoin suppresses glucose-induced insulin release by decreasing cytoplasmic H+ concentration in pancreatic islets.

Diphenylhydantoin (DPH), which is clinically used in the treatment of epilepsy, inhibits glucose-induced insulin release from pancreatic islets by a mechanism that remains unknown. In the present study, DPH is shown to suppress glucose-induced insulin release concentration-dependently. In dynamic experiments, 20 microm DPH suppressed 16.7 mm glucose-induced biphasic insulin release. DPH also suppressed insulin release in the presence of 16.7 mm glucose, 200 microm diazoxide, and 30 mm K+ without affecting the intracellular Ca2+ concentration. DPH suppressed ATP content and mitochondrial membrane hyperpolarization in the presence of 16.7 mm glucose without affecting glucose utilization, glucose oxidation, and reduced nicotinamide adenine dinucleotide phosphate fluorescence. DPH increased cytoplasmic pH in the presence of high glucose, but the increase was abolished under Na+ -deprived conditions and HCO3- -deprived conditions, suggesting that Na+ and HCO3- transport across the plasma membrane are involved in the increase in cytoplasmic pH by DPH. Alkalization by adding NH4+ to the extracellular medium also suppressed insulin release, ATP content, and mitochondrial membrane hyperpolarization. Because ATP production from the mitochondrial fraction in the presence of substrates was decreased by increased pH in the medium, DPH suppresses mitochondrial ATP production by reducing the H+ gradient across mitochondrial membrane. Using permeabilized islets, the increase in pH was shown to decrease Ca2+ efficacy at a clamped concentration of ATP in the exocytotic system. Taken together, DPH inhibits glucose-induced insulin secretion not only by inhibiting mitochondrial ATP production, but also by reducing Ca2+ efficacy in the exocytotic system through its alkalizing effect on cytoplasm.

Adenosine Triphosphate↗
PubMed2006

Gastric inhibitory polypeptide as an endogenous factor promoting new bone formation after food ingestion.

Calcium plays a fundamental role as second messenger in intracellular signaling and bone serves as the body's calcium reserve to tightly maintain blood calcium levels. Calcium in ingested meal is the main supply and inadequate calcium intake causes osteoporosis and bone fracture. Here, we describe a novel mechanism of how ingested calcium is deposited on bone. Meal ingestion elicits secretion of the gut hormone gastric inhibitory polypeptide (GIP) from endocrine K cells in the duodenum. Bone histomorphometrical analyses revealed that bone formation parameters in the mice lacking GIP receptor (GIPR(-/-)) were significantly lower than those of wild-type (GIPR(+/+)) mice, and that the number of osteoclasts, especially multinuclear osteoclasts, was significantly increased in GIPR(-/-) mice, indicating that GIPR(-/-) mice have high-turnover osteoporosis. In vitro examination showed the percentage of osteoblastic cells undergoing apoptosis to be significantly decreased in the presence of GIP. Because GIPR(-/-) mice exhibited an increased plasma calcium concentration after meal ingestion, GIP directly links calcium contained in meal to calcium deposition on bone.

Animals↗
PubMed2006

Factors responsible for deteriorating glucose tolerance in newly diagnosed type 2 diabetes in Japanese men.

Hyperglycemia frequently continues to worsen even after the diagnosis of overt diabetes. The aim of this study is to evaluate the factors contributing to increasing glucose intolerance after onset of type 2 diabetes in Japanese subjects. Five hundred fifty newly diagnosed type 2 diabetic patients were classified into 3 degrees of hyperglycemia based on plasma glucose levels estimated by 75-g oral glucose tolerance test: diabetes mellitus with isolated fasting hyperglycemia (DM/IFH), DM with isolated postchallenge hyperglycemia (DM/IPH), and DM with fasting and postchallenge hyperglycemia (DM/FPH). In addition, the DM/IFH and DM/IPH groups were subdivided to clarify the determinants of fasting and postchallenge hyperglycemia. Insulin secretion was evaluated by insulinogenic index, and insulin sensitivity was evaluated by composite index of insulin sensitivity (ISI composite). The insulinogenic index in DM/IFH was highest of the 3 groups (P < .0001). The insulinogenic index in DM/IPH was higher than in DM/FPH (P < .0001). The international sensitivity index composite in DM/IPH was highest of the 3 groups (P < .05). Although impaired early-phase insulin secretion plays the crucial role in deterioration from DM/IFH to DM/FPH in Japanese subjects, impaired early-phase insulin secretion and decreased insulin sensitivity both are factors in deterioration from DM/IPH to DM/FPH. In addition, comparison of subgroups of DM/IFH and DM/IPH shows that although decreased early-phase insulin secretion plays the more significant role in postchallenge hyperglycemia in Japanese subjects, insulin sensitivity is the more important factor in fasting hyperglycemia.

Adult↗
PubMed2006

Video-assisted thoracoscopy to treat atrial tachycardia arising from left atrial appendage.

A 17-year-old male with tachycardia-induced cardiomyopathy presented with persistent, drug-resistant atrial tachycardia (AT). An electrophysiological study suggested focal abnormal automaticity, and localized the AT origin to the left atrial appendage. Radiofrequency catheter ablation at the site of the earliest endocardial activation during AT failed. A minimally invasive, video-assisted thoracoscopic (VAT) atrial appendectomy terminated the AT and restored left ventricular contractility. The patient remained free of AT and normal left ventricular function was maintained over a 24-month follow-up period. To our knowledge, we are the first to use VAT atrial appendectomy to treat focal AT.

Adolescent↗
PubMed2006

Living donor islet transplantation, the alternative approach to overcome the obstacles limiting transplant.

We performed the world's first successful living donor islet transplantation for unstable diabetes. A total of 408,114 islet equivalents were isolated from half a living pancreas and transplanted immediately to the recipient who was a 27-year-old female. The donor was a 56-year-old female in good health, mother of the recipient. The islets functioned immediately, and the recipient was weaned completely from insulin on the 22nd posttransplant day, and has maintained excellent glycemic control since. The donor was discharged on the 18th postoperative day with normal oral glucose tolerance test and without complications. Living donor islet transplantation could cure one insulin-dependent diabetes mellitus patients with a single donor. There are some advantages in the living donor islet transplantation: (a) living donor can alleviate the issue of donor shortage; (b) highly potent islets can be isolated from a living donor; and (c) the recipient can be treated with immunosuppressant and controlled blood glucose level tightly prior to the transplantation. These are important factors in overcoming the obstacles limiting islet transplantation. We believe that the living donor islet transplantation may become an additional option in treating insulin-dependent diabetes.

Adult↗
PubMed2006

Association studies of variants in the genes involved in pancreatic beta-cell function in type 2 diabetes in Japanese subjects.

Because impaired insulin secretion is characteristic of type 2 diabetes in Asians, including Japanese, the genes involved in pancreatic beta-cell function are candidate susceptibility genes for type 2 diabetes. We examined the association of variants in genes encoding several transcription factors (TCF1, TCF2, HNF4A, ISL1, IPF1, NEUROG3, PAX6, NKX2-2, NKX6-1, and NEUROD1) and genes encoding the ATP-sensitive K(+) channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) with type 2 diabetes in a Japanese cohort of 2,834 subjects. The exon 16 -3c/t variant rs1799854 in ABCC8 showed a significant association (P = 0.0073), and variants in several genes showed nominally significant associations (P < 0.05) with type 2 diabetes. Although the E23K variant rs5219 in KCNJ11 showed no association with diabetes in Japanese (for the K allele, odds ratio [OR] 1.08 [95% CI 0.97-1.21], P = 0.15), 95% CI around the OR overlaps in meta-analysis of European populations, suggesting that our results are not inconsistent with the previous studies. This is the largest association study so far conducted on these genes in Japanese and provides valuable information for comparison with other ethnic groups.

ATP-Binding Cassette Transporters↗