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Shinichi Matsumoto

Publications and source records attributed to Shinichi Matsumoto.

At least 19 recordsLinked to original sources
PubMed2007

BETA2/NeuroD protein transduction requires cell surface heparan sulfate proteoglycans.

BETA2/NeuroD protein is important for regulating insulin gene transcription and for the terminal differentiation of islet cells, including insulin- and glucagon-producing cells. We reported that BETA2/NeuroD protein can permeate several cell types, including pancreatic islets, because of an arginine- and lysine-rich protein transduction domain (PTD) sequence in its structure. Here we provide genetic and biochemical evidence that cell membrane heparan sulfate proteoglycans are involved in extracellular BETA2/NeuroD internalization. We tested whether soluble glycosaminoglycans (GAGs) could inhibit BETA2/NeuroD internalization. Heparin almost completely prevented BETA2/NeuroD entry, whereas chondroitin sulfate A, B, and C caused only limited inhibition. Moreover, treatment with heparinase III impaired BETA2/NeuroD internalization, whereas treatment with chondroitinase ABC, or with chondroitinase AC, was completely ineffective in inhibiting BETA2/NeuroD internalization. We also examined various mutant cell lines originating from CHOK1 cells and defective in GAG biosynthesis. The observation using mutant cell lines supports the notion that the selective sulfation of heparan sulfate is an important determinant for NeuroD/heparan sulfate recognition. These data indicate that cell surface heparan sulfate proteoglycans are required for BETA2/NeuroD internalization and that BETA2/NeuroD protein transduction could be a safe and valuable strategy for enhancing insulin gene transcription without requiring gene transfer technology.

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

A new mouse model for intraportal islet transplantation with limited hepatic lobe as a graft site.

Intraportal site is the standard for grafting in clinical islet transplantation. In the mouse model, the whole liver has been used as the grafting site to mimic clinical islet transplantation. However, this model lacks the potency to directly assess the contribution of the islet graft to diabetes control. Only demonstrating the immediate recurrence of diabetes in a surviving recipient after the removal of the islet graft can validate this assessment. In this study, we develop a mouse model of intraportal islet transplantation equipped with the potency of this assessment by injecting islets selectively into the right hepatic lobe under temporal clamp of the left portal vein. The mouse of this model survives after the right hepatectomy by which the islet graft is removed. This model can be applied to investigate both the specific graft-recipient interaction in the liver and the islet graft contribution to the control of diabetes.

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

Procurement of the human pancreas for pancreatic islet transplantation from marginal cadaver donors.

BACKGROUND: Recent advances in pancreatic islet transplantation (PIT) have contributed significantly to the treatment of patients with type 1 diabetes. The specific aim of this study was to develop an effective technique for the procurement of pancreas for PIT from nonheart-beating-donor (NHBDs). METHODS: Between January 2004 and August 2004, eight human pancreata were procured and processed for isolation of islets at a cell processing center. After confirmation of brain death status, a double balloon catheter was inserted to prevent warm ischemic damage to the donor pancreas by using an in situ regional organ cooling system that was originally developed for procurement of kidneys. The catheter position of the cooling system was modified specifically for the pancreas and kidney. Furthermore, we worked in cooperation with a kidney procurement team to protect the pancreas during kidney procurement. RESULTS: Warm ischemic time could be controlled with the modified in situ regional cooling system at 3.0 +/- 0.8 min (mean +/- SE). The operations for procurement of the kidneys and pancreata lasted 45.6 +/- 3.6 min and 10.6 +/- 1.8 min, respectively. Islet yield per isolation was 444,426 +/- 35,172 IE (islet equivalent). All eight cases met the criteria for PIT based on the Edmonton protocol. CONCLUSION: We developed a novel procurement technique in cooperation with our kidney procurement team. This protocol for the procurement of pancreas and kidney from a NHBD enabled us to transplant islets into a type 1 diabetic patient and kidney into a renal failure patient.

Cadaver↗
PubMed2006

Anticoagulant-induced pseudothrombocytopenia occurring after transcatheter arterial embolization for hepatocellular carcinoma.

Pseudothrombocytopenia (PTCP) is the in vitro phenomenon of anticoagulant-activated platelet agglutination that results in spuriously low platelet counts. We report the case of a 65-year-old man with EDTA- and sodium citrate-dependent PTCP occurring after transcatheter arterial embolization (TAE) for hepatocellular carcinoma (HCC) due to hepatitis C cirrhosis. Invasion of the portal and hepatic veins by HCC formed severe trans-tumoral arterio-venous shunts that were effectively treated by TAE. Two days after the therapy, PTCP was seen on blood count and continued for 4 months. The patient received unnecessary treatment for disseminated intravascular coagulation (DIC) until the diagnosis of PTCP was established. PTCP is a rare complication but should be considered after TAE for HCC; lack of recognition may lead the physician to misdiagnosis and patient mismanagement.

Aged↗
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

Protein transduction technology offers a novel therapeutic approach for diabetes.

Diabetes remains a major burden, with more than 200 million people affected worldwide, representing 6% of the population. New technology, known as protein transduction technology, has been recently developed. A variety of peptides, known as protein transduction domains or cell-penetrating peptides, have been characterized for their ability to translocate into live cells. There are numerous examples of biologically active full-length proteins and peptides that have been delivered to cells and tissues both in vitro and in vivo, suggesting new avenues for the treatment of several diseases. Some studies have shown that this technology is useful for the treatment of diabetes. In islet isolation and transplantation, cell-permeable peptides deliver anti-apoptotic molecules to protect islets. Another peptide provides immunosuppression for fully mismatched islet allografts in mice. These findings suggest that peptide drugs could lead to outcome improvement for pancreatic islet transplantation. In mice with type 2 diabetes, a cell-penetrating peptide markedly improves insulin resistance and ameliorates glucose tolerance. Moreover, the technology facilitates the differentiation of stem cells into insulin-producing cells. Protein transduction technology has opened up several possibilities for the development of new peptide/protein drugs for the treatment of diabetes.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Improve islet yields and quality when clinical grade pancreata are preserved by the two-layer method.

BACKGROUND: Research grade pancreata preserved by the two-layer method (TLM) yield significantly greater numbers of islets than organs stored with University of Wisconsin solution (UW). The goal of this study was to determine whether this would hold true for pancreata that meet selection criteria for clinical grade organs. METHODS: Pancreata were chosen based upon a pre-defined set of criteria used for selecting clinical grade pancreata. Thirteen of these organs were preserved in UW and five pancreata were preserved by the TLM. Islets were isolated and evaluated according to the Edmonton protocol. RESULTS: The average preservation time was significantly longer for organ preserved with TLM (9.5 + 2.0 h) as compared to UW (5.8 + 0.6 h, p = 0.015). The pancreata of TLM group resulted in a significant increase in islet yields (3588 +/- 500 vs. 2536 +/- 312 IE/g pancreas, p<0.05). Visual scoring of islets indicated that islets were better from TLM group (8.3 +/- 0.3 vs. 7.3 +/- 0.2), and islet survival rates after culture were higher from organs stored with the TLM (87 +/- 17 vs. 55 +/- 7.4, p<0.05). Other parameters such as viability, insulin content, and stimulation index were similar between the two groups. All the preparations from the TLM group, but only 54% of preparations from the UW group, qualified for islet transplantation. The two recipients receiving islets from TLM group, daily insulin requirements were reduced and C-peptide levels were increased. CONCLUSION: Compared to storage with UW, exposure of pancreata to the TLM resulted in greater islet yields and improved quality of islets despite longer preservation period. Consequently, pancreata that meet clinical grade status should be preserved by the TLM prior to islet isolation.

Adenosine↗
PubMed2006

A newly developed bioartificial pancreas successfully controls blood glucose in totally pancreatectomized diabetic pigs.

Construction of a safe and functional bioartificial pancreas (BAP) that provides an adequate environment for islet cells may be an important approach to treating diabetic patients. Various types of BAP devices have been developed, but most of them involve extravascular implantation of islets in microcapsules or diffusion chambers. These devices have poor diffusive exchange between the islets and blood, and often rupture. To overcome these problems, we developed a new type of BAP composed of polyethylene-vinyl alcohol (EVAL) hollow fibers that are permeable to glucose and insulin and a poly-amino-urethane-coated, non-woven polytetrafluoroethylene (PTFE) fabric that allows cell adhesion. Porcine islets attached to the surface of the PTFE fabric, but not to the surface of the EVAL hollow fibers, allowing nutrient and oxygen exchange between blood flowing inside the fibers and cells outside. We inoculated this BAP with porcine islets and connected it to the circulation of totally pancreatectomized diabetic pigs. We found that blood glucose levels were reduced to a normal range and general health was improved, resulting in longer survival times. In addition, regulation of insulin secretion from the BAP was properly controlled in response to glucose both in vitro and in vivo. These results indicate that our newly developed BAP may be a potential therapy for the treatment of diabetes in humans.

Animals↗
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

Pancreatic islet transplantation for treating diabetes.

Pancreatic islet transplantation is one of the options for treating diabetes and has been shown to improve the quality of life of severe diabetic patients. Since the Edmonton protocol was announced, islet transplantation have advanced considerably, including islet after kidney transplantation, utilisation of non-heart-beating donors, single-donor islet transplantation and living-donor islet transplantation. These advances were based on revised immunosuppression protocols, improved pancreas procurement and islet isolation methods, and enhanced islet engraftment. Further improvements are necessary to make islet transplantation a routine clinical treatment. To synergise efforts towards a cure for type 1 diabetes, a Diabetes Research Institute (DRI) Federation is currently being established to include leading diabetes research centres worldwide, including DRIs in Miami, Edmonton and Kyoto among others.

Animals↗
PubMed2006

Immunosuppression for islet transplantation.

The development by the Edmonton group of a sirolimus-based, steroid-free, low-tacrolimus regimen is a significant breakthrough that allows the rate of insulin independence after islet transplantation to increase from 13% to 80% at 1 year; however, the rate is reduced to 50% at 3 years, attributed to prolonged tacrolimus exposure. Recently, immunosuppression agents such as cyclosporine, mycophenolate mofetil, and the novel agent FTY 720 have been used instead of tacrolimus. Lymphocyte-depleting antibodies such as anti-thymocyte globulin, alemtuzumab, and hOKT3gamma 1 (ala, ala) have been launched, and a costimulatory blockade of anti-CD40 monoclonal antibodies and CTLA4-Ig will be attempted in the near future. Moreover, the potential of a novel immunosuppressing peptide could now be realized using new technology called the protein transduction system. In this review, we show some of the most recent contributions to the advancement of knowledge in this field.

Animals↗
PubMed2006

Protein transduction technology: a novel therapeutic perspective.

The direct intracellular delivery of proteins has, until recently, been difficult to achieve, due primarily to the bioavailability barrier of the plasma membrane. During the past 15 years, a variety of peptides called protein transduction domains (PTDs) or cell penetrating peptides (CPPs), have been characterized for their ability to translocate into live cells. The most commonly studied are homeodomain transcription factors such as Antennapedia, the herpes simplex virus (HSV) type 1 protein VP22, and the human immunodeficiency virus (HIV-1) transactivator TAT protein. Recently, polyarginine exhibits even greater efficiency in terms of delivery of several peptides and proteins. Numerous examples of biologically active full-length proteins and peptides have been delivered to cells and tissues, both in vitro and in vivo. These studies offer new avenues for treatment of several diseases. The main mechanism of protein transduction is an electrostatic interaction with the plasma membrane, penetration into cells by macropinocytosis, and a release to cytoplasm and nuclei by retrograde transport. Moreover, the intercellular transfer of endogenous transcription factors, such as TAT and homeoproteins, seems to point to an original and important mode of signal transduction. The protein transduction systems have opened up several possibilities, not only for the development of new peptide/protein drugs but also for consideration of their physiological and developmental implications.

Cell Membrane↗
PubMed2006

Maintenance of mouse, rat, and pig pancreatic islet functions by coculture with human islet-derived fibroblasts.

Development of an efficient preculture system of islets is ideal. Toward that goal, we constructed a human pancreatic islet-derived fibroblast cell line MNNK-1 for a source as a coculture system for freshly isolated islets to maintain islet functions. Human pancreatic islet cells were nucleofected with a plasmid vector pYK-1 expressing simian virus 40 large T antigen gene (SV40T) and hygromycin resistance gene (HygroR). One of the transduced cell lines, MNNK-1, was established and served as a feeder cell in the coculture for freshly isolated mouse, rat, and pig islets. Morphology, viability, and glucose-responding insulin secretion were analyzed in the coculture system. MNNK-1 cells were morphologically spindle shaped and were negative for pancreatic endocrine markers. MNNK-1 cells were positive for alpha-smooth muscle actin and collagen type I and produced fibroblast growth factor. Coculture of the mouse, rat, and pig islets with MNNK-1 cells maintained their viability and insulin secretion with glucose responsiveness. A human pancreatic islet-derived fibroblast cell line MNNK-1 was established. MNNK-1 cells were a useful means for maintaining morphology and insulin secretion of islets in the coculture system.

Actins↗
PubMed2005

Gadolinium-enhanced phase-contrast magnetic resonance portography.

PURPOSE: The purpose of this study was to investigate the effect and usefulness of gadolinium-chelated contrast medium in phase-contrast magnetic resonance (MR) portography. METHODS: Twenty-six patients (21 men, 5 women; aged 34 to 79 years, mean 62 years) underwent respiratory-triggered 3-dimensional phase-contrast portography before and after administration of gadolinium in a 1.5T MR unit. Coronal maximum intensity projection (MIP) images of the portal vein were reconstructed and compared to conventional arterial portograms regarding visualization. Signal-to-noise ratio (SNR) and portal vein-to-liver contrast-to-noise ratios (CNR) of main, right, right anterior, right posterior, left portal veins, and umbilical portion were measured on both non-enhanced and gadolinium-enhanced images and compared. RESULTS: Portal veins and branches were more clearly visualized on the gadolinium-enhanced than on the non-enhanced images. Compared to arterial portography, gadolinium-enhanced portography showed similar performances in visualization, except in the right posterior branch and left portal vein. No severe image degradation from respiration was experienced. SNR was significantly higher on the gadolinium-enhanced than on non-enhanced images except in the right anterior branch. CNR was significantly higher on the gadolinium-enhanced than on the non-enhanced images at all measured locations. CONCLUSIONS: Administration of gadolinium improves the SNR and CNR of phase-contrast portography and visualization of the portal vein. The phase-contrast technique with gadolinium enhancement can be used to evaluate the portal vein as a supplemental technique.

Adult↗