Acetate and Butyrate Improve β-cell Metabolism and Mitochondrial Respiration under Oxidative Stress

Islet dysfunction mediated by oxidative and mitochondrial stress contributes to the development of type 1 and 2 diabetes. Acetate and butyrate, produced by gut microbiota via fermentation, have been shown to protect against oxidative and mitochondrial stress in many cell types, but their effect on pancreatic β-cell metabolism has not been studied. Here, human islets and the mouse insulinoma cell line MIN6 were pre-incubated with 1, 2, and 4 mM of acetate or butyrate with and without exposure to the apoptosis inducer and metabolic stressor streptozotocin (STZ). Both short-chain fatty acids (SCFAs) enhanced the viability of islets and β-cells, but the beneficial effects were more pronounced in the presence of STZ. Both SCFAs prevented STZ-induced cell apoptosis, viability reduction, mitochondrial dysfunction, and the overproduction of reactive oxygen species (ROS) and nitric oxide (NO) at a concentration of 1 mM but not at higher concentrations. These rescue effects of SCFAs were accompanied by preventing reduction of the mitochondrial fusion genes MFN, MFN2, and OPA1. In addition, elevation of the fission genes DRP1 and FIS1 during STZ exposure was prevented. Acetate showed more efficiency in enhancing metabolism and inhibiting ROS, while butyrate had less effect but was stronger in inhibiting the SCFA receptor GPR41 and NO generation. Our data suggest that SCFAs play an essential role in supporting β-cell metabolism and promoting survival under stressful conditions. It therewith provides a novel mechanism by which enhanced dietary fiber intake contributes to the reduction of Western diseases such as diabetes

Applying Immunomodulation to Promote Longevity of Immunoisolated Pancreatic Islet Grafts

Islet transplantation is a promising therapy for insulin-dependent diabetes, but large-scale application is hampered by the lack of a consistent source of insulin-producing cells and need for lifelong administration of immunosuppressive drugs, which are associated with severe side effects. To avoid chronic immunosuppression, islet grafts can be enveloped in immunoisolating polymeric membranes. These immunoisolating polymeric membranes protect islet grafts from cell-mediated rejection while allowing diffusion of oxygen, nutrients, and insulin. Although clinical trials have shown the safety and feasibility of encapsulated islets to control glucose homeostasis, the strategy does up till now not support long-term graft survival. This partly can be explained by a significant loss of insulin-producing cells in the immediate period after implantation. The loss can be prevented by combining immunoisolation with immunomodulation, such as combined administration of immunomodulating cytokines or coencapsulation of immunomodulating cell types such as regulatory T cells, mesenchymal stem cells, or Sertoli cells. Also, administration of specific antibodies or apoptotic donor leucocytes is considered to create a tolerant microenvironment around immunoisolated grafts. In this review, we describe the outcomes and limitations of these approaches, as well as the recent progress in immunoisolating devices. Impact statement Immunoisolation by enveloping islets in semipermeable membranes allows for successful transplantation of islet grafts in the absence of chronic immunosuppression, but the duration of graft survival is still not permanent. The reasons for long-term final graft failure is not fully understood, but combining immunoisolation with immunomodulation of tissues or host immune system has been proposed to enhance the longevity of grafts. This article reviews the recent progress and challenges of immunoisolation, as well as the benefits and feasibility of combining encapsulation approaches with immunomodulation to promote longevity of encapsulated grafts

Low methyl-esterified pectin protects pancreatic beta-cells against diabetes-induced oxidative and inflammatory stress via galectin-3

Insufficient intake of dietary fibers in Western societies is considered a major contributing factor in the high incidence rates of diabetes. The dietary fiber pectin has been suggested to be beneficial for management of both Diabetes Type 1 and Type 2, but mechanisms and effects of pectin on insulin producing pancreatic beta-cells are unknown. Our study aimed to determine the effects of lemon pectins with different degree of methyl-esterification (DM) on beta-cells under oxidative (streptozotocin) and inflammatory (cytokine) stress and to elucidate the underlying rescuing mechanisms, including effects on galectin-3. We found that specific pectins had rescuing effects on toxin and cytokine induced stress on beta-cells but effects depended on the pectin concentration and DM value. Protection was more pronounced with low DM5 pectin and was enhanced with higher pectin-concentrations. Our findings show that specific pectins might prevent diabetes by making insulin producing beta-cells less susceptible for stress

Toll-like receptor 2-modulating pectin-polymers in alginate-based microcapsules attenuate immune responses and support islet-xenograft survival

Encapsulation of pancreatic islets in alginate-microcapsules is used to reduce or avoid the application of life-long immunosuppression in preventing rejection. Long-term graft function, however, is limited due to varying degrees of host tissue responses against the capsules. Major graft-longevity limiting responses include inflammatory responses provoked by biomaterials and islet-derived danger-associated molecular patterns (DAMPs). This paper reports on a novel strategy for engineering alginate microcapsules presenting immunomodulatory polymer pectin with varying degrees of methyl-esterification (DM) to reduce these host tissue responses. DM18-pectin/alginate microcapsules show a significant decrease of DAMP-induced Toll-Like Receptor-2 mediated immune activation in vitro, and reduce peri-capsular fibrosis in vivo in mice compared to higher DM-pectin/alginate microcapsules and conventional alginate microcapsules. By testing efficacy of DM18-pectin/alginate microcapsules in vivo, we demonstrate that low-DM pectin support long-term survival of xenotransplanted rat islets in diabetic mice. This study provides a novel strategy to attenuate host responses by creating immunomodulatory capsule surfaces that attenuate activation of specific pro-inflammatory immune receptors locally at the transplantation site

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Multi-messenger Observations of a Binary Neutron Star Merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ∼ 1.7 {{s}} with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of {40}-8+8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 {M}ȯ . An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ∼ 40 {{Mpc}}) less than 11 hours after the merger by the One-Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ∼10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ∼ 9 and ∼ 16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC 4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta.</p

血管誘導因子担持ハイドロゲルにより皮下に形成された血管の豊富な部位への同種膵島の移植

京都大学0048新制・課程博士博士(工学)甲第21272号工博第4500号新制||工||1700(附属図書館)京都大学大学院工学研究科高分子化学専攻(主査)教授 秋吉 一成, 教授 木村 俊作, 教授 永樂 元次学位規則第4条第1項該当Doctor of Philosophy (Engineering)Kyoto UniversityDFA