Regulation of Cellular Senescence in Type 2 Diabetes Mellitus: From Mechanisms to Clinical Applications

Cellular senescence is accelerated by hyperglycemia through multiple pathways. Therefore, senescence is an important cellular mechanism to consider in the pathophysiology of type 2 diabetes mellitus (T2DM) and an additional therapeutic target. The use of drugs that remove senescent cells has led to improvements in blood glucose levels and diabetic complications in animal studies. Although the removal of senescent cells is a promising approach for the treatment of T2DM, two main challenges limit its clinical application: the molecular basis of cellular senescence in each organ is yet to be understood, and the specific effect of removing senescent cells in each organ has to be determined. This review aims to discuss future applications of targeting senescence as a therapeutic option in T2DM and elucidate the characteristics of cellular senescence and senescence-associated secretory phenotype in the tissues important for regulating glucose levels: pancreas, liver, adipocytes, and skeletal muscle

The Impact of Nutritional Status and Body Mass Index on Rehabilitation Outcomes in Patients Receiving Home-Based Medical Care

Background: Home-based medical care is expanding rapidly in Japan.Objectives: We aimed to identify the factors associated with outcomes of therapy in patients receiving home-visit rehabilitation.Methods: One hundred twenty-one patients receiving home-based rehabilitation were investigated. Nutritional status was assessed by the Mini Nutritional Assessment Short Form (MNA-SF). The Functional Independence Measure (FIM) was employed to assess the activities of daily living (ADL). The body mass index (BMI), medical history, and orthopedic disease-related pain were also recorded. The primary outcome was the improvement in FIM scores in one year.Results: A total of 19 (17%) patients were malnourished and 58 (48%) were at risk of malnutrition. Malnourished patients had a lower FIM score at initiation than those at risk of malnutrition or with normal nutritional status. Only changes in patients’ BMI and MNA-SF scores over one year were significantly associated with improved FIM scores (p = 0.0079 and p = 0.0049, respectively). No association was noted with the other factors.Conclusions: This is the first report to demonstrate that changes in MNA-SF scores and BMI are significantly associated with rehabilitation outcomes in home-based care. Nutritional management is essential along with rehabilitation to improve ADL in the long-term home care setting

Oral health status: relationship to nutrient and food intake among 80‐year‐old Japanese adults

Objectives The aim of this cross‐sectional study was to investigate the relationship of oral health status defined on the basis of presence of posterior occluding pairs ( POP s) and adequacy of removable denture fit as determined by self‐report to nutrient and food intake among older Japanese. Methods The subjects were 353 Japanese aged 80 years in 2008 and were classified into four groups according to the number of POP s, defined as pairs of occluding natural, restored, or fixed prosthetic postcanine teeth (range: 0–8) and removable denture status. The groups were: (i) good dentition ( n  =   56; 8 POP s and no removable prosthesis), (ii) well‐fitting dentures ( n  =   158; <8 POP s with self‐reported good‐fitting dentures), (iii) ill‐fitting dentures ( n  =   70; <8 POP s with self‐reported ill‐fitting dentures), and (iv) compromised dentition ( n  =   69; <8 POP s and no removable prosthesis). Multivariable analysis of the differences in nutrient and food intake outcome variables which were collected via validated food frequency questionnaire among the four oral health status groups was conducted using general linear models. Results Intake of multiple nutrients was significantly ( P  <   0.05) lower in the group with ill‐fitting dentures or compromised dentition than in the good dentition group. Vegetable, fish, and shellfish consumption was significantly lower in the ill‐fitting dentures or compromised dentition groups. No significant differences were seen in dietary intake between the well‐fitting dentures and good dentition groups. Conclusions Dietary intake was poorer in those with self‐perceived ill‐fitting dentures or fewer POP s than among those having all POP s. Regular dental care to maintain intact dentition, as well as dental treatment to replace missing teeth and ensure adequate denture fit and function, may be important to the diet intake and subsequent nutritional status of older Japanese.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108691/1/cdoe12100.pd

Free fatty acid receptors, G protein-coupled receptor 120 and G protein-coupled receptor 40, are essential for oil-induced gastric inhibitory polypeptide secretion

Aims/Introduction: Incretin hormone glucose‐dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) plays a key role in high‐fat diet‐induced obesity and insulin resistance. GIP is strongly secreted from enteroendocrine K cells by oil ingestion. G protein‐coupled receptor (GPR)120 and GPR40 are two major receptors for long chain fatty acids, and are expressed in enteroendocrine K cells. In the present study, we investigated the effect of the two receptors on oil‐induced GIP secretion using GPR120‐ and GPR40‐double knockout (DKO) mice. Materials and Methods: Global knockout mice of GPR120 and GPR40 were crossbred to generate DKO mice. Oral glucose tolerance test and oral corn oil tolerance test were carried out. For analysis of the number of K cells and gene expression in K cells, DKO mice were crossbred with GIP‐green fluorescent protein knock‐in mice in which visualization and isolation of K cells can be achieved. Results: Double knockout mice showed normal glucose‐induced GIP secretion, but no GIP secretion by oil. We then investigated the number of K cells and gene characteristics in K cells isolated from GIP‐green fluorescent protein knock‐in mice. Deficiency of both receptors did not affect the number of K cells in the small intestine or expression of GIP messenger ribonucleic acid in K cells. Furthermore, there was no significant difference in the expression of the genes associated with lipid absorption or GIP secretion in K cells between wild‐type and DKO mice. Conclusions: Oil‐induced GIP secretion is triggered by the two major fatty acid receptors, GPR120 and GPR40, without changing K‐cell number or K‐cell characteristics

Decreased IGF1R attenuates senescence and improves function in pancreatic β-cells

IntroductionThe enhanced β-cell senescence that accompanies insulin resistance and aging contributes to cellular dysfunction and loss of transcriptional identity leading to type 2 diabetes (T2D). While senescence is among the 12 recognized hallmarks of aging, its relation to other hallmarks including altered nutrient sensing (insulin/IGF1 pathway) in β-cells is not fully understood. We previously reported that an increased expression of IGF1R in mouse and human β-cells is a marker of older β-cells; however, its contribution to age-related dysfunction and cellular senescence remains to be determined.MethodsIn this study, we explored the direct role of IGF1R in β-cell function and senescence using two independent mouse models with decreased IGF1/IGF1R signaling: a) Ames Dwarf mice (Dwarf +/+), which lack growth hormone and therefore have reduced circulating levels of IGF1, and b) inducible β-cell-specific IGF1R knockdown (βIgf1rKD) mice.ResultsCompared to Dwarf+/- mice, Dwarf+/+ mice had lower body and pancreas weight, lower circulating IGF1 and insulin levels, and lower IGF1R and p21Cip1 protein expression in β-cells, suggesting the suppression of senescence. Adult βIgf1rKD mice showed improved glucose clearance and glucose-induced insulin secretion, accompanied by decreased p21Cip1 protein expression in β-cells. RNA-Seq of islets isolated from these βIgf1rKD mice revealed the restoration of three signaling pathways known to be downregulated by aging: sulfide oxidation, autophagy, and mTOR signaling. Additionally, deletion of IGF1R in mouse β-cells increased transcription of genes important for maintaining β-cell identity and function, such as Mafa, Nkx6.1, and Kcnj11, while decreasing senescence-related genes, such as Cdkn2a, Il1b, and Serpine 1. Decreased senescence and improved insulin-secretory function of β-cells were also evident when the βIgf1rKD mice were fed a high-fat diet (HFD; 60% kcal from fat, for 5 weeks).DiscussionThese results suggest that IGF1R signaling plays a causal role in aging-induced β-cell dysfunction. Our data also demonstrate a relationship between decreased IGF1R signaling and suppressed cellular senescence in pancreatic β-cells. Future studies can further our understanding of the interaction between senescence and aging, developing interventions that restore β-cell function and identity, therefore preventing the progression to T2D

Malt1-Induced Cleavage of Regnase-1 in CD4+ Helper T Cells Regulates Immune Activation

SummaryRegnase-1 (also known as Zc3h12a and MCPIP1) is an RNase that destabilizes a set of mRNAs, including Il6 and Il12b, through cleavage of their 3′ UTRs. Although Regnase-1 inactivation leads to development of an autoimmune disease characterized by T cell activation and hyperimmunoglobulinemia in mice, the mechanism of Regnase-1-mediated immune regulation has remained unclear. We show that Regnase-1 is essential for preventing aberrant effector CD4+ T cell generation cell autonomously. Moreover, in T cells, Regnase-1 regulates the mRNAs of a set of genes, including c-Rel, Ox40, and Il2, through cleavage of their 3′ UTRs. Interestingly, T cell receptor (TCR) stimulation leads to cleavage of Regnase-1 at R111 by Malt1/paracaspase, freeing T cells from Regnase-1-mediated suppression. Furthermore, Malt1 protease activity is critical for controlling the mRNA stability of T cell effector genes. Collectively, these results indicate that dynamic control of Regnase-1 expression in T cells is critical for controlling T cell activation

Human NK cell development in hIL-7 and hIL-15 knockin NOD/SCID/IL2rgKO mice.

The immune system encompasses acquired and innate immunity that matures through interaction with microenvironmental components. Cytokines serve as environmental factors that foster functional maturation of immune cells. Although NOD/SCID/IL2rgKO (NSG) humanized mice support investigation of human immunity in vivo, a species barrier between human immune cells and the mouse microenvironment limits human acquired as well as innate immune function. To study the roles of human cytokines in human acquired and innate immune cell development, we created NSG mice expressing hIL-7 and hIL-15. Although hIL-7 alone was not sufficient for supporting human NK cell development in vivo, increased frequencies of human NK cells were confirmed in multiple organs of hIL-7 and hIL-15 double knockin (hIL-7xhIL-15 KI) NSG mice engrafted with human hematopoietic stem cells. hIL-7xhIL-15 KI NSG humanized mice provide a valuable in vivo model to investigate development and function of human NK cells

Genetic Predisposition to Ischemic Stroke

Background and Purpose—The prediction of genetic predispositions to ischemic stroke (IS) may allow the identification of individuals at elevated risk and thereby prevent IS in clinical practice. Previously developed weighted multilocus genetic risk scores showed limited predictive ability for IS. Here, we investigated the predictive ability of a newer method, polygenic risk score (polyGRS), based on the idea that a few strong signals, as well as several weaker signals, can be collectively informative to determine IS risk.Methods—We genotyped 13 214 Japanese individuals with IS and 26 470 controls (derivation samples) and generated both multilocus genetic risk scores and polyGRS, using the same derivation data set. The predictive abilities of each scoring system were then assessed using 2 independent sets of Japanese samples (KyushuU and JPJM data sets).Results—In both validation data sets, polyGRS was shown to be significantly associated with IS, but weighted multilocus genetic risk scores was not. Comparing the highest with the lowest polyGRS quintile, the odds ratios for IS were 1.75 (95% confidence interval, 1.33–2.31) and 1.99 (95% confidence interval, 1.19–3.33) in the KyushuU and JPJM samples, respectively. Using the KyushuU samples, the addition of polyGRS to a nongenetic risk model resulted in a significant improvement of the predictive ability (net reclassification improvement=0.151; P<0.001).Conclusions—The polyGRS was shown to be superior to weighted multilocus genetic risk scores as an IS prediction model. Thus, together with the nongenetic risk factors, polyGRS will provide valuable information for individual risk assessment and management of modifiable risk factors

コウダイ レンケイ ニ ヨル セツゾクキョウイク プログラム カイハツ ノ ココロミ

高大連携により効率的な接続教育プログラムを開発するため,高校向けアンケートを実施した。職業に就いた際に必要とされるキャリア基礎能力として本学で過去実施したアンケート結果を基にした10 要素,ならびに経済産業省の「社会人基礎力」12 要素の必要性と達成度を設問とした。その結果,社会人にもっとも必要とされるキャリア基礎能力は「コミュニケーション能力」であること,また,高校教科「情報」によりPC 基礎操作能力は十分獲得されていること,がわかった。この結果を踏まえ,高大連携プログラムの一環として高校-大学教員によるコミュニケーション教育研究会を開催し,全12 講からなる接続教育プログラム「コミュニケーションリテラシー」を開講した。Enquiries were made to upper secondary school teachers on basic vocational abilities necessary for thegraduates. Since "information literacy" was introduced recently as compulsory subject in secondary schools, itsrelation with elements necessary for an ordinary person who wishes to work in a company was investigated. Basedon the results, a project was set up with members from secondary school teachers and Shohoku College teachersand library staff. As a result, a novel coordination program, namely, "communication literacy", consisting of 12lessons, was held for secondary school third grade students

コウダイレンケイ ニ ヨル キョウイク コウリュウ ネットワーク ノ コウチク : コミュニケーション キョウイク ケンキュウカイ ノ カツドウ ト コミュニケーションリテラシー

高大連携校より本学への入学が決定した生徒を対象とした単位認定科目「コミュニケーションリテラシー」を開講した。同科目の内容やスケジュールは、平成19 年度よりほぼ月に一度のペースで高大連携協定校教員と本学教職員で構成する「コミュニケーション教育研究会」で調査研究・見学・参観・討議などを重ねて決定されたものである。この研究会の中ではまた、ブレインストーミングにより、経済産業省の「社会人基礎能力」を基本とした「職業を持った社会人に必要とされる能力要素」の洗い出しを行ない、これら要素の必要性や獲得度のアンケート調査を実施した。対象は高大連携校と全国の高校である。その結果、職業をもった社会人にもっとも必要とされる基本的な基礎能力は、「コミュニケーション能力」と「一般常識」であること、さらには「課題発見能力や企画・提案能力」や「表現力やプレゼンテーション能力」が不十分であるととらえられていることがわかった。こうした問題意識を踏まえて「コミュニケーションリテラシー」の実施内容を組み立てた。本年度の「コミュニケーションリテラシー」受講生は110 名となった。この効果を検証することは容易ではないが、受講生に対しアンケート調査などを行った結果に関しても報告する。Novel coordination program, namely, "Communication Literacy", consisting of 15 lesson classes, was developed and held for secondary school third grade students. This class was developed and implemented in a project set up with members from secondary school teachers and Shohoku College teachers and staff. Survey on basic vocational abilities necessary for the graduates was made by sending questionnaires to secondary school teachers. Questionnaires were made to students participated in the program to clarify the effect of the program