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Genome-wide association studies have identified several gene polymorphisms, including UBE2E2 , associated with type 2 diabetes. Although UBE2E2 is one of the ubiquitin-conjugating enzymes involved in the process of ubiquitin modifications, the pathophysiological roles of UBE2E2 in metabolic dysfunction are not yet understood. Here, we showed upregulated UBE2E2 expression in the islets of a mouse model of diet-induced obesity. The diabetes risk allele of UBE2E2 (rs13094957) in noncoding regions was associated with upregulation of UBE2E 2 mRNA in the human pancreas. Although glucose-stimulated insulin secretion was intact in the isolated islets, pancreatic β-cell–specific UBE2E2 -transgenic (TG) mice exhibited reduced insulin secretion and decreased β-cell mass. In TG mice, suppressed proliferation of β-cells before the weaning period and while receiving a high-fat diet was accompanied by elevated gene expression levels of p21 , resulting in decreased postnatal β-cell mass expansion and compensatory β-cell hyperplasia, respectively. In TG islets, proteomic analysis identified enhanced formation of various types of polyubiquitin chains, accompanied by increased expression of Nedd4 E3 ubiquitin protein ligase. Ubiquitination assays showed that UBE2E2 mediated the elongation of ubiquitin chains by Nedd4. The data suggest that UBE2E2-mediated ubiquitin modifications in β-cells play an important role in regulating glucose homeostasis and β-cell mass. [ABSTRACT FROM AUTHOR]

In a recent publication in Science , Zocher et al. 1 identify and characterize long-lived nuclear RNA in the mouse brain, suggesting their potential roles as guardians of neuronal longevity. In a recent publication in Science , Zocher et al. identify and characterize long-lived nuclear RNA in the mouse brain, suggesting their potential roles as guardians of neuronal longevity. [ABSTRACT FROM AUTHOR]

Background and study aims: The diagnostic ability of endoscopists to determine invasion depth of early gastric cancer is not favorable. We designed an artificial intelligence (AI) classifier for differentiating intramucosal and submucosal gastric cancers and examined it to establish a diagnostic method based on cooperation between AI and endoscopists. Patients and methods: We prepared 500 training images using cases of mainly depressed-type early gastric cancer from 250 intramucosal cancers and 250 submucosal cancers. We also prepared 200 test images each of 100 cancers from another institution. We designed an AI classifier to differentiate between intramucosal and submucosal cancers by deep learning. We examined the performance of the AI classifier and the majority vote of the endoscopists as high confidence and low confidence diagnostic probability, respectively, and cooperatively combined them to establish a diagnostic method providing high accuracy. Results: Internal evaluation of the training images showed that accuracy, sensitivity, specificity, and F1 measure by the AI classifier were 77%, 76%, 78%, and 0.768, and those of the majority vote of the endoscopists were 72.6%, 53.6%, 91.6%, and 0.662, respectively. A diagnostic method based on cooperation between AI and the endoscopists showed that the respective values were 78.0%, 76.0%, 80.0%, and 0.776 for the test images. The value of F1 measure was especially higher than those by AI or the endoscopists alone. Conclusions: Cooperation between AI and endoscopists improved the diagnostic ability to determine invasion depth of early gastric cancer. [ABSTRACT FROM AUTHOR]

Genomic variations are associated with gene expression levels, which are called expression quantitative trait loci (eQTL). Most eQTL may affect the total gene expression levels by regulating transcriptional activities of a specific promoter. However, the direct exploration of genomic loci associated with promoter activities using RNA-seq data has been challenging because eQTL analyses treat the total expression levels estimated by summing those of all isoforms transcribed from distinct promoters. Here we propose a new method for identifying genomic loci associated with promoter activities, called promoter usage quantitative trait loci (puQTL), using conventional RNA-seq data. By leveraging public RNA-seq datasets from the lymphoblastoid cell lines of 438 individuals from the GEUVADIS project, we obtained promoter activity estimates and mapped 2,592 puQTL at the 10% FDR level. The results of puQTL mapping enabled us to interpret the manner in which genomic variations regulate gene expression. We found that 310 puQTL genes (16.1%) were not detected by eQTL analysis, suggesting that our pipeline can identify novel variant–gene associations. Furthermore, we identified genomic loci associated with the activity of "hidden" promoters, which the standard eQTL studies have ignored. We found that most puQTL signals were concordant with at least one genome-wide association study (GWAS) signal, enabling novel interpretations of the molecular mechanisms of complex traits. Our results emphasize the importance of the re-analysis of public RNA-seq datasets to obtain novel insights into gene regulation by genomic variations and their contributions to complex traits. Author summary: Many variations exist in the human genome, creating phenotypic diversity among individuals. It is well known that they are associated with the risk of disease development by affecting the expression levels of genes. Genes are transcribed from regulatory elements called promoters. Although some genes are transcribed from multiple promoters and translated into proteins with different functions, the relationship between genomic variations and promoter activities has not been investigated in depth compared to the relationship between genomic variations and gene expression levels. In this study, we proposed a new method to detect the association between genomic variations and promoter activities. Our method identified the associations between many variations and promoters using genomic and promoter activity data from blood cells of 438 individuals. This study allowed us to identify new functional associations between genomic variations and genes. Furthermore, we identified previously undiscovered variation-gene-disease associations. Our results will help to elucidate the molecular mechanisms of diseases in which genetic factors are involved. [ABSTRACT FROM AUTHOR]

Background: The aim of our study was to evaluate the influence of changes of nutritional status and body composition on the results of comprehensive geriatric assessment (CGA) in inpatients of a geriatric ward. Sex differences in these relationships were also investigated. Methods: A total of 212 elderly patients (>65 years old) admitted to the geriatric ward at the University of Tokyo hospital between 2012 and 2019 were enrolled in this study. CGA (ADL, IADL, MMSE, GDS, Vitality Index) was performed, along with assessment of body compositions (appendicular muscle mass, abdominal muscle mass, body fat mass) and blood malnutrition biomarkers (serum albumin, pre-albumin, 25-hydroxy vitamin D, zinc, hemoglobin concentrations). Results: Multiple linear regression analysis showed that upper, lower limbs and abdominal muscle masses were significantly associated with the score on ADL in men. On the other hand, abdominal muscle mass was negatively associated with the scores on GDS. Body fat mass was also negatively associated with the score on IADL. In contrast, in women, multiple linear regression analysis failed to show any significant associations between body composition parameters and scores on any domains of CGA. Unlike in men, however, blood malnutrition biomarkers were significantly associated with ADL, IADL, MMSE, and Vitality Index in women. Conclusions: Our study findings revealed that the association of the nutritional status and body composition with the functional status in the elderly differs by sex. These results suggest that intensification of exercise in men and improvement of the nutritional status in women are particularly useful to maintain the functional status. [ABSTRACT FROM AUTHOR]

Aims/Introduction: To prevent diabetic complications, strict glucose control and frequent monitoring of blood glucose levels with invasive methods are necessary. We considered the monitoring of tear glucose levels might be a possible method for non‐invasive glucose monitoring. To develop tear glucose monitoring for clinical application, we investigated the precise correlation between the blood and tear glucose concentrations. Materials and Methods: A total of 10 participants and 20 participants with diabetes were admitted, and blood and tear samples were collected. Before statistical analysis, we eliminated tear samples contaminated with blood. We observed the daily blood and tear glucose dynamics, and carried out a random intercept model analysis to examine the association between the blood and tear glucose concentrations. Results: Tear occult blood tests showed that the tear glucose concentrations and their variation increased in both participants with and without diabetes as contamination of blood increased. In both participants with and without diabetes, fluctuations of the plasma glucose concentrations were observed depending on the timing of collection of the samples, and the dynamics of the tear glucose concentrations paralleled those of the plasma glucose concentrations. The random intercept model analysis showed a significant association between the plasma and tear glucose concentrations in participants with diabetes (P < 0.001). This association still existed even after adjusting for the glycated hemoglobin levels and the prandial state (P < 0.001). Conclusions: It is important to eliminate the tear samples contaminated with blood. Tear glucose monitoring might be a reliable and non‐invasive substitute method for monitoring the blood glucose concentrations for diabetes patients, irrespective of glycated hemoglobin levels and timing of sample collection. [ABSTRACT FROM AUTHOR]

Tumor tissue is composed of tumor cells and tumor stroma. Tumor stroma contains various immune cells and non‐immune stromal cells, forming a complex tumor microenvironment which plays pivotal roles in regulating tumor growth. Recent successes in immunotherapies against tumors, including immune checkpoint inhibitors, have further raised interests in the immune microenvironment of liver carcinoma. The immune microenvironment of tumors is formed because of interactions among tumor cells, immune cells and non‐immune stromal cells, including fibroblasts and endothelial cells. Different patterns of immune microenvironment are observed among different tumor subtypes, and their clinicopathological significance and intertumor/intratumor heterogeneity are being intensively studied. Here, we review the immune microenvironment of hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma, focusing on its histopathological appearance, clinicopathological significance, and relationship with histological and molecular classifications. Understanding the comprehensive histopathological picture of a tumor immune microenvironment, in addition to molecular and genetic approaches, will further potentiate the effort for precision medicine in the era of tumor‐targeting immunotherapy. [ABSTRACT FROM AUTHOR]

The clinicopathological characteristics of steatosis in hepatocellular carcinoma (HCC) remain unclear. Here, we elucidate the features of macrovesicular steatosis (MaS) and microvesicular steatosis (MiS) in HCC and their relationships with background liver steatosis. A total of 165 HCC lesions were classified as MaS‐HCC, MiS‐HCC, or conventional HCC (cHCC) according to the cutoff value of 30% MaS or MiS in tumor cells. We analyzed the clinicopathological differences among these groups. MaS‐HCC had less portal vein invasion, a higher proportion of HCC with intratumoral fibrosis, and a lower cumulative risk of recurrence than MiS‐HCC or cHCC. Moreover, both MaS‐HCC and MiS‐HCC had lower incidences of hepatitis virus infection and higher levels of HbA1c than cHCC. Background liver steatosis was also higher in MaS‐HCC than in cHCC. Immunohistochemical expression of perilipin (Plin1) and adipophilin (ADRP), major proteins expressed on lipid droplet membranes, revealed that almost all lipid droplets in HCC were Plin1 negative, whereas those in background liver were positive. In contrast, ADRP was expressed on lipid droplets in both HCC and background liver. We concluded that MaS‐HCC and MiS‐HCC were associated with metabolic abnormalities but exhibited different biologic behaviors. Furthermore, lipid droplets in HCC were pathophysiologically different from those in background liver. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is a chronic inflammatory skin disease, for which genome-wide association studies (GWAS) have identified many genetic variants as risk markers. However, the details of underlying molecular mechanisms, especially which variants are functional, are poorly understood. Methods: We utilized a computational approach to survey psoriasis-associated functional variants that might affect protein functions or gene expression levels. We developed a pipeline by integrating publicly available datasets provided by GWAS Catalog, FANTOM5, GTEx, SNP2TFBS, and DeepBlue. To identify functional variants on exons or splice sites, we used a web-based annotation tool in the Ensembl database. To search for noncoding functional variants within promoters or enhancers, we used eQTL data calculated by GTEx. The data of variants lying on transcription factor binding sites provided by SNP2TFBS were used to predict detailed functions of the variants. Results: We discovered 22 functional variant candidates, of which 8 were in noncoding regions. We focused on the enhancer variant rs72635708 (T > C) in the 1p36.23 region; this variant is within the enhancer region of the ERRFI1 gene, which regulates lipid metabolism in the liver and skin morphogenesis via EGF signaling. Further analysis showed that the ERRFI1 promoter spatially contacts with the enhancer, despite the 170 kb distance between them. We found that this variant lies on the AP-1 complex binding motif and may modulate binding levels. Conclusions: The minor allele rs72635708 (rs72635708-C) might affect the ERRFI1 promoter activity, which results in unstable expression of ERRFI1, enhancing the risk of psoriasis via disruption of lipid metabolism and skin cell proliferation. Our study represents a successful example of predicting molecular pathogenesis by integration and reanalysis of public data. [ABSTRACT FROM AUTHOR]

Cerebral palsy (CP) is a major neuronal disease and the most common movement disorder in children. Although environmental factors leading to CP have been greatly investigated, the genetic mechanism underlying CP is not well understood. Here we focused on two clinical reports that characterized a deletion involving the KANK1 gene locus in the 9p24.3 region. One report shows spastic CP and the other shows no spastic CP phenotype. Based on the epigenetic status and evolutionary conservation, we first found a functional genomic element at the noncoding region that was deleted only in patients with spastic CP. This element contains the retinoic acid receptor/retinoid X receptor (RAR/RXR) complex-binding motif that is widely conserved among placental mammals. RAR/RXR ChIP-seq data from mouse F9 embryonal carcinoma cells that were treated with trans -retinoic acids showed that the element has a binding ability. In addition, data regarding chromosome conformation capture from mouse neural progenitor and ES cells suggested that the element spatially interacts with the Doublesex and mab-3 related transcription factor 3 ( Dmrt3) gene promoter that is located approximately 120 kb downstream of the RAR/RXR-binding site. Dmrt3 is detected in the developing mouse forebrain and in some interneurons in the spinal cord, and it works as a locomotion coordinator in horses and mice. Thus, the deletion of the cis -regulatory element for DMRT3 in humans may cause impaired development of the forebrain and gait abnormalities, resulting in spastic CP. In conclusion, this study provides new mechanistic insights into the genetic basis of CP. [ABSTRACT FROM AUTHOR]

Objectives. To evaluate the abdominal visceral fat area (VFA), we developed novel ultrasonographic (US) methods for estimating. Methods. 100 male volunteers were recruited, and their VFA was calculated by two novel US methods, the triangle method and the ellipse method. The VFA calculated by these methods was compared with the VFA calculated by CT. Results. Both the VFA calculated by the triangle method (r=0.766, p<0.001) and the ellipse method (r=0.781, p<0.001) showed a high correlation coefficient with the VFA calculated by CT. Also, the VFA calculated by our novel methods were significantly increased in subjects with one or more metabolic risk factors than in those without any risk factors. Furthermore, the correlation coefficients obtained using the two methods were enhanced by the addition of multiple regression analysis (with the triangle method, r=0.8586, p<0.001; with the ellipse method, r=0.8642, p<0.001). Conclusions. The VFA calculated by the triangle or ellipse method showed a high correlation coefficient with the VFA calculated by CT. These US methods are easy to use, they involve no radiation exposure, and the measurements can be conducted frequently. We hope that our simple methods would be widely adopted for the evaluation of VFA. [ABSTRACT FROM AUTHOR]

Our previous study revealed the diurnal change in the indigenous bacteria settling on the terminal region of the rat ileum. In the present study, we investigated the diurnal change in indigenous bacteria on the most distal ileal Peyer's patch (PP) and surrounding ileal mucosa and explored how stimulation from indigenous bacteria for a day affects the intestinal immune system at the beginning of the light phase. Histological measurement revealed that bacteria adjacent to the follicle-associated epithelium of PP and to the villous epithelium of the surrounding ileal mucosa are more abundant at zeitgeber time (ZT)0 and ZT18 than at ZT12. On the other hand, tissue-section 16S rRNA amplicon sequencing revealed no significant difference between ZT0 and ZT12 in the bacterial composition on the ileal tissue including the PP. One-day treatment with an antibiotic (Abx) successfully impaired the settlement of bacteria around the ileal PP. In transcriptome analysis, 1-day Abx treatment led to the downregulation of several chemokines in both PP and ordinary ileal mucosa at ZT0. Histological analysis of the 1-day Abx group revealed decreases in both CD68+ macrophages in PP and naphthol AS-D chloroacetate esterase stain-positive mast cells in the ileal villi. Together, these findings suggest that the colonies of indigenous bacteria on the distal ileal PP and surrounding mucosa expand during the dark phase, which might lead to the expression of genes to regulate the intestinal immune system and contribute to the homeostasis of at least macrophages in PP and mast cells in the ileal mucosa. [ABSTRACT FROM AUTHOR]

Despite several technical challenges, human induced pluripotent stem cell (hiPSC)-derived organoids enable biologically and clinically relevant functional study of physiology and disease. In a recent Cell Systems article, Velazquez et al. report a novel strategy to identify regulators of multilineage organoid maturation by reverse-engineering from the global transcriptome of human tissues. [ABSTRACT FROM AUTHOR]

Rimonabant has been shown to not only decrease the food intake and body weight but also to increase serum adiponectin levels. This increase of the serum adiponectin levels has been hypothesized to be related to the rimonabant-induced amelioration of insulin resistance linked to obesity, although experimental evidence to support this hypothesis is lacking. To test this hypothesis experimentally, we generated adiponectin knock-out (adipo(-/-))ob/ob mice. After 21 days of 30 mg/kg rimonabant, the body weight and food intake decreased to similar degrees in the ob/ob and adipo(-/-)- ob/ob mice. Significant improvement of insulin resistance was observed in the ob/ob mice following rimonabant treatment, associated with significant up-regulation of the plasma adiponectin levels, in particular, of high molecular weight adiponectin. Amelioration of insulin resistance in the ob/ob mice was attributed to the decrease of glucose production and activation of AMP-activated protein kinase (AMPK) in the liver induced by rimonabant but not to increased glucose uptake by the skeletal muscle. Interestingly, the rimonabanttreated adipo(-/-)ob/ob mice also exhibited significant amelioration of insulin resistance, although the degree of improvement was significantly lower as compared with that in the ob/ob mice. The effects of rimonabant on the liver metabolism, namely decrease of glucose production and activation of AMPK, were also less pronounced in the adipo(-/-)-ob/ob mice. Thus, it was concluded that rimonabant ameliorates insulin resistance via both adiponectin-dependent and adiponectin-independent pathways. [ABSTRACT FROM AUTHOR]

The article presents the findings of studies on the role of adipose tissue-derived adiponectin in amelioration of insulin resistance and diabetes by thiazolidinediones (TZD), a group of insulin sensitizers. TZD may upregulate adiponectin via generating small adipocytes that secrete adiponectin and/or directly activating adiponectin gene transcription. The amelioration of diabetes and insulin resistance in adipo[sup -/-] ob/ob mice was due in part to increased glucose uptake in skeletal muscle.

Thiazolidinediones have been shown to up-regulate adiponectin expression in white adipose tissue and plasma adiponectin levels, and these up-regulations have been proposed to be a major mechanism of the thiazolidinedione-induced amelioration of insulin resistance linked to obesity. To test this hypothesis, we generated adiponectin knock-out (adipo-/-) ob/ob mice with a C57B/6 background. After 14 days of 10 mg/kg pioglitazone, the insulin resistance and diabetes of ob/ob mice were significantly improved in association with significant up-regulation of serum adiponectin levels. Amelioration of insulin resistance in ob/ob mice was attributed to decreased glucose production and increased AMP-activated protein kinase in the liver but not to increased glucose uptake in skeletal muscle. In contrast, insulin resistance and diabetes were not improved in adipo-/- ob/ob mice. After 14 days of 30 mg/kg pioglitazone, insulin resistance and diabetes of ob/ob mice were again significantly ameliorated, which was attributed not only to decreased glucose production in the liver but also to increased glucose uptake in skeletal muscle. Interestingly, adipo ob/ob mice also displayed significant amelioration of insulin resistance and diabetes, which was attributed to increased glucose uptake in skeletal muscle but not to decreased glucose production in the liver. The serum-free fatty acid and triglyceride levels as well as adipocyte sizes in ob/ob and adipo-/- ob/ob mice were unchanged after 10 mg/kg pioglitazone but were significantly reduced to a similar degree after 30 mg/kg pioglitazone. Moreover, the expressions of TNFα and resistin in adipose tissues of ob/ob and adipo-/- ob/ob mice were unchanged after 10 mg/kg pioglitazone but were decreased after 30 mg/kg pioglitazone. Thus, pioglitazone-induced amelioration of insulin resistance and diabetes may occur adiponectin dependently in the liver and adiponectin independently in skeletal muscle. [ABSTRACT FROM AUTHOR]

We previously demonstrated that insulin receptor substrate 2 (Irs2) KO mice develop diabetes associated with hepatic insulin resistance, lack of compensatory β cell hyperplasia, and leptin resistance. To more precisely determine the roles of lrs2 in β cells and the hypothalamus, we generated β cell-specific Irs2 KO and hypothalamus-specific Irs2 knockdown (I3HT-IRS2) mice. Expression of Irs2 mRNA was reduced by approximately 90% in pancreatic islets and was markedly reduced in the arcuate nucleus of the hypothalamus. By contrast, Irs2 expression in liver, muscle, and adipose tissue of βHT-IRS2 mice was indistinguishable from that of control mice. The βHT-IRS2 mice displayed obesity and leptin resistance. At 4 weeks of age, the βHT-IRS2 mice showed normal insulin sensitivity, but at 8 and 12 weeks, they were insulin resistant with progressive obesity. Despite their normal insulin sensitivity at 8 weeks with caloric restriction, the βHT-IRS2 mice exhibited glucose intolerance and impaired glucose-induced insulin secretion. β Cell mass and βcell proliferation in the βHT-IRS2 mice were reduced significantly at 8 and 12 weeks but not at 10 clays. Insulin secretion, normalized by cell number per islet, was significantly increased at high glucose concentrations in the βHT-IRS2 mice. We conclude that, in β cells and the hypothalamus, Irs2 is crucially involved in the regulation of β cell mass and leptin sensitivity. [ABSTRACT FROM AUTHOR]

To investigate the role of insulin receptor substrate (IRS)-2 in vivo, we generated IRS-2-deficient mice by gene targeting. Although homozygous IRS-2-deficient mice (IRS-2-/- mice) had a body weight similar to wild-type mice, they progressively developed type 2 diabetes at 10 weeks. IRS-2-/- mice showed insulin resistance and a defect in the insulin-stimulated signaling pathway in liver but not in skeletal muscle. Despite insulin resistance, the amount of beta-cells was reduced to 83% of that in wild-type mice, which was in marked contrast to the 85% increase in the amount of beta-cells in IRS-1-deficient mice (IRS-1-/- mice) to compensate for insulin resistance. Thus, IRS-2 plays a crucial role in the regulation of beta-cell mass. On the other hand, insulin secretion by the same number of cells in response to glucose measured ex vivo was significantly increased in IRS-2-/- mice compared with wild-type mice but was decreased in IRS-1-/- mice. These results suggest that IRS-1 and IRS-2 may play different roles in the regulation of beta-cell mass and the function of individual beta-cells. [ABSTRACT FROM AUTHOR]

Low birth weight has been reported to be associated with impaired insulin secretion and insulin resistance. It has been proposed that this association results from fetal programming in response to the intrauterine environment (the thrifty phenotype hypothesis). To elucidate the relationship between birth weight and genetically determined defects in insulin secretion, we measured the birth weights of neonates derived from crosses of male pancreatic beta-cell type glucokinase knockout (Gck+/-) mice and female wild-type (WT) or Gck+/- mice. In 135 offspring, birth weights were lower in the presence of a fetal heterozygous mutation and higher in the presence of a maternal heterozygous mutation. Moreover, Gck-/- neonates had significantly smaller birth weights than WT or Gck+/- neonates (means +/- SE 1.49+/-0.03 [n = 30] vs. 1.63+/-0.03 [n = 30] or 1.63+/-0.02 [n = 50] g, respectively; P<0.01). Thus, Gck mutations in beta-cells may impair insulin response to glucose and alter intrauterine growth as well as glucose metabolism after birth. This study has confirmed the results of a previous report that human subjects carrying mutations in Gck had reduced birth weights and has provided direct evidence for a link between insulin and fetal growth. Moreover, birth weights were reduced in insulin receptor substrate-1 knockout mice despite normal insulin levels. Taken together, these results suggest that a genetically programmed insulin effect during embryogenesis determines fetal growth and provides a possible molecular link between birth weight and susceptibility to type 2 diabetes. [ABSTRACT FROM AUTHOR]

Mutations in human nonsense-mediated mRNA decay (NMD) factors are enriched in neurodevelopmental disorders. We show that deletion of key NMD factor Upf2 in mouse embryonic neural progenitor cells causes perinatal microcephaly but deletion in immature neurons does not, indicating NMD's critical roles in progenitors. Upf2 knockout (KO) prolongs the cell cycle of radial glia progenitor cells, promotes their transition into intermediate progenitors, and leads to reduced upper-layer neurons. CRISPRi screening identified Trp53 knockdown rescuing Upf2 KO progenitors without globally reversing NMD inhibition, implying marginal contributions of most NMD targets to the cell cycle defect. Integrated functional genomics shows that NMD degrades selective TRP53 downstream targets, including Cdkn1a , which, without NMD suppression, slow the cell cycle. Trp53 KO restores the progenitor cell pool and rescues the microcephaly of Upf2 KO mice. Therefore, one physiological role of NMD in the developing brain is to degrade selective TRP53 targets to control progenitor cell cycle and brain size. [Display omitted] • Upf2 KO in neural progenitors prolongs cell cycle and causes microcephaly • Trp53 depletion rescues Upf2KO progenitor cell cycle and microcephaly • Most NMD targets have a marginal contribution to the cell-cycle defect • NMD degrades TRP53 target, Cdkn1a , to maintain progenitor cell pools Lin et al. discover that NMD counteracts the TRP53 pathway to regulate neuronal progenitors' cell-cycle progression in vitro and in vivo. These findings demonstrate that through the selective degradation of TRP53 targets, such as Cdkn1a , continuous NMD activity is needed to control progenitor cell cycle and brain size during development. [ABSTRACT FROM AUTHOR]

Introduction: Lifestyle management, including appropriate modifications of nutrition, exercise, and medication behaviors, is essential for optimal glycemic control. The absence of appropriate monitoring methods to validate the lifestyle change may hinder the modification and continuation of behaviors. In this study, we evaluated whether once-weekly glycated albumin (GA) measurement received via a smartphone application could improve glycemia management in patients with type 2 diabetes mellitus by supporting self-review and modification of lifestyle behaviors. Methods: This open-label, randomized controlled, single-center study in Japan with an 8-week intervention period was conducted in individuals with type 2 diabetes mellitus and HbA1c levels between 7.0 and 9.0% (53‒75 mmol/mol). The intervention was once-weekly home monitoring of GA with a daily self-review of lifestyle behaviors using a smartphone application, in addition to conventional treatment. Results: A total of 98 participants (72.0% males; age 63.2 ± 11.4 years; HbA1c 7.39 ± 0.39% [57.3 ± 4.3 mmol/mol]) were randomly assigned to the intervention or control group. Significant decreases of the GA and HbA1c levels from the baseline to the last observation day were observed in the intervention group (− 1.71 ± 1.37% [− 39.1 ± 31.3 mmol/mol] and − 0.32 ± 0.32% [− 3.5 ± 3.5 mmol/mol], respectively). Significant decreases of the body weight, waist circumference, and caloric expenditure (p < 0.0001 and p = 0.0003, p = 0.0346, respectively), but not of the caloric intake (p = 0.678), were also observed in the intervention group as compared with the control group. Conclusions: Self-review of lifestyle behaviors in combination with once-weekly GA home testing received via a smartphone application might potentially benefit glycemic management in people with type 2 diabetes mellitus. Trial Registration: jRCTs042220048. [ABSTRACT FROM AUTHOR]

The potential liability to hypercatabolism in lipodystrophy remains to be fully elucidated. Here we report a 28‐year‐old Japanese woman with acquired generalized lipodystrophy, who presented with recurrence of panniculitis and anemia. After corticosteroid treatment was started, she showed rapid reductions in body weight and lean mass by 15% at maximum, accompanied by an elevated urea nitrogen/creatinine ratio, which recovered almost fully as the corticosteroid treatment was tapered and discontinued. She had multiple risk factors for hypercatabolism: lack of metabolic reserves, insulin resistance, and hyperglycemia due to lipodystrophy, lowered daily activity due to anemia, persistent inflammation, and wasting associated with panniculitis, and relatively insufficient energy and protein intake during hospitalization. More attention should be paid to the potential liability to hypercatabolism in patients with lipodystrophy, and to skeletal muscle loss as an adverse effect of corticosteroid treatment in patients at high risk, such as those with diabetes or decreased metabolic reserves. [ABSTRACT FROM AUTHOR]

Many studies have reported that metabolic dysfunction is closely involved in the complex mechanism underlying the development of non-alcoholic fatty liver disease (NAFLD), which has prompted a movement to consider renaming NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD). Metabolic dysfunction in this context encompasses obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome, with insulin resistance as the common underlying pathophysiology. Imbalance between energy intake and expenditure results in insulin resistance in various tissues and alteration of the gut microbiota, resulting in fat accumulation in the liver. The role of genetics has also been revealed in hepatic fat accumulation and fibrosis. In the process of fat accumulation in the liver, intracellular damage as well as hepatic insulin resistance further potentiates inflammation, fibrosis, and carcinogenesis. Increased lipogenic substrate supply from other tissues, hepatic zonation of Irs1, and other factors, including ER stress, play crucial roles in increased hepatic de novo lipogenesis in MAFLD with hepatic insulin resistance. Herein, we provide an overview of the factors contributing to and the role of systemic and local insulin resistance in the development and progression of MAFLD. [ABSTRACT FROM AUTHOR]

Prediction of hepatocellular carcinoma (HCC) risk becomes increasingly important with recently emerging HCC-predisposing conditions, namely non-alcoholic fatty liver disease and cured hepatitis C virus infection. These etiologies are accompanied with a relatively low HCC incidence rate (~1% per year or less), while affecting a large patient population. Hepatitis B virus infection remains a major HCC risk factor, but a majority of the patients are now on antiviral therapy, which substantially lowers, but does not eliminate, HCC risk. Thus, it is critically important to identify a small subset of patients who have elevated likelihood of developing HCC, to optimize the allocation of limited HCC screening resources to those who need it most and enable cost-effective early HCC diagnosis to prolong patient survival. To date, numerous clinical-variable-based HCC risk scores have been developed for specific clinical contexts defined by liver disease etiology, severity, and other factors. In parallel, various molecular features have been reported as potential HCC risk biomarkers, utilizing both tissue and body-fluid specimens. Deep-learning-based risk modeling is an emerging strategy. Although none of them has been widely incorporated in clinical care of liver disease patients yet, some have been undergoing the process of validation and clinical development. In this review, these risk scores and biomarker candidates are overviewed, and strategic issues in their validation and clinical translation are discussed. [ABSTRACT FROM AUTHOR]

Aims/Background: To prevent diabetic complications, strict glucose control and frequent monitoring of blood glucose levels with invasive methods are necessary. We considered monitoring of diabetes-related biomarkers in tears may be the possible methods for diabetes monitoring methods. Many studies about tear glucose levels have been reported and tear glucose levels correlate with blood glucose levels. This time, we focused on glycoalbumin (GA) levels, which reflect an average of blood glucose levels over the preceding 2 weeks, and studied the correlation between GA levels in blood and tears. Methods: We recruited 100 diabetic subjects and collected blood and tear samples. GA levels in blood were measured by an enzymatic method, and GA levels in tears were measured by Liquid Chromatography/Mass Spectrometry (LC-MS/MS). Results: The GA levels in tears of 99 out of 100 samples were appropriately measured by LC-MS/MS. GA levels in blood and tears were significantly correlated (P < 0.001). Multiple regression analysis revealed that this correlation was maintained even after adjustment for age, gender, nephropathy stage, and obesity (P < 0.001). Conclusions: GA in tears was the first measured diabetes-related biomarker. GA levels in tears were strongly correlated with those in blood, considering various factors. As GA value is a ratio, GA levels in tears were not thought to be influenced by dilution or concentration of tears and showed strong correlation with those in blood. From the above, GA in tears could be a diabetes-related biomarker that can be measured noninvasively. In the future, we plan to optimize measurement conditions, develop measurement equipment and verify the effectiveness and usefulness of this diabetes monitoring method. Disclosure: M. Aihara: None. N. Kubota: None. T. Kadowaki: Research Support; Self; Astellas Pharma Inc., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, MSD Corporation, Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Abbott, Astellas Pharma Inc., AstraZeneca K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Cosmic Corporation, Daiichi Sankyo, Eli Lilly Japan K.K., FUJIFILM, Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Medscape Education, Medtronic, Mitsubishi Tanabe Pharma Corporation, MSD Corporation, NIPRO Medical Corporation, Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Asahi Mutual Life Insurance. [ABSTRACT FROM AUTHOR]

Introduction: Hemoglobin A1c (HbA1c), representing the average blood glucose over 1–2 months, is the most commonly used glycemic marker in people with diabetes. Glycated albumin (GA) reflects the average blood glucose over the most recent 1–2 weeks. We considered whether the faster response of GA compared with HbA1c could make people with diabetes realize their glycemic control intuitively and effectively. Methods: We randomized 61 people with diabetes into the control and intervention groups. Blood samples were collected from both every fortnight over an 8-week period (five times; visit 1–5). Only the intervention group was notified of the GA levels on the same day. At the beginning and end of the study, International Physical Activity Questionnaire and Eating Behavior Questionnaire assessments, and body composition measurements were conducted. Results: The body weight change was significantly lower in the intervention group at visit 2 and visit 5. The percent body fat change was lower, while the percent skeletal muscle mass change at visit 5 was higher in the intervention group. Increasing GA trend was observed in the control group, but not in the intervention group. The fasting plasma glucose and HbA1c changes at visit 5 were similar in the two groups. Physical activity level change tended to be higher in the intervention group. The YN Eating Behavior Questionnaire score changes were similar in the two groups. Conclusion: Bi-weekly GA measurement over an 8-week period in people with type 2 diabetes induced behavioral changes. Development of this method is expected to improve diabetes management. Trial Registration: UMIN000037795. [ABSTRACT FROM AUTHOR]

Aim: To investigate the impact of the COVID‐19 pandemic and its preventive measures on the glycemic and lipid control in people with diabetes mellitus (DM). Materials and methods: We conducted this retrospective cohort study from April 2019 to March 2021; we termed the period from April 2019 to March 2020 as the pre‐COVID‐19 period, and the period from April 2020 to March 2021 as the COVID‐19 period, and divided each of these two periods into four quarters. Results: In the 1st quarter of the COVID period, when the Japanese government declared the first public health emergency, 3,465 people with diabetes mellitus were receiving treatment, which was 10.4% lower than that in the pre‐COVID period. The annual mean HbA1c level was significantly elevated in the COVID‐19 period. The annual mean total cholesterol (TC) and triglyceride (TG) levels were also significantly higher in the COVID‐19 period. Although there were no significant differences in the glycemic control or annual medication between the two periods in people with type 1 diabetes mellitus, the annual mean HbA1c, TC, and TG levels were significantly higher in the COVID‐19 period in people with type 2 diabetes mellitus. Furthermore, a significant increase in the percentage of prescriptions for glinides, biguanides, sodium‐glucose cotransporter 2 inhibitors, and glucagon‐like peptide‐1 receptor agonists for people with type 2 diabetes mellitus was observed in the COVID period. Conclusions: It appears from our study that COVID‐19 and its preventive measures had a negative impact on the glycemic and lipid control in people with diabetes mellitus. [ABSTRACT FROM AUTHOR]

The effect of insulin action on vascular tissues have been proposed to be related to glucose homeostasis, control of blood pressure and blood flow, and development of vascular complications. We have previously reported that insulin receptor substrate (IRS)-2 deficient mice showed insulin resistance not only in liver but in skeletal muscle, type 2 diabetes, hypertension and endothelial dysfunction. We also reported that IRS-2 was more abundantly expressed than IRS-1 in mouse vessel tissue. In this study we generated endothelial-cell specific IRS-2 deficient (ET-IRS-2) mice to investigate the physiological role of IRS-2 in vasculature. Expression levels of IRS-2 mRNA and protein in, endothelial ceils were reduced by approximately 95% in ET-IRS-2 mice. ET-IRS-2 mice were born according to Mendelian frequency, were fertile, and showed no defects in growth or any gross morphological or functional abnormality. Endothelial-dependent vascular relaxation was almost normal in response to acetylcholine, but it was significantly impaired in response to insulin and IGF-1 in ET-IRS-2 mice. Mild hypertension was also observed in these mice. Interestingly, ET-IRS-2 mice showed insulin resistance and impaired glucose tolerance. In hyperinsulinemic-euglycemic clamp, glucose infusion rate (GIR) and rote of glucose disappearance (Rd) were significantly lower in ET-IRS-2 mice than wild-type mice, whereas endogenous glucose production (EGP) did not differ between ET-IRS-2 and wild-type mice. These data indicate that ET-IRS-2 mice showed insulin resistance in skeletal muscle. ET-IRS-2 mice also showed impaired insulin-induced Akt activation and decreased blood flow, and impairment in insulin transport from capillary to interstitium in skeletal muscle. In isolated skeletal, however, insulin-stimulated glucose uptake muscle did not differ between ET-IRS-2 and wild-type mice. Taken together, endothelial dysfunction caused by impaired insulin signaling in endothelial cells decreased blood flow and thereby impairing glucose uptake in skeletal muscle. [ABSTRACT FROM AUTHOR]

Aims/Introduction: To evaluate the impact of the COVID‐19 pandemic on the glycemic control, eating habits, and body composition of people with diabetes mellitus; to identify the determinants of worsening glycemic control in people with diabetes mellitus. Materials and methods: This retrospective, longitudinal observational study was performed in outpatients with diabetes mellitus who visited our hospital between April 2019 and March 2020 (pre‐COVID‐19 period) and continued for follow up from April 2020 to March 2021 (COVID‐19 period). We compared the glycemic control, nutritional intakes, and body composition of people with diabetes mellitus between the two periods. The changes in the HbA1c values (ΔHbA1c) and other study variables were compared between the two periods. Logistic regression analysis was performed to identify the factors associated with the increase of HbA1c levels. Results: A significant increase of HbA1c was observed during the COVID‐19 period. The percent fat mass (FM) also increased, while the percent skeletal muscle mass (SMM) decreased during the COVID‐19 period. After adjustments for age and sex, the ΔBMI (OR:2.33), ΔFM (OR:1.45), and ΔSMM (OR:0.51) were identified as being associated with elevated levels of HbA1c. Conclusions: The COVID‐19 pandemic had a negative impact on the glycemic control and body composition of people with diabetes mellitus. The increased body weight and FM and decreased SMM observed during the pandemic were associated with poor glycemic control in people with diabetes mellitus. [ABSTRACT FROM AUTHOR]

The adipocyte-derived hormone adiponectin plays central roles as antidiabetic and antiatherogenic adipokine. AdipoR1 and R2 have been shown to serve as receptors for adiponectin in vitro, and their reduction in obesity appeared to be correlated with reduced adiponectin sensitivity. Here we show that adenovirus-mediated expression of AdipoR1 in liver of db/db mice increased adiponectin effects, such as increased AMPK activation, decreases in gluconeogenic enzymes and endogenous glucose production (EGP), and that of AdipoR2 activated PPARalpha pathways, including stimulation of fatty-acid oxidation and inhibition of inflammation and oxidative stress, both ameliorating diabetes. Targeted disruption of AdipoR1 resulted in abrogation of adiponectin-induced AMPK activation and increased EGP, whereas targeted disruption of AdipoR2 resulted in decreased PPARalpha activation and decreased glucose uptake. Targeted disruption of both AdipoR1 and R2 abolished adiponectin binding and adiponectin actions, and resulted in increased tissue triglyceride content, inflammation and oxidative stress, leading to insulin resistance and marked glucose intolerance. In conclusion, AdipoR1 and R2 serve as major receptors for adiponectin in vivo, and they play crucial roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo. [ABSTRACT FROM AUTHOR]

Adiponectin is an adipokine that is specifically and abundantly expressed in adipose tissue: it activates AMP-activated protein kinase (AMPK) in peripheral tissues, mediating increased fatty acid combustion and increased insulin sensitivity. The central effects of adiponectin, such as on AMPK activity and food intake, however, are poorly understood. Two major adiponectin receptors, AdipoR1 and AdipoR2, were both found to be abundantly expressed in the in the arcuate hypothalamus (ARH). Adiponectin was detected in the cerebrospinal fluid (CSF) of C57B1/6 mice at approximately four thousandth its concentration in serum, and it also became detectable in the CSF of adiponectin deficient (adipo(-/-)) mice 3 hours after intravenous injection of full-length adiponectin (1 mg/kg) to raise their serum adiponectin levels approximately to the same level as in wild-type mice. Interestingly, unlike in serum, only trimer and hexamer, but not HMW multimer, were found in CSF of wild-type and adipo(-/-) mice after intravenous injection of full-length adiponectin. Adiponectin was found to stimulate AMPK activity in the ARH and to increase food intake via AdipoR1, and the increase in food intake was diminished by dominant-negative AMPK expression in the ARH. Moreover, adiponectin decreased energy consumption. Consistent with these findings, adipo(-/-) mice showed decreased AMPK phosphorylation and neuropeptide Y (NPY) expression in the ARH. They also showed decreased food intake and increased energy expenditure, thereby exhibiting resistance to high-fat HF diet-induced obesity. We also found that serum and CSF adiponectin levels and AdipoR1 expression in the ARH increased during fasting and decreased after refeeding, suggesting that adiponectin acts mainly under fasting conditions. Moreover, the reduction in visceral and subcutaneous fat mass as a result of the 12-hour fast was greater in adipo(-/-) mice. Based on these results, we propose that adiponectin serves as a starvation hormone which facilitates fat storage in white adipose tissue efficiently under fasting conditions. Taken together, these findings indicate a novel physiological role of adiponectin in the regulation of food intake via regulation of AMPK activity in the ARH. [ABSTRACT FROM AUTHOR]

DNA methylation of both viral and host DNA is one of the major mechanisms involved in the development of Epstein–Barr virus-associated gastric carcinoma (EBVaGC); thus, epigenetic treatment using demethylating agents would seem to be promising. We have verified the effect of MC180295, which was discovered by screening for demethylating agents. MC180295 inhibited cell growth of the EBVaGC cell lines YCCEL1 and SNU719 in a dose-dependent manner. In a cell cycle analysis, growth arrest and apoptosis were observed in both YCCEL1 and SNU719 cells treated with MC180295. MKN28 cells infected with EBV were sensitive to MC180295 and showed more significant inhibition of cell growth compared to controls without EBV infection. Serial analysis of gene expression analysis showed the expression of genes belonging to the role of BRCA1 in DNA damage response and cell cycle control chromosomal replication to be significantly reduced after MC180295 treatment. We confirmed with quantitative PCR that the expression levels of BRCA2, FANCM, RAD51, TOP2A, and CDC45 were significantly decreased by MC180295. LMP1 and BZLF1 are EBV genes with expression that is epigenetically regulated, and MC180295 could up-regulate their expression. In conclusion, MC180295 inhibited the growth of EBVaGC cells by suppressing DNA repair and the cell cycle. [ABSTRACT FROM AUTHOR]

Epidemiological and animal studies have revealed that sodium‐glucose cotransporter 2 (SGLT2) inhibitors suppress cardiovascular events in subjects with type 2 diabetes and atherosclerosis in animal models of diabetes. However, it still remains unclear if the anti‐atherosclerotic effect of SGLT2 inhibitors is entirely dependent on their glucose‐lowering effect. Tofogliflozin, a highly specific SGLT2 inhibitor, was administrated to apolipoprotein‐E‐deficient (ApoEKO) with streptozotocin (STZ)‐induced diabetes and nondiabetic ApoEKO mice. After 6 weeks, samples were collected to investigate the histological changes and peritoneal macrophage inflammatory cytokine levels. Tofogliflozin suppressed atherosclerosis in the diabetic ApoEKO mice. The atherosclerosis lesion areas and accumulation of macrophages in these areas were reduced by tofogliflozin treatment. The expression levels of interleukin (IL)‐1β and IL‐6 in the peritoneal macrophages were significantly suppressed in the tofogliflozin‐treated diabetic ApoEKO mice. Tofogliflozin treatment failed to inhibit atherosclerosis in the nondiabetic ApoEKO mice. No significant difference in the anti‐atherosclerotic effects of insulin and tofogliflozin was observed between diabetic ApoEKO mice with equivalent degrees of glycemic control achieved with the two treatments. Insulin treatment significantly reduced the IL‐1β and IL‐6 expression levels in the peritoneal macrophages of the diabetic ApoEKO mice. Significant decrease of the LPS‐stimulated IL‐1β concentrations was also observed in the conditioned medium of the peritoneal macrophages collected from insulin‐ and tofogliflozin‐treated diabetic ApoEKO mice. These results suggest that tofogliflozin suppresses atherosclerosis by improving glucose intolerance associated with inhibition of inflammation. Tofogliflozin suppresses atherosclerosis in ApoEKO mice with STZ‐induced diabetes via its glucose‐lowering effect. [ABSTRACT FROM AUTHOR]

Effective tumor immunotherapy requires physical contact of T cells with cancer cells. However, tumors often constitute a specialized microenvironment that excludes T cells from the vicinity of cancer cells, and its underlying mechanisms are still poorly understood. DOCK2 is a Rac activator critical for migration and activation of lymphocytes. We herein show that cancer-derived cholesterol sulfate (CS), a lipid product of the sulfotransferase SULT2B1b, acts as a DOCK2 inhibitor and prevents tumor infiltration by effector T cells. Using clinical samples, we found that CS was abundantly produced in certain types of human cancers such as colon cancers. Functionally, CS-producing cancer cells exhibited resistance to cancer-specific T-cell transfer and immune checkpoint blockade. Although SULT2B1b is known to sulfate oxysterols and inactivate their tumor-promoting activity, the expression levels of cholesterol hydroxylases, which mediate oxysterol production, are low in SULT2B1b-expressing cancers. Therefore, SULT2B1b inhibition could be a therapeutic strategy to disrupt tumor immune evasion in oxysterol-non-producing cancers. Thus, our findings define a previously unknown mechanism for tumor immune evasion and provide a novel insight into the development of effective immunotherapies. [ABSTRACT FROM AUTHOR]

Background and Aim: Low levels of serum adiponectin have been reported to be associated with obesity, diabetes, and non-alcoholic steatohepatitis (NASH), as well as several malignancies. Adiponectin knockout (KO) mice have been reported to cause insulin resistance and neointimal formation of the artery. We used adiponectin KO mice fed a high fat (HF) diet, and investigated the effect of adiponectin on the progression of steatohepatitis and carcinogenesis in vivo. Methods: Adiponectin KO mice and wild type (WT) mice were fed a HF diet or normal chow for the periods of 24 and 48 weeks. The HF diet contained 60% of calories from fat. Results: The adiponectin KO mice on the HF diet showed obesity, marked elevation of serum transaminase levels, and hyperlipidemia. At 24 weeks, hepatic expression of tumor necrosis factor-α and procollagen α (I) was higher in KO mice as compared with WT mice. At 48 weeks, liver triglyceride contents in KO mice on normal chow were significantly higher than those in WT mice. Hepatocyte ballooning, spotty necrosis, and pericellular fibrosis around central veins were observed in KO mice on the HF diet. The pericellular fibrosis was more severe in KO mice on the HF diet than that in WT mice (1.62% vs 1.16%, P = 0.033). Liver adenoma and hyperplastic nodules developed in a KO mouse on the HF diet at 48 weeks (12.5%, n = 1/8), whereas no tumor was detected in WT mice ( n = 10). Conclusions: Adiponectin may play a protective role in the progression of NASH in the early stages by suppressing tumor necrosis factor-α expression and liver fibrosis. [ABSTRACT FROM AUTHOR]

The accumulation of photo-sensitizer Talaporfin (another name is NPe6) in cancer cells after incubating in NPe6 solution has been investigated. It was confirmed that Talaporfin can only kill cancer cells selectively by photo-irradiation at certain wavelengths. In this experiment, the WFB (rat fetus fibroblast) and W31 (the malignant transformed cell from WFB) were used as normal and cancer cell. The measurement of the optical absorbance of Talaporfin within the cell confirmed that the Talaporfin was accumulated in cancer cells more than in normal cells. Fluorescence image of cancer cell after incubating in Talaporfin solution was measured with a fluorescence microspectrometer. For comparison the standard white light image of cancer cell was also taken. A semiconductor laser was used as PDT (photodynamic therapy) optical source to compare the photocytotoxicity effect of the W31 and WFB cell. The viability of the cells was assessed by use Trypan Blue Stain. It was clarified that Talaporfin could be accumulated in cancer cells more than in normal cells and lead to cancer cell death selectively after irradiation. [ABSTRACT FROM AUTHOR]

Phosphoinositide 3-kinase (P13K) p85cs-deficient mice exhibit hypoglycemia as a result of increased insulin sensitivity and glucose uptake in peripheral tissues. Although P13K is central to the metabolic actions of insulin, its mechanism of action in liver is not well understood. In the present study, we investigated hepatic insulin signaling and glucose ho- meostasis in p85α-deficient and wild-type mice. In the livers of p85α-deficient mice, p50α played a compensatory role in insulin- stimulated P13K activation by binding to insulin receptor substrate (IRS)-1/2. In p85α-deficient mice, the ratio of p50α over p110 catalytic subunit of P13K in the liver was higher than in the muscles. P13K activity associated with IRS-½ was not affected by the lack of p85α in the liver. Insulin-stimulated Akt and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) activities in the liver were similar in p85α-deficient and wild-type mice. A hyperinsulinemic-euglycemic clamp study revealed that the glucose infusion rate and the rate of disappearance were higher in p85α-deficient mice than in wild-type mice but that endogenous glucose production tended to be higher in p85α-deficient mice than in wild-type mice. Consistent with this finding, the expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in livers after fasting was higher in p85α-deficient mice than in wild-type mice. After mice were fasted, the intrahepatic glucose-6-phosphate level was almost completely depleted in p85α-deficient mice. The glycogen content fell to nearly zero as a result of glycogenolysis shortly after the initiation of fasting in p85α-deficient mice. The absence of an increase in insulin-stimulated P13K activation in the liver of p85α-deficient mice, unlike the muscles, may be associated with the molecular balance between the regulatory subunit and the catalytic subunit of P13K. Gluconeogenesis was rather elevated in p85α-deficient mice, compared with in wild- type mice, and the liver seemed to partially compensate for the increase in glucose uptake in peripheral tissues. [ABSTRACT FROM AUTHOR]

Abstract: Adiponectin is an abundantly expressed adipokine in adipose tissue and has direct insulin sensitizing activity. A decrease in the circulating levels of adiponectin by interactions between genetic factors and environmental factors causing obesity has been shown to contribute to the development of insulin resistance, type 2 diabetes, metabolic syndrome and atherosclerosis. In addition to its insulin sensitizing actions, adiponectin has central actions in the regulation of energy homeostasis. Adiponectin enhances AMP-activated protein kinase activity in the arcuate hypothalamus via its receptor AdipoR1 to stimulate food intake and decreases energy expenditure. We propose a hypothesis on the physiological role of adiponectin: a starvation gene in the course of evolution by promoting fat storage on facing the loss of adiposity. [Copyright &y& Elsevier]

Glucokinase (Gck) functions as a glucose sensor for insulin secretion, and in mice fed standard chow, haploinsufficiency of β cell-specific Gck (Gck+/-) causes impaired insulin secretion to glucose, although the animals have a normal β cell mass. When fed a high-fat (HF) diet, wild-type mice showed marked β cell hyperplasia, whereas Gck+/- mice demonstrated decreased β cell replication and insufficient β cell hyperplasia despite showing a similar degree of insulin resistance. DNA chip analysis revealed decreased insulin receptor substrate 2 (Irs2) expression in HF diet-fed Gck+/- mouse islets compared with wild-type islets. Western blot analyses confirmed upregulated Irs2 expression in the islets of HF diet-fed wild-type mice compared with those fed standard chow and reduced expression in HF diet-fed Gck+/- mice compared with those of HF diet-fed wild-type mice. HF diet-fed Irs2+/- mice failed to show a sufficient increase in β cell mass, and overexpression of Irs2 in β cells of HF diet-fed Gck+/- mice partially prevented diabetes by increasing β cell mass. These results suggest that Gck and Irs2 are critical requirements for β cell hyperplasia to occur in response to HF diet-induced insulin resistance. [ABSTRACT FROM AUTHOR]

Adiponectin is an adipokine that is specifically and abundantly expressed in adipose tissue and directly sensitizes the body to insulin. Hypoadiponectinemia, caused by interactions of genetic factors such as SNPs in the Adiponectin gene and environmental factors causing obesity, appears to play an important causal role in insulin resistance, type 2 diabetes, and the metabolic syndrome, which are linked to obesity. The adiponectin receptors, AdipoR1 and AdipoR2, which mediate the antidiabetic metabolic actions of adiponectin, have been cloned and are downregulated in obesity-linked insulin resistance. Upregulation of adiponectin is a partial cause of the insulin-sensitizing and antidiabetic actions of thiazolidinediones. Therefore, adiponectin and adiponectin receptors represent potential versatile therapeutic targets to combat obesity-linked diseases characterized by insulin resistance. This Review describes the pathophysiology of adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. [ABSTRACT FROM AUTHOR]

Heterozygous peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-deficient (PPARgamma(+/-)) mice were protected from high-fat diet-induced insulin resistance. To determine the impact of systemic reduction of PPAR-gamma activity on beta-cell function, we investigated insulin secretion in PPARgamma(+/-) mice on a high-fat diet. Glucose-induced insulin secretion in PPARgamma(+/-) mice was impaired in vitro. The tissue triglyceride (TG) content of the white adipose tissue, skeletal muscle, and liver was decreased in PPARgamma(+/-) mice, but it was unexpectedly increased in the islets, and the increased TG content in the islets was associated with decreased glucose oxidation. Administration of a PPAR-gamma agonist, pioglitazone, reduced the islet TG content in PPARgamma(+/-) mice on a high-fat diet and ameliorated the impaired insulin secretion in vitro. Our results demonstrate that PPAR-gamma protects islets from lipotoxicity by regulating TG partitioning among tissues and that a PPAR-gamma agonist can restore impaired insulin secretion under conditions of islet fat accumulation. [ABSTRACT FROM AUTHOR]

Reduced glucose uptake into the skeletal muscle is an important pathophysiological abnormality in type 2 diabetes, and is caused by impaired translocation of glucose transporter 4 (GLUT4) to the skeletal muscle cell surface. Here, we show a xanthene derivative, DS20060511, induces GLUT4 translocation to the skeletal muscle cell surface, thereby stimulating glucose uptake into the tissue. DS20060511 induced GLUT4 translocation and stimulated glucose uptake into differentiated L6-myotubes and into the skeletal muscles in mice. These effects were completely abolished in GLUT4 knockout mice. Induction of GLUT4 translocation by DS20060511 was independent of the insulin signaling pathways including IRS1-Akt-AS160 phosphorylation and IRS1-Rac1-actin polymerization, eNOS pathway, and AMPK pathway. Acute and chronic DS20060511 treatment attenuated the glucose intolerance in obese diabetic mice. Taken together, DS20060511 acts as a skeletal muscle-specific GLUT4 translocation enhancer to facilitate glucose uptake. Further studies of DS20060511 may pave the way for the development of novel antidiabetic medicines. Furuzono et al. identify DS20060511, a skeletal muscle cell-specific GLUT4 translocation enhancer. They find that DS20060511 have remarkable effects on lowering blood glucose and enhancing skeletal muscle glucose uptake via GLUT4, highlighting its potential as antidiabetic medicine. [ABSTRACT FROM AUTHOR]

Insulin receptor substrate-1 (Irs1) is one of the major substrates for insulin receptor and insulin-like growth factor-1 (IGF-1) receptor tyrosine kinases. Systemic Irs1-deficient mice show growth retardation, with resistance to insulin and IGF-1, although the underlying mechanisms remain poorly understood. For this study, we generated mice with brain-specific deletion of Irs1 (NIrs1KO mice). The NIrs1KO mice exhibited lower body weights, shorter bodies and bone lengths, and decreased bone density. Moreover, the NIrs1KO mice exhibited increased insulin sensitivity and glucose utilization in the skeletal muscle. Although the ability of the pituitary to secrete growth hormone (GH) remained intact, the amount of hypothalamic growth hormone-releasing hormone (GHRH) was significantly decreased and, accordingly, the pituitary GH mRNA expression levels were impaired in these mice. Plasma GH and IGF-1 levels were also lower in the NIrs1KO mice. The expression levels of GHRH protein in the median eminence, where Irs1 antibody staining is observed, were markedly decreased in the NIrs1KO mice. In vitro, neurite elongation after IGF-1 stimulation was significantly impaired by Irs1 downregulation in the cultured N-38 hypothalamic neurons. In conclusion, brain Irs1 plays important roles in the regulation of neurite outgrowth of GHRH neurons, somatic growth, and glucose homeostasis. [ABSTRACT FROM AUTHOR]

It has been well demonstrated that insulin resistance plays an important role in the clustering of coronary risk factors through the progression of atherosclerosis in animal models of insulin resistance. In humans, a high-fat diet is the major cause of obesity and insulin resistance. In this study, we investigated the role of peroxisome proliferator-activated receptor γ (PPARγ) in high-fat diet induced-obesity and insulin resistance by gene targeting and case-control study using the common PPARγ2 polymorphism in human subjects. Homozygous PPARγ-deficient embryos died at 10.5–11.5 dpc due to placental dysfunction. Heterozygous PPARγ-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet and the phenotypes were abrogated by PPARγ agonist treatment. Heterozygous PPARγ-deficient mice showed overexpression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. This study reveals a hitherto unpredicted role for PPARγ in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPARγ. A Pro12Ala polymorphism has been detected in the human PPARγ2 gene. Since this amino acid substitution may cause a reduction in the transcriptional activity of PPARγ, this polymorphism may be associated with decreased insulin resistance and decreased risk of Type 2 diabetes. To investigate this hypothesis, we performed a case-control study of the Pro12Ala PPARγ2 polymorphism. In an obese group, subjects with Ala12 were more insulin sensitive than those without. The frequency of Ala12 was significantly lower in the diabetic group, suggesting that this polymorphism protects against Type 2 diabetes. These results revealed that both in mice and humans, PPARγ is a thrifty gene mediating Type 2 diabetes. [Copyright &y& Elsevier]

Background: Colibactin-producing Escherichia coli containing polyketide synthase (pks+E. coli) has been shown to be involved in colorectal cancer (CRC) development through gut microbiota analysis in animal models. Stool status has been associated with potentially adverse gut microbiome profiles from fecal analysis in adults. We examined the association between stool patterns and the prevalence of pks+E. coli isolated from microbiota in fecal samples of 224 healthy Japanese individuals. Results: Stool patterns were determined through factorial analysis using a previously validated questionnaire that included stool frequency, volume, color, shape, and odor. Factor scores were classified into tertiles. The prevalence of pks+E. coli was determined by using specific primers for pks+E. coli in fecal samples. Plasma and fecal fatty acids were measured via gas chromatography-mass spectrometry. The prevalence of pks+E. coli was 26.8%. Three stool patterns identified by factorial analysis accounted for 70.1% of all patterns seen (factor 1: lower frequency, darker color, and harder shape; factor 2: higher volume and softer shape; and factor 3: darker color and stronger odor). Multivariable-adjusted odds ratios (95% confidence intervals) of the prevalence of pks+E. coli for the highest versus the lowest third of the factor 1 score was 3.16 (1.38 to 7.24; P for trend = 0.006). This stool pattern exhibited a significant positive correlation with fecal isobutyrate, isovalerate, valerate, and hexanoate but showed a significant negative correlation with plasma eicosenoic acid and α-linoleic acid, as well as fecal propionate and succinate. No other stool patterns were significant. Conclusions: These results suggest that stool patterns may be useful in the evaluation of the presence of tumorigenic bacteria and fecal fatty acids through self-monitoring of stool status without the requirement for specialist technology or skill. Furthermore, it may provide valuable insight about effective strategies for the early discovery of CRC. [ABSTRACT FROM AUTHOR]

Background: Although type 2 diabetes mellitus (T2DM) is a known risk factor for hepatocellular carcinoma (HCC) development, the annual incidence in diabetes patients is far below the threshold of efficient surveillance. This study aimed to elucidate the risk factors for HCC in diabetic patients and to determine the best criteria to identify surveillance candidates. Methods: The study included 239 patients with T2DM who were diagnosed with non-viral HCC between 2010 and 2015, with ≥ 5 years of follow-up at diabetes clinics of 81 teaching hospitals in Japan before HCC diagnosis, and 3277 non-HCC T2DM patients from a prospective cohort study, as controls. Clinical data at the time of and 5 years before HCC diagnosis were collected. Results: The mean patient age at HCC diagnosis was approximately 73 years, and 80% of the patients were male. The proportion of patients with insulin use increased, whereas the body mass index (BMI), proportion of patients with fatty liver, fasting glucose levels, and hemoglobin A1c (HbA1c) levels decreased significantly in 5 years. In the cohort study, 18 patients developed HCC during the mean follow-up period of 4.7 years with an annual incidence of 0.11%. Multivariate logistic regression analyses showed that the FIB-4 index was an outstanding predictor of HCC development along with male sex, presence of hypertension, lower HbA1c and albumin levels, and higher BMI and gamma-glutamyl transpeptidase levels. Receiver-operating characteristic analyses showed that a FIB-4 cut-off value of 3.61 could help identify high-risk patients, with a corresponding annual HCC incidence rate of 1.1%. Conclusion: A simple calculation of the FIB-4 index in diabetes clinics can be the first step toward surveillance of HCC with a non-viral etiology. [ABSTRACT FROM AUTHOR]

Objective: Refeeding hypophosphatemia (RH) is a potentially fatal complication in patients with anorexia nervosa (AN), and its dietary preventive strategy is not well established. We aimed to examine the association between carbohydrate content in the diet and the occurrence of RH in inpatients with AN via retrospective medical chart review. Method: We performed a chart review to collect data of patients with AN hospitalized at the Department of Psychosomatic Medicine of the University of Tokyo Hospital between April 1, 2012, and February 29, 2020. Receiver operating characteristic (ROC) analysis was performed to determine the cutoff point of the percentage of carbohydrate content in the diet for the occurrence of RH. Multivariate logistic regression analysis was performed with occurrence of RH as the dependent variable and the carbohydrate content of more than the identified cutoff point as the independent variable adjusting for the risk factors for RH. Results: The percentage of carbohydrate content that is higher than the cutoff point obtained from the ROC analysis (58.4%) was significantly associated with the occurrence of RH, even after adjusting for variables associated with RH in univariate logistic regression analysis (age and body mass index) as well as the average daily calorie intake (odds ratio, 5.37; 95% confidence interval, 1.60–18.1; p =.0066). Discussion We identified that diets with higher carbohydrate contents were associated with RH in inpatients with AN, even after adjusting for known risk factors. Our findings may promote the development of dietary preventive strategies against RH in inpatients with AN. [ABSTRACT FROM AUTHOR]