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Metabolism in each organ of multi-organ organisms, including humans, is regulated in a coordinated manner to dynamically maintain whole-body homeostasis. Metabolic information exchange among organs/tissues, i.e., inter-organ communication, which is necessary for this purpose, has been a subject of ongoing research. In particular, it has become clear that metabolism of energy, glucose, lipids, and amino acids is dynamically regulated at the whole-body level mediated by the nervous system, including afferent, central, and efferent nerves. These findings imply that the central nervous system obtains metabolic information from peripheral organs at all times and sends signals selectively to peripheral organs/tissues to maintain metabolic homeostasis, and that the liver plays an important role in sensing and transmitting information on the metabolic status of the body. Furthermore, the utilization of these endogenous mechanisms is expected to lead to the development of novel preventive/curative therapies for metabolic diseases such as diabetes and obesity.(This is a summarized version of the subject matter presented at Symposium 7 presented at the 43rd Annual Meeting of the Japanese Society of Inflammation and Regeneration.).

The liver possesses a high regenerative capacity. Liver regeneration is a compensatory response overcoming disturbances of whole-body homeostasis provoked by organ defects. Here we show that a vagus-macrophage-hepatocyte link regulates acute liver regeneration after liver injury and that this system is critical for promoting survival. Hepatic Foxm1 is rapidly upregulated after partial hepatectomy (PHx). Hepatic branch vagotomy (HV) suppresses this upregulation and hepatocyte proliferation, thereby increasing mortality. In addition, hepatic FoxM1 supplementation in vagotomized mice reverses the suppression of liver regeneration and blocks the increase in post-PHx mortality. Hepatic macrophage depletion suppresses both post-PHx Foxm1 upregulation and remnant liver regeneration, and increases mortality. Hepatic Il-6 rises rapidly after PHx and this is suppressed by HV, muscarinic blockade or resident macrophage depletion. Furthermore, IL-6 neutralization suppresses post-PHx Foxm1 upregulation and remnant liver regeneration. Collectively, vagal signal-mediated IL-6 production in hepatic macrophages upregulates hepatocyte FoxM1, leading to liver regeneration and assures survival. The mechanisms underlying the regenerative capacity of the liver are not fully understood. Here, the authors show that the acute regenerative response to liver injury in mice is regulated by the communication involving the vagus nerve, macrophages, and hepatocytes, leading to hepatic FoxM1 activation and promotion of overall survival.

Recently, along with increasing use of immune checkpoint inhibitors such as nivolumab, the incidence of immune-related adverse events, including type 1 diabetes mellitus, has become a serious problem. We report a patient who had immune checkpoint inhibitor‒associated type 1 diabetes mellitus that developed after a second mRNA-based SARS-CoV-2 vaccination.

The liver synthesizes and releases bile acids into the gut. Bile acids, either directly or indirectly, inhibit agouti‐related peptide (AGRP)‐B cells in the pars tuberalis of the pituitary gland. AGRP‐B cells are assumed to promote pancreatic insulin secretion and/or to improve insulin sensitivities in insulin sensitive organs, resulting in improved glucose tolerance.

Corporate bankruptcy prediction has become increasingly critical amid economic uncertainty. This study proposes a novel two-stage machine learning approach to enhance bankruptcy prediction accuracy, applied to Tokyo Stock Exchange-listed companies. First, models were trained using 173 financial indicators. Second, a wrapper-based feature selection process was employed to reduce dimensionality and eliminate noise, thereby identifying an optimal seven-feature set. Two ensemble learning methods, Random Forest and Light Gradient Boosting Machine (LightGBM), were used. Random Forest correctly predicted 566 bankruptcies using the reduced feature set (88 more than when using all features) compared with 451 by LightGBM (31 more than when using all features). LightGBM is a gradient boosting–based ensemble learning method that employs a leaf-wise tree growth strategy, enabling fast computation and high predictive accuracy, especially in large-scale and high-dimensional datasets. The study also addresses challenges posed by imbalanced data by employing resampling techniques (SMOTE, SMOTE-ENN, and KMeans). Additionally, the need for industry-specific modeling is recognized by constructing models for the six industry sectors. These findings highlight the importance of feature selection and ensemble learning for improving model generalizability and uncovering industry-specific patterns. This study contributes to the field of bankruptcy prediction by providing a robust framework for accurate and interpretable predictions for both academic research and practical applications. Future work will focus on further enhancing prediction accuracy to identify more potential bankruptcies.

Background/objective:Insulin signals, via the regulation of key enzyme expression, both suppress gluconeogenesis and enhance lipid synthesis in the liver. Animal studies have revealed insulin signaling favoring gluconeogenesis suppression to be selectively impaired in steatotic livers. However, whether, and if so how, such selective insulin resistance occurs in human steatotic livers remains unknown. Our aim was to investigate selective insulin resistance in human livers with non-alcoholic fatty liver disease (NAFLD).Subjects/methods:We examined mRNA expressions of key molecules for insulin signaling, gluconeogenesis and lipogenesis in human liver biopsy samples obtained from 51 non-diabetic subjects: 9 healthy controls and 42 NAFLD patients, and analyzed associations of these molecules with each other and with detailed pathological and clinical biochemistry data.Results:In NAFLD patients, insulin receptor substrate (IRS)-2 expression was decreased, while those of key enzymes for gluconeogenesis were increased. These alterations of IRS-2 and gluconeogenesis enzymes were induced both in simple steatosis (SS) and non-alcoholic steatohepatitis (NASH), while these expression levels did not differ between SS and NASH. Furthermore, alterations in the expressions of IRS-2 and gluconeogenesis enzymes showed strong negative correlations and were concurrently induced in the early histological stage of NAFLD. In contrast, fatty acid synthase (FAS) expression was not decreased in NAFLD, despite IRS-2 downregulation, but correlated strongly with IRS-1 expression. Furthermore, no histological scores were associated with these molecules. Thus, IRS-1 signaling, which is not impaired in NAFLD, appears to modulate FAS expression.Conclusion:These analyses revealed that selective insulin resistance is present in human NAFLD livers and occurs in its early phases. The effect of insulin, during the IRS step, on gene expressions for lipogenesis and gluconeogenesis are apparently distinct and preferential downregulation of IRS-2 may contribute to selective resistance to the suppressive effects of insulin on gluconeogenesis.

Based on these results, the authors hypothesized that DUSP8-JNK signaling in the hypothalamus, including CRH-producing neurons, affects HPA axis reactivity involving the GR phosphorylation level, thereby modulating systemic glucose tolerance in male mice (Figure 1). [...]this line of research provides a novel insight into the role of the hypothalamus in systemic glucose metabolism. [...]it is not clear whether DUSP8 polymorphism affects its expression level and/or phosphatase activity. [...]why the effects of DUSP8 on insulin sensitivity in both humans and mice are present only in males remains to be elucidated. [...]although a meta-analysis showed that the association of DUSP8 single-nucleotide polymorphism re2334499 with type 2 diabetes was limited to males 2, a genome-wide association study, initially identifying DUSP8 as a type 2 diabetes risk gene, showed that the type 2 diabetes risk associated with re2334499 was inherited with the paternal allele 5. [...]details of the complexity of the association between type 2 diabetes susceptibility and DUSP8 polymorphism await future research.

Insulin like growth factor-1 (IGF-1) plays important roles in metabolic functions, especially in adulthood. Additionally, obese subjects are reportedly predisposed to having low absolute IGF-1 levels. However, the prevalence and clinical characteristics of obese subjects with low IGF-1 levels are unknown. We examined 64 obese subjects with a body mass index (BMI) ≥ 35 kg/m 2 , with no history of endocrinological disorders, receiving inpatient care. IGF-1 levels were interpreted based on the IGF-1 standard deviation score (SDS) clinically used and standardized by age and sex (low IGF-1 group; ≤ − 2.0 SDS and standard IGF-1 group; − 2.0 < and <  + 2.0 SDS). Notably, 26.6% of the subjects had low IGF-1. Body fat mass and percentage, but not BMI, were significantly higher in the low than in the standard IGF-1 group. Furthermore, natural log-transformed high-sensitivity C-reactive protein, and the frequencies of dyslipidemia and hyperuricemia were higher in the low IGF-1 group. Moreover, among the subjects without diabetes, fasting glucose levels were significantly higher in the low IGF-1 group. Stepwise variable selection procedure revealed body fat percentage to be a parameter most strongly associated with low IGF-1. Thus, low IGF-1 levels may be an important marker of adiposity-associated metabolic disorders in obese patients.

We experienced a case with insulin allergy which manifested soon after COVID‐19 vaccination.

The measurement evolution enabled more accurate evaluation of aldosterone production in hypertensive patients. However, the cut-off values for novel assays have been not sufficiently validated. The present study was undertaken to validate the novel chemiluminescent enzyme immunoassay for aldosterone in conjunction with other methods. Moreover, we also aimed to establish a new cut-off value for primary aldosteronism in the captopril challenge test using the novel assay. First, we collected 390 plasma samples, in which aldosterone levels measured using liquid chromatography-mass spectrometry ranged between 0.18 and 1346 ng/dL. The novel chemiluminescent enzyme immunoassay showed identical correlation of plasma aldosterone with liquid chromatography-mass spectrometry, in contrast to conventional radioimmunoassay. Further, we enrolled 299 and 39 patients with primary aldosteronism and essential hypertension, respectively. Plasma aldosterone concentrations measured using the novel assay were lower than those measured by radioimmunoassay, which resulted in decreased aldosterone-to-renin ratios. Subsequently, positive results of the captopril challenge test based on radioimmunoassay turned into “negative” based on the novel assay in 45% patients with primary aldosteronism, using the conventional cut-off value (aldosterone-to-renin activity ratio > 20 ng/dL per ng/mL/h). Receiver operating characteristic curve analysis demonstrated that aldosterone-to-renin activity ratios > 8.2 ng/dL per ng/mL/h in the novel assay was compatible with the conventional diagnosis (sensitivity, 0.874; specificity, 0.980). Our study indicates the great measurement accuracy of the novel chemiluminescent enzyme immunoassay for aldosterone, and the importance of measurement-adjusted cut-offs in the diagnosis of primary aldosteronism.