Soluble T-cadherin secretion from endothelial cells is regulated via insulin/PI3K/Akt signalling.

AIM AND OBJECTIVE: Our recent report showed that soluble T-cadherin promotes pancreatic beta-cell proliferation. However, how and where the secretion of soluble T-cadherin is regulated remain unclear. METHODS AND RESULTS: Soluble T-cadherin levels significantly increased in leptin receptor-deficient db/db mice with hypoinsulinaemia or in wild-type mice treated with insulin receptor blockade by S961. Similar results were observed in human subjects; Diabetic ketoacidosis patients at the time of hospitalization had increased plasma soluble T-cadherin levels, which decreased after insulin infusion therapy. Patients with recurrent ovarian cancer who were administered a phosphatidylinositol-3 kinase (PI3K)-alpha inhibitor (a new anticancer drug) had increased plasma soluble T-cadherin and plasma C-peptide levels. Endothelial cell-specific T-cadherin knockout mice, but not skeletal muscle- or cardiac muscle-specific T-cadherin knockout mice, showed a 26 % reduction in plasma soluble T-cadherin levels and a significant increase in blood glucose levels in streptozocin-induced diabetes. The secretion of soluble T-cadherin from human endothelial cells was approximately 20 % decreased by insulin and this decrease was canceled by blockade of insulin receptor/Akt signalling, not Erk signalling. CONCLUSION: We conclude that insulin regulates soluble T-cadherin levels and soluble T-cadherin secretion from endothelial cells is positively regulated by insulin/insulin receptor/Akt signalling.

Association between COVID-19 severity and relatively high serum adiponectin levels at the time of admission.

At the beginning of 2020, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to epidemics worldwide. Obesity and visceral fat accumulation have been reported to be independent risk factors for severe COVID-19. Several reports have focused on the levels of adipocytokines/adipokines, including adiponectin (APN), which is exclusively secreted from adipocytes, although the importance of these factors in acute disease conditions remains unclear. Therefore, we investigated the relationship between serum adiponectin levels and COVID-19 severity. Patients with COVID-19 who were admitted to Sumitomo Hospital (Osaka, Japan) from May through October 2021 were included. A total of 107 patients were enrolled in this study. We obtained the anthropometric and clinical laboratory data of the patients at the time of admission and examined the associations between various parameters and COVID-19 severity. The mean period from onset to admission was 6.5 ± 2.8 days. We divided the patients into "non-severe" (mild, moderate-I and moderate-II) (n = 80) and "severe" (n = 27) groups. The "severe" patients were significantly older than "non-severe" patients. Additionally, no significant differences were observed in BMI, sex, or the period from onset to admission. The serum adiponectin levels of "severe" patients at the time of admission were significantly greater than those of "non-severe" patients even after adjusting for age, sex, and BMI. These results suggest that the serum APN levels at the time of admission can predict COVID-19 severity. However, further investigations on the changes in APN levels in acute diseases are needed.

Pharmacological HIF-1 activation upregulates extracellular vesicle production synergistically with adiponectin through transcriptional induction and protein stabilization of T-cadherin.

Pharmacological activation of hypoxia-inducible factor 1 (HIF-1), a hypoxia-responsive transcription factor, has attracted increasing attention due to its efficacy not only in renal anemia but also in various disease models. Our study demonstrated that a HIF-1 activator enhanced extracellular vesicle (EV) production from cultured endothelial cells synergistically with adiponectin, an adipocyte-derived factor, through both transcriptional induction and posttranscriptional stabilization of an adiponectin binding partner, T-cadherin. Increased EV levels were observed in wild-type mice but not in T-cadherin null mice after consecutive administration of roxadustat. Adiponectin- and T-cadherin-dependent increased EV production may be involved in the pleiotropic effects of HIF-1 activators.

Correlation between plasma glutamate and adiponectin in patients with type 2 diabetes.

Visceral fat accumulation is a major determinant of type 2 diabetes mellitus and cardiovascular diseases. Recent studies have reported that glutamate is the most elevated amino acid in the plasma amino acid profile in patients with obesity and/or visceral fat accumulation. Here, we show the relationship between plasma glutamate and the clinical features of patients with type 2 diabetes. The study subjects were 62 (28 men and 34 women) Japanese patients with type 2 diabetes. Blood profiles, including glutamate and adiponectin (APN) levels and estimated visceral fat area (eVFA), were measured. We also evaluated the plasma amino acid levels in mice with or without obesity by GC/MS analysis. In patients with type 2 diabetes, plasma glutamate was positively correlated with BMI, eVFA, and fasting insulin but negatively correlated with APN and duration of diabetes. Additionally, multiple regression analysis revealed that plasma glutamate was a significant determinant of APN. The plasma glutamate level was most significantly increased in obese mice compared to control mice, and it was negatively correlated with APN. These results suggest that the level of plasma glutamate could be a strong indicator of adipocyte dysfunction in patients with type 2 diabetes.

Feasibility pilot study of a Japanese teaching kitchen program.

Background: This pilot study examined the feasibility of a new lifestyle modification program involving a "Teaching Kitchen" in Japan. Our goal was to explore (1) feasibility of the program; (2) acceptability for class frequency (weekly vs. bi-weekly); and (3) changes in biometrics, dietary intakes, and lifestyle factors. Methods: A total of 24 employees with obesity in a Japanese company were recruited. Participants were randomly divided into two groups (weekly or bi-weekly group), each attending the program consisting of four two-hour classes (lectures on nutrition, exercise, mindfulness, and culinary instructions). Participants were observed for changes in dietary intakes, biometrics, and health related quality of life over the subsequent 3 months. We tested the between-group differences in changes using linear mixed-effect models. Results: The program completion rates were 83.3% in total (91.7% for weekly group and 75.0% for bi-weekly group). From baseline to post-intervention, significant decreases were observed in weight (p < 0.001), body mass index (p < 0.001), diastolic blood pressure (p = 0.03), body fat mass (p < 0.001), and dietary intakes in total fat (p = 0.03) and sodium (p = 0.008) among 17 participants who were available for measurements. Improvements in biometrics remained significant 1 month after the intervention (all p ≤ 0.03 in 14 participants). Participants' health related quality of life was significantly improved in bodily pain, general health, vitality, and mental component score (all p ≤ 0.047). Conclusions: The new Japanese Teaching Kitchen program is feasible with high program completion rates in Japanese office workers with obesity. While this was a small feasibility study, significant multiple improvements in dietary intakes, biometrics, and health related quality of life suggest that this line of inquiry warrants further exploration to address obesity and obesity-related diseases in Japan.

ER stress decreases exosome production through adiponectin/T-cadherin-dependent and -independent pathways.

Exosomes, extracellular vesicles (EVs) produced within cells, mediate both the disposal of intracellular waste and communication with distant cells, and they are involved in a variety of disease processes. Although disease modifications of exosome cargos have been well studied, it has been poorly investigated how disease processes, such as endoplasmic reticulum (ER) stress, affect EV production. We previously reported that adiponectin, an adipocyte-secreted salutary factor, increases systemic exosome levels through T-cadherin-mediated enhancement of exosome biogenesis. In the present study, we demonstrated that adiponectin/T-cadherin-dependent EV production was susceptible to ER stress and that low-dose tunicamycin significantly reduced EV production in the presence, but not in the absence, of adiponectin. Moreover, pharmacological or genetic activation of inositol-requiring enzyme 1α, a central regulator of ER stress, downregulated T-cadherin at the mRNA and protein levels as well as attenuated EV production. In addition, adiponectin/T-cadherin-independent EV production was attenuated under ER stress conditions. Repeated administration of tunicamycin to mice decreased circulating small EVs without decreasing tissue T-cadherin expression. Mechanistically, inositol-requiring enzyme 1α activation by silencing of the X-box binding protein 1 transcription factor upregulated the canonical interferon pathway and decreased EV production. The interferon pathway, when it was activated by polyinosinic-polycytidylic acid, also significantly attenuated EV production. Thus, we concluded that ER stress decreases exosome production through adiponectin/T-cadherin-dependent and -independent pathways.

Cardiovascular significance of adipose-derived adiponectin and liver-derived xanthine oxidoreductase in metabolic syndrome.

Visceral fat-based metabolic syndrome has a strong impact on atherosclerotic cardiovascular disease (CVD), clustering diabetes, dyslipidemia, hypertension, hyperuricemia, and non-alcoholic fatty liver disease (NAFLD). Adiponectin, a protein specifically secreted by adipocytes, circulates abundantly in the human bloodstream, but its concentration decreases under pathological conditions such as visceral fat accumulation. Extensive clinical evidence has demonstrated that hypoadiponectinemia is associated with the development of CVD and chronic organ diseases. Although several binding partners of adiponectin, such as AdipoR1/2, have been identified, how adiponectin exerts its multiple beneficial effects on various organs remains to be fully elucidated. Recent progress in adiponectin research has revealed that adiponectin accumulates on cardiovascular tissues by binding to a unique glycosylphosphatidylinositol-anchored T-cadherin. The adiponectin/T-cadherin complex enhances exosome biogenesis and secretion, which may contribute to the maintenance of cellular homeostasis and tissue regeneration, particularly in the vasculature. Xanthine oxidoreductase (XOR) is a rate-limiting enzyme that catabolizes hypoxanthine and xanthine to uric acid. XOR produces reactive oxygen species in the reaction process, suggesting that XOR is involved in the pathological mechanism underlying CVD progression. Recent findings from clinical and laboratory studies have shown strong positive correlations between plasma XOR activity and liver enzymes. Furthermore, especially in NAFLD conditions, excessive hepatic XOR leaked into the bloodstream accelerates purine catabolism in the circulation, using hypoxanthine secreted from vascular endothelial cells and adipocytes, which can promote vascular remodeling. In this review, we focused on the cardiovascular significance of adipose-derived adiponectin and liver-derived XOR in the development of CVD associated with metabolic syndrome.

Chronic hyperadiponectinemia induced by transgenic overexpression increases plasma exosomes without significantly improving glucose and lipid metabolism.

The fat-derived factor, adiponectin, is considered a salutary circulating factor. We recently demonstrated that native adiponectin binds T-cadherin and promotes intracellular biogenesis and secretion of the exosome. Exosomes play important roles in various aspects of homeostasis, including glucose and energy metabolism. However, it remains unclear whether and how the promotion of exosome production by adiponectin in vivo is beneficial for glucose and lipid metabolism. In the present study, overexpression of human adiponectin in mice resulted in an increased number of circulating exosomes, but it did not significantly improve glucose metabolism, change body weights, or change triglyceride clearance under a high-fat diet. Multiple small doses of streptozotocin increased blood glucose and decreased triglyceride clearance similarly in both wild-type and transgenic mice. Thus, these results indicated that human adiponectin overexpression in mice increases plasma exosomes but does not significantly influence glucose and lipid metabolism.

Laughter yoga as an enjoyable therapeutic approach for glycemic control in individuals with type 2 diabetes: A randomized controlled trial.

Background: Laughter has been reported to have various health benefits. However, data on the long-term effects of laughter interventions on diabetes are limited. This study aimed to investigate whether laughter yoga can improve glycemic control among individuals with type 2 diabetes. Methods: In a single-center, randomized controlled trial, 42 participants with type 2 diabetes were randomly assigned to either the intervention or the control group. The intervention consisted of a 12-week laughter yoga program. Hemoglobin A1c (HbA1c), body weight, waist circumference, psychological factors, and sleep duration were evaluated at baseline and week 12. Results: Intention-to-treat analysis showed that participants in the laughter yoga group experienced significant improvements in HbA1c levels (between-group difference: -0.31%; 95% CI -0.54, -0.09) and positive affect scores (between-group difference: 0.62 points; 95% CI 0.003, 1.23). Sleep duration tended to increase in the laughter yoga group with a between-group difference of 0.4 hours (95% CI -0.05, 0.86; P = 0.080). The mean attendance rate for laughter yoga program was high (92.9%). Conclusions: A 12-week laughter yoga program is feasible for individuals with type 2 diabetes and improves glycemic control. These findings suggest that having fun could be a self-care intervention. Further studies with larger numbers of participants are warranted to better evaluate the effects of laughter yoga. Clinical trial registration: http://www.chinadrugtrials.org.cn, identifier UMIN000047164.

Myocardial fat accumulation is associated with cardiac dysfunction in patients with type 2 diabetes, especially in elderly or female patients: a retrospective observational study.

BACKGROUND: Ectopic fat is fat that accumulates in or around specific organs or compartments of the body including myocardium. The clinical features of type 2 diabetes patients with high fat accumulation in the myocardium remain unknown. Moreover, little is known about the influence of myocardial fat accumulation in type 2 diabetes on coronary artery disease and cardiac dysfunction. We aimed to clarify the clinical features, including cardiac functions, of type 2 diabetes patients with myocardial fat accumulation. METHODS: We retrospectively enrolled type 2 diabetes patients who underwent ECG-gated coronary computed tomography angiography (CCTA) and abdominal computed tomography (CT) scan examinations within 1 year of CCTA from January 2000 to March 2021. High fat accumulation in the myocardium was defined as the low mean myocardial CT value of three regions of interest, and the associations between CT values and clinical characteristics or cardiac functions were assessed. RESULTS: In total, 124 patients were enrolled (72 males and 52 females). The mean age was 66.6 years, the mean BMI was 26.2 kg/m2, the mean ejection fraction (EF) was 67.6%, and the mean myocardial CT value was 47.7 Hounsfield unit. A significant positive correlation was found between myocardial CT value and EF (r = 0.3644, p = 0.0004). The multiple regression analyses also showed that myocardial CT value was independently associated with EF (estimate, 0.304; 95% confidence interval (CI) 0.092 to 0.517; p = 0.0056). Myocardial CT value showed significant negative correlations with BMI, visceral fat area and subcutaneous fat area (r = - 0.1923, - 0.2654, and -0.3569, respectively, p < 0.05). In patients who were ≥ 65 years or female, myocardial CT value showed significant positive correlations with not only EF (r = 0.3542 and 0.4085, respectively, p < 0.01) but also early lateral annular tissue Doppler velocity (Lat e') (r = 0.5148 and 0.5361, respectively, p < 0.05). The multiple regression analyses showed that myocardial CT value was independently associated with EF and Lat e' in these subgroups (p < 0.05). CONCLUSIONS: Patients with type 2 diabetes, especially in elderly or female patients, who had more myocardial fat had more severe left ventricular systolic and diastolic dysfunctions. Reducing myocardial fat accumulation may be a therapeutic target for type 2 diabetes patients.

Effect of a Community-Based Program to Accelerate Referral to Physicians for Individuals at High-Risk of Lifestyle-Related Diseases: A Cluster Randomized Trial.

AIM: A cluster randomized trial was conducted within 43 Japanese municipalities (21 intervention and 22 usual care) to examine whether the standardized health counseling for individuals at high cardiovascular risk screened at community sites accelerates clinic visits to strengthen the primary health care system. METHODS: Among high-risk individuals aged 40-74 years screened by health checkups, 8,977 and 6,733 were allocated to the intervention and usual care groups, respectively, who were not under medical treatment but had high levels of blood pressure (systolic/diastolic ≥ 160/100 mmHg), hemoglobin A1c or glucose (≥ 7.0% or corresponding glucose levels), LDL-cholesterol (≥ 180 mg/dL for men), and/or proteinuria of ≥ 2+. The intervention was performed from May 2014 to March 2016 under a standardized health counseling program based on the health belief model primarily by public health nurses. The usual care group was provided with local counseling protocols. RESULTS: The cumulative proportions of clinic visits for 12 months after health checkups were 58.1% (95% confidence interval, 57.0%, 59.3%) versus 44.5% (43.2%, 45.8%), with the probability ratio of clinic visits between the groups being 1.46 (1.24, 1.72). The between-group differences between the baseline and 1-year surveys were -1.50 (-2.59, -0.41) mmHg for diastolic blood pressure in the hypertension category, -0.30% (-0.53%, -0.07%) for HbA1c in the diabetes category, -0.37 (-0.48, -0.27) mmol/L for LDL-cholesterol in the dyslipidemia category, and none for proteinuria. CONCLUSION: Standardized health counseling for high-risk individuals accelerated clinic visits, with larger reductions in blood pressure, HbA1c, and LDL-cholesterol levels. The nationwide use of counseling after health checkups for high-risk individuals could help in controlling risk factors and in preventing lifestyle-related diseases.

The Effects of Topiroxostat, a Selective Xanthine Oxidoreductase Inhibitor, on Arterial Stiffness in Hyperuricemic Patients with Liver Dysfunction: A Sub-Analysis of the BEYOND-UA Study.

BACKGROUND: The effects of uric acid (UA)-lowering therapy with xanthine oxidoreductase (XOR) inhibitors on the development of cardiovascular diseases remain controversial. Based on recent findings that plasma XOR activity increased in liver disease conditions, we conducted a sub-analysis of the BEYOND-UA study to examine the differential effects of topiroxostat on arterial stiffness based on liver function in hyperuricemic individuals with hypertension. METHODS: Sixty-three subjects treated with topiroxostat were grouped according to baseline alanine aminotransferase (ALT) levels (above or below cut-off values of 22, 30, or 40 U/L). The primary endpoint was changes in the cardio-ankle vascular index (CAVI) from baseline to 24 weeks. RESULTS: Significant reductions in CAVI during topiroxostat therapy occurred in subjects with baseline ALT ≥30 U/L or ≥40 U/L, and significant between-group differences were detected. Brachial-ankle pulse wave velocity significantly decreased in the ALT-high groups at all cut-off values. Reductions in morning home blood pressure and serum UA were similar regardless of the baseline ALT level. For eleven subjects with available data, ALT-high groups showed high plasma XOR activity, which was significantly suppressed by topiroxostat. CONCLUSIONS: Topiroxostat improved arterial stiffness parameters in hyperuricemic patients with liver dysfunction, which might be related to its inhibitory effect on plasma XOR.

Changes in Eating Behaviors and Their Associations with Weight Loss in Japanese Patients Who Underwent Laparoscopic Sleeve Gastrectomy.

BACKGROUND: Metabolic and bariatric surgery (MBS) has been established to provide long-term weight loss in severe obesity. In this study, we investigated the factors that affect post-operative weight loss, with a particular focus on changes in eating behaviors. METHODS: Time-course changes in body weight and eating behaviors were examined in 49 Japanese patients who underwent laparoscopic sleeve gastrectomy from the first visit to 12 months after surgery. Each eating behavior was evaluated via the questionnaire of the Japan Society for the Study of Obesity. RESULTS: Pre-operative weight reduction mediated by dietary and lifestyle interventions showed significant positive correlations with weight loss outcomes at 12 months after surgery. We observed significant decreases in scores for most of the eating behaviors 12 months after surgery. However, "emotional eating behavior" scores declined temporarily in the early post-operative period of one month but thereafter returned to the pre-operative level at 12 months. Furthermore, increases in the scores for "emotional eating behavior" and "sense of hunger" from 1 to 12 months post-operatively were significantly associated with poor weight loss. CONCLUSIONS: Our results demonstrate the beneficial effects of MBS on obesity-related eating behaviors, as well as highlighting "emotional eating behavior" as requiring particular attention.

Change in fatty acid composition of plasma triglyceride caused by a 2 week comprehensive risk management for diabetes: A prospective observational study of type 2 diabetes patients with supercritical fluid chromatography/mass spectrometry-based semi-target lipidomic analysis.

AIMS/INTRODUCTION: Hypertriglyceridemia is common in patients with diabetes. Although the fatty acid (FA) composition of triglycerides (TGs) is suggested to be related to the pathology of diabetes and its complications, changes in the fatty acid composition caused by diabetes treatment remain unclear. This study aimed to identify short-term changes in the fatty acid composition of plasma triglycerides after diabetes treatment. MATERIALS AND METHODS: This study was a sub-analysis of a prospective observational study of patients with type 2 diabetes aged between 20 and 75 years who were hospitalized to improve glycemic control (n = 31). A lipidomic analysis of plasma samples on the 2nd and 16th hospital days was conducted by supercritical fluid chromatography coupled with mass spectrometry. RESULTS: In total, 104 types of triglycerides with different compositions were identified. Most of them tended to decrease after treatment. In particular, triglycerides with a lower carbon number and fewer double bonds showed a relatively larger reduction. The inclusion of FA 14:0 (myristic acid), as a constituent of triglyceride, was significantly associated with a more than 50%, and statistically significant, reduction (odds ratio 39.0; P < 0.001). The total amount of FA 14:0 as a constituent of triglycerides also decreased significantly, and its rate of decrease was the greatest of all the fatty acid constituents. CONCLUSIONS: A 2 week comprehensive risk management for diabetes resulted in decreased levels of plasma triglycerides and a change in the fatty acid composition of triglycerides, characterized by a relatively large reduction in FA 14:0 as a constituent of triglycerides.

Soluble T-cadherin promotes pancreatic ß-cell proliferation by upregulating Notch signaling.

Endogenous humoral factors that link systemic and/or local insulin demand to pancreatic ß-cells have not been identified. Here, we demonstrated that T-cadherin, a unique glycosylphosphatidylinositol-anchored cadherin primarily expressed in vascular endothelial cells and cardiac and skeletal muscle cells, but not in pancreatic ß-cells, was secreted as soluble forms and was important for ß-cell proliferation. Cdh13 (T-cadherin) knockout mice exhibited impaired glucose handling due to attenuated ß-cell proliferation under high-fat diet conditions. The gene expression analyses indicated the impairment in cell cycle and Notch signaling in the islets of T-cadherin knockout mice under high-fat diet conditions. In streptozotocin-induced diabetes, the replacement of soluble T-cadherin improved ß-cell mass and blood glucose levels in T-cadherin knockout mice. Recombinant soluble T-cadherin upregulated Notch signaling in cultured murine islets. We concluded that soluble T-cadherin could work as an endogenous humoral factor whose signaling pathways including Notch signaling regulate ß-cell proliferation under diabetic conditions in mice.

Relationship between Health Counselor Characteristics and Counseling Impact on Individuals at High-Risk for Lifestyle-Related Disease: Sub-Analysis of the J-HARP Cluster-Randomized Controlled Trial.

Early diagnosis and treatment are necessary to prevent lifestyle-related diseases among high-risk individuals. This study aimed to examine the impact of counselor characteristics on clinic visits among individuals at high risk for lifestyle-related diseases. A total of 8975 patients aged 40 to 74 years with lifestyle-related comorbidities, who underwent an annual health checkup and received health counseling, were included in this study. Data intervention timing, mode of counseling, number of counseling sessions, and explanation methods were collected. We assessed the impact of counselor characteristics, including profession (public health nurse, clinical nurse, and nutritionist), age, and years of counseling experience, on counseling outcomes. The probability ratios (95% confidence intervals) of clinic visits were 1.22 (1.11-1.35) for public health nurses and 1.04 (0.90-1.20) for nurses compared with nutritionists. After adjustment for participant and counselor characteristics and initial timing, mode, and number of counseling sessions, the corresponding probability ratios (95% confidence intervals) were 1.16 (1.05-1.29) and 1.12 (0.95-1.31), respectively. Counselor age and years of experience did not influence clinic visits of the target population. Public health nurses were more effective in increasing clinic visits among the target population owing to their profession-specific knowledge, skills, and experience.

Human adipose-derived mesenchymal stem cells prevent type 1 diabetes induced by immune checkpoint blockade.

AIMS/HYPOTHESIS: Immunomodulators blocking cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) have improved the treatment of a broad spectrum of cancers. These immune checkpoint inhibitors (ICIs) reactivate the immune system against tumour cells but can also trigger autoimmune side effects, including type 1 diabetes. Mesenchymal stem cell (MSC) therapy is the most prevalent cell therapy, with tissue-regenerating, anti-fibrosis and immunomodulatory functions provided by the secretome of the cells. Here, we examined whether systemic MSC treatment could prevent the development of type 1 diabetes in a NOD mouse model. METHODS: The purified PD-L1 monoclonal antibody was administered to induce diabetes in male NOD mice which normally do not develop diabetes. Human adipose-derived MSCs were administered by tail vein injections. T cells, macrophages and monocyte-derived macrophages expressing C-X-C motif chemokine ligand 9 (CXCL9) in pancreatic sections of NOD mice and a cancer patient who developed diabetes following the ICI treatments were analysed by immunofluorescence. Tissue localisation of the injected MSCs, plasma exosome levels and plasma cytokine profiles were also investigated. RESULTS: PD-1/PD-L1 blockade induced diabetes in 16 of 25 (64%) NOD mice which received anti-PD-L1 mAb without hMSCs [MSC(-)], whereas MSC administration decreased the incidence to four of 21 (19%) NOD mice which received anti-PD-L1 mAb and hMSCs [MSC(+)]. The PD-1/PD-L1 blockade significantly increased the area of CD3-positive T cells (6.2-fold) and macrophage-2 (Mac-2) antigen (2.5-fold)- and CXCL9 (40.3-fold)-positive macrophages in the islets. MSCs significantly reduced T cell (45%) and CXCL9-positive macrophage (67%) accumulation in the islets and the occurrence of diabetes. The insulin content (1.9-fold) and islet beta cell area (2.7-fold) were also improved by MSCs. T cells and CXCL9-positive macrophages infiltrated into the intricate gaps between the beta cells in the islets by PD-1/PD-L1 blockade. Such immune cell infiltration was largely prevented by MSCs. The most striking difference was observed in the CXCL9-positive macrophages, which normally did not reside in the beta cell region in the islets but abundantly accumulated in this area after PD-1/PD-L1 blockade and were prevented by MSCs. The CXCL9-positive macrophages were also observed in the islets of a cancer patient who developed diabetes following the administration of ICIs but few CXCL9-positive macrophages were observed in a control patient. Mechanistically, the injected MSCs accumulated in the lung but not in the pancreas and strongly increased plasma exosome levels and changed plasma cytokine profiles. CONCLUSIONS/INTERPRETATION: Our results suggest that MSCs can prevent the incidence of diabetes associated with immune checkpoint cancer therapy and may be worth further consideration for new adjuvant cell therapy.

Genetic assessment using whole-exome sequencing for a young hypertriglyceridemic patient with repeated acute pancreatitis.

Hypertriglyceridemia is caused not only by environmental factors but also by genetic factors. Severe hypertriglyceridemia is prone to complications of acute pancreatitis. Here, we report a whole-exome sequencing (WES) analysis for a young hypertriglyceridemic patient with recurrent acute pancreatitis and the patient's mother. A 28-year-old hypertriglyceridemic female was admitted to our hospital. At 23 years old, a health checkup clarified her hypertriglyceridemia. At the age of 26 and 27, she had repeated acute pancreatitis with severe hypertriglyceridemia (serum triglyceride level were 3,888 mg/dL and 12,080 mg/dL, respectively). The patient's BMI was 29.0 kg/m2, and blood samples under fibrate medication showed triglyceride 451 mg/dL and HbA1c 7.2%. Type V dyslipidemia became more apparent at postprandial state. The WES analysis showed that the patients had two heterozygous variants in Apolipoprotein A5 (APOA5) gene (p.G185C and p.V153M), a heterozygous variant in Apolipoprotein E (APOE) gene (p.R176C), three heterozygous variants in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene (p.T1220I, p.R1453W and p.V470M). On the other hand, her mother, who had moderate hypertriglyceridemia without acute pancreatitis, had a heterozygous variant in APOA5 gene (p.G185C) and two heterozygous variants in CFTR gene (p.T1220I and p.V470M). These results suggest that the more severe pathology of the patient than her mother might be due to the possible compound heterozygous APOA5 variants, the heterozygous APOE variant, and the possible compound heterozygous CFTR variants. In this case, WES analyses were useful to evaluate not only the causative genes of hypertriglyceridemia (APOA5 and APOE) but also the genes involved in the development of acute pancreatitis (CFTR) simultaneously.

Time-Series Change of Serum Soluble T-Cadherin Concentrations and Its Association with Creatine Kinase-MB Levels in ST-Segment Elevation Myocardial Infarction.

AIMS: T-cadherin (T-cad) is a specific binding partner of adiponectin (APN), adipocyte-specific secretory protein. APN exhibits organ protection via the T-cad-dependent accumulation onto several tissues such as the aorta, heart, and muscle. Recently, for the first time, we showed that three forms (130, 100, and 30 kDa) of soluble T-cad existed in human serum and correlated with several clinical parameters in patients with type 2 diabetes. Nevertheless, the significance of soluble T-cad has not been elucidated in the acute stage of cardiovascular diseases. We herein examined soluble T-cad concentrations and investigated their clinical significance in patients with emergency hospital admission due to ST-segment elevation myocardial infarction (STEMI). METHODS: This observational study enrolled 47 patients with STEMI who were treated via primary percutaneous coronary intervention (PCI). Soluble T-cad and APN concentrations were measured by using an enzyme-linked immunosorbent assay. This study is registered with the University Hospital Medical Information Network (Number: UMIN 000014418). RESULTS: Serum concentrations of soluble 130 and 100 kDa T-cad rapidly and significantly decreased after hospitalization and reached the bottom at 72 h after admission (p＜0.001 and p＜0.001, respectively). The patients with high soluble T-cad and low APN concentrations on admission showed a significantly higher area under the curve of serum creatine kinase-MB (p＜0.01). CONCLUSION: Serum soluble T-cad concentration changed dramatically in patients with STEMI, and the high T-cad and low APN concentrations on admission were associated with the myocardial infarction size. Further study is needed to investigate the usefulness of categorizing patients with STEMI by serum T-cad and APN for the prediction of severe prognoses.