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Abstract Continuous glucose monitoring (CGM) values obtained from CGM systems using the same sensor but with different internal algorithms (the first- and third-generation FreeStyle Libre (1st-gen-libre and 3rd-gen-libre, respectively)) were compared. We used 19,819 paired and simultaneously measured CGM values of 13 patients with diabetes. The average CGM value was significantly higher (P

Abstract 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.

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.

Abstract 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

Summary: Although chronic kidney disease (CKD) is a major health problem worldwide, its underlining mechanism is incompletely understood. We previously identified adipolin as an adipokine which provides benefits for cardiometabolic diseases. Here, we investigated the role of adipolin in the development of CKD. Adipolin-deficiency exacerbated urinary albumin excretion, tubulointerstitial fibrosis and oxidative stress of remnant kidneys in mice after subtotal nephrectomy through inflammasome activation. Adipolin positively regulated the production of ketone body, β-hydroxybutyrate (BHB) and expression of a catalytic enzyme producing BHB, HMGCS2 in the remnant kidney. Treatment of proximal tubular cells with adipolin attenuated inflammasome activation through the PPARα/HMGCS2-dependent pathway. Furthermore, systemic administration of adipolin to wild-type mice with subtotal nephrectomy ameliorated renal injury, and these protective effects of adipolin were diminished in PPARα-deficient mice. Thus, adipolin protects against renal injury by reducing renal inflammasome activation through its ability to induce HMGCS2-dependent ketone body production via PPARα activation.

Abstract Adiponectin (APN), a protein abundantly secreted from adipocytes, has been reported to possess beneficial effects on cardiovascular diseases in association with its accumulation on target organs and cells by binding to T-cadherin. However, little is known about the role of APN in the development of diabetic microvascular complications, such as diabetic retinopathy (DR). Here we investigated the impact of APN on the progression of early retinal vascular damage using a streptozotocin (STZ)-induced diabetic mouse model. Our immunofluorescence results clearly showed T-cadherin-dependent localization of APN in the vascular endothelium of retinal arterioles, which was progressively decreased during the course of diabetes. Such reduction of retinal APN accompanied the early features of DR, represented by increased vascular permeability, and was prevented by glucose-lowering therapy with dapagliflozin, a selective sodium-glucose co-transporter 2 inhibitor. In addition, APN deficiency resulted in severe vascular permeability under relatively short-term hyperglycemia, together with a significant increase in vascular cellular adhesion molecule-1 (VCAM-1) and a reduction in claudin-5 in the retinal endothelium. The present study demonstrated a possible protective role of APN against the development of DR.

ABSTRACT 2p25.3 deletion syndrome is a rare genetic disorder that accompanies various phenotypic features, including early‐onset obesity and intellectual disability. Here, we report the first Japanese case of this deletion associated with severe obesity and diabetes mellitus. Microarray‐based comparative genomic hybridization analysis identified a 3.1‐Mb deletion of distal chromosome band 2p25.3, which was suspected as de novo. The patient also presented bilateral cataracts and adolescent‐onset muscular weakness of the upper limbs, both of which were uncommon in previously reported cases. It is possible that these symptoms are also important clinical features suggestive of this syndrome.

Abstract Background Since sodium-glucose cotransporter 2 (SGLT2) inhibitors have a pleiotropic antiatherogenic effect, they are expected to attenuate the progression of atherosclerosis. However, whether SGLT2 inhibitors affect the tissue characteristics of the human arterial wall remains unclear. This study aimed to evaluate the effects of tofogliflozin, a selective SGLT2 inhibitor, on the tissue characteristics of the human arterial wall in type 2 diabetes (T2DM) patients without apparent cardiovascular disease (CVD). Methods The present study was a post hoc analysis based on data obtained from the Using Tofogliflozin for Possible Better Intervention against Atherosclerosis for Type 2 Diabetes Patients (UTOPIA) trial, which was a multicenter prospective, randomized, open-label, blinded-endpoint study conducted to evaluate the efficacy of tofogliflozin in preventing the progression of atherosclerosis in patients with T2DM. We evaluated the longitudinal change in the ultrasonic tissue characteristics of the carotid wall using gray-scale median (GSM), an established index of ultrasonic tissue characteristics. The right and left intima-medial areas were delineated, and the GSM values were evaluated (right GSM-CCA and left GSM-CCA). The average values of the right and left carotid arteries were defined as “mean GSM-CCA value.” Results In a mixed-effects model for repeated measures, mean GSM-CCA, along with the right and left GSM-CCA values, did not significantly change in either the tofogliflozin (n = 168) or conventional treatment group (n = 169). In addition, the tofogliflozin and conventional treatment groups did not significantly differ regarding the change of the mean GSM-CCA (mean difference [95% CI] − 1.24[− 3.87, 1.38], P = 0.35), along with the right (mean difference [95% CI] − 2.33[− 5.70, 1.05], P = 0.18) and the left GSM-CCA (mean difference [95% CI] − 0.29 [− 3.53, 2.95], P = 0.86) values. Similar findings were obtained even after adjusting for traditional cardiovascular risk factors and/or the administration of drugs at baseline. Conclusions The tissue characteristics of the carotid arterial wall did not change in either the tofogliflozin or conventional treatment group during the 104-week treatment period, and there was no significant difference between the treatment groups. Clinical trial registration UMIN000017607 ( https://www.umin.ac.jp/icdr/index.html )

Abstract Aims/Introduction Xanthine oxidoreductase (XOR) is an enzyme that catalyzes hypoxanthine and xanthine to xanthine and uric acid, respectively. Plasma XOR activity has recently been measured in humans. However, limited information is known about plasma XOR activity in patients with type 2 diabetes mellitus, and its changes after short‐term glycemic control treatment. Materials and Methods We enrolled 28 Japanese patients (10 men/18 women) with type 2 diabetes mellitus who were hospitalized to undergo medical treatment for diabetes. Plasma XOR activity, quantified using triple quadrupole mass spectrometry and liquid chromatography, and other clinical parameters were examined at admission and 2 weeks after treatment during hospitalization. Changes in plasma XOR activity after treatment during hospitalization and associated clinical parameters were assessed. Results At the time of admission, the median plasma XOR activity was 83.1 pmol/h/mL, with a wide range of 14.4–1150 pmol/h/mL. Multiple regression analysis identified serum aspartate transaminase and alanine transaminase levels as significant and independent factors correlating with the baseline plasma XOR. Two weeks of treatment during hospitalization was associated with a significant decrease in plasma XOR activity. Changes in serum aspartate transaminase were also the only significant and independent factor correlating with changes in plasma XOR activity. Conclusions A close relationship was observed between plasma XOR activity and liver transaminases in patients with type 2 diabetes mellitus, cross‐sectionally, and also across treatment during hospitalization.

Abstract Aims/Introduction Crossing capillaries in the finger nailfold might potentially be a novel diabetic retinopathy (DR) biomarker that could be assessed non‐invasively in the clinical setting. However, the association between crossing capillaries and DR is controversial. This study aimed to investigate the association between the percentage of crossing capillaries in the finger nailfold and DR in patients with type 2 diabetes mellitus. Materials and Methods This cross‐sectional study enrolled 108 type 2 diabetes mellitus patients (aged 40–75 years) who visited the outpatient diabetic clinic at Osaka University Hospital, Osaka, Japan, between May and October 2019. Capillary morphology was assessed using nailfold capillaroscopy based on the simple capillaroscopic definitions of the European League Against Rheumatism Study Group. Details of DR and other laboratory data were obtained from medical records. The association between the tertile of the percentage of the crossing capillary and DR was analyzed using multivariable logistic regression. Results After adjusting for age, sex, diabetes duration, glycated hemoglobin, systolic blood pressure, body mass index, and use of renin–angiotensin system inhibitor and antihyperlipidemic medication, the percentage of crossing capillaries was significantly associated with DR (multivariable‐adjusted odds ratios for increasing tertiles of the percentage of crossing capillary: 1 [reference], 2.05 [95% confidence interval 0.53–7.94], and 4.33 [95% confidence interval 1.16–16.21]; P‐trend = 0.028). Conclusions A higher percentage of crossing capillaries in the nailfold was associated with a higher risk of DR, independent of traditional risk and inhibiting factors, in patients with type 2 diabetes mellitus.

Abstract Neurofilament light chain (NfL) is a novel biomarker of neurodegenerative diseases. It is detectable in the peripheral blood, allowing low-invasive assessment of early signs of neurodegeneration. The level of NfL gradually increases with age; however, what other factors affect it remains unclear. The present study examined the association between blood NfL level and renal function among healthy participants undergoing a health check (n = 43, serum NfL) and patients with diabetes mellitus (n = 188, plasma NfL). All participants were 60 years of age or older; none were diagnosed with dementia. In each group, levels of blood NfL and serum creatinine significantly correlated (coefficient r = 0.50, 0.56). These associations remained statistically significant even after adjustment for age, sex, and body mass index. These findings indicate that blood NfL level might be partially affected by renal function. We recommend measuring renal function for a more precise evaluation of neuroaxonal damage, in particular, among older adults.

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.

Xanthine oxidoreductase (XOR) is an enzyme that catalyzes hypoxanthine to xanthine and xanthine to uric acid, respectively. However, the underlying mechanisms of increased plasma XOR and its pathological roles in systemic diseases, such as atherosclerosis, are not fully understood. In this study, we found that changes in plasma XOR activity after bariatric surgery closely associated with those in liver enzymes, but not with those in BMI. In a mouse model of nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), plasma XOR activity markedly increased. Besides, purine catabolism was accelerated in the plasma per se of NASH mice and human patients with high XOR activity. In our NASH mice, we observed an increased vascular neointima formation consisting of dedifferentiated vascular smooth muscle cells (SMCs), which was significantly attenuated by topiroxostat, a selective XOR inhibitor. In vitro, human liver S9–derived XOR promoted proliferation of SMCs with phenotypic modulation and induced ROS production by catabolizing hypoxanthine released from human endothelial cells. Collectively, the results from human and mouse models suggest that increased plasma XOR activity, mainly explained by excess hepatic leakage, was involved in the pathogenesis of vascular injury, especially in NAFLD/NASH conditions.

Abstract Background The efficacy of cell transplantation in heart failure is reportedly modest, but adjuvant drugs combined with cell therapy may improve this efficacy. Peroxisome proliferator-activated receptor (PPAR)γ, one of the hypoglycemic medicine for diabetes mellitus, reportedly enhances cytokine production in adipose tissue-derived regenerative cells (ADRCs). We hypothesized that combined administration of PPARγ agonists and ADRCs may enhance the paracrine effects of adiponectin (APN), leading to functional recovery in a chronic myocardial infarction (MI) model. Methods ADRCs were isolated from adipose tissues of adult rats by gradient centrifugation and embedded in bio-compatible fibrin-glue to produce ADRCs grafts. In the in vitro study, the ADRCs grafts released APN, which was significantly enhanced by the PPARγ agonist (PGZ, pioglitazone). Transplantation of ADRCs grafts (group A), ADRCs mixed with PGZ (group AP), APN knockdown-ADRCs (group Si) or PGZ (group P) onto the epicardium or a sham operation (group C) was performed (n = 10–20 per group). Results The AP group showed significant improvement in ejection fraction compared to that in the other groups. In the AP group, a significantly larger number of M2-polarized macrophages was detected and existed for a significantly longer duration in the infarct area. Furthermore, comparing Si group and P group, western blotting of T-cadherin revealed that exogenous APN and local expression of T-cadherin were essential to this histological change and recovery of cardiac function. Conclusions Combined administration of PPARγ agonist and ADRSCs activated M2-polarized macrophages with enhancement of APN paracrine effects and lead to better cardiac function in a rat infarction model.

Abstract Background Although obesity-related type 2 diabetes mellitus (T2DM) and sarcopenia in the elderly have been increasing worldwide, the associations among visceral fat accumulation, skeletal muscle indices (mass, strength, and quality) and cardiovascular diseases in T2DM remain poorly investigated. Methods We enrolled 183 Japanese T2DM inpatients (126 men, 57 women; mean age 64.7 ± 12.6 years, ± SD). The estimated-visceral fat area (eVFA) and skeletal muscle mass were measured by each device using bioelectrical impedance analysis method. We also measured grip strength by dynamometer and motor nerve conduction velocity (MCV). We analyzed the difference in skeletal muscle indices between T2DM patients with and without visceral fat accumulation, and examined the impact of skeletal muscle indices on cardiovascular diseases in patients with visceral fat accumulation. Results The prevalence of sarcopenia defined by the Consensus of Asian Working Group for Sarcopenia and low skeletal muscle mass were both lower in the visceral fat accumulation (+) group than in (−) group. However, the prevalence of weak hand grip strength was similar in the visceral fat accumulation (−) and (+) groups, indicating that considerable patients with visceral fat accumulation had weak grip strength in spite of fair skeletal muscle mass. Muscle quality [grip strength (kg)/arm muscle mass (kg)] was significantly lower in patients with visceral fat accumulation. Multiple regression analysis identified eVFA, MCV and sex as significant and independent determinants of muscle quality. In visceral fat accumulation (+) group, the patients with low muscle quality had longer duration of diabetes, lower eGFR, higher serum adiponectin, lower MCV and higher prevalence of cardiovascular diseases, compared to the patients with high muscle quality. Finally, sex- and age-adjusted models showed significant association between low muscle quality and cardiovascular diseases in all subjects (odds ratio 2.28, p = 0.012), especially in patients with visceral fat accumulation (odds ratio 2.72, p = 0.018). Conclusions T2DM patients with visceral fat accumulation had low muscle quality, and patients with low muscle quality were more affected with cardiovascular diseases.

Abstract Background Although Japanese–Americans and native Japanese share the same genetic predispositions, they live different lifestyles, resulting in insulin resistance in Japanese–Americans. We investigated whether the quantitative and qualitative changes in adiponectin (APN) due to differences in lifestyle contribute to the development of insulin resistance. Methods We evaluated 325 native Japanese in Hiroshima, Japan and 304 Japanese–Americans in Los Angeles, the United States, who were aged between 30 and 70 years and underwent medical examinations between 2009 and 2010. All participants underwent a 75-g oral glucose tolerance test (OGTT) to assess their glucose tolerance. The insulin response to oral glucose load, the Matsuda index, total APN levels, and C1q-APN/total-APN ratios were compared between native Japanese and Japanese–Americans. Results Compared with the native Japanese, the Japanese–Americans had significantly lower Matsuda index and higher area under the curve values for serum insulin concentration during OGTT in the normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) groups, but not in the diabetes mellitus (DM) group. Furthermore, the Japanese–Americans had significantly lower total APN levels and higher C1q-APN/total-APN ratios than the native Japanese in the NGT and IGT groups, but not in the DM group. Conclusions This study suggested that, in Japanese people, the westernization of their lifestyle might affect quantitative and qualitative changes in APN and induce insulin resistance.

Adiponectin is an adipocyte-derived atypically abundant circulating factor that protects various organs and tissues through its receptors, AdipoRs, calreticulin, and T-cadherin. To identify the major binding partner of circulating native adiponectin, we expressed these receptors on the surface of HEK293 cells. Adiponectin, either that in mouse or human serum, purified from serum, or produced by mammalian cells, bound to cells expressing T-cadherin, but not to those expressing AdipoR1 or calreticulin. The stable introduction of T-cadherin and AdipoR1 into CHO cells resulted in the cell surface localization of these receptors. Native adiponectin in serum bound to cells expressing T-cadherin, not to those expressing AdipoR1. The knockdown of T-cadherin, but not AdipoRs resulted in the significant attenuation of native adiponectin binding to C2C12 myotubes. Therefore, native adiponectin binding depended on the amount of T-cadherin expressed in HEK293 cells, CHO cells, and C2C12 myotubes. Collectively, our mammalian cell-based studies suggest that T-cadherin is the major binding partner of native adiponectin in serum.

Aims: Glucagon plays pivotal roles in systemic glucose homeostasis mainly by promoting hepatic glucose output. Using a sandwich enzyme-linked immunosorbent assay (ELISA), we evaluated fasting plasma glucagon levels in hospitalized patients with type 1 or type 2 diabetes, and assessed the relationships between glucagon levels and various clinical parameters. Methods: We enrolled adult Japanese diabetes patients admitted to Osaka University Medical Hospital for glycemic control between July 2017 and May 2018 in this study. After patients had fasted for 12 h, blood samples were obtained and plasma glucagon levels were measured using a sandwich ELISA. Results: Total 107 patients participated in the study. The mean fasting plasma glucagon level of patients with acute onset type 1 diabetes was significantly lower than that of patients with type 2 diabetes (p < 0.05). Plasma glucagon levels were not significantly correlated with plasma glucose levels in patients with type 1 diabetes or in patients with type 2 diabetes. Multiple regression analysis indicated that fasting glucagon levels were independently and significantly correlated with fasting serum C-peptide levels in patients with type 2 diabetes. Conclusions: Our results suggest that insulin and glucagon secretion are balanced in the fasting state in patients with type 2 diabetes.

Obesity is an epidemic matter increasing risk for cardiovascular diseases and metabolic disorders such as type 2 diabetes. We recently examined the association between visceral fat adiposity and gene expression profile of peripheral blood cells in human subjects. In a series of studies, Opa (Neisseria gonorrhoeae opacity-associated)-interacting protein 5 (OIP5) was nominated as a molecule of unknown function in adipocytes and thus the present study was performed to investigate the role of OIP5 in obesity. Adenovirus overexpressing Oip5 (Ad-Oip5) was generated and infected to 3T3-L1 cells stably expressing Coxsackie-Adenovirus Receptor (CAR-3T3-L1) and to mouse subcutaneous fat. For a knockdown experiment, siRNA against Oip5 (Oip5-siRNA) was introduced into 3T3-L1 cells. Proliferation of adipose cells was measured by BrdU uptake, EdU-staining, and cell count. Significant increase of Oip5 mRNA level was observed in obese white adipose tissues and such increase was detected in both mature adipocytes fraction and stromal vascular cell fraction. Ad-Oip5-infected CAR-3T3-L1 preadipocytes and adipocytes proliferated rapidly, while a significant reduction of proliferation was observed in Oip5-siRNA-introduced 3T3-L1 preadipocytes. Fat weight and number of adipocytes were significantly increased in Ad-Oip5-administered fat tissues. Oip5 promotes proliferation of pre- and mature-adipocytes and contributes adipose hyperplasia. Increase of Oip5 may associate with development of obesity.

Visceral fat adiposity plays an important role in the development of metabolic syndrome. We reported previously the impact of human visceral fat adiposity on gene expression profile of peripheral blood cells. Genes related to circadian rhythm were highly associated with visceral fat area and period homolog 1 (PER1) showed the most significant negative correlation with visceral fat area. However, regulation of adipose Per1 remains poorly understood. The present study was designed to understand the regulation of Per1 in adipose tissues. Adipose Per1 mRNA levels of ob/ob mice were markedly low at 25 and 35 weeks of age. The levels of other core clock genes of white adipose tissues were also low in ob/ob mice at 25 and 35 weeks of age. Per1 mRNA was mainly expressed in the mature adipocyte fraction (MAF) and it was significantly low in MAF of ob/ob mice. To examine the possible mechanisms, 3T3-L1 adipocytes were treated with H2O2, tumor necrosis factor-α (TNF-α), S100A8, and lipopolysaccharide (LPS). However, no significant changes in Per1 mRNA level were observed by these agents. Exposure of cultured 3T3-L1 adipocytes to low temperature (33°C) decreased Per1 and catalase, and increased monocyte chemoattractant protein-1 (Mcp-1) mRNA levels. Hypothermia also worsened insulin-mediated Akt phosphorylation in 3T3-L1 adipocytes. Finally, telemetric analysis showed low temperature of adipose tissues in ob/ob mice. In obesity, adipose hypothermia seems to accelerate adipocyte dysfunction.

AIMS: Ephrin-B1 (EfnB1) was selected among genes of unknown function in adipocytes or adipose tissue and subjected to thorough analysis to understand its role in the development of obesity. METHODS AND RESULTS: EfnB1 mRNA and protein levels were significantly decreased in adipose tissues of obese mice and such reduction was mainly observed in mature adipocytes. Exposure of 3T3-L1 adipocytes to tumor necrosis factor-α (TNF-α) and their culture with RAW264.7 cells reduced EFNB1 levels. Knockdown of adipose EFNB1 increased monocyte chemoattractant protein-1 (Mcp-1) mRNA level and augmented the TNF-α-mediated THP-1 monocyte adhesion to adipocytes. Adenovirus-mediated adipose EFNB1-overexpression significantly reduced the increase in Mcp-1 mRNA level induced by coculture of 3T3-L1 adipocytes with RAW264.7 cells. Monocyte adherent assay showed that adipose EfnB1-overexpression significantly decreased the increase of monocyte adhesion by coculture with RAW264.7 cells. TNF-α-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) was reduced by EFNB1-overexpression. CONCLUSIONS: EFNB1 contributes to the suppression of adipose inflammatory response. In obesity, reduction of adipose EFNB1 may accelerate the vicious cycle involved in adipose tissue inflammation.

AIMS: Inflammation is closely associated with the development of atherosclerosis and metabolic syndrome. Adiponectin, an adipose-derived secretory protein, possesses an anti-atherosclerotic property. The present study was undertaken to elucidate the presence and significance of adiponectin in vasculature. METHODS AND RESULTS: Immunofluorescence staining was performed in aorta of wild-type (WT) mice and demonstrated that adiponectin was co-stained with CD31. Thoracic aorta was cut through and then aortic intima was carefully shaved from aorta. Western blotting showed the existence of adiponectin protein in aortic intima, while there was no adiponectin mRNA expression. Adiponectin knockout (Adipo-KO) and WT mice were administered with a low-dose and short-term lipopolysaccharide (LPS) (1 mg/kg of LPS for 4 hours). The endothelium vascular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were highly increased in Adipo-KO mice compared to WT mice after LPS administration. CONCLUSIONS: Adiponectin protein exists in aortic endothelium under steady state and may protect vasculature from the initiation of atherosclerosis.

Evidence suggests that visceral fat accumulation plays a central role in the development of metabolic syndrome. Excess visceral fat causes local chronic low-grade inflammation and dysregulation of adipocytokines, which contribute in the pathogenesis of the metabolic syndrome. These changes may affect the gene expression in peripheral blood cells. This study for the first time examined the association between visceral fat adiposity and gene expression profile in peripheral blood cells. The gene expression profile was analyzed in peripheral blood cells from 28 obese subjects by microarray analysis. Reverse transcription-polymerase chain reaction (RT-PCR) was performed using peripheral blood cells from 57 obese subjects. Obesity was defined as body mass index (BMI) greater than 25 kg/m(2) according to the Japanese criteria, and the estimated visceral fat area (eVFA) was measured by abdominal bioelectrical impedance. Analysis of gene expression profile was carried out with Agilent whole human genome 4 × 44 K oligo-DNA microarray. The expression of several genes related to circadian rhythm, inflammation, and oxidative stress correlated significantly with visceral fat accumulation. Period homolog 1 (PER1) mRNA level in blood cells correlated negatively with visceral fat adiposity. Stepwise multiple regression analysis identified eVFA as a significant determinant of PER1 expression. In conclusion, visceral fat adiposity correlated with the expression of genes related to circadian rhythm and inflammation in peripheral blood cells.

Context: Glucose tolerance worsens after distal pancreatectomy (DP); however, the long-term incidence and factors affecting interindividual variation in this worsening are unclear. Objective: To investigate the changes in diabetes-related traits before and after DP and to clarify the incidence of diabetes and its predictors. Methods: Among 493 registered patients, 117 underwent DP. Among these, 56 patients without diabetes before surgery were included in the study. Glucose and endocrine function were prospectively assessed using a 75-g oral glucose tolerance test preoperatively, 1 month after DP, and every 6 months thereafter for up to 36 months. Pancreatic volumetry was performed using multidetector row computed tomography before and after surgery. Results: Insulin secretion decreased and blood glucose levels worsened after DP. Residual pancreatic volume was significantly associated with the reserve capacity of insulin secretion but not with blood glucose levels or the development of diabetes. Among 56 patients, 33 developed diabetes mellitus. The cumulative incidence of diabetes at 36 months after DP was 74.1%. Multivariate Cox regression analysis showed that impaired glucose tolerance as a preoperative factor as well as a decreased insulinogenic index and impaired glucose tolerance at 1 month postoperatively were identified as risk factors for diabetes following DP. Conclusion: Impaired glucose tolerance and reduced early-phase insulin response to glucose are involved in the development of new-onset diabetes after DP; the latter is an additional factor in the development of diabetes and becomes apparent when pancreatic beta cell mass is reduced after DP. [ABSTRACT FROM AUTHOR]