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CONTEXT: Moon-like facies (MLF) are a typical side effect of glucocorticoid (GC) therapy; however, its predisposing factors, relationship with GC-induced complications, and effects on body image are not well understood. OBJECTIVE: This study aimed to determine the predisposing factors for MLF during GC therapy; its association with GC-induced diabetes, hypertension, and dyslipidemia; and its effects on body image. METHODS: This prospective observational study spanned 24 weeks and targeted patients who received GC therapy at the University of Yamanashi Hospital from June 2020 to August 2022. The MLF was defined based on the following 3 factors: (1) an increase in facial measurement lengths, (2) subjective facial changes by patients' self-assessment using a visual analog scale; (3) objective and qualitative facial changes assessed by physicians. We examined the predisposing factors for MLF and the association of MLF with GC-induced diabetes, hypertension, dyslipidemia, and body image. RESULTS: The cumulative incidence rate of MLF at 24 weeks was 37.6%. Predisposing factors for MLF were an initial oral prednisolone dosage of ≥ 30 mg/day [odds ratio (OR) 63.91, 95% confidence interval (CI) 5.82-701.81] and female (OR 6.66, 95% CI 1.35-32.79). MLF showed a significant association with the onset of GC-induced diabetes (OR 6.58, 95% CI 1.25-34.74). MLF was also an independent factor contributing to body image disturbance (β = -18.94, P = .01). CONCLUSION: MLF contributes to body image disturbance and is associated with the development of GC-induced diabetes; therefore, it is clinically important as a physical manifestation of GC therapy.

DOI： 10.1210/jendso/bvae036

PubMed

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Production of the high-molecular-weight forms of adrenocorticotropic hormone (big-ACTH) has been reported in a small number of ectopic ACTH syndrome and ACTH-producing pituitary macroadenoma. However, perioperative changes in big-ACTH in patients with subclinical Cushing's disease have not been reported. A 63-year-old woman presented 25 × 20 × 20-mm-sized macroadenoma in the pituitary gland. Her early morning plasma ACTH and cortisol levels were 111 pg/mL and 11.6 μg/dL, respectively. Cushingoid features and diurnal variation in plasma cortisol levels were not observed. The patient's urinary free cortisol (UFC) was 59.3 μg/day. The corticotropin-releasing hormone (CRH) test showed that plasma ACTH levels were 1.5 times higher than the preload value. The overnight dexamethasone suppression test (DST) showed that the plasma cortisol level was not suppressed by 0.5 mg of dexamethasone (DEX) but was suppressed by 8 mg of DEX. Inferior pyramidal sinus sampling was consistent with Cushing's disease. Taken together, the patient was clinically diagnosed with subclinical Cushing's disease caused by an ACTH-producing pituitary adenoma. Endoscopic transsphenoidal adenomectomy was performed. In the postoperative CRH test, plasma ACTH levels showed six-fold increase. The postoperative DST showed cortisol suppression at 0.5 mg of DEX. The UFC levels decreased to 35.1 μg/day. Pituitary contrast-enhanced MRI revealed no residual tumor, and plasma ACTH and cortisol levels remained within normal ranges. Gel filtration of preoperative and postoperative plasma ACTH was performed, and a high molecular weight fraction of ACTH was detected, which markedly decreased postoperatively. The absence of Cushingoid features and the lack of significant cortisol hypersecretion in this case were thought to be due in part to big-ACTH, which has low bioactivity. By careful evaluation of laboratory and clinical findings, we identified it as a big-ACTH-producing adenoma. This is the first report of a case in which the big-ACTH transition was observed perioperative and is a valuable case.

DOI： 10.1155/2024/8721614

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Obesity is recognized as an independent risk factor for abdominal aortic aneurysm (AAA). While mutations in the melanocortin-4 receptor (MC4R) gene is the most common cause of obesity caused by mutations in a single gene, the link between MC4R function and vascular disease has still remained unclear. Here, by using melanocortin-4 receptor (MC4R) deficient mice, we confirmed MC4R deficiency promotes AAA and atherosclerosis. We demonstrated the contribution of two novel factors towards vascular vulnerability in this model: leptin signaling in vascular smooth muscle cells (VSMCs) and loss of MC4R signaling in macrophages. Leptin was shown to promote vascular vulnerability via PI3K-dependent upregulation of Spp1 expression in VSMC. Additionally, Ang II-induced AAA incidence was significantly reduced when MC4R gene expression was myeloid cell-specifically rescued in MC4R deficient (MC4RTB/TB) mice. Ex vivo analysis showed a suppression in NF-κB activity in bone marrow-derived macrophages from LysM(+);MC4RTB/TB mice compared to LysM(-);MC4RTB/TB mice, which exaggerates with endogenous MC4R ligand treatment; α-MSH. These results suggest that MC4R signaling in macrophages attenuates AAA by inhibiting NF-κB activity and subsequent vascular inflammation.

DOI： 10.1038/s41598-023-46831-4

PubMed

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Gaucher disease (GD) causes the accumulation of glucocerebrosides in various organs, resulting in hepatosplenomegaly, anemia, decreased platelet counts, and bone disorders. Glucosylsphingosine accumulates in the brain and causes central nervous system (CNS) disorders. GD can be classified into types I (without CNS disorders), II, and III. Substrate reduction therapy (SRT) is an oral therapy that improves patients' quality of life; however, its effect on type III GD is unknown. We administered SRT to GD types I and III patients and found it effective. Malignancy is a late complication of GD, but this is the first report of Barrett adenocarcinoma.

DOI： 10.2169/internalmedicine.1425-22

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[This corrects the article DOI: 10.1007/s13340-022-00601-1.].

DOI： 10.1007/s13340-023-00636-y

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Cerebrovascular diseases, such as stroke and cardiovascular disease, are one of the leading causes of death in Japan. Type 2 diabetes is the most common form of diabetes and an important risk factor for these diseases. Among various pathological conditions associated with type 2 diabetes, insulin resistance has already been reported to be an important risk factor for diabetic complications. The major sites of insulin action in glucose metabolism in the body include the liver, skeletal muscle, and adipose tissue. However, insulin signaling molecules are also constitutively expressed in vascular endothelial cells, vascular smooth muscle, and monocytes/macrophages. Forkhead box class O family member proteins (FoxOs) of transcription factors play important roles in regulating glucose and lipid metabolism, oxidative stress response and redox signaling, and cell cycle progression and apoptosis. FoxOs in vascular endothelial cells strongly promote arteriosclerosis by suppressing nitric oxide production, enhancing inflammatory response, and promoting cellular senescence. In addition, primary aldosteronism and Cushing's syndrome are known to have adverse effects on the cardiovascular system, apart from hypertension, diabetes, and dyslipidemia. In the treatment of endocrine disorders, hormonal normalization by surgical treatment and receptor antagonists play an important role in preventing cardiovascular complications.

DOI： 10.1507/endocrj.EJ22-0457

PubMed

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Among the various pathological conditions associated with type 2 diabetes, insulin resistance has long been reported to be a potent risk factor for diabetic complications. The liver, skeletal muscle, and adipose tissue are the major organs of action of insulin in systemic glucose metabolism, but insulin receptors and their downstream insulin signaling molecules are also constitutively expressed in vascular endothelial cells, vascular smooth muscle, and monocytes/macrophages. Forkhead box class O family member proteins (FoxOs) of transcription factors are essential regulators of cellular homeostasis, including glucose and lipid metabolism, oxidative stress response and redox signaling, cell cycle progression and apoptosis. In vascular endothelial cells, FoxOs strongly promote atherosclerosis via suppressing nitric oxide production and enhancing inflammatory responses. In liver sinusoidal endothelial cells, FoxOs induces hepatic insulin resistance by inducing nitration of insulin receptor in hepatocytes. Insulin resistance in adipose tissue limits capacity of lipid accumulation in adipose tissue, which promotes ectopic lipid accumulation and organ dysfunction in liver, vascular, and kidney. Modulation of insulin sensitivity in adipose tissue to induce healthy adipose expansion is expected to be a promising strategy for diabetic complications.

DOI： 10.1007/s13340-022-00601-1

PubMed

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Gestational diabetes mellitus (GDM) is one of the most common pregnancy-related complications; it is associated with adverse pregnancy outcomes and metabolic disorders in offspring, consistent with the concept of the developmental origins of health and disease. This cohort study of women without diabetes (n = 761), who were part of the Yamanashi Adjunct Study of the Japan Environment and Children's Study, aimed to explore the associations between maternal GDM and their offspring's level of high-sensitivity C-reactive protein (hsCRP), a biomarker of inflammatory and cardiovascular diseases. We analyzed the associations between GDM and the offspring's hsCRP levels using a multiple logistic regression model. A mother with GDM significantly increased the risk for high hsCRP level by 4.07-fold (≥2.0 mg/L) in the child. As such, maternal GDM was significantly associated with increased serum hsCRP levels in 8-year-old children.

DOI： 10.1111/jdi.13796

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DOI： 10.1038/s41366-022-01147-7

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DOI： 10.1038/s41366-022-01110-6

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DOI： 10.1038/s41366-022-01097-0

PubMed

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A 72-year-old woman presented with gradually-worsening myalgia and muscle weakness of the proximal lower limbs as well as elevated serum creatine kinase level. Based on a clinicoseropathological examination including a muscle biopsy, she was diagnosed with anti-signal recognition particle (SRP) myopathy. Although the myopathy relapsed two times in two years under oral prednisolone and intravenous immunoglobulin therapy, the myopathy remained in remission for more than three years after resection of gastric cancer. Although the anti-SRP myopathy is not considered to be cancer-associated in general, we should note that some cases of anti-SRP myopathy may be ameliorated with appropriate cancer treatment.

DOI： 10.2169/internalmedicine.9055-21

PubMed

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Catabolic conditions, such as starvation, inactivity, and cancer cachexia, induce Forkhead box O (FOXO) transcription factor(s) expression and severe muscle atrophy via the induction of ubiquitin-proteasome system-mediated muscle proteolysis, resulting in frailty and poor quality of life. Although FOXOs are clearly essential for the induction of muscle atrophy, it is unclear whether there are other factors involved in the FOXO-mediated transcriptional regulation. As such, we identified FOXO-CCAAT/enhancer-binding protein δ (C/EBPδ) signaling pathway as a novel proteolytic pathway. By comparing the gene expression profiles of FOXO1-transgenic (gain-of-function model) and FOXO1,3a,4-/- (loss-of-function model) mice, we identified several novel FOXO1-target genes in skeletal muscle including Redd1, Sestrin1, Castor2, Chac1, Depp1, Lat3, as well as C/EBPδ. During starvation, C/EBPδ abundance was increased in a FOXOs-dependent manner. Notably, knockdown of C/EBPδ prevented the induction of the ubiquitin-proteasome system and decrease of myofibers in FOXO1-activated myotubes. Conversely, C/EBPδ overexpression in primary myotubes induced myotube atrophy. Furthermore, we demonstrated that FOXO1 enhances the promoter activity of target genes in cooperation with C/EBPδ and ATF4. This research comprehensively identifies novel FOXO1 target genes in skeletal muscle and clarifies the pathophysiological role of FOXO1, a master regulator of skeletal muscle atrophy.

DOI： 10.1096/fj.202101385RR

PubMed

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Study Objectives: Aging is a risk factor for sleep apnoea syndrome (SAS), which is associated with lower quality of life and sudden mortality. However, SAS is often overlooked in older adults without suspicions. Therefore, this study aimed to evaluate SAS incidence and 48 other general factors in older adults. Methods: This cross-sectional study included all non-caregiver-certified, healthy individuals (N = 32) who survived during the long-term cohort study and agreed to participate in apnoea-hypopnoea index (AHI) measurement (aged 83-95 years). AHI and 48 other general factors were evaluated, and simple linear regression analysis was used to identify potential AHI-related factors. Stepwise evaluation was further performed using multiple linear regression analyses. Results: Although no individuals were previously diagnosed with SAS, 30 (93.75%) participants had some degree of SAS (AHI > 5/h), and 22 (68.75%) had severe or moderate SAS (AHI > 15/h). Compared with typical single risk factors represented by body mass index, combining daily steps and other factors improved the fit to the multiple linear regression. Combining daily steps and body mass index improved the fit for males and combining daily steps and red blood cell count improved the fit for females. Conclusion: SAS was highly prevalent in unaware healthy Japanese older adults; combinations of daily steps and body mass index, and daily steps and red blood cell count may predict AHI in such individuals without the need for a specific AHI test.

DOI： 10.3389/fragi.2022.965199

PubMed

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Inteletin1 (Itln1) is an adipokine that is abundantly expressed in intestine, ovary, and lung. The expression levels of ITLN1 are decreased in the presence of diabetes or obesity, but the mechanisms of its production and function are still controversial. The aim of this study is to elucidate the mechanisms of ITLN1 synthesis and ITLN1-associated macrophage activation. To analyze the effects of high fat and high-carbohydrate diet (HFHCD) on the expression of ITLN1 in the intestine, the mice were fed a HFHCD for 8 weeks. HFHCD feeding enhanced the endoplasmic reticulum (ER)-stress in the intestine and inhibited the expression of Itln1 in the intestinal endocrine cells and lowered circulating ITLN1 levels. In contrast, treatment with a chemical chaperone and reduction of ER-stress restored the expression of Itln1 in the intestine of HFHCD-fed mice. Furthermore, in vitro studies indicated that ITLN1 physically interacts with adiponectin receptor 1 and suppresses lipopolysaccharide-induced mRNA expressions of pro-inflammatory cytokines and phagocytosis activities via inhibition of the nuclear factor kappa B-signaling pathway in macrophages. These results suggest that diet-induced ER-stress decreases circulating ITLN1 via inhibition of its synthesis in the intestine, and a reduction of circulating ITLN1 might enhanced the expression of proinflammatory cytokines and macrophage activation, following exacerbate the chronic inflammation of metabolic syndrome.

DOI： 10.1507/endocrj.EJ21-0438

PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

AIMS/INTRODUCTION: Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy and is associated with adverse pregnancy outcomes. This study aimed to explore the associations between glycated hemoglobin (HbA1c) levels at the early stage of pregnancy and the GDM risk among non-diabetic women in a nationwide study in Japan. In addition, the relationship between GDM and adverse pregnancy outcomes was also analyzed. MATERIALS AND METHODS: This cohort study (n = 89,799) used data from the Japan Environment and Children's Study. We stratified the participants into four groups according to HbA1c levels at an early stage of pregnancy. We investigated the association of HbA1c at an early stage of pregnancy with the risk of GDM, and of GDM with the risk of some representative adverse pregnancy outcomes, using the multiple logistic regression model with adjustment for potential confounders. RESULTS: The adjusted odds ratio for GDM per 0.1 percentage point increase in HbA1c (%) was 1.20. The adjusted odds ratio for developing GDM was significantly increased in women from the HbA1c 5.0-5.4% category. GDM significantly increased the adjusted odds ratio for adverse pregnancy outcomes, such as hypertensive disorders of pregnancy, polyhydramnios and premature birth. CONCLUSIONS: High-normal HbA1c levels at the early stage of pregnancy are significantly associated with GDM risk in women in Japan. GDM was significantly associated with adverse pregnancy outcomes.

DOI： 10.1111/jdi.13701

PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

A 61-year-old man with a history of total gastrectomy for cancer with Roux-en-Y reconstruction showed severe postprandial hypoglycemia accompanied by endogenous hyperinsulinemia. Abdominal ultrasonography and contrast-enhanced computed tomography showed no abnormal findings in the pancreas. A selective arterial secretagogue injection test showed the marked induction of serum immunoreactive insulin when calcium was injected into the splenic artery. A pathological analysis following distal pancreatectomy with splenectomy revealed a pancreatic neuroendocrine microadenoma containing insulin-producing cells in the resected pancreas. This case highlights the importance of carefully evaluating refractory and severe hypoglycemia in patients with a history of gastric surgery to exclude insulinoma.

DOI： 10.2169/internalmedicine.7428-21

PubMed

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Type 1 diabetes (T1D) is classified into three subtypes: acute-onset, slowly progressive, and fulminant T1D, according to the heterogeneity of clinical course in Japan. Although several cross-sectional databases of T1D have been reported, prospective longitudinal databases to investigate clinical outcomes are lacking in our country. Therefore, we herein construct multi-center prospective longitudinal database of the three subtypes of T1D, accompanied with genetic information and biobanking, which is named Japanese Type 1 Diabetes Database Study (TIDE-J). Inclusion criteria of this study are as follows: (1) the duration of T1D was less than 5 years, (2) the patients had one or more islet-related autoantibodies and/or fasting serum C-peptide levels were less than 1.0 ng/mL, (3) the patients could clearly understand the study consent in writing. In the TIDE-J, clinical data, including glycemic control, endogenous insulin secretion, islet-related autoantibodies, diabetic complications, and treatment, are collected annually using electric data collection system, which is named REDCap. Furthermore, HLA genotypes of each participant were analyzed at entry and the blood samples were stored for assessing exploratory markers and further genetic analysis annually. The TIDE-J certainly helps in revealing distinct clinical course of each T1D subtype. Moreover, this database may help in identifying novel markers for diagnosing each subtype of T1D and predicting clinical outcomes (including pancreatic beta cell function and disease severity) in patients.

DOI： 10.1007/s13340-021-00541-2

PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: Both maternal prepregnancy body mass index (BMI) and gestational weight gain (GWG) influence maternal and pediatric outcomes. We sought to clarify the impact of prepregnancy BMI-specific GWG and its patterns on the risk of low birth weight (LBW) or macrosomia using data from a large nationwide study in Japan. METHODS: This cohort study (n = 98,052) used data from the Japan Environment and Children's Study (JECS). The outcome variables in this study were LBW and macrosomia. We stratified the subjects into groups according to prepregnancy BMI. RESULTS: GWG from pre-pregnancy to the first trimester had a small effect on the risk of LBW and macrosomia. From the first to second trimesters, insufficient GWG was associated with the risk of LBW, and from the second trimester to delivery, a GWG of less than 2 kg was associated with the risk of LBW. These associations were commonly observed in all prepregnancy BMI categories. Irrespective of the GWG from pre-pregnancy to the first trimester, GWG from the first to second trimesters affects LBW and/or macrosomia. Irrespective of the GWG from the first to second trimesters, GWG from the second trimester to delivery affects LBW and/or macrosomia. LBW or macrosomia was associated with the prevalence of a sustained low or high BMI percentile until three years of age, respectively. CONCLUSIONS: The present large national cohort study indicates that the risk of LBW or macrosomia is associated with GWG in women in Japan; the significance of this risk depends on the GWG patterns.

DOI： 10.1038/s41366-021-00947-7

PubMed

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

The liver has a most indispensable role in glucose and lipid metabolism where we see some of the most serious worldwide health problems. The serine protease prostasin (PRSS8) cleaves toll-like receptor 4 (TLR4) and regulates hepatic insulin sensitivity under PRSS8 knockout condition. However, liver substrate proteins of PRSS8 other than TLR4 and the effect to glucose and lipid metabolism remain unclarified with hepatic elevation of PRSS8 expression. Here we show that high-fat-diet-fed liver-specific PRSS8 transgenic mice improved glucose tolerance and hepatic steatosis independent of body weight. PRSS8 amplified extracellular signal-regulated kinase phosphorylation associated with matrix metalloproteinase 14 activation in vivo and in vitro. Moreover, in humans, serum PRSS8 levels reduced more in type 2 diabetes mellitus (T2DM) patients than healthy controls and were lower in T2DM patients with increased maximum carotid artery intima media thickness (>1.1 mm). These results identify the regulatory mechanisms of PRSS8 overexpression over glucose and lipid metabolism, as well as excessive hepatic fat storage.

DOI： 10.3390/ijms22158314

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Language：English   Publishing type：Research paper (scientific journal)  

Sodium glucose cotransporter-2 (SGLT2) inhibitors inhibit the development of diabetic nephropathy (DN). We determined whether changes in perirenal fat (PRAT) by a SGLT2 inhibitor ipragliflozin (Ipra) contribute to the suppression of DN development. High-fat diet (HFD)-fed mice were used as a DN model and were treated with or without Ipra for 6 weeks. Ipra treatment reduced urinary albumin excretion (UAE) and glomerular hypertrophy in HFD-fed mice. In the PRAT of Ipra-treated mice, adipocyte size was increased, and inflammation, fibrosis, and adipocyte death were suppressed. In conditioned medium made from PRAT (PRAT-CM) of Ipra-treated mice, the concentration of leptin was significantly lower than PRAT-CM of mice without Ipra treatment. Serum leptin concentration in renal vein positively correlated with UAE. PRAT-CM from HFD-fed mice showed greater cell proliferation signaling in mouse glomerular endothelial cells (GECs) than PRAT-CM from standard diet-fed mice via p38MAPK and leptin-dependent pathways, whose effects were significantly attenuated in PRAT-CM from Ipra-treated mice. These findings suggest that Ipra-induced PRAT expansion may play an important role in the improvement of DN in HFD-fed mice. In vitro experiments suggest that reduced PRAT-derived leptin by Ipra could inhibit GECs proliferation, possibly contributing to the suppression of DN development.

DOI： 10.3390/ijms22147329

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: It is unclear whether monocyte/macrophage insulin signaling in humans is affected by type 2 diabetes (T2DM), systemic insulin sensitivity, and other unknown factors. RESEARCH DESIGN AND METHODS: Fifty-three adult volunteers (control group) not taking any medication and without cardiovascular risk factors, and 59 patients with T2DM (T2DM group) were included. Monocytes were isolated and cultured from all participants. RESULTS: In cultured monocytes, insulin-stimulated AKT and FOXO3 phosphorylation was significantly suppressed in T2DM compared with that in the control group. Insulin-stimulated phosphorylation of AKT was significantly correlated with body mass index and serum insulin level only in the control group. In both groups, significant negative correlation between age and insulin-stimulated phosphorylation of AKT and FOXO3 was commonly observed. In the control group, lipopolysaccharide (LPS)-stimulated induction of TNFA, and NOS2 was significantly and negatively correlated with insulin-stimulated AKT phosphorylation. Age was also significantly correlated with LPS-stimulated induction of TNFA. DISCUSSION: Aging plays an important role in the development of monocyte insulin resistance, not only in patients with T2DM but also in healthy participants. Monocyte insulin sensitivity is negatively correlated with inflammatory responses and may be helpful for subclinical risk assessment of CVDs and/or insulin resistance in participants without risk factors.

DOI： 10.1177/1479164121989281

PubMed

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

A 66-year-old man with type 2 diabetes was admitted for glycemic control and weight loss. The rectal mucosa was unfortunately injured during glycerin enema administration in preparation for colonoscopy, after which dark red urine and renal dysfunction were observed. Considering the clinical diagnosis of glycerol-induced hemolysis and acute kidney injury, intravenous hydration and haptoglobin administration were started, which successfully treated the dark red urine and renal dysfunction. This case highlights the importance of appropriate glycerin enema administration and emphasizes the need to recognize glycerol-induced hemolysis and acute kidney injury as complications of glycerin enemas. This case also provides insight into glycerol-induced hemolysis and acute kidney injury as complications of glycerin enemas.

DOI： 10.2169/internalmedicine.4217-19

PubMed

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Glucocorticoid (GC)-induced hyperglycemia is characterized by elevated postprandial blood glucose, which commonly requires multiple insulin injections. We investigated whether a long-acting glucagon-like peptide-1 receptor agonist, dulaglutide (Dula), safely improved GC-induced hyperglycemia in inpatients, to reduce insulin injection frequency. METHODS: The data of hospitalized patients with GC-induced hyperglycemia treated with Dula (Dula group, n = 38) or without (non-Dula group, n = 38) were retrospectively evaluated. Baseline data were collected at the beginning of GC treatment. The primary outcome in this study was glycemic control, which was compared between the groups using the six-point blood glucose (before and 2 h after each meal) profiles at discharge. The daily injection frequency of injectable drugs at discharge were also compared between groups. RESULTS: No specific trend of underlying diseases was observed between the non-Dula and Dula groups. The proportion of patients previously administered with GC pulse therapy was comparable between the two groups. No significant differences were observed between groups, in the starting maintenance GC dose, GC dose at pretreatment of Dula and discharge, and cumulative GC dose during the observation. Six-point blood glucose levels at pretreatment and discharge were comparable between the two groups. However, daily injection frequency of injectable drugs and insulin dose were significantly lower in the Dula group than that in the non-Dula group. No differences were observed in the number of hypoglycemic events, the elevation of serum pancreatic enzyme levels, or gastrointestinal adverse events. CONCLUSION: These findings suggest that Dula could provide glycemic control while reducing the insulin dose and injection frequency in inpatients with GC-induced hyperglycemia. The occurrence of adverse events such as gastrointestinal symptoms and hypoglycemia did not increase in the Dula-treated patients compared to those not treated, suggesting its safety.

DOI： 10.1186/s12902-020-0542-5

PubMed

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

A 30-year-old woman with multiple ovarian cysts presented with high serum estradiol levels. She had a pituitary adenoma, but the follicle-stimulating hormone (FSH) concentration was within the normal range. The patient complained of neck pain and palpitations during the disease course, and laboratory results revealed thyrotoxicosis and a systemic inflammatory response with negative findings for anti-thyroid stimulating hormone (TSH) receptor antibody and positive findings for anti-thyroglobulin and anti-thyroid peroxidase antibodies. Prednisolone improved the symptoms and the thyroid function and was discontinued after two months. A histological examination of the pituitary tumor confirmed it to be FSH-producing pituitary adenoma, with subsequent normalization of the serum estradiol concentration.

DOI： 10.2169/internalmedicine.3667-19

PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Perivascular adipose tissue (PVAT) plays a critical role in the pathogenesis of cardiovascular disease. It is unclear whether inhibition of sodium glucose cotransporter 2 (SGLT2) in subjects with type 2 diabetes (T2DM) could affect PVAT characters, and whether the SGLT2 inhibitors-induced changes of adipose tissue, especially the alternation of adipose tissue-derived secretory factors, affect vascular pathophysiology. METHODS: Western-type diet (WD) fed wild-type mice were treated with or without an SGLT2 inhibitor ipragliflozin (Ipra) for 10 weeks. WEHI 274.1 and primary vascular smooth muscle cells were incubated with conditioned media (CM) of epididymal adipose tissue (Epi) or abdominal PVAT of Ipra- or vehicle-treated mice fed a WD. Epi of Ipra- or vehicle-treated mice fed a WD was implanted onto cuff-placed femoral arteries of apoE-deficient mice. RESULTS: Ipra increased adipocyte size associated with decreased expression of pro-inflammatory and fibrosis-related genes in abdominal PVAT of WD-fed mice. Ipra also suppressed WD-induced macrophages accumulation, fibrosis, and adipocyte death in abdominal PVAT. In CM of abdominal PVAT from Ipra-treated mice, concentration of leptin was significantly lower than that from vehicle-treated mice. In vitro, migration of WEHI 274.1 and primary vascular smooth muscle cells were more enhanced by CM of Epi or abdominal PVAT from vehicle-treated mice than that from Ipra-treated mice. Perivascular implantation of Epi from Ipra-treated mice to apolipoprotein E-deficient mice attenuated cuff-induced neointimal hyperplasia and vascular remodeling compared to that from vehicle-treated mice. CONCLUSIONS: The Ipra-induced changes of abdominal PVAT will lead to a better understanding of unveiled mechanisms by which SGLT2 inhibitors prevent cardiovascular complications in T2DM, and the development of new therapeutic strategies targeting PVAT.

DOI： 10.1186/s12933-019-0886-1

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

The adipose tissue includes various stromal cells, such as preadipocytes, endothelial cells, fibroblasts, and immune cells, which are involved in adipose tissue functions. We previously reported that, in obese mice, the sodium-glucose cotransporter 2 inhibitor ipragliflozin (Ipra) promoted the expansion of the epididymal adipose tissue (Epi) with increase of serum ketone body concentration. The Ipra-induced adipose tissue expansion did not deteriorate adipose inflammation, or systemic glucose/lipid metabolism, referred to as "healthy adipose tissue expansion." Here we found that Ipra promoted healthy adipose tissue expansion with a reduced ratio of pro-inflammatory M1-like adipose tissue macrophages (ATMs) to anti-inflammatory M2-like ATMs. Ipra downregulated the gene expression of interleukin (IL)-15 (Il15) in stromal cells of Epi. IL-15 inhibited lipogenesis in 3T3-L1 cells associated with downregulation of the lipogenic gene. Ketone body β-hydroxybutyrate suppressed Il15 gene induction in M1-polarized cultured macrophages, and a ketogenic diet reproduced the adipose tissue expansion without deteriorating systemic glucose metabolism in mice. Our data indicate that the phenotypic switch of ATMs could mediate healthy adipose tissue expansion by treatment with Ipra, and it may offer new insights into the pathophysiological mechanisms of adipose tissue expansion.

DOI： 10.1038/s41598-018-34305-x

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Sodium glucose cotransporter 2 (SGLT2) inhibitors, an antidiabetic drug, promotes urinary excretion of glucose by blocking its reabsorption in the renal proximal tubules. It is unclear whether SGLT2 inhibition could attenuate nonalcoholic steatohepatitis (NASH) and NASH-associated hepatocellular carcinoma. We examined the preventive effects of an SGLT2 inhibitor canagliflozin (CANA) in Western diet (WD)-fed melanocortin 4 receptor-deficient (MC4R-KO) mice, a mouse model of human NASH. An eight-week CANA treatment attenuated hepatic steatosis in WD-fed MC4R-KO mice, with increased epididymal fat mass without inflammatory changes. CANA treatment for 20 weeks inhibited the development of hepatic fibrosis in WD-fed MC4R-KO mice. After one year of CANA treatment, the number of liver tumors was significantly reduced in WD-fed MC4R-KO mice. In adipose tissue, CANA suppressed the ratio of oxidative to reduced forms of glutathiones (GSSG/GSH) in WD-fed MC4R-KO mice. Treatment with GSH significantly attenuated the H2O2-induced upregulation of genes related to NADPH oxidase in 3T3-L1 adipocytes, and that of Il6, Tgfb, and Pdgfb in RAW264.7 cells. This study provides evidence that SGLT2 inhibitors represent the unique class of drugs that can attenuate or delay the onset of NASH and eventually hepatocellular carcinoma, at least partly, through "healthy adipose expansion".

DOI： 10.1038/s41598-018-19658-7

PubMed

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Forkhead box class O family member proteins (FoxOs) of transcription factors are essential regulators of cellular homeostasis, including glucose and lipid metabolism, oxidative stress response and redox signaling, cell cycle progression, and apoptosis. Altered FoxO1 expression and activity have been associated with glucose intolerance, dyslipidemia and complications of diabetes. In the liver, they direct carbons to glucose or lipid utilization, thus providing a unifying mechanism for the two abnormalities of the diabetic liver: excessive glucose production, and increased lipid synthesis and secretion. In the pancreas, FoxO1 is necessary to maintain β-cell differentiation, and could be promising targets for β-cell regeneration. In endothelial cells, FoxOs strongly promote atherosclerosis through suppressing nitric oxide production and enhancing inflammatory responses. In the present review, we summarize the basic biology and pathophysiological significance of FoxOs in diabetes.

DOI： 10.1111/jdi.12651

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

The pathophysiology of aldosterone-producing adenomas (APAs) has been investigated via genetic approaches and the pathogenic significance of a series of somatic mutations, including KCNJ5, has been uncovered. However, how the mutational status of an APA is associated with its molecular characteristics, including its transcriptome and methylome, has not been fully understood. This study was undertaken to explore the molecular characteristics of APAs, specifically focusing on APAs with KCNJ5 mutations as opposed to those without KCNJ5 mutations, by comparing their transcriptome and methylome status. Cortisol-producing adenomas (CPAs) were used as reference. We conducted transcriptome and methylome analyses of 29 APAs with KCNJ5 mutations, 8 APAs without KCNJ5 mutations and 5 CPAs. Genome-wide gene expression and CpG methylation profiles were obtained from RNA and DNA samples extracted from these 42 adrenal tumors. Cluster analysis of the transcriptome and methylome revealed molecular heterogeneity in APAs depending on their mutational status. DNA hypomethylation and gene expression changes in Wnt signaling and inflammatory response pathways were characteristic of APAs with KCNJ5 mutations. Comparisons between transcriptome data from our APAs and that from normal adrenal cortex obtained from the Gene Expression Omnibus suggested similarities between APAs with KCNJ5 mutations and zona glomerulosa. The present study, which is based on transcriptome and methylome analyses, indicates the molecular heterogeneity of APAs depends on their mutational status. Here, we report the unique characteristics of APAs with KCNJ5 mutations.

DOI： 10.1530/ERC-17-0117

PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Non-alcoholic steatohepatitis (NASH) is characterized by steatosis with lobular inflammation and hepatocyte injury. Pirfenidone (PFD) is an orally bioavailable pyridone derivative that has been clinically used for the treatment of idiopathic pulmonary fibrosis. However, it remains unknown whether PFD improves liver fibrosis in a mouse model with human NASH-like phenotypes. In this study, we employed melanocortin 4 receptor-deficient (MC4R-KO) mice as a mouse model with human NASH-like phenotypes to elucidate the effect and action mechanisms of PFD on the development of NASH. PFD markedly attenuated liver fibrosis in western diet (WD)-fed MC4R-KO mice without affecting metabolic profiles or steatosis. PFD prevented liver injury and fibrosis associated with decreased apoptosis of liver cells in WD-fed MC4R-KO mice. Pretreatment of PFD inhibited the tumor necrosis factor-α (TNF-α)-induced liver injury and fibrogenic responses associated with decreased apoptosis of liver cells in wild-type mice. PFD also prevented TNF-α-induced hepatocyte apoptosis in vitro with reduced activation of caspase-8 and -3. This study provides evidence for the antifibrotic effect of PFD in a mouse model of human NASH. The data of this study highlight hepatocyte apoptosis as a potential therapeutic target, and suggest that PFD can be repositioned as an antifibrotic drug for human NASH.

DOI： 10.1038/srep44754

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Obesity promotes infiltration of inflammatory cells into various tissues, leading to parenchymal and stromal cell interaction and development of cellular and organ dysfunction. Liver sinusoidal endothelial cells (LSECs) are the first cells that contact portal blood cells and substances in the liver, but their functions in the development of obesity-associated glucose metabolism remain unclear. Here, we find that LSECs are involved in obesity-associated accumulation of myeloid cells via VLA-4-dependent cell-cell adhesion. VLA-4 blockade in mice fed a high-fat diet attenuated myeloid cell accumulation in the liver to improve hepatic inflammation and systemic glucose intolerance. Ex vivo studies further show that cell-cell contact between intrahepatic leukocytes and parenchymal hepatocytes induces gluconeogenesis via a Notch-dependent pathway. These findings suggest that cell-cell interaction between parenchymal and stromal cells regulates hepatic glucose metabolism and offers potential strategies for treatment or prevention of obesity-associated glucose intolerance.

DOI： 10.1016/j.celrep.2017.02.039

PubMed

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The adrenocortical cells have been shown to produce various inflammatory cytokines such as TNFα and IL-6, which could modulate steroidogenesis. However, the role of inflammatory cytokines in aldosterone-producing adenomas (APAs) is not fully understood. In the present study, we examined the relationships between mRNA expression levels of the inflammation-related genes and somatic mutations in APA tissues. METHODS: We evaluated mRNA expression levels of TNFA, IL6, and NFKB1 in APA tissues obtained from 44 Japanese APA patients. RESULTS: We revealed that mRNA expression patterns of the inflammation-related genes depended on a KCNJ5 somatic mutation. In addition, we showed that mRNA expression levels of the inflammation-related genes correlated with those of the steroidogenic enzyme CYP11B1 in the patients with APAs. CONCLUSION: The present study documented for the first time the expression of inflammation-related genes in APAs and the correlation of their expression levels with the KCNJ5 mutation status and mRNA expression levels of steroidogenic enzymes, indicating the pathophysiological relevance of inflammation-related genes in APAs.

DOI： 10.1016/j.bbrc.2016.06.007

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: Plasma high-density lipoproteins have several putative antiatherogenic effects, including preservation of endothelial functions. This is thought to be mediated, in part, by the ability of high-density lipoproteins to promote cholesterol efflux from endothelial cells (ECs). The ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) interact with high-density lipoproteins to promote cholesterol efflux from ECs. To determine the impact of endothelial cholesterol efflux pathways on atherogenesis, we prepared mice with endothelium-specific knockout of Abca1 and Abcg1. APPROACH AND RESULTS: Generation of mice with EC-ABCA1 and ABCG1 deficiency required crossbreeding Abca1(fl/fl)Abcg1(fl/fl)Ldlr(-/-) mice with the Tie2Cre strain, followed by irradiation and transplantation of Abca1(fl/fl)Abcg1(fl/fl) bone marrow to abrogate the effects of macrophage ABCA1 and ABCG1 deficiency induced by Tie2Cre. After 20 to 22 weeks of Western-type diet, both single EC-Abca1 and Abcg1 deficiency increased atherosclerosis in the aortic root and whole aorta. Combined EC-Abca1/g1 deficiency caused a significant further increase in lesion area at both sites. EC-Abca1/g1 deficiency dramatically enhanced macrophage lipid accumulation in the branches of the aorta that are exposed to disturbed blood flow, decreased aortic endothelial NO synthase activity, and increased monocyte infiltration into the atherosclerotic plaque. Abca1/g1 deficiency enhanced lipopolysaccharide-induced inflammatory gene expression in mouse aortic ECs, which was recapitulated by ABCG1 deficiency in human aortic ECs. CONCLUSIONS: These studies provide direct evidence that endothelial cholesterol efflux pathways mediated by ABCA1 and ABCG1 are nonredundant and atheroprotective, reflecting preservation of endothelial NO synthase activity and suppression of endothelial inflammation, especially in regions of disturbed arterial blood flow.

DOI： 10.1161/ATVBAHA.115.306670

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

A 58-year-old woman was referred to our hospital for Cushingoid features and diagnosed as adrenal Cushing's syndrome due to a right adrenocortical mass (60 × 55 mm). The mass was composed of three different tumors; the first one was homogeneously lipid-poor neoplasm measuring 20 × 13 mm located at the most dorsal region, the second one was heterogeneous and lipid-rich tumor containing multiple foci of calcification measuring 50 × 32 mm located at the central region, and the last one was heterogeneous harboring dilated and tortuous vessels and lipid-poor one measuring 35 × 18 mm at the most ventral region of the adrenal gland. A right adrenalectomy was subsequently performed by open surgery. Macroscopic and microscopic analyses revealed that all three tumors were adrenocortical adenomas; the first one represents a pigmented adrenocortical adenoma, the second one adrenocortical adenoma associated with degeneration, and the third one adrenocortical adenoma harboring extensive degeneration. Immunohistochemical analysis of the steroidogenic enzymes also revealed that all of the tumors had the capacity of synthesizing cortisol. This is a very rare case of Cushing's syndrome caused by multiple adrenocortical adenomas including a pigmented adenoma. Immunohistochemical analysis of steroidogenic enzymes contributed to understanding of steroidogenesis in each of these three different adrenocortical adenomas in this case.

DOI： 10.1007/s12022-016-9423-x

PubMed

Language：English   Publishing type：(MISC) Summary of the papers read (international conference)   Publisher：AMER DIABETES ASSOC  

Web of Science

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Lifestyle-related diseases such as type 2 diabetes, hypertension and dyslipidemia are a prominent cause of mortality in Japan, and there is a strong requirement for elucidation of detailed molecular mechanisms and effective therapeutic strategies. Obesity-induced adipose tissue inflammation leads to dysregulation of adipokine production, which can cause lifestyle-related diseases. The interaction of organ systems via endocrine or neural networks is recognized as an important factor in the pathogenesis and promotion of lifestyle-related diseases. Therefore, further investigation for the interaction between adipose tissues and bones can provide new treatment strategies of metabolic bone disorders.

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Type 2 diabetes mellitus (T2DM) is associated with a high incidence of non-alcoholic fatty liver disease (NAFLD) related to obesity and insulin resistance. Currently, medical interventions for NAFLD have focused on diet control and exercise to reduce body weight, and there is a requirement for effective pharmacological therapies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral antidiabetic drugs that promote the urinary excretion of glucose by blocking its reabsorption in renal proximal tubules. SGLT2 inhibitors lower blood glucose independent of insulin action and are expected to reduce body weight because of urinary calorie loss. Here we show that an SGLT2 inhibitor ipragliflozin improves hepatic steatosis in high-fat diet-induced and leptin-deficient (ob/ob) obese mice irrespective of body weight reduction. In the obese mice, ipragliflozin-induced hyperphagia occurred to increase energy intake, attenuating body weight reduction with increased epididymal fat mass. There is an inverse correlation between weights of liver and epididymal fat in ipragliflozin-treated obese mice, suggesting that ipragliflozin treatment promotes normotopic fat accumulation in the epididymal fat and prevents ectopic fat accumulation in the liver. Despite increased adiposity, ipragliflozin ameliorates obesity-associated inflammation and insulin resistance in epididymal fat. Clinically, ipragliflozin improves liver dysfunction in patients with T2DM irrespective of body weight reduction. These findings provide new insight into the effects of SGLT2 inhibitors on energy homeostasis and fat accumulation and indicate their potential therapeutic efficacy in T2DM-associated hepatic steatosis.

DOI： 10.1371/journal.pone.0151511

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Aldosterone-producing adenoma (APA) is a form of primary aldosteronism (PA). Recent studies suggested that somatic mutations in the KCNJ5, ATP1A1, ATP2B3, and CACNA1D genes are involved in the pathogenesis of APA. We report a case of a 62-year-old man diagnosed as PA with left adrenal mass. He underwent adrenalectomy for treatment. We identified a novel somatic deletion mutation in ATP2B3 in the adrenal tumor: c.1269_1274delTGTGCT which spans three codons (423-425) resulting in p.Val424_Leu425del. Immunohistochemical analysis revealed strong expression of aldosterone synthase (CYP11B2) in the tumor tissue, which is consistent with APA. Here, we identified a novel somatic deletion mutation in ATP2B3, which results in the amino acid sequences increasing intracellular calcium concentrations as reported previously, leading to increased aldosterone synthase (CYP11B2) expression and following excess aldosterone production in the APA cells. The novel ATP2B3 mutation detected in our case supports the pathogenic significance of the locus spanning the codon 424-426 of ATP2B3.

DOI： 10.1007/s12022-015-9400-9

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: The pathophysiology of aldosterone-producing adenomas (APA) has been investigated intensively through genetic and genomic approaches. However, the role of epigenetics in APA is not fully understood. In the present study, we explored the relationship between gene expression and DNA methylation status in APA. METHODS: We conducted an integrated analysis of transcriptome and methylome data of paired APA-adjacent adrenal gland (AAG) samples from the same patient. The adrenal specimens were obtained from seven Japanese patients with APA who underwent adrenalectomy. Gene expression and genome-wide CpG methylation profiles were obtained from RNA and DNA samples that were extracted from those seven paired tissues. RESULTS: Methylome analysis showed global CpG hypomethylation in APA relative to AAG. The integration of gene expression and methylation status showed that 34 genes were up-regulated with CpG hypomethylation in APA. Of these, three genes (CYP11B2, MC2R, and HPX) may be related to aldosterone production, and five genes (PRRX1, RAB38, FAP, GCNT2, and ASB4) are potentially involved in tumorigenesis. CONCLUSION: The present study is the first methylome analysis to compare APA with AAG in the same patients. Our integrated analysis of transcriptome and methylome revealed DNA hypomethylation in APA and identified several up-regulated genes with DNA hypomethylation that may be involved in aldosterone production and tumorigenesis.

DOI： 10.1530/EJE-15-0148

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Insulin signaling in the liver blunts glucose production and stimulates triglyceride biosynthesis. FoxO1 is required for cAMP induction of hepatic glucose production and is permissive for the effect of insulin to suppress this process. Moreover, FoxO1 ablation increases lipogenesis. In this study, we investigated the pleiotropic actions of FoxO1 on glucose and lipid metabolism. To this end, we reconstituted FoxO1 function in mice with a liver-specific deletion of Foxo1 using targeted knock-in of an allele encoding a DNA binding-deficient FoxO1 mutant (L-DBD). Chow-reared L-DBD mice showed defects in hepatic glucose production but normal liver triglyceride content despite increased rates of de novo lipogenesis and impaired fatty acid oxidation in isolated hepatocytes. Gene expression studies indicated that FoxO1 regulates the expression of glucokinase via a cell-nonautonomous coregulatory mechanism, while its regulation of glucose-6-phosphatase proceeds via a cell-autonomous action as a direct transcriptional activator. These conclusions support a differential regulation of hepatic glucose and lipid metabolism by FoxO1 based on the mechanism by which it alters the expression of key target genes involved in each process.

DOI： 10.2337/db14-1506

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Generation of surrogate sources of insulin-producing β-cells remains a goal of diabetes therapy. While most efforts have been directed at differentiating embryonic or induced pluripotent stem (iPS) cells into β-like-cells through endodermal progenitors, we have shown that gut endocrine progenitor cells of mice can be differentiated into glucose-responsive, insulin-producing cells by ablation of transcription factor Foxo1. Here we show that FOXO1 is present in human gut endocrine progenitor and serotonin-producing cells. Using gut organoids derived from human iPS cells, we show that FOXO1 inhibition using a dominant-negative mutant or lentivirus-encoded small hairpin RNA promotes generation of insulin-positive cells that express all markers of mature pancreatic β-cells, release C-peptide in response to secretagogues and survive in vivo following transplantation into mice. The findings raise the possibility of using gut-targeted FOXO1 inhibition or gut organoids as a source of insulin-producing cells to treat human diabetes.

DOI： 10.1038/ncomms5242

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Insulin signaling in vascular endothelial cells (ECs) is critical to maintain endothelial function but also to mediate insulin action on peripheral glucose disposal. However, gene knockout studies have reached disparate conclusions. Thus, insulin receptor inactivation in ECs does not impair insulin action, whereas inactivation of Irs2 does. Previously, we have shown that endothelial ablation of the three Foxo genes protects mice from atherosclerosis. Interestingly, here we show that mice lacking FoxO isoforms in ECs develop hepatic insulin resistance through excessive generation of nitric oxide (NO) that impairs insulin action in hepatocytes via tyrosine nitration of insulin receptors. Coculture experiments demonstrate that NO produced in liver sinusoidal ECs impairs insulin's ability to suppress glucose production in hepatocytes. The effects of liver sinusoidal ECs can be mimicked by NO donors and can be reversed by NO inhibitors in vivo and ex vivo. The findings are consistent with a model in which excessive, rather than reduced, insulin signaling in ECs predisposes to systemic insulin resistance, prompting a reevaluation of current approaches to insulin sensitization.

DOI： 10.2337/db12-1296

PubMed

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

RATIONALE: Increased neutrophil and monocyte counts are often associated with an increased risk of atherosclerosis, but their relationship to insulin sensitivity is unknown. OBJECTIVE: To investigate the contribution of forkhead transcription factors (FoxO) in myeloid cells to neutrophil and monocyte counts, atherosclerosis, and systemic insulin sensitivity. METHODS AND RESULTS: Genetic ablation of the 3 genes encoding FoxO isoforms 1, 3a, and 4, in myeloid cells resulted in an expansion of the granulocyte/monocyte progenitor compartment and was associated with increased atherosclerotic lesion formation in low-density lipoprotein receptor knockout mice. In vivo and ex vivo studies indicate that FoxO ablation in myeloid cells increased generation of reactive oxygen species. Accordingly, treatment with the antioxidant N-acetyl-l-cysteine reversed the phenotype, normalizing atherosclerosis. CONCLUSIONS: Our data indicate that myeloid cell proliferation and oxidative stress can be modulated via the FoxO branch of insulin receptor signaling, highlighting a heretofore-unknown link between insulin sensitivity and leukocytosis that can affect the predisposition to atherosclerosis.

DOI： 10.1161/CIRCRESAHA.112.300749

PubMed

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: Saturated fatty acids, such as palmitic and stearic acid, cause detrimental effects in endothelial cells and have been suggested to contribute to macrophage accumulation in adipose tissue and the vascular wall, in states of obesity and insulin resistance. Long-chain fatty acids are believed to require conversion into acyl-CoA derivatives to exert most of their detrimental effects, a reaction catalyzed by acyl-CoA synthetases (ACSLs). The objective of this study was to investigate the role of ACSL1, an ACSL isoform previously shown to mediate inflammatory effects in myeloid cells, in regulating endothelial cell responses to a saturated fatty acid-rich environment in vitro and in vivo. METHODS AND RESULTS: Saturated fatty acids caused increased inflammatory activation, endoplasmic reticulum stress, and apoptosis in mouse microvascular endothelial cells. Forced ACSL1 overexpression exacerbated the effects of saturated fatty acids on apoptosis and endoplasmic reticulum stress. However, endothelial ACSL1 deficiency did not protect against the effects of saturated fatty acids in vitro, nor did it protect insulin-resistant mice fed a saturated fatty acid-rich diet from macrophage adipose tissue accumulation or increased aortic adhesion molecule expression. CONCLUSIONS: Endothelial ACSL1 is not required for inflammatory and apoptotic effects of a saturated fatty acid-rich environment.

DOI： 10.1161/ATVBAHA.112.252239

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Complications of atherosclerosis are the leading cause of death of patients with type 2 (insulin-resistant) diabetes. Understanding the mechanisms by which insulin resistance and hyperglycemia contribute to atherogenesis in key target tissues (liver, vessel wall, hematopoietic cells) can assist in the design of therapeutic approaches. We have shown that hyperglycemia induces FoxO1 deacetylation and that targeted knock-in of alleles encoding constitutively deacetylated FoxO1 in mice (Foxo1(KR/KR)) improves hepatic lipid metabolism and decreases macrophage inflammation, setting the stage for a potential anti-atherogenic effect of this mutation. Surprisingly, we report here that when Foxo1(KR/KR) mice are intercrossed with low density lipoprotein receptor knock-out mice (Ldlr(-/-)), they develop larger aortic root atherosclerotic lesions than Ldlr(-/-) controls despite lower plasma cholesterol and triglyceride levels. The phenotype is unaffected by transplanting bone marrow from Ldlr(-/-) mice into Foxo1(KR/KR) mice, indicating that it is independent of hematopoietic cells and suggesting that the primary lesion in Foxo1(KR/KR) mice occurs in the vessel wall. Experiments in isolated endothelial cells from Foxo1(KR/KR) mice indicate that deacetylation favors FoxO1 nuclear accumulation and exerts target gene-specific effects, resulting in higher Icam1 and Tnfα expression and increased monocyte adhesion. The data indicate that FoxO1 deacetylation can promote vascular endothelial changes conducive to atherosclerotic plaque formation.

DOI： 10.1074/jbc.M111.332767

PubMed

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Atherosclerotic cardiovascular disease is the leading cause of death in insulin-resistant (type 2) diabetes. Vascular endothelial dysfunction paves the way for atherosclerosis through impaired nitric oxide availability, inflammation, and generation of superoxide. Surprisingly, we show that ablation of the three genes encoding isoforms of transcription factor FoxO in endothelial cells prevents atherosclerosis in low-density lipoprotein receptor knockout mice by reversing these subphenotypes. Paradoxically, the atheroprotective effect of FoxO deletion is associated with a marked decrease of insulin-dependent Akt phosphorylation in endothelial cells, owing to reduced FoxO-dependent expression of the insulin receptor adaptor proteins Irs1 and Irs2. These findings support a model in which FoxO is the shared effector of multiple atherogenic pathways in endothelial cells. FoxO ablation lowers the threshold of Akt activity required for protection from atherosclerosis. The data demonstrate that FoxO inhibition in endothelial cells has the potential to mediate wide-ranging therapeutic benefits for diabetes-associated cardiovascular disease.

DOI： 10.1016/j.cmet.2012.01.018

PubMed

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: Insulin resistance renders macrophages more prone to cholesterol-induced apoptosis by promoting nuclear localization of transcription factor forkhead box transcription factor (Fox) O1. However, FoxO1 also decreases macrophage inflammation, raising the question of how the balance between proapoptotic and antiinflammatory effects is determined. We sought to identify the mechanism whereby FoxO1 dampens inflammation without promoting apoptosis. We hypothesized that nutrient-dependent FoxO1 acetylation plays a role in this process. METHODS AND RESULTS: We generated knock-in mice bearing alleles that encode constitutively deacetylated FoxO1 and studied the ex vivo response of primary peritoneal macrophages. We show that macrophages derived from mice homozygous for constitutively deacetylated FoxO1 alleles retain antiinflammatory properties in response to free cholesterol loading, without increasing apoptosis. Deacetylated FoxO1 inhibits free cholesterol-induced Akt phosphorylation and increases levels of the nuclear factor-κB precursor p105, decreasing nuclear translocation of nuclear factor-κB p65 subunit and dampening mitogen-activated protein/extracellular signal-regulated kinase activation to prevent inflammation. CONCLUSIONS: Deacetylated FoxO1 regulates p105 to prevent macrophage inflammation without causing apoptosis, suggesting a potential novel therapeutic approach to atherosclerosis through FoxO1 deacetylation.

DOI： 10.1161/ATVBAHA.110.219477

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Primary aldosteronism (PA), an autonomous aldosterone hypersecretion from adrenal adenoma and/or hyperplasia, and subclinical Cushing syndrome (SCS), a mild but autonomous cortisol hypersecretion from adrenal adenoma without signs or symptoms of Cuhing's syndrome, are now well-recognized clinical entities of adrenal incidentaloma. However, the clinicopathological features of PA associated with SCS (PA/SCS) remain unknown. The present study was undertaken to study the prevalence of PA/SCS among PA patients diagnosed at our institute, and characterize their clinicopathlogical features. The prevalence of PA/SCS was 8 of 38 PA patients (21%) studied. These 8 PA/SCS patients were significantly older and had larger tumor, higher serum potassium levels, lower basal plasma levels of aldosterone, ACTH and DHEA-S as well as lower response of aldosterone after ACTH stimulation than those in 12 patients with aldosterone-producing adenoma without hypercortisolism. All 8 PA/SCS patients showed unilateral uptake by adrenal scintigraphy at the ipsilateral side, whereas the laterality of aldosterone hypersecretion as determined by adrenal venous sampling varied from ipsilateral (3), contralateral (2), and bilateral side (2). 6 PA/SCS patinets who underwent adrenalectomy required hydrocortisone replacement postoperatively. Histopathological analysis of the resected adrenal tumors from 5 PA/SCS patients revealed a single adenoma in 3, and double adenomas in 2, with varying degrees of positive immunoreactivities for steroidgenic enzymes (3β-HSD, P450(C17)) by immunohistochemical study as well as CYP11B2 mRNA expression as measured by real-time RT-PCR. In conclusion, PA/SCS consists of a variety of adrenal pathologies so that therapeutic approach differs depending on the disease subtype.

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Telmisartan, a selective antagonist for angiotensin type1 receptor and a partial agonist for peroxisome proliferator-activated receptor-gamma, decreases blood pressure and has been shown to improve glucose and lipid metabolism, suggesting potential cardiovascular protective effects. In this study, we investigated whether long-term treatment with telmisartan improved endothelial function in 35 hypertensive patients with type 2 diabetes mellitus (T2DM). Office and home early morning blood pressure levels and flow-mediated vasodilation (FMD) were evaluated before and after 12 months of treatment with telmisartan. Blood samples were also obtained for measurement of several biochemical parameters and of adiponectin (AN) and highly sensitive C-reactive protein (hs-CRP) before and after treatment. After 12 months of treatment, office and morning blood pressure levels had significantly decreased, and levels of plasma glucose, glycosylated hemoglobin, total cholesterol, triglyceride and low-density lipoprotein cholesterol had also significantly decreased. Plasma AN and high-density lipoprotein cholesterol levels increased, but hs-CRP levels decreased. Furthermore, FMD significantly increased; changes in percent FMD showed a significant negative correlation with changes in systolic and diastolic blood pressure and a significant positive correlation with changes in AN. Stepwise multivariate regression analysis revealed that changes in plasma AN and office systolic blood pressure were both independent determinants for endothelial function after telmisartan treatment. In conclusion, this study shows that long-term treatment with telmisartan improves not only blood pressure and glucose and lipid metabolism but also endothelial function in hypertensive patients with T2DM, possibly by increased circulating AN and decreased blood pressure.

DOI： 10.1038/hr.2010.107

PubMed

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Cushing's syndrome (CS) as represented by chronic glucocorticoid excess is associated with increased rate of cardiovascular morbidity and mortality. Because endothelial dysfunction is an early event of atherosclerosis, we investigated whether endothelial dysfunction is associated with CS and reversible. Twenty-one CS patients due to different causes were studied for vascular endothelial function by ultrasound measurement of flow-mediated vasodilation (FMD), among whom 12 patients were re-evaluated after surgical and medical treatment; 12 age- and gender-matched subjects served as control. Percent (%) FMD in CS patients (5.8+/-1.9 %) was significantly (p =0.0014) lower than that in control subjects (8.1+/-1.7 %). In CS patients, %FMD showed significant (p < 0.01) negative correlations with morning serum cortisol levels (r =-0.58) and 24-h urinary free cortisol excretion (r =-0.58). After surgical and medical treatment in CS patients, morning cortisol levels significantly (p =0.0025) decreased from 23.4 [15.6-37.3] to 10.2 [7.7-12.9] microg/dL, whereas %FMD significantly (p =0.0024) increased from 5.2+/-1.9 to 7.8+/-2.3 %; changes of %FMD after treatment significantly (p =0.0004) and inversely correlated with those of morning cortisol levels (r =-0.85), but not with those of body mass index, blood pressure, glycemic or lipid profiles. Taken together, the present study clearly revealed that endothelial dysfunction in CS patients is related to hypercortisolemia and reversible after treatment, suggesting the possible role of cortisol excess in the development of endothelial dysfunction, thereby possibly leading to increased cardiovascular complications.

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

A 56-year-old man was admitted to our hospital for the surgical removal of renal cell carcinoma (RCC). He was diagnosed with acromegaly due to his characteristic clinical features, endocrine data, and the presence of pituitary tumor. He was found to have colon cancer and follicular thyroid tumor. Pathological examination of the pituitary tumor after transsphenoidal surgery was compatible with growth hormone (GH)-secreting pituitary adenoma. We also detected the transcripts and/or immunoreactivity of GH/insulin-like growth factor I components in the tumor specimen. This is a rare case of acromegaly associated with multiple tumors, including RCC, colon cancer and thyroid tumor.

PubMed

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A 59-year-old man was admitted because of congestive heart failure. He was suspected to have acromegaly, and magnetic resonance imaging revealed a pituitary macroadenoma. Endocrine examination revealed elevated plasma levels of growth hormone (GH) and insulin-like growth factor (IGF)-1, and an oral glucose tolerance test failed to suppress plasma GH levels, consistent with the diagnosis of GH-producing pituitary tumor. Treatment with octreotide, followed by transsphenoidal surgery resulted in normalization of plasma GH/IGF-1 levels, accompanied by the improvement of cardiac function. Thus, it is suggested that excess GH/IGF-1 axis is involved in the development of acromegaly-related cardiomyopathy in the present case.

PubMed

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Primary aldosteronism (PA) is a secondary hypertension characterized by autonomous aldosterone hypersecretion from adrenocortical adenoma and/or hyperplasia. Recently it has been suggested that aldosterone excess is directly involved in the development of cardiovascular injury in PA independent of its hypertensive effect. The present study was designed to examine the relationship between aldosterone excess and endothelial dysfunction in PA patients. 25 PA patients were studied for vascular endothelial function by ultrasound measurement of flow-mediated vasodilation (FMD), and 10 PA patients were re-evaluated 3 months after surgical or medical treatment; 10 age-, gender-, and blood pressurematched hypertensive patients served as control subjects. Percent (%) FMD in PA patients (4.6+/-2.0%) was significantly (p < 0.0001) lower than that in the control subjects (7.9+/-2.0%). %FMD showed significant (p < 0.05) negative correlations with systolic blood pressure (SBP) (r=-0.48), brachial-ankle pulse wave velocity (r=-0.52), plasma aldosterone concentration (PAC) (r=-0.42), and aldosterone-renin ratio (ARR) (r=-0.42), while SBP showed a positive correlation with PAC (r=0.47). Percent FMD, SBP, PAC, and ARR significantly (p < 0.05) improved after surgical and medical treatment, although the changes of %FMD did not correlate with those of SBP, PAC or ARR. In conclusion, the present study has demonstrated that PA patients have endothelial dysfunction, which is related to aldosterone excess and raised blood pressure, and reversible after treatment, suggesting that aldosterone excess contributes to the development of endothelial dysfunction due to its hypertensive effect and/or its direct effect on the cardiovascular system.

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Endothelial dysfunction is considered to be an early event in the development of atherosclerosis. The present study was undertaken to evaluate endothelial function and biochemical markers in type 2 diabetes mellitus (T2DM) patients before and after treatment with or without pioglitazone (PIO). Forty-one T2DM patients without macroangiopathy were randomized to treatment with (n=20) or without (control, n=21) PIO for 12 weeks. Endothelial function was assessed by flow-mediated vasodilation (FMD) using a high-resolution ultrasound method before and after treatment. After treatment, HbA1c levels equally decreased in both groups, but PIO-treated group had significantly increased high-density lipoprotein cholesterol (HDL-C) levels, and decreased triglyceride, fasting insulin levels and HOMA-R. After treatment, increases in %FMD, plasma HDL-C and adiponectin (APN) levels were significantly greater in PIO-treated group than those in control group. Changes of %FMD showed significant positive correlations with those of plasma APN and HDL-C levels. In conclusion, the present study showed that treatment of T2DM improved endothelial function with greater increases in %FMD, APN and HDL-C levels in PIO-treated group than those in control group, suggesting the beneficial effect of PIO on endothelial function in T2DM.

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Flow-mediated vasodilatation (FMD) is a vascular functional test to detect endothelial dysfunction at the early stage of cardiovascular diseases. Patients with active acromegaly have higher morbidity and mortality due to cardiovascular events. To determine whether active acromegaly is associated with endothelial dysfunction, we studied 17 patients with active acromegaly for measurements of FMD, carotid intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV), and other biochemical parameters before and 3 months after transsphenoidal surgery (TSS). Baseline %FMD in patients with active acromegaly was significantly lower than that in age- and sex-matched control subjects. After TSS, the mean %FMD in acromegaly significantly increased from 5.3% to 7.4%; 12 patients had increased %FMD (responders), whereas 5 patients had decreased or unchanged %FMD (non-responders). However, neither carotid IMT nor baPWV changed after TSS. Serum levels of GH, insulin-like growth factor (IGF)-1, total cholesterol, low-density lipoprotein cholesterol (LDL-C), hemoglobin HA(1C), fasting plasma glucose and insulin levels, and homeostasis model assessment (HOMA)-R significantly decreased, whereas high-density lipoprotein cholesterol significantly increased. Responders had significantly lower baseline %FMD than did non-responders and both insulin levels and HOMA-R significantly decreased in responders, but not in non-responders after TSS. Simple regression analysis revealed that the change of %FMD showed a significant negative correlation with that of LDL-C, but not of IGF-1 or GH, in responders. In conclusion, it is suggested that endothelial dysfunction associated with active acromegaly improves soon after TSS, which is related to LDL-C and/or insulin resistance, but not to excess GH and/or IGF-1 itself.

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Measurement of late-night and/or midnight salivary cortisol currently used in US and European countries is a simple and convenient screening test for the initial diagnosis of Cushing's syndrome (CS). Unfortunately, this test has not been widely used in Japan. The purpose of this study was to evaluate the usefulness of the measurement of late-night salivary cortisol as a screening test for the diagnosis of CS in Japan. We studied 27 patients with various causes of CS, consisting of ACTH-dependent Cushing's disease [5] and ectopic ACTH syndrome [4] and ACTH-independent adrenal CS [11] and subclinical CS [7]. Eleven patients with type 2 diabetes and obesity and 16 normal subjects served as control group. Saliva samples were collected at late-night (23:00) in a commercially available device and assayed for cortisol by radioimmunoassay. There were highly significant correlations (P<0.0001) between late-night serum and salivary cortisol levels in normal subjects (r = 0.861) and in patients with CS (r = 0.788). Late-night salivary cortisol levels in CS patients (0.975 +/- 1.56 microg/dl) were significantly higher than those in normal subjects (0.124 +/- 0.031 microg/dl) and in obese diabetic patients (0.146 +/- 0.043 microg/dl), respectively. Twenty-five out of 27 CS patients had late-night salivary cortisol concentrations greater than 0.21 microg/dl, whereas those in control group were less than 0.2 microg/dl. Receiver operating characteristic curve (ROC) analysis showed that the cut-off point of 0.21 microg/dl provides a sensitivity of 93% and a specificity of 100%. Therefore, it is concluded that the measurement of late-night salivary cortisol is an easy and reliable noninvasive screening test for the initial diagnosis of CS, especially useful for large high-risk populations, such as diabetes and obesity.

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

AIM: Endothelial dysfunction is considered an early event in the development of atherosclerosis. The present study was undertaken to determine whether the accumulation of cardiovascular risk factors and insulin resistance are associated with endothelial function in diabetic patients. METHODS: 101 patients with type 2 diabetes without macroangiopathy stratified by the number of cardiovascular risk factors (dyslipidemia, hypertension, obesity) and 9 normal control subjects were studied for vascular endothelial functions by measuring flow-mediated vasodilation (FMD) using a high-resolution ultrasound method, brachial-ankle pulse wave velocity (baPWV), carotid intima-media thickness (IMT), and the ankle-brachial index (ABI). RESULTS: FMD negatively correlated with baPWV and carotid IMT, and positively correlated with ABI. FMD was significantly lower in diabetic patients associated with 3 other risk factors than in those with diabetes alone. In subjects with fasting plasma glucose < or = 140mg/dL, FMD showed significant negative correlations with fasting insulin levels and homeostasis model assessment (HOMA)-R. Multivariate analysis revealed that insulin resistance as represented by HOMA-R and systolic blood pressure showed a significant association with impaired FMD. CONCLUSION: The present results suggest that the accumulation of cardiovascular risk factors is associated with endothelial dysfunction in diabetic patients, and that insulin resistance as well as high blood pressure could play a pathogenic role in the development of endothelial dysfunction.

PubMed

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Genetic deletion of inducible nitric oxide synthase (NOS) in mice has been shown to improve high-fat diet (HFD)-induced insulin resistance. However, a pathophysiological role of endogenous nitric oxide (NO) in obesity-related insulin resistance remains controversial. To address this issue, we examined the metabolic phenotypes in HFD-induced obese mice with chronic blockade of NO synthesis by a NOS inhibitor, N(G)-nitro-l-arginine methyl ester (L-NAME). Six-week-old male C57BL/6j mice were provided free access to either a standard diet (SD) or a HFD and tap water with or without L-NAME (100 mg/kg.d) for 12 wk. L-NAME treatment significantly attenuated body weight gain of mice fed either SD or HFD without affecting calorie intake. L-NAME treatment in HFD-fed mice improved glucose tolerance and insulin sensitivity. HFD feeding induced inducible NOS mRNA expression, but not the other two NOS isoforms, in white adipose tissue (WAT) and skeletal muscle. L-NAME treatment up-regulated uncoupling protein-1 in brown adipose tissue of HFD-fed mice but down-regulated monocyte chemoattractant protein-1 and CD68 mRNAs levels in WAT. HFD feeding up-regulated leptin mRNA levels but conversely down-regulated adiponectin mRNA levels in WAT, but these effects were unaffected by L-NAME treatment. Moreover, L-NAME treatment also increased peroxisome proliferator-uncoupling protein-3 mRNA levels in skeletal muscles of HFD-fed mice. Increased urinary excretion of norepinephrine after HFD feeding was augmented in L-NAME-treated mice. Insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 and serine phosphorylation of Akt/Akt2 in soleus muscle was markedly impaired in HFD-fed mice but reversed by L-NAME treatment. In conclusion, chronic NOS blockade by L-NAME in mice ameliorates HFD-induced adiposity and glucose intolerance, accompanied by reduced adipose inflammation and improved insulin signaling in skeletal muscle, suggesting that endogenous NO plays a modulatory role in the development of obesity-related insulin resistance.

PubMed

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

A 54-year-old man with type 2 diabetes was referred to our hospital for endocrine evaluation of acromegaly. Physical examination showed typical acromegalic features without Cushingoid features. Magnetic resonance imaging of the brain revealed the presence of a pituitary macroadenoma. Basal plasma levels of GH and insulin-like growth factor-I under fasting hyperglycemia (202 mg/dl) were markedly elevated. Plasma GH levels paradoxically increased after stimulation with TRH and LH-RH, and decreased after bromocriptine and octreotide administration. Endocrine examination of the hypothalamo-pituitary-adrenal (HPA) axis showed a lack of circadian rhythm of ACTH and cortisol, non-suppressibility to low-dose (1 mg), but suppressibility to high-dose (8 mg) dexamethasone, and normal response to CRH stimulation. The tumor resected by transsphenoidal surgery was histopathologically consistent with the diagnosis of eosinophilic adenoma: positive immunoreactivities of GH, PRL and ACTH were demonstrated, but negative immunoreactivities of prohormone convertase (PC) 1/3 by immunohistochemical method. After surgery, plasma GH and IGF-I levels decreased along with normalization of HPA axis. Metabolic co-morbidities such as diabetes and hypertension disappeared after removal of the pituitary tumor. This is a very rare case of GH-producing pituitary adenoma causing typical acromegaly with concomitant production of ACTH causing subclinical Cushing's disease.

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Both monocyte chemoattractant protein-1 (MCP-1), a member of chemokine family, and angiotensinogen, a precursor of angiotensin (ANG) II, are produced by adipose tissue and increased in obese state. MCP-1 has been shown to decrease insulin-stimulated glucose uptake and several adipogenic genes expression in adipocytes in vitro, suggesting its pathophysiological significance in obesity. However, the pathophysiological interaction between MCP-1 and ANG II in adipose tissue remains unknown. The present study was undertaken to investigate the potential mechanisms by which ANG II affects MCP-1 gene expression in rat primary cultured preadipocytes and adipose tissue in vivo. ANG II significantly increased steady-state MCP-1 mRNA levels in a time- and dose-dependent manner. The ANG II-induced MCP-1 mRNA and protein expression was completely abolished by ANG II type 1 (AT1)-receptor antagonist (valsartan). An antioxidant/NF-kappaB inhibitor (pyrrolidine dithiocarbamate) and an inhibitor of 1kappaB-alpha phosphorylation (Bay 11-7085) also blocked ANG II-induced MCP-1 mRNA expression. ANG II induced translocation of NF-kappaB p65 subunit from cytoplasm to nucleus by immunocytochemical study. Luciferase assay using reporter constructs containing MCP-1 promoter region revealed that two NF-kappaB binding sites in its enhancer region were essential for the ANG II-induced promoter activities. Furthermore, basal mRNA and protein of MCP-1 during preadipocyte differentiation were significantly greater in preadipocytes than in differentiated adipocytes, whose effect was more pronounced in the presence of ANG II. Exogenous administration of ANG II to rats led to increased MCP-1 expression in epididymal, subcutaneous, and mesenteric adipose tissue. In conclusion, our present study demonstrates that ANG II increases MCP-1 gene expression via ANG II type 1 receptor-mediated and NF-kappaB-dependent pathway in rat preadipocytes as well as adipose MCP-1 expression in vivo. Thus the augmented MCP-1 expression by ANG II in preadipocytes may provide a new link between obesity and cardiovascular disease.

PubMed

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Discrepancy of plasma ACTH levels measured by different immunoradiometric assays (IRMA) in a case with malignant gastric carcinoid causing ectopic ACTH syndrome was examined by gel chromatography and immunohistochemical analysis. A 49-year-old male was found to have a large gastric tumor, with muscle wasting, hypertension, diabetes and hypokalemia caused by hypercortisolemia. His plasma ACTH levels, although initially elevated, were found to be almost in normal ranges. The discrepancy of plasma ACTH levels was proven to be due to different IRMA kits used; the initial assay was performed by a kit that could recognize high-molecular weight (HMW) form as well as ACTH(1-39), but the later assay by another kit that could recognize only ACTH(1-39). Pathological examination of the gastric tumor was consistent with the diagnosis of malignant carcinoid. Immunohistochemical study revealed that immunoreactivity of proopiomelanocortin (POMC) was positive within the tumor cells, whereas those of ACTH and prohormone convertase 1/3 were negative. Molecular sieving analysis of patient's plasma by gel chromatography coupled with ACTH radioimmunoassay which could recognize HMW form and ACTH(1-39) and two different IRMAs revealed that the predominant form of ACTH was HMW form with a minor peak of ACTH(1-39). This is a rare case of ectopic ACTH syndrome caused by malignant gastric carcinoid with preferential production of HMW form of ACTH, possibly due to unprocessed POMC.

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Aldosterone is currently recognized as one of the important risk hormones for cardiovascular disease. However, the cellular mechanism by which aldosterone affects the process of cardiovascular injury has not been well understood. In the present study, we investigated whether aldosterone induces pro-inflammatory genes expression in rat aortic endothelial cells. Aldosterone significantly increased steady-state osteopontin mRNA and protein levels, but not those of adhesion molecules or chemokine. The stimulatory effect of aldosterone on osteopontin expression was time-dependent (3-24h) and dose-dependent (10(-10)-10(-6)M), and abolished by a mineralocorticoid receptor (MR) antagonist spironolactone, but not by a glucocorticoid receptor antagonist RU486. The aldosterone-induced osteopontin mRNA expression was completely blocked by a transcription inhibitor, actinomycin D, and a protein synthesis inhibitor, cycloheximide. Thus, the present study demonstrated for the first time that aldosterone directly acts on endothelial cells to induce osteopontin gene expression via MR-mediated genomic action, which may be responsible for the initiation of inflammation and fibrosis in cardiovascular tissue induced by aldosterone.

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Aldosterone is currently recognized as a risk hormone for cardiovascular disease. However, the cellular mechanism by which aldosterone acts on vasculature has not been well understood. In the present study, we investigated whether aldosterone affects angiotensin-converting enzyme (ACE) gene expression in rat endothelial cells. Cultured rat aortic endothelial cells (RAECs) from Sprague-Dawley rats were used in the study. ACE mRNA levels and its enzyme activities in RAECs were examined by real-time RT-PCR and enzyme assay using hippuryl-His-Leu as substrates, respectively. Aldosterone significantly increased steady-state ACE mRNA levels and its enzymatic activities. This effect was dose dependent and time dependent and abolished by mineralocorticoid receptor antagonist spironolactone or transcription inhibitor actinomycin D. Dexamethasone also increased steady-state ACE mRNA levels, whose effect was completely blocked by glucocorticoid receptor antagonist RU486, but not by spironolactone. By contrast, the aldosterone-induced ACE mRNA expression was only partially blocked by RU486. The stimulatory effect of aldosterone on ACE mRNA expression was completely blocked by a protein tyrosine kinase inhibitor (genistein) and JAK2 inhibitor (AG490), partially by Src kinase inhibitor (PP2) and epidermal growth factor receptor kinase inhibitor (AG1478), but not by platelet-derived growth factor receptor kinase inhibitor (AG1296). Transfection of dominant-negative JAK2 construct, but not wild-type construct, significantly blocked the aldosterone-induced ACE mRNA up-regulation. Furthermore, aldosterone induced phosphorylation of JAK2, whose effect was blocked by spironolactone and actinomycin D. In conclusion, the present study demonstrates for the first time that aldosterone induces ACE gene expression and its enzyme activity mainly via a mineralocorticoid receptor-mediated and JAK2-dependent pathway in rat endothelial cells. This may constitute a positive feedback loop for a local renin-angiotensin system, possibly involved in the development of aldosterone-induced endothelial dysfunction and vascular injury.

PubMed

Award type：Award from Japanese society, conference, symposium, etc. 

Award type：Award from Japanese society, conference, symposium, etc. 

Award type：Award from Japanese society, conference, symposium, etc. 

Award type：Award from Japanese society, conference, symposium, etc. 

Award type：Award from Japanese society, conference, symposium, etc. 

Award type：Award from Japanese society, conference, symposium, etc. 

Award type：Award from Japanese society, conference, symposium, etc. 

Award type：Award from Japanese society, conference, symposium, etc. 

Country：United States

Country：United States

Country：Canada

Country：Canada

Award type：Award from Japanese society, conference, symposium, etc. 

Award type：Award from Japanese society, conference, symposium, etc.