Endocrine Journal
Online ISSN : 1348-4540
Print ISSN : 0918-8959
ISSN-L : 0918-8959
Volume 60 , Issue 10
Showing 1-9 articles out of 9 articles from the selected issue
ORIGINALS
  • Tsutomu Sasaki, Mayumi Shimpuku, Tomoya Kitazumi, Haruna Hiraga, Yuko ...
    2013 Volume 60 Issue 10 Pages 1117-1129
    Published: 2013
    Released: October 31, 2013
    [Advance publication] Released: August 30, 2013
    JOURNALS FREE ACCESS
    Miglitol is an alpha-glucosidase inhibitor that improves post-prandial hyperglycemia, and it is the only drug in its class that enters the bloodstream. Anecdotally, miglitol lowers patient body weight more effectively than other alpha-glucosidase inhibitors, but the precise mechanism has not been addressed. Therefore, we analyzed the anti-obesity effects of miglitol in mice and in the HB2 brown adipocyte cell line. Miglitol prevented diet-induced obesity by stimulating energy expenditure without affecting food intake in mice. Long-term miglitol treatment dose-dependently prevented diet-induced obesity and induced mitochondrial gene expression in brown adipose tissue. The anti-obesity effect was independent of preventing carbohydrate digestion in the gastrointestinal tract. Miglitol effectively stimulated energy expenditure in mice fed a high-fat high-monocarbohydrate diet, and intraperitoneal injection of miglitol was sufficient to stimulate energy expenditure in mice. Acarbose, which is a non-absorbable alpha glucosidase inhibitor, also prevented diet-induced obesity, but through a different mechanism: it did not stimulate energy expenditure, but caused indigestion, leading to less energy absorption. Miglitol promoted adrenergic signaling in brown adipocytes in vitro. These data indicate that circulating miglitol stimulates brown adipose tissue and increases energy expenditure, thereby preventing diet-induced obesity. Further optimizing miglitol’s effect on brown adipose tissue could lead to a novel anti-obesity drug.
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  • Akira Shimatsu, Shigeru Tai, Makoto Imori, Katsuichiro Ihara, Masanori ...
    2013 Volume 60 Issue 10 Pages 1131-1144
    Published: 2013
    Released: October 31, 2013
    [Advance publication] Released: July 04, 2013
    JOURNALS FREE ACCESS
    This large-scale observational study examined the long-term effectiveness and safety of growth hormone (GH) replacement therapy for adult GH deficiency (GHD) in Japanese clinical practice using the Hypopituitary Control and Complications Study database. The study included 402 GHD patients for safety analyses and a subset of 209 patients (149 adult-onset and 60 childhood-onset GHD patients) who had not previously received GH replacement therapy for the efficacy analyses. Data on clinical, metabolic, quality of life (QoL) characteristics, and all adverse events (AEs) were collected at baseline (start of GH treatment), 6 months, 1 year and 2 years. Over the observation period, there were improvements from baseline in insulin-like growth factor-I standard deviation scores (P < 0.001), although the changes in metabolic parameters were minimal. QoL (Short Form-36) Z-scores significantly increased from baseline in both onset-type groups for several subscale domains (P < 0.05). A total of 145 (36.1%) patients experienced ≥1 AE. Common AEs were hyperlipidaemia (2.7%) and hyperinsulinaemia (2.2%). Some patients experienced recurrent hypothalamic/pituitary tumour (events per 1000 patient-years: 2.78), new benign (0.93), malignant tumour (10.28) or other new tumour (0.93), new diabetes mellitus (7.45), and new stroke (3.71). Seven patients died during the observation period. Our safety findings are inconclusive about the associations between GH replacement and AEs, although the incidence of diabetes mellitus and cardiovascular events are similar to those reported in the Japanese general population. In conclusion, the key beneficial effects of GH replacement therapy for GHD are observed in routine clinical practice in Japan.
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  • Katsumi Iizuka, Wudelehu Wu, Yukio Horikawa, Masayuki Saito, Jun Taked ...
    2013 Volume 60 Issue 10 Pages 1145-1153
    Published: 2013
    Released: October 31, 2013
    [Advance publication] Released: July 05, 2013
    JOURNALS FREE ACCESS
    Carbohydrate response element binding protein (ChREBP) and peroxisome proliferator-activated receptor alpha (PPARα) play an important role in the regulation of lipid metabolism in the liver. Chrebp and Ppara mRNA levels are equally abundant in brown adipose tissue and liver. However, their functions in brown adipose tissues are unclear. In this study, we attempted to clarify the role of ChREBP and PPARα using brown adipose HB2 cell lines and tissues from wild type and Chrebp-/- C57BL/6J mice. In liver and brown adipose tissues, Chrebpb mRNA levels in the fasting state were much lower than those fed ad libitum, while Ppara mRNA levels in the fasting state were much higher than in the fed state. In differentiated brown adipose HB2 cell lines, glucose increased mRNA levels of ChREBP target genes such as Chrebpb, Fasn, and Glut4 in a dose dependent manner, while glucose decreased both Chrebpa and Ppara mRNA levels. Accordingly, adenoviral overexpression of ChREBP and a reporter assay demonstrated that ChREBP partially suppressed Ppara and Acox mRNA expression. Moreover, in brown adipose tissues from Chrebp-/- mice, Chrebpb and Fasn mRNA levels in the ad libitum fed state were much lower than those in the fasting state, while Ppara and Acox mRNA levels were not. Finally, using Wy14,643, a selective PPARα agonist, and overexpression of PPARα partially suppressed glucose induction of Chrebpb and Fasn mRNA in HB2 cells. In conclusion, the feedback loop between ChREBP and PPARα plays an important role in the regulation of lipogenesis in brown adipocytes.
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  • Takashi Kajitani, Tetsuo Maruyama, Hironori Asada, Hiroshi Uchida, Hid ...
    2013 Volume 60 Issue 10 Pages 1155-1164
    Published: 2013
    Released: October 31, 2013
    [Advance publication] Released: July 24, 2013
    JOURNALS FREE ACCESS
    Nerve growth factor (NGF) has been recently proposed as one of the key factors responsible not only for promotion of nerve fiber growth but also for the onset and maintenance of pain in a variety of diseases. The aim of this study was to investigate the role of NGF in the pelvic pain associated with endometriosis. Tissue and peritoneal fluid samples were collected from 95 women with laparoscopically and histopathologically confirmed endometriosis and 59 control women without endometriosis. Expression levels of NGF mRNA and protein were examined using real-time RT-PCR and immunohistochemistry, respectively. Concentration of NGF in the peritoneal fluid (PF-NGF) was measured using ELISA. The degree of dyspareunia and dysmenorrhea was evaluated using a verbal rating scale. Real-time RT-PCR analysis revealed that NGF mRNA was significantly more abundant in the ovarian endometriomas and peritoneal endometriosis than in the normal control endometrium. Immunohistochemical analyses demonstrated that NGF was prominently expressed and preferentially localized to the glands of the ovarian endometriomas and peritoneal endometriosis, whereas it was only weakly detectable in the normal endometrium. Although PF-NGF was undetectable in some normal subjects and endometriosis patients, elevated PF-NGF in the peritoneal fluid was more frequently observed in endometriosis patients with severe pain than in those with less severe pain. Our results suggest that NGF produced locally in the peritoneal cavity may be involved in the generation of endometriosis-associated pelvic pain.
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  • Tetsuhiro Kitamura, Michio Otsuki, Masaya Yamaoka, Youichi Saitoh, Ii ...
    2013 Volume 60 Issue 10 Pages 1165-1169
    Published: 2013
    Released: October 31, 2013
    [Advance publication] Released: July 12, 2013
    JOURNALS FREE ACCESS
    Acromegaly is frequently accompanied by left ventricular hypertrophy (LVH) which causes ventricular dysfunction. Ventricular arrhythmia is one of the important complications in acromegalic patients. Hypertrophic cardiomyopathy (HCM) is characterized by LVH with a nondilated chamber. About 10 % of HCM evolve into dilated phase of HCM, which is associated with an increased incidence of ventricular tachycardia (VT). However there is no report about a combination of dilated phase of HCM and VT in acromegalic patients. Octreotide is a somatostatin analog that has been used for medical therapy for acromegaly. We herein report that the first case of the change of serum octreotide concentration affected the control of VT, which was induced by dilated phase of HCM. A 56-year-old Japanese man was referred to our hospital for treatment of acromegaly. The patient was diagnosed the dilated phase of HCM with sustained VT. The frequency and severity of VT were gradually ameliorated by subcutaneous octreotide injection. However VT was deteriorated when its injection was changed to octreotide long-acting release (LAR) injection. The temporary drop in serum octreotide concentration was known at the transition from subcutaneous injection to LAR injection. This clinical course gives us the important information that subcutaneous octreotide injection for two weeks should be necessary to keep serum octreotide concentration when switing to octreotide LAR administration in acromegalic patients with severe arrhythmia.
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  • Min Joo Kim, Kwan Jae Lee, Ji-Yeon Hwang, Hye Seung Lee, Sung Hee Chio ...
    2013 Volume 60 Issue 10 Pages 1171-1177
    Published: 2013
    Released: October 31, 2013
    [Advance publication] Released: August 03, 2013
    JOURNALS FREE ACCESS
    Small heterodimer partner (SHP) is involved in bile, lipid, and glucose metabolism. The aim of this study was to investigate the effect of SHP on the development of atherosclerosis. Apolipoprotein E knockout (ApoE-/-) mice were crossed with SHP knockout (SHP-/-) mice to generate double knockout (ApoE-/-SHP-/-) mice. ApoE-/- and ApoE-/-SHP-/- male mice were fed a western diet for 20 weeks. Body weight in ApoE-/-SHP-/- mice was significantly lower than that in ApoE-/- mice (37 ± 1 g vs. 42 ± 1 g, p < 0.01). Loss of SHP in ApoE-/- mice decreased the size of adipocytes in white adipose tissue and reduced lipid accumulation in the liver. Glucose intolerance was improved in ApoE-/-SHP-/- mice as compared with ApoE-/- mice (p < 0.01). There was no statistical difference in non-high density lipoprotein cholesterol levels between ApoE-/-SHP-/- mice and ApoE-/- mice despite an increase of cholesterol 7α-hydroxylase expression in the liver. The proportion of atherosclerotic lesions in the aorta was significantly lower in ApoE-/-SHP-/- mice than in ApoE-/- mice (2.8 ± 2.0% vs. 9.1 ± 1.9%, p < 0.01). In conclusion, loss of SHP function can prevent atherosclerosis, and resistance to diet-induced obesity is the primary factor contributing to this protective effect.
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  • Yang-Hyun Kim, Ga-Eun Nam, Kyung-Hwan Cho, Youn Seon Choi, Seon-Mee Ki ...
    2013 Volume 60 Issue 10 Pages 1179-1189
    Published: 2013
    Released: October 31, 2013
    [Advance publication] Released: July 23, 2013
    JOURNALS FREE ACCESS
    This study examined the relationship between bone mineral density (BMD) and dyslipidemia in South Korean men. Data from 6,300 men who participated in the Korean National Health and Nutrition Examination Survey from 2008 to 2010 were analyzed, including serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) after 8 hours of fasting and mean BMD measured at the lumbar spine (LS), total hip (TH), and femoral neck (FN). Dyslipidemia was defined according to the criteria of the National Cholesterol Education Program Adult Treatment Panel ΙΙΙ. Other parameters of dyslipidemia were also calculated, such as TG/HDL-C, TC/HDL-C, non–HDL-C (NHDL-C), and LDL-C/HDL-C. Men with dyslipidemia and high levels of TG, TG/HDL-C, TC/HDL-C, NHDL-C, and LDL-C/HDL-C had lower BMD than men without dyslipidemia at the LS, TH, and FN after adjustment for age and body mass index (all p<0.01). On multivariable regression analysis, all odds ratios for high levels of TG, TG/HDL-C, TC/HDL-C, NHDL-C, and LDL-C/HDL-C with an increase in BMD (per standard deviation) were <1 at all 3 sites after adjustment for age and body mass index (model 1). After adjustment for all covariates, only odds ratios for high levels of TG, TG/HDL-C, TC/HDL-C, and NHDL-C were <1 at all 3 sites (model 2), but an increase in BMD was not associated with high LDL-C levels in models 1 and 2. In conclusion, BMD was inversely correlated with parameters of atherogenic dyslipidemia in South Korean men.
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  • Yuko Nakagawa, Masahiro Nagasawa, Hideo Mogami, Martin Lohse, Yuzo Nin ...
    2013 Volume 60 Issue 10 Pages 1191-1206
    Published: 2013
    Released: October 31, 2013
    [Advance publication] Released: August 09, 2013
    JOURNALS FREE ACCESS
    Supplementary material
    The sweet taste receptor is expressed in the taste bud and is activated by numerous sweet molecules with diverse chemical structures. It is, however, not known whether these sweet agonists induce a similar cellular response in target cells. Using MIN6 cells, a pancreatic β-cell line expressing endogenous sweet taste receptor, we addressed this question by monitoring changes in cytoplasmic Ca2+ ([Ca2+]i) and cAMP ([cAMP]i) induced by four sweet taste receptor agonists. Glycyrrhizin evoked sustained elevation of [Ca2+]i but [cAMP]i was not affected. Conversely, an artificial sweetener saccharin induced sustained elevation of [cAMP]i but did not increase [Ca2+]i. In contrast, sucralose and acesulfame K induced rapid and sustained increases in both [Ca2+]i and [cAMP]i. Although the latter two sweeteners increased [Ca2+]i and [cAMP]i, their actions were not identical: [Ca2+]i response to sucralose but not acesulfame K was inhibited by gurmarin, an antagonist of the sweet taste receptor which blocks the gustducin-dependent pathway. In addition, [Ca2+]i response to acesulfame K but not to sucralose was resistant to a Gq inhibitor. These results indicate that four types of sweeteners activate the sweet taste receptor differently and generate distinct patterns of intracellular signals. The sweet taste receptor has amazing multimodal functions producing multiple patterns of intracellular signals.
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  • Seiya Shimoda, Shinsuke Iwashita, Shinji Ichimori, Yasuto Matsuo, Riek ...
    2013 Volume 60 Issue 10 Pages 1207-1214
    Published: 2013
    Released: October 31, 2013
    [Advance publication] Released: August 03, 2013
    JOURNALS FREE ACCESS
    To assess the efficacy and safety of adding sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in subjects with type 2 diabetes inadequately controlled with multiple daily insulin injections therapy (MDI). HbA1c, 1,5-anhydroglucitol (1,5-AG), body mass index (BMI), insulin doses, six-point self-measured plasma glucose (SMPG) profiles were assessed before, after 12 weeks, and after 24 weeks of MDI with 50 mg/day of sitagliptin in 40 subjects with type 2 diabetes. Safety endpoints included hypoglycemia and any adverse events. HbA1c significantly decreased during the first 12 weeks ( −0.64 ± 0.60 %), and was sustained over 24 weeks ( −0.69 ± 0.85 %). 1,5-AG increased significantly from 7.5 ± 4.5 μg/mL at baseline to 9.6 ± 5.5 μg/mL after 24 weeks. The bolus insulin dose at 12 weeks was decreased, and the mean plasma glucose, the SD of daily glucose, M-value, and the mean amplitude of glycemic excursions (MAGE) also decreased significantly as compared with baseline values. BMI and frequency of hypoglycemia were not changed significantly. Univariate linear regression analyses revealed that % change in HbA1c was significantly associated with BMI, and % changes in the indexes of glycemic instability (SD of daily glucose and MAGE) were significantly associated with age. In conclusion, adding sitagliptin to MDI significantly improved glycemic control and decreased the daily glucose fluctuation in subjects with type 2 diabetes inadequately controlled with MDI, without weight gain or an increase in the incidence of hypoglycemia. This trial was registered with UMIN (no. UMIN000010157).
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