-
Koji Nojima, Ken Sugimoto, Hironori Ueda, Naru Babaya, Hiroshi Ikegami ...
2013 Volume 60 Issue 3 Pages
261-274
Published: 2013
Released on J-STAGE: March 31, 2013
Advance online publication: November 06, 2012
JOURNAL
FREE ACCESS
Both genetic factors and diabetogenic environmental factors, such as a high-sucrose diet (HSD), are involved in the development of type 2 diabetes. In this study, the Nagoya-Shibata-Yasuda (NSY) mouse, an animal model of type 2 diabetes and C3H mice used as controls, were fed a HSD, a high-fat diet (HFD) or a regular diet (RD) from weaning. In C3H mice, HFD significantly increased body weight gain, but maintained glucose tolerance. In contrast, in NSY mice, HSD resulted in increased body weight gain and liver steatosis and increased glucose intolerance to a greater extent than HFD. Furthermore, we performed DNA microarray analysis to detect differences in hepatic gene expression levels in both strains under HSD. We then performed RT-PCR analysis on selected genes to evaluate basal expression level under RD and changes under HSD conditions. HSD-fed NSY, but not C3H mice, exhibited increased hepatic expression levels of
Pparg2, an isoform of
Pparg as well as
G0s2, a target of
Pparg, which are known to be adipocyte-specific genes. Compared to RD-fed C3H mice, hepatic expression levels of
Kat2b (transcriptional regulation),
Hsd3b5 (steroid hormone metabolism) and
Cyp7b1 (bile acid metabolism) were initially lower in RD-fed NSY mice, and were further decreased in HSD-fed NSY mice. Expression of Metallothionein (
Mt1) and Metallothionein 2 (
Mt2) was significantly lower in NSY mice compared to C3H mice, irrespective of dietary condition. These data suggest that elucidation of this heterogeneity in response to HSD might contribute to further understanding of the gene-environment interactions leading to diabetes in humans.
View full abstract
-
Aya Nakamura, Masami Watanabe, Morito Sugimoto, Tomoko Sako, Sabina Ma ...
2013 Volume 60 Issue 3 Pages
275-281
Published: 2013
Released on J-STAGE: March 31, 2013
Advance online publication: October 27, 2012
JOURNAL
FREE ACCESS
Gender identity disorder (GID) is a conflict between a person’s actual physical gender and the one they identify him or herself with. Testosterone is the key agent in the medical treatment of female to male GID patients. We conducted a dose-response analysis of testosterone replacement therapy (TRT) in 138 patients to determine the onset of the therapeutic effects. The TRT consisted of intramuscular injection of testosterone enanthate and patients were divided into three groups; 250 mg every two weeks, 250 mg every three weeks and 125 mg every two weeks. The onset of deepening of voice, increase in facial hair and cessation of menses was evaluated in each group. At one month after the start of TRT, the onset of these physical changes was more prevalent in the group receiving the higher dose of testosterone, and there were dose-dependent effects observed between the three treatment groups. On the other hand, at six months after the start of TRT, most of the patients had achieved treatment responses and there were no dose-dependent effects with regard to the percentage of patients with therapeutic effects. No significant side effects were observed in any of the treatment groups. We demonstrated that the early onset of the treatment effects of TRT is dose-dependent, but within six months of starting TRT, all three doses were highly effective. Current study provides useful information to determine the initial dose of TRT and to suggest possible changes that should be made in the continuous dosage for long term TRT.
View full abstract
-
Kohei Okita, Hiromi Iwahashi, Junji Kozawa, Yukiyoshi Okauchi, Tohru F ...
2013 Volume 60 Issue 3 Pages
283-290
Published: 2013
Released on J-STAGE: March 31, 2013
Advance online publication: November 10, 2012
JOURNAL
FREE ACCESS
Homeostasis model assessment of insulin resistance (HOMA-IR) is a simple and useful method for evaluating insulin sensitivity. But it is difficult to apply to type2 diabetes patients treated with insulin. We have devised a method for measuring HOMA-IR and investigated the validity of HOMA-IR for evaluating insulin sensitivity in patients with type 2 diabetes on insulin therapy. In the first arm of the study, 19 poorly controlled diabetic subjects were treated with insulin and underwent euglycemic clamp study. Then the relationship between insulin resistance index assessed by the clamp test (clamp-IR) and HOMA-IR was investigated in these subjects. Log transformed HOMA-IR correlated with log transformed M/I values derived from the standard euglycemic clamp (
r=-0.753,
p=0.002). In the second arm of the study, we investigated the relationship between HOMA-IR and various clinical parameters in 156 patients with poorly controlled diabetes after glycemic control. Log transformed HOMA-IR correlated negatively with age (
r=-0.292,
p=0.0002), HDL-C (
r=-0.342,
p<0.0001), log transformed serum adiponectin (
r=-0.309,
p=0.0006) and log transformed KITT (
r=-0.264,
p=0.0009), and positively with body mass index (
r=0.499,
p<0.0001), waist circumstance (
r=0.461,
p<0.0001), visceral fat area (
r=0.401,
p<0.0001), diastolic blood pressure (
r=0.223,
p=0.0054), log transformed triglyceride (
r=0.497,
p<0.0001), urinary CPR (
r=0.216,
p=0.0099), ΔCPR of glucagon stimulation test (
r=0.496,
p<0.0001) and log transformed insulinogenic index (
r=0.325,
p=0.0002). These results suggest that HOMA-IR is a useful test for the evaluation of insulin sensitivity even in patients with type 2 diabetes treated with insulin.
View full abstract
-
Kwang Min Kim, Joon Beom Park, Keum Seok Bae, Chun Bae Kim, Dae Ryong ...
2013 Volume 60 Issue 3 Pages
291-297
Published: 2013
Released on J-STAGE: March 31, 2013
Advance online publication: November 06, 2012
JOURNAL
FREE ACCESS
This study created a new staging system using a risk model that employed clinical factors that were associated with recurrence, verified by preoperative clinical information and intraoperative finding and was compared with other staging systems. A review was conducted of patients who have undergone thyroidectomy and followed-up between January 1, 1983 and September 31, 2007 at Yonsei University Wonju Christian Hospital. The final prognostic staging system was defined as University of Yonsei clinical staging system (Prognostic score = 0.03 × Age + 0.8 × (if male gender) + 0.5 × (if extrathyroidal tumor extension present) + 0.7 × (if clinically apparent lymph node metastasis present), Stage I, less than 1.50; Stage II, 1.50 to 2.29; Stage III, 2.30 to 3.29; Stage IV 4, 3.3 or more). Compared with the other staging systems, the proportion of variation explained (PVE %) was calculated for each. The University of Yonsei clinical staging system appeared to be first as an accurate prognosis predictor with 11.9%. New staging system can predict recurrence and has advantage can use preoperative clinical information and intraoperative finding. Those who are diagnosed as high risk patients using the new staging system should be treated with aggressive surgical treatment and close follow-up.
View full abstract
-
Yoriko Hatta, Akie Nakamura, Shinya Hara, Takashi Kamijo, Junko Iwata, ...
2013 Volume 60 Issue 3 Pages
299-304
Published: 2013
Released on J-STAGE: March 31, 2013
Advance online publication: November 30, 2012
JOURNAL
FREE ACCESS
Pseudohypoaldosteronism type 1 (PHA1) is a rare condition characterized by neonatal salt loss with elevated plasma aldosterone and renin levels. Two types of PHA1 have been described: an autosomal recessive systemic form and an autosomal dominant renal form, in which the target organ defect is confined to the renal tubules. The dominant renal form of PHA1 is caused by heterozygous mutations in the
NR3C2 gene, which encodes the mineralocorticoid receptor (MR). We determined clinical and biochemical parameters in two familial and four sporadic Japanese patient and analyzed the status of the
NR3C2 gene. Failure to thrive was noted in five of the six patients. In one of the familial cases, the mother had an episode of failure to thrive when she was a toddler, but received no medical treatment. NaCl supplementation was discontinued in four of the six patients after they reached one year of age and they have grown normally thereafter. However, in one patient, 9 g/day of salt has been required to maintain serum Na concentration after 1 year of age. Analysis of
NR3C2 identified three novel mutations [c. C1951T (p.R651X), c.304_305delGC (p.A102fsX103), c.del 603A (p.T201fsX34)] and one previously reported mutation [c.A2839G (p.947X)]. p.R651X was identified in one familial case and one unrelated sporadic patient. The patient who has been supplemented with large amount of salt was heterozygous for c.del 603A in exon 2. In conclusion, our study expands the spectrum of phenotypes, and characterized mutations of
NR3C2 in the renal form of PHA1.
View full abstract
-
Keiko Arai, Koichi Hirao, Mikio Yamauchi, Masashi Kobayashi, Atsunori ...
2013 Volume 60 Issue 3 Pages
305-310
Published: 2013
Released on J-STAGE: March 31, 2013
Advance online publication: November 10, 2012
JOURNAL
FREE ACCESS
Insulin therapy is often required to achieve good glycemic control for the patients with type 2 diabetes mellitus (T2DM), while protraction of glycemic control without insulin therapy may be preferable for patients. To determine the characteristics of and therapeutic regimen in outpatients with T2DM who were able to stop insulin therapy with satisfactory glycemic control in a real clinical practice setting in Japan by a case-control study. The present study was performed on 928 patients with T2DM who started insulin therapy in 2007. Data regarding age, sex, body mass index, duration of diabetes, HbA1c, postprandial plasma glucose, plasma fasting C-peptide immunoreactivity and treatment modality were compared between patients who were able to stop insulin therapy and those who continued with insulin. Of the 928 patients, 37 had stopped insulin therapy within 1 year. In the patients who stopped insulin therapy, the duration of diabetes was significantly shorter and the daily insulin dosage at initiation and the prevalence of sulfonylurea pretreatment significantly lower compared with patients who continued on insulin. In conclusion, almost 4% of T2DM patients were able to stop insulin therapy with satisfactory glycemic control in a real clinical practice setting in Japan. Shorter duration of diabetes and disuse of sulfonylureas prior to insulin may associate with stopping insulin therapy as a near-normoglycemic remission in outpatients with T2DM in Japan.
View full abstract
-
Kazuo Sonoki, Masanori Iwase, Yutaka Takata, Tetsuji Nakamoto, Chihiro ...
2013 Volume 60 Issue 3 Pages
311-319
Published: 2013
Released on J-STAGE: March 31, 2013
Advance online publication: November 09, 2012
JOURNAL
FREE ACCESS
Glucagon-like peptide 1 (GLP-1) is secreted from the small intestine to the blood in response to glucose intake during a meal; however, it is not known whether mastication affects GLP-1 secretion. Here, we examined the relationship between mastication and GLP-1 secretion, along with postprandial blood glucose and insulin concentrations. We compared the levels of blood glucose, serum insulin, and plasma active GLP-1 concentrations after young healthy volunteers ate a test meal either by usual eating (control) or in one of three specified ways: 1. unilateral chewing, 2. quick eating, 3. 30-times chewing per bite. Ten volunteers participated in each of the three groups. Plasma active GLP-1 concentrations did not change by unilateral chewing or quick eating, but did increase by the third method, without affecting the concentrations of blood glucose or serum insulin. Next, we tested whether 30-times chewing per bite increased plasma active GLP-1 concentrations in 15 patients with type 2 diabetes mellitus, but there was no difference in results between usual eating and 30-times chewing per bite. This is a pilot trial with a small number of subjects, but is the first study to investigate the relationships between various styles of mastication and the GLP-1 secretion in young healthy volunteers and type 2 diabetic patients.
View full abstract
-
Mee Kyoung Kim, Ki Hyun Baek, Moo Il Kang, Se Eun Park, Eun-Jung Rhee, ...
2013 Volume 60 Issue 3 Pages
321-328
Published: 2013
Released on J-STAGE: March 31, 2013
Advance online publication: November 10, 2012
JOURNAL
FREE ACCESS
Some papers have suggested that alkaline phosphatase (ALP) level is a predictor of the metabolic syndrome (MetS) in the general population. However, the association is still controversial, and the mechanisms underlying an association between ALP level and the MetS have not been elucidated. We analyzed the association between serum ALP level and the development of the MetS over a 4-year period. A total of 14,224 subjects who visited the Health Promotion Center for a medical examination in 2005 were followed up after 4 years. Serum ALP level correlated positively with body fat mass and visceral fat mass. The adjusted geometric mean ALP levels were higher in subjects with elevated C-reactive protein level or greater fat mass (
P < 0.001). None of the subjects had the MetS at baseline, but 1,179 exhibited the MetS at the 4-year follow-up. After multiple adjustments, the odds ratio (OR) was substantially higher for development of the MetS (OR 1.56, 95% confidence intervals, 1.21-2.01) in subjects in the highest ALP quintile compared with those in the lowest quintile. After adjusting for various covariates, we found significant associations between the quintile of serum ALP level and abdominal obesity, low high-density lipoprotein cholesterol level, and high triglyceride level. Higher serum ALP level was a significant predictor of the MetS in middle-aged Koreans. Serum ALP level correlated positively with body fat mass and independently with a more atherogenic lipid profile in the general population in Korea.
View full abstract
-
Ikki Sakuma, Sachiko Suematsu, Yoko Matsuzawa, Jun Saito, Masao Omura, ...
2013 Volume 60 Issue 3 Pages
329-336
Published: 2013
Released on J-STAGE: March 31, 2013
Advance online publication: December 18, 2012
JOURNAL
FREE ACCESS
We analyzed the expression profiles of several steroidogenic enzymes in normal adrenals, aldosterone-producing adenomas (APA), cortisol-producing adenomas combined with Cushing’s syndrome (CPA) or with subclinical Cushing’s syndrome (SCPA), and nonfunctioning adrenal adenomas (NFA) to clarify the nature and characteristics of steroidogenesis in APA. Clinical data were collected for all subjects. In resected adrenal glands (normal adrenals, APA, CPA, SCPA, and NFA), the mRNA expression levels of the
CYP17,
HSD3B2,
CYP11B1, and
CYP11B2 genes were studied using real-time quantitative PCR and immunohistochemistry. The
CYP11B2 mRNA level in APA was significantly higher than that in other groups. The
CYP17/HSD3B2 ratio for mRNA in APA was significantly lower than those in the other groups. Low ratio of
CYP17/HSD3B2 with high expression of
CYP11B2 seems to explain steroidogenic characteristics of APA.
View full abstract
-
Shiho Yamato Kodera, Masashi Yoshida, Katsuya Dezaki, Toshihiko Yada, ...
2013 Volume 60 Issue 3 Pages
337-346
Published: 2013
Released on J-STAGE: March 31, 2013
Advance online publication: November 22, 2012
JOURNAL
FREE ACCESS
The aim of this study was to determine whether dexmedetomidine (DEX) and medetomidine (MED), α
2-adrenergic agonists clinically used as sedatives, influence insulin secretion from rat pancreatic islets. Islets were isolated from adult male Wistar rats after collagenase digestion. Static incubation was used to determine effects of DEX or MED on insulin secretion and ionic-channel currents of β-cells. Results indicate that both drugs dose-dependently inhibit insulin secretion, DEX more potently than MED. The inhibitory effects were attenuated by addition of yohimbine or by pretreatment of rats with pertussis toxin (PTX). 10 nM DEX decreased the current amplitude of voltage-dependent Ca
2+ channels, but this did not occur when the N-type Ca
2+ channel blocker ω-conotoxin was added. In the presence of tetraethylammonium, a classical voltage-gated K
+ channel (Kv channel) blocker, the magnitude of inhibition of insulin secretion by MED was reduced. However, when tolbutamide, a specific blocker of the ATP-sensitive K
+ channel (K
ATP channel), was present, the magnitude of MED inhibition of insulin secretion was not influenced, suggesting that Kv-channel activity alteration, but not that of K
ATP channels, is involved in MED-associated insulin secretory inhibition. The Kv-channel currents were increased during 1 nM MED exposure at membrane potentials ranging from -30 mV to -10 mV, where action potentials were generated in response to glucose stimulation. These results indicate that DEX and MED inhibit insulin secretion through an α
2-adrenoceptor and PTX-sensitive GTP-binding protein pathway that eventually involves Kv channel activation and Ca
2+ channel inhibition.
View full abstract
-
Jianxia Hu, Xiaolong Yu, Zhongchao Wang, Fang Wang, Li Wang, Hong Gao, ...
2013 Volume 60 Issue 3 Pages
347-357
Published: 2013
Released on J-STAGE: March 31, 2013
Advance online publication: November 16, 2012
JOURNAL
FREE ACCESS
Type 1 Diabetes Mellitus (T1DM) is an autoimmune disorder resulted from T cell-mediated destruction of pancreatic β-cells, how to regenerate β-cells and prevent the autoimmune destruction of remnant and neogenetic β-cells is a tough problem. Immunomodulatory propertity of mesenchymal stem cell make it illuminated to overcome it. We assessed the long-term effects of the implantation of Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) from the umbilical cord for Newly-onset T1DM. Twenty-nine patients with newly onset T1DM were randomly divided into two groups, patients in group I were treated with WJ-MSCs and patients in group II were treated with normal saline based on insulin intensive therapy. Patients were followed-up after the operation at monthly intervals for the first 3 months and thereafter every 3 months for the next 21 months, the occurrence of any side effects and results of laboratory examinations were evaluated. There were no reported acute or chronic side effects in group I compared with group II, both the HbA1c and C peptide in group I patients were significantly better than either pretherapy values or group II patients during the follow-up period. These data suggested that the implantation of WJ-MSCs for the treatment of newly-onset T1DM is safe and effective. This therapy can restore the function of islet β cells in a longer time, although precise mechanisms are unknown, the implantation of WJ-MSCs is expected to be an effective strategy for treatment of type1 diabetes.
View full abstract
-
Reiko Mayama, Tomoko Izawa, Keiji Sakai, Nicolae Suciu, Mitutoshi Iwas ...
2013 Volume 60 Issue 3 Pages
359-368
Published: 2013
Released on J-STAGE: March 31, 2013
Advance online publication: November 30, 2012
JOURNAL
FREE ACCESS
Insulin-like growth factor-I (IGF-I) has been shown to stimulate extravillous trophoblast (EVT) cell migration and invasion, and to play a crucial role in placental function, thereby, influencing placental development and fetal growth. Insufficient invasion of EVT cells into the uterine endometrium leads to pregnancy-related complications, including spontaneous abortion, fetal growth restriction (FGR), and pregnancy-induced hypertension (PIH). Insulin-resistant conditions such as polycystic ovary syndrome (PCOS) and gestational diabetes mellitus (GDM) have also been associated with abortion and PIH. However, the effects of IGF-I on EVT cells under insulin-resistant conditions have not been elucidated yet. The current study was undertaken to analyze the effects of IGF-I under insulin-resistant conditions and to determine whether improvement in insulin sensitivity alters IGF signaling and cell migration in the EVT. Incubation with pioglitazone, an insulin sensitizer, increased peroxisome proliferator-activated receptor-γ (PPARγ) expression after 48 h. A 48-h pre-incubation with insulin reduced the phosphorylation and concentration of the insulin receptors, which were increased by insulin treatment. Long-term exposure to insulin reduced phosphorylation of the IGF-I receptor, insulin receptor substrate-1 (IRS-1), and Akt, and also reduced EVT cell migration. However, when the cells were incubated with pioglitazone in addition to insulin for 48 h, the phosphorylation of these proteins was restored. This combination partially reversed the inhibitory effect of insulin on EVT cell migration. These results suggest that abnormalities in pregnancy that are induced by loss of insulin sensitivity can be treated by improving insulin sensitivity.
View full abstract
-
Toshio Hirohata, Nobuhito Saito, Koji Takano, So Yamada, Jae-Hyun Son, ...
2013 Volume 60 Issue 3 Pages
369-373
Published: 2013
Released on J-STAGE: March 31, 2013
Advance online publication: November 29, 2012
JOURNAL
FREE ACCESS
Adult growth hormone (GH) deficiency (AGHD) in Japan is diagnosed based on peak GH concentrations during GH provocative tests such as GHRP-2 stimulation test. In this study, we aimed to evaluate the ability of serum insulin-like growth factor-1 (sIGF-1) and urinary GH (uGH) at the time of awakening to diagnose AGHD. Fifty-nine patients with pituitary disease (32 men and 27 women; age 20-85 y (57.5 ± 15.5, mean ± SD) underwent GHRP-2 stimulation and sIGF-1 testing. Thirty-six and 23 patients were diagnosed with and without severe AGHD, respectively based on a peak GH response of <9 ng/mL to GHRP-2 stimulation. Serum IGF-1 was evaluated as a standard deviation score (IGF-1 SDS) based on age and sex. We determined whether uGH levels in urine samples from 42 of the 59 patients at awakening were above or below the sensitivity limit. We evaluated IGF-1 SDS and uGH levels in a control group of 15 healthy volunteers. Values for IGF-1 SDS were significantly lower in patients with, than without (-2.07 ± 1.77
vs.-0.03 ± 0.92, mean ± SD;
p < 0.001) AGHD whereas the range of IGF-1 SDS substantially overlapped at >-1.4. IGF-1 SDS discriminated AGHD more effectively in patients aged ≤60 years. The χ
2 test revealed a statistical relationship between uGH and AGHD (test statistic: 7.0104 ≥ χ
2 (1; 0.01) = 6.6349). When IGF-1 SDS is <-1.4 or uGH is below the sensitivity limit, AGHD can be detected with high sensitivity.
View full abstract
-
Kiminori Sugino, Koichi Ito, Mitsuji Nagahama, Wataru Kitagawa, Hirosh ...
2013 Volume 60 Issue 3 Pages
375-382
Published: 2013
Released on J-STAGE: March 31, 2013
Advance online publication: November 29, 2012
JOURNAL
FREE ACCESS
Fine-needle aspiration biopsy cytology (FNABC) and ultrasonography (US) play an important role in differentiating benign thyroid nodules from malignant nodules. We retrospectively investigated the prevalence of follicular thyroid carcinoma (FTC) in patients with thyroid nodules whose FNABC and US readings were not malignant before thyroidectomy. Between 2007 and 2008, 3333 patients underwent thyroidectomy at our institution, and the 737 of them who had thyroid nodule that had been diagnosed as hyperplastic nodule or follicular tumor by FNABC and US preoperatively were the subjects in this study. Postoperative histopathology showed hyperplastic nodule in 416 patients, follicular adenoma in 200 patients, FTC in 99 patients, and other disease in 22 patients. By FNABC, 34 (6.7%) of the 505 patients with diagnosis as benign and 65 (28%) of the 232 patients with diagnosis as indeterminate, were diagnosed as having FTC. The diagnosis was FTC in 56 (9.6%) of the 582 patients with a preoperative diagnosis of hyperplastic nodule by US and 43 (27.7%) of the 155 patients with a diagnosis of follicular tumor by US. The diagnosis of FTC was made in 21 (4.8%) of 438 patients who were concurrently diagnosed as benign by FNABC and as hyperplastic nodule by US, and in 30 (34.1%) of 88 patients who were diagnosed as indeterminate by FNABC and follicular tumor by US. FNABC has been the mainstay for the preoperative evaluation of thyroid nodule. The results of this study showed that US can also be a useful tool for diagnosing FTC.
View full abstract