Mari Sawada, Hisashi Masuyama, Kei Hayata, Yasuhiko Kamada, Keiichiro Nakamura, Yuji Hiramatsu
Vol 62. No. 11
Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by insulin resistance and hyperandrogenism. The interaction of these factors might result in increased risks of miscarriage and pregnancy complications such as gestational diabetes mellitus (GDM). To examine the pregnancy risks in women with PCOS, we compared obstetrical outcomes between patients with and without PCOS. We also studied the differences in maternal characteristics, glucose intolerance and pregnancy complications between PCOS patients with and without GDM, with and without obesity, and between successful pregnancies and miscarriages. We observed a high incidence of GDM and prevalence of GDM diagnosis in the first trimester in PCOS. Patients with GDM had higher body mass index (BMI) and lower homeostasis model assessment of β-cell function (HOMA-β) at preconception than those without GDM. Obese pregnant women with PCOS demonstrated a high incidence of GDM with severe insulin resistance, including high fasting insulin, HOMA of insulin resistance (HOMA-IR), and HOMA-β at preconception compared with normal-weight patients. BMI was significantly correlated with HOMA-IR or HOMA-β, and both indices were lower in PCOS patients with than without GDM for the same BMI. There were no significant differences in maternal characteristics (excluding maternal age) between PCOS patients with successful pregnancy and PCOS patients with miscarriages. Our data suggest that pregnant women with PCOS have an increased risk of GDM, especially if they have obesity and/or poorer insulin secretion. Measure of β-cell function, such as HOMA-β, at preconception might be a useful predictor of the risk of GDM in pregnant PCOS patients.
Vol 62. No. 4
Meta-analyses have revealed that the relative risk of hip fractures in patients with type 1 and type 2 diabetes mellitus is higher than that in non-diabetic subjects. The risk of fracture in patients with diabetes mellitus increases along with a decrease in bone mineral density (BMD) similarly to those in non-diabetic patients. However, the observed risk of fracture is higher than expected one by BMD in both type 1 and type 2 diabetic patients, indicating that precise estimation of bone fragility by BMD values in patients with diabetes is difficult. Bone strength consists of BMD and bone quality, for this reason, poor bone quality is a most suitable and explicable cause for elevated fracture risk in this population. This bone fragility observed in patients with diabetes mellitus is caused by unique pathogenesis in diabetes, suggesting that osteoporosis in diabetic patients may be one of the diabetic complications and that specific diagnostic criteria for this osteoporosis is required. Bone quality indicators closely related to bone fragility are required to be identified to establish a diagnostic method for osteoporosis in patients with diabetes mellitus.
Tomohiko Urano, Satoshi Inoue
Vol 62 No. 6
Osteoporosis is a skeletal disorder characterized by low bone mineral density (BMD) and an increased susceptibility to fractures. Evidence from genetic studies indicates that BMD, a complex quantitative trait with a normal distribution, is genetically controlled. Genome-wide association studies (GWAS) as well as studies using candidate gene approaches have identified single-nucleotide polymorphisms (SNPs) that are associated with BMD, osteoporosis and osteoporotic fractures. These SNPs have been mapped close to or within genes including those encoding WNT/β-catenin signaling proteins. Understanding the genetics of osteoporosis will help to identify novel candidates for diagnostic and therapeutic targets. Genetic factors are also important for the development of sarcopenia, which is characterized by a loss of lean body mass, and obesity, which is characterized by high fat mass. Hence, in this review, we discuss the genetic factors, identified by genetic studies, which regulate the body components related to osteoporosis, sarcopenia, and obesity.
Lara Giovannini, Giacomo Tirabassi, Giovanna Muscogiuri, Carolina Di Somma, Annamaria Colao, Giancarlo Balercia
Vol 62 No. 12
Adult growth hormone deficiency (GHD) is a well defined clinical condition, which is characterized by abnormal body composition, impaired physical activity and decreased quality of life. In addition, in recent years, growing interest has been shown towards cardiovascular risks in adult patients affected by GHD. In this regard, GHD is widely known to be associated with increased mortality, likely due to the increase of risk factors, such as central obesity, impaired lipid and glucose profiles and other less-known risk factors, such as inflammatory cytokines, endothelial dysfunction and oxidative stress. However, very few papers have recently discussed this topic. In this review, the aim is to clarify this issue by discussing evidence regarding the effects of adult GHD on metabolic and cardiovascular profiles.
Hao-Neng Tang, Xiao-Fei Man, Ya-Qing Liu, Yue Guo, Ai-Guo Tang, Er-Yuan Liao, Hou-De Zhou
Vol 62 No. 9
The objective of this study was to investigate the impact of neuropeptide Y (NPY) on preadipocyte proliferation and differentiation. Preadipocytes were incubated with a range of concentrations of NPY (10-15M - 10-7M). After NPY-induced differentiation, the extent of preadipocyte adipogenesis was evaluated. The expressions levels of related adipocyte markers such as PPARγ, C/EBPα and DLK-1 were examined by real-time PCR (RT-PCR) or western blot analysis. Furthermore, the mitogen-activated protein kinase (MAPK) signaling pathway proteins were also analyzed by western blot. Our results showed that low doses of NPY stimulated preadipocyte viability and proliferation, while high NPY doses inhibited cell viability. At high concentrations of NPY significantly promoted lipid accumulation and increased the size of lipid droplets. DLK-1 mRNA expression was inhibited, but the expression levels of PPARγ and C/EBPα were increased during differentiation with the presence of high concentration of NPY. High-dose NPY also suppressed the phosphorylation of the extracellular signal-regulated kinase (ERK) 1/2 protein. We conclude that NPY has a biphasic effect on preadipocyte proliferation. A high dose inhibits the proliferation of 3T3-L1 cell while promotes adipocyte differentiation, increasing lipid accumulation especially enlarged lipid droplets’ size. NPY may lead to a better understanding for drug development to prevent hyperplastic obesity and hypertrophic obesity.
Liang Zhao, Jun Li, Zhao-Liang Li, Jie Yang, Ming-Long Li, Gong-Ling Wang
Vol 62 No. 10
Irisin is a newly identified myokine. Several studies have reported irisin concentrations in patients with gestational diabetes mellitus (GDM), but because of smaller sample sizes, the data from previous reports showed a wide range in serum/plasma irisin. Therefore, the present investigation is designed to summarize a precise confidence interval of circulating irisin in participants with GDM from a cross-sectional study in Chinese population and a meta-analysis for validation. Serum irisin was tested in patients with GDM and healthy controls (newly diagnosed cases: 61 and matched controls: 61) in the cross-sectional study. The two groups of participants were matched for age and pregnancy duration. Furthermore, we did a comprehensive meta-analysis to confirm whether serum/plasma irisin differs between participants with GDM and controls. Articles reported “circulating irisin and GDM” in Medline, PubMed, and EMBase were obtained, with the key word “myokine” or “irisin”. The comparison was analyzed by Review Manager 5.2. In the cross-sectional investigation, serum irisin showed a significant lower level in the GDM patients, compared with that in the control group. In the meta-analysis study, the summarized results of the present 5 studies in which 632 participants were included indicated that there was a lower level irisin of -58.68 ng/mL [95% confidence interval (CI)](-113.42, -3.93, P=0.04) in GDM patients than in the control group. The present cross-sectional investigation and meta-analysis is the first to show significant lower circulating irisin in subjects with GDM.
Vol 61 No. 5
Brown adipose tissue (BAT) is the site of sympathetically activated adaptive thermognenesis during cold exposure and after hyperphagia, thereby controlling whole-body energy expenditure (EE) and body fat. Radionuclide imaging studies have demonstrated that adult humans have metabolically active BAT composed of mainly beige/brite adipocytes, recently identified brown-like adipocytes. The inverse relationship between the BAT activity and body fatness suggests that BAT is, because of its energy dissipating activity, protective against body fat accumulation in humans as it is in small rodents. In fact, either repeated cold exposure or daily ingestion of some food ingredients acting on transient receptor potential channels recruits BAT in parallel with increased EE and decreased body fat. In addition to the sympathetic nervous system, several endocrine factors are also shown to recruit BAT. Thus, BAT is a promising therapeutic target for combating human obesity and related metabolic disorders.
Hiroki Fujita, Hisanori Taniai, Hiroko Murayama, Haruyo Ohshiro, Hikaru Hayashi, Seiko Sato, Nyuko Kikuchi, Taiga Komatsu, Koga Komatsu, Kanji Komatsu, Takuma Narita, Yuichiro Yamada
Vol 61 No. 2
Dipeptidyl peptidase-4 (DPP-4) inhibitor is a new class of anti-diabetic drug which exerts its glucose-lowering action by suppressing the degradation of a gut incretin hormone glucagon-like peptide-1 (GLP-1). To elucidate whether treatment with stronger DPP-4 inhibitor on top of angiotensin II type 1 receptor blocker (ARB) provides greater renal protective effects, we performed a crossover study with two DPP-4 inhibitors, sitagliptin and alogliptin, in twelve type 2 diabetic patients with incipient nephropathy taking ARBs. This study consisted of three treatment periods: sitagliptin 50 mg/day for 4 weeks (first period), alogliptin 25 mg/day for 4 weeks (second period), and sitagliptin 50 mg/day for 4 weeks (third period). Significant changes in body mass index, blood pressure, serum lipids, serum creatinine, estimated glomerular filtration rate, and HbA1c were not observed among the three treatment periods. Reduced urinary levels of albumin and an oxidative stress marker 8-hydroxy-2’-deoxyguanosine (8-OHdG), increased urinary cAMP levels, and elevated plasma levels of stromal cell-derived factor-1α (SDF-1α) which is a physiological substrate of DPP-4 were observed after the switch from sitagliptin to a stronger DPP-4 inhibitor alogliptin. Given a large body of evidence indicating anti-oxidative action of cAMP and up-regulation of cellular cAMP production by SDF-1α, the present results suggest that more powerful DPP-4 inhibition on top of angiotensin II type 1 receptor blockade would offer additional protection against early-stage diabetic nephropathy beyond that attributed to glycemic control, via reduction of renal oxidative stress by SDF-1α-cAMP pathway activation.
Monotherapy with the once weekly GLP-1 receptor agonist dulaglutide for 12 weeks in Japanese patients with type 2 diabetes: dose-dependent effects on glycaemic control in a randomised, double-blind, placebo-controlled study
Yasuo Terauchi, Yoichi Satoi, Masakazu Takeuchi, Takeshi Imaoka
Vol 61 No. 10
The aim of this study was to evaluate the dose-dependent effect of dulaglutide, a glucagon-like peptide-1 receptor agonist, on glycaemic control in Japanese patients with type 2 diabetes mellitus who were treated with diet/exercise or oral antidiabetic drug monotherapy. In this randomised, double-blind, placebo-controlled, parallel-group, 12-week study, patients received once weekly subcutaneous dulaglutide doses of 0.25, 0.5, or 0.75 mg (DU 0.25, DU 0.5, and DU 0.75, respectively) or placebo (n=36, 37, 35, and 37, respectively). The primary measure was change from baseline in glycated haemoglobin (HbA1c; %) at 12 weeks. Continuous variables were analysed using a mixed-effects model for repeated measures. Significant dose-dependent reductions in HbA1c were observed (least squares mean difference versus placebo [95% confidence interval]): DU 0.25=-0.72% (-0.95, -0.48), DU 0.5=-0.97% (-1.20, -0.73), and DU 0.75=-1.17% (-1.41, -0.93); p<0.001. Significant improvements in plasma glucose (PG), both fasting and average 7-point self-monitored blood glucose, were also observed with dulaglutide versus placebo (p<0.001). Dulaglutide was well-tolerated. Gastrointestinal adverse events (AEs) were more common in dulaglutide-treated patients, with nausea the most frequent (8 [5.5%]). Few dulaglutide-treated patients discontinued due to AEs (4 [3.7%]), and no serious AEs related to study medication occurred. Three patients (DU 0.5=1 and DU 0.75=2) reported asymptomatic hypoglycaemia (PG ≤70 mg/dL). The observed dose-dependent reduction in HbA1c and acceptable safety profile support further clinical development of dulaglutide for treatment of type 2 diabetes mellitus in Japan.
Umit Aydogan, Aydogan Aydogdu, Halil Akbulut, Alper Sonmez, Servet Yuksel, Yalcin Basaran, Ozcan Uzun, Erol Bolu, Kenan Saglam
Vol. 59 (2012) No. 12
Hypogonadotropic hypogonadism is defined as the failure in production of gonadal hormones, thus resulting in lower amounts of testosterone. Depression, anxiety and decreased quality of life are the most common psychopathological conditions in young hypogonadal men. The aim of the present study was to assess the still debated relationship with testosterone levels and psychological symptoms in young male patients with congenital hypogonadotropic hypogonadism (CHH). Thirty-nine young male patients with CHH and 40 age-matched healthy males were enrolled in the present study. The impact of testosterone replacement treatment (TRT) on the patients’ anxiety and depression levels, sexual function and quality of life were assessed before and after 6 months of treatment using valid and reliable scales, including the Short Form-36 (SF-36), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Arizona Sexual Experiences (ASEX). Patients with CHH had significantly higher scores for BDI, BAI, and ASEX than the control subjects at baseline (p=0.011, p=0.036, p<0.001, respectively). The ASEX and BDI scores significantly improved after the TRT (p<0.001 for both), while the improvement in the BAI score was not statistically significant (p=0.135). When compared to the control group, treatment naïve hypogonadal patients had more severe symptoms of sexual dysfunction, anxiety, depression, and worse quality of life. After 6 months of TRT, we observed improvements in the above parameters, suggesting that low endogenous levels of testosterone might be related to the increased incidence of psychological symptoms.
Tetsurou Satoh, Osamu Isozaki, Atsushi Suzuki, Shu Wakino, Tadao Iburi, Kumiko Tsuboi, Naotetsu Kanamoto, Hajime Otani, Yasushi Furukawa, Satoshi Teramukai, Takashi Akamizu
Vol. 63 (2016) No. 12
Thyroid storm is an endocrine emergency which is characterized by multiple organ failure due to severe thyrotoxicosis, often associated with triggering illnesses. Early suspicion, prompt diagnosis and intensive treatment will improve survival in thyroid storm patients. Because of its rarity and high mortality, prospective intervention studies for the treatment of thyroid storm are difficult to carry out. We, the Japan Thyroid Association and Japan Endocrine Society taskforce committee, previously developed new diagnostic criteria and conducted nationwide surveys for thyroid storm in Japan. Detailed analyses of clinical data from 356 patients revealed that the mortality in Japan was still high (∼11%) and that multiple organ failure and acute heart failure were common causes of death. In addition, multimodal treatment with antithyroid drugs, inorganic iodide, corticosteroids and beta-adrenergic antagonists has been suggested to improve mortality of these patients. Based on the evidence obtained by nationwide surveys and additional literature searches, we herein established clinical guidelines for the management of thyroid storm. The present guideline includes 15 recommendations for the treatment of thyrotoxicosis and organ failure in the central nervous system, cardiovascular system, and hepato-gastrointestinal tract, admission criteria for the intensive care unit, and prognostic evaluation. We also proposed preventive approaches to thyroid storm, roles of definitive therapy, and future prospective trial plans for the treatment of thyroid storm. We hope that this guideline will be useful for many physicians all over the world as well as in Japan in the management of thyroid storm and the improvement of its outcome.
Yuko Nakagawa, Yoshiaki Ohtsu, Masahiro Nagasawa, Hiroshi Shibata, Itaru Kojima
Vol. 61 (2014) No. 2
A homodimer of taste type 1 receptor 3 (T1R3) functions as a sweet taste-sensing receptor in pancreatic β-cells. This receptor is activated by various sweet molecules including sugars such as glucose. To determine the role of this receptor in glucose-induced insulin secretion, we addressed whether or not this receptor modulates glucose metabolism in MIN6 cells. We measured changes in intracellular ATP ([ATP]i) in MIN6 cells expressing luciferase. Sucralose, an agonist of T1R3, induced immediate and sustained elevation of [ATP]i in the presence of 5.5 mM glucose. The effect of sucralose was dose-dependent and, at 5 mM, was greater than that induced by 25 mM glucose. In contrast, carbachol, GLP-1 or high concentration of potassium did not reproduce the sucralose action. Sucralose facilitated the increase in [ATP]i induced by a mitochondrial fuel methylsuccinate, and potentiated glucose-induced elevation of [ATP]i. Administration of a non-metabolizable glucose analogue, 3-O-methylglucose, which acts as an agonist of T1R3, induced a small and transient increase in [ATP]i. 3-O-Methylglucose augmented elevation of [ATP]i induced by methylsuccinate, and also enhanced glucose-induced increase in [ATP]i. Knock down of T1R3 by using shRNA attenuated [ATP]i-response to high concentration of glucose and also reduced the glucose-induced insulin secretion. These results indicate that activation of the homodimer of T1R3 facilitates the metabolic pathway in mitochondria and augments ATP production. The results obtained by using 3-O-methylglucose suggest that glucose, by acting on the homodimer of T1R3, promotes its own metabolism.