Vol 63 No. 1
Insulin controls hepatic glucose production (HGP) and maintains glucose homeostasis through the direct action of hepatic insulin receptors, as well as the indirect action of insulin receptors in the central nervous system. Insulin acts on insulin receptors in the hypothalamic arcuate nucleus, activates ATP-sensitive potassium channels in a phosphoinositide 3-kinase (PI3K)-dependent manner, induces hyperpolarization of the hypothalamic neurons, and regulates HGP via the vagus nerve. In the liver, central insulin action augments IL-6 expression in Kupffer cells and activates STAT3 transcription factors in hepatocytes. Activated STAT3 suppresses the gene expression of gluconeogenic enzymes, thereby reducing HGP. It has become evident that nutrients such as glucose, fatty acids, and amino acids act upon the hypothalamus together with insulin, affecting HGP. On the other hand, HGP control by central insulin action is impeded in obesity and impeded by insulin resistance due to disturbance of PI3K signaling and inflammation in the hypothalamus or inhibition of STAT3 signaling in the liver. Although the mechanism of control of hepatic gluconeogenic gene expression by central insulin action is conserved across species, its importance in human glucose metabolism has not been made entirely clear and its elucidation is anticipated in the future.
Tetsurou Satoh, Osamu Isozaki, Atsushi Suzuki, Shu Wakino, Tadao Iburi, Kumiko Tsuboi, Naotetsu Kanamoto, Hajime Otani, Yasushi Furukawa, Satoshi Teramukai, Takashi Akamizu
Vol 63 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.
Yoshitaka Hashimoto, Takafumi Osaka, Takuya Fukuda, Muhei Tanaka, Masahiro Yamazaki, Michiaki Fukui
Vol 63 No. 10
Recent cross-sectional studies revealed that sarcopenia is associated with non-alcoholic fatty liver disease (NAFLD) in general population. However, it remains to be elucidated that the association between skeletal muscle mass index (SMI) and hepatic steatosis in patients with type 2 diabetes. In this cross-sectional study of 145 Japanese patients (79 men and 66 women) with type 2 diabetes, we examined the correlation of SMI with hepatic steatosis. Skeletal muscle mass was estimated from bioimpedance analysis measurements and SMI (%) was defined as skeletal muscle mass (kg)/total body weight (kg) × 100. Controlled attenuation parameter (CAP) evaluated with transient elastography, was used for assessment of hepatic steatosis. In addition, we also investigated the association between SMI and prevalence of NAFLD, which was defined as CAP over 237.8 dm-1, using logistic regression analysis. Fifty-eight (74%) men and thirty-nine (60%) women had NAFLD. Multiple regression analysis demonstrated that SMI was independently correlated with CAP (β = -0.35, P = 0.007) in men after adjusting for age, body mass index, hemoglobin A1c, triglycerides/ HDL-C ratio, C-reactive protein and gamma-glutamyl transferase. On the other hand, SMI was not associated with CAP in women. Odds ratio per incremental 1% of SMI for prevalence of NAFLD was 0.80 (95% CI 0.64-0.97, P = 0.021) after adjusting for age, BMI, smoking statues, triglycerides/ HDL-C ratio, HbA1c, and gamma-glutamyl transferase in men. In conclusion, SMI was negatively associated with hepatic steatosis in men with type 2 diabetes.
Yuka Kinoshita, Makoto Arai, Nobuaki Ito, Yuichi Takashi, Noriko Makita, Masaomi Nangaku, Yusuke Shinoda, Seiji Fukumoto
Vol 63 No. 5
Metastatic bone disease is one of the most common complications of advanced cancers. Pathological fractures, spinal cord compression, and radiotherapy or surgery to the bone are collectively called skeletal-related events (SREs), which cause severe pain, increase hospitalization rates, and impair the quality of life (QOL) of patients with bone metastases. The receptor activator of nuclear factor-kB ligand (RANKL)/RANK pathway is critical in the progression of bone metastases. Previous studies have demonstrated that an anti-RANKL antibody (denosumab) was superior to zoledronic acid in prolonging time to first SRE in patients with bone metastases from prostate and breast cancers. However, severe hypocalcemic events occur more frequently after treatment with denosumab compared with zoledronic acid. In this study, 368 administrations of denosumab in 219 patients with metastatic bone disease from solid tumors were analyzed to clarify the risk factors for developing hypocalcemia. The results showed that grade 2/3 hypocalcemia was observed in 10.4% of the total number of denosumab administrations. Patients with higher baseline serum ALP, higher performance status (PS), or gastric cancer were at higher risk for developing hypocalcemia. The cut-off value for ALP to predict denosumab-related hypocalcemia was 587 U/L with a sensitivity of 0.77 and a specificity of 0.81. Close monitoring of serum calcium, especially after the first treatment with denosumab, is strongly recommended in these patients.
Shinichi Suzuki, Shunichi Yamashita, Toshihiko Fukushima, Keiichi Nakano, Sanae Midorikawa, Akira Ohtsuru, Seiji Yasumura, Mitsunori Hosoya, Kenji Kamiya, Hiroki Shimura, Satoru Suzuki, Izumi Nakamura, Masafumi Abe
Vol 63 No. 3
After the Fukushima nuclear power plant accident on March 11, 2011, the public of Japan became particularly concerned about the possibility of an increased risk of childhood thyroid cancer, similar to what was observed after the Chernobyl’s accident. Due to serious public health perception, there was an urgency to evaluate the baseline levels of childhood thyroid status in Fukushima prefecture. Therefore we have commenced a thyroid ultrasound examination (TUE) survey of the approximately 360,000 pediatric inhabitants (0 to 18 years of age) who lived in Fukushima at the time of the accident in October 2011. The subjects were divided into three categories according to the standardized diagnostic criteria of ultrasound findings. Category A contained the subjects whose TUE findings were intact or benign. Category B were recommended a confirmatory TUE. Category C was recommended an immediate confirmatory TUE. Results: The survey of 40,302 subjects in the first year was completed in March, 2013. There were 40,097 (99.5%), 205 (0.50%) and 0 subjects in categories A, B and C, respectively. Of the 82 category B subjects who underwent fine needle aspiration cytology (FNAC), 12 were diagnosed with a malignant tumor or were suspected to have malignancy. The 12 subjects received thyroid surgery and 11 thyroid cancers and one benign nodule were confirmed histologically after surgery. This is the first large-scaled TUE survey to employ sophisticated ultrasound screening and aim to evaluate the baseline frequency of childhood thyroid nodules and cysts. The results will become the golden standard of future comparative TUE in Fukushima, Japan.
Feyza Yener Ozturk, Selvinaz Erol, Muhammed Masum Canat, Savas Karatas, Idris Kuzu, Sezin Dogan Cakir, Yuksel Altuntas
Vol 63 No. 2
Primary hyperparathyroidism is well known to be associated with cardiovascular morbidity and mortality. However, it is unclear whether normocalcemic primary hyperparathyroidism (NC-PHPT) and hypercalcemic primary hyperparathyroidism (HC-PHPT) share the same risk factors. We aimed to determine prevalence of metabolic syndrome in NC-PHPT and compare metabolic syndrome parameters and insulin resistance in NC-PHPT subjects with those in HC-PHPT and control subjects. After excluding patients with secondary hyperparathyroidism, the study enrolled 25 patients with NC-PHPT, 24 patients with HC-PHPT and 30 age-gender matched controls. All participants were evaluated using the International Diabetes Federation (IDF)-2006 metabolic syndrome criteria. Compared with HC-PHPT patients, NC-PHPT patients had similar prevalence of metabolic syndrome, glucose intolerance, and previous history of hypertension/anti-hypertensive medications, but compared with controls, NC-PHPT patients had significantly higher prevalence of glucose intolerance and previous history of hypertension/anti-hypertensive medications. Not serum calcium but PTH concentration was found to be significantly higher in those with glucose intolerance. Serum fasting triglyceride concentration and waist circumference were found to be positively correlated only with serum PTH concentration. In conclusion, patients with NC-PHPT may be prone to similar metabolic disturbances linked to higher cardiovascular risk like patients with HC-PHPT. Although NC-PHPT is thought to occur early in the development of the classical disease, it should be monitored regularly because of its metabolic consequences.
Tatsuhiko Urakami, Remi Kuwabara, Masako Aoki, Misako Okuno, Junichi Suzuki
Vol 63 No. 2
We evaluated the efficacy and safety of switching to insulin degludec (IDeg) from insulin glargine (IGlar) as basal-bolus therapy in young people with type 1 diabetes. The subjects were 36 patients, 21.3±1.0 years of age, with type 1 diabetes. IGlar had previously been injected once daily in 25 patients and twice daily in 11. They were then switched from IGlar to once-daily injection of IDeg. Both fasting plasma glucose (FPG) and HbA1c levels decreased significantly from 134±3.9 mg/dL and 7.9±0.2% at baseline to 116±2.2 mg/dL and 7.4±0.2% at 12 months after starting IDeg (P<0.0001 and P≤0.001, respectively). Overall and nocturnal hypoglycemia (PG<70 mg/dL) frequencies also decreased significantly from 4.9±0.7 and 2.0±0.3 times/month to 2.4±0.3 and 0.4±0.1 times/month at 12 months after starting IDeg (P≤0.005 and P<0.0005, respectively). The daily basal insulin dose was significantly reduced from 0.48±0.04 units/kg/day at baseline to 0.38±0.03 units/kg/day at the end of the study period (P<0.0001), which corresponded to 79.2% of the baseline value. Trends were similar in patients receiving the once-daily injection and those given twice-daily injections, but basal-insulin value reductions from baseline were more marked in patients receiving twice-daily injections of basal insulin (76.0% vs. 82.6% of the baseline value). These results suggest that switching from IGlar to an appropriate dose of IDeg may effectively control hyperglycemia while reducing the frequency of hypoglycemia episodes in young Japanese people with type 1 diabetes.
Satoru Suzuki, Sanae Midorikawa, Toshihiko Fukushima, Hiroki Shimura, Tetsuya Ohira, Akira Ohtsuru, Masafumi Abe, Yoshisada Shibata, Shunichi Yamashita, Shinichi Suzuki
Vol 62. No. 3
Although several reports have defined normal thyroid volume depending on either age or body surface, there are no sequential reference values on childhood thyroid volume evaluated by using ultrasonography and epidemiological analysis in Japan. The aim of the present study was to establish updated reference values for thyroid volume by ultrasound examination and epidemiological analysis in 0-19 year-old Japanese children. It is based on a cross-sectional study conducted from October 9, 2011 to March 31, 2012. The subjects were 38,063 children who were examined by ultrasonography as the initial preliminary survey of the Fukushima Health Management Survey in October 9, 2011 to March 31, 2012. The width, thickness, and height of each lobe were measured and the volume of each lobe was calculated by the mean of the elliptical shape volume formula. The values of thyroid volume at the 2.5 and 97.5 percentiles of age and body surface area for each gender group were obtained from 0-19 year-old children. Positive correlation was observed between thyroid volume and either age or body surface. The right lobe was significantly larger than the left lobe. The thyroid volume in females was larger than that in males after adjusting body surface area. The reference values of childhood thyroid for each age or body surface area were obtained by this extensive survey using ultrasound. These reference values may be used to define the normal size of thyroid gland by echosonography in Japanese children, although thyroid volume may be affected by dimorphic factors such as sex hormones.
Makito Tanabe, Yuko Akehi, Takashi Nomiyama, Junji Murakami, Toshihiko Yanase
Vol 62. No. 2
Endogenous testosterone is known to be protective against metabolic syndrome (MetS) in men. While various markers of testosterone status including serum total testosterone (TT), free testosterone (measured using analogue ligand RIA [aFT]), calculated FT (cFT), calculated bioavailable testosterone (cbT), and sex-hormone binding globulin (SHBG) are recognized, it is unclear which of these markers are the most appropriate ones for the detection of MetS. We measured various testosterone values and metabolic markers in 249 healthy Japanese males (mean age 52.7 ± 7.4 yr) and analyzed which testosterone value is most associated with various metabolic parameters, including MetS as diagnosed according to the International Diabetes Federation (IDF, 2009 version) or with the Japanese criteria. Age had no effect on the TT level but significantly decreased aFT, cFT, and cbT levels and significantly increased the SHBG level. All testosterone values and SHBG showed weak inverse relationships with the metabolic markers BMI, waist circumference, insulin, HOMA-R, and HOMA-β, with the strongest relationship being to TT. TT and SHBG were significantly lower in men with MetS than in men without MetS. All testosterone values gradually decreased as the number of MetS components increased. Multivariate analysis revealed that the TT median value of <4.0 ng/mL was the only significant marker for the detection of MetS. These results were essentially the same regardless of whether the diagnosis of MetS was based on the IDF or the Japanese criteria. In conclusion, among various testosterone values, TT is the most reliable indicator of MetS in middle-aged Japanese men.
Qian Wu, Mei Zhang, Yao Qin, Ruimei Jiang, Heng Chen, Xinyu Xu, Tao Yang, Kuirong Jiang, Yi Miao
Vol 62 No. 3
Islet autotransplantation (IAT) is a viable treatment for patients with severe chronic pancreatitis, this modality may prevent brittle diabetes mellitus after pancreatectomy. This systematic review and meta-analysis was performed to evaluated the outcomes of IAT after TP and discuss the factors that may affect the efficacy of this procedure. MEDLINE, Embase, Web of Science and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from 1977 to 30 April 2014. Cohort Studies reported patients with IAT after TP were included. The studies and data were identified and extracted by two reviewers independently. Data were analyzed using STATA 12.0 and Comprehensive Meta AnalysisV2 software. Random effects model, meta-regression analysis, sensitivity analysis and publication bias were conducted to improve the comprehens ive analysis. Twelve studies reporting the outcomes of 677 patients were included in this review. The insulin independent rate for IAT after TP at last follow-up was 3.72 per 100 person-years (95% CI: 1.00-6.44). The 30-day mortality was 2.1% (95% CI: 1.2-3.8%). The mortality at last follow-up was 1.09 per 100 person-years (95% CI: 0.21-1.97). Factors associated with incidence density of insulin independence in univariate meta-regression analyses included islet equivalents per kg body weight (IEQ/kgBW) (P=0.026). Our systematic review suggests that IAT is a safe modality for patients with CP need to undergo TP. A significant number of patients will achieve insulin independence for a long time after receiving enough IEQ/kgBW.
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