We aimed to evaluate the long-term safety and effectiveness of growth hormone (GH) therapy in Japanese patients with adult growth hormone deficiency (AGHD). In this observational, multicenter study, Norditropin^® (Novo Nordisk A/S, Bagsvaerd, Denmark) was administered as injections of 0.021 mg/kg/week as a starting dose divided into 6-7 doses/week. The dose was increased according to clinical response. Patients’ data were obtained from medical records. Measurements (lipids, glucose metabolism, and body composition) taken at baseline; 3, 6, and 12 months; and yearly until the end of the study were collected. Adverse drug reactions (ADRs), serious ADRs, and serious adverse events (SAEs) were evaluated. Of 387 registered patients, 334 were eligible for safety. After GH treatment initiation, a marked decrease in total cholesterol was observed earlier in the child-onset group than in the adult-onset group. LDL-cholesterol also decreased, but no significant differences in changes in LDL-cholesterol between adult-onset and child-onset groups were found. A significant increase in HDL-cholesterol starting 1 year after GH treatment initiation was found in the adult-onset group. There was no effect of GH treatment on glucose metabolism. Because of the small number of dual-energy X-ray absorptiometry data, the overall assessment of changes of body composition was difficult. Fifty-six (16.8%), 12 (3.6%), and 35 (10.5%) patients experienced ADRs, serious ADRs, and SAEs, respectively. This study demonstrated a favorable long-term safety and effectiveness profile of GH therapy in AGHD patients in the real-life Japanese clinical practice setting.

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The purpose of this study was to determine whether treatment using the active form of vitamin D (1,25(OH)₂D₃) could protect against high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in rats and ameliorate oxidative stress. Male Sprague-Dawley rats were divided into three groups and treated with standard chow, HFD, or HFD plus intraperitoneal injection of 1,25(OH)₂D₃ (5 μg/kg body weight, twice per week), respectively, for 16 weeks. Serum lipid profiles, hepatic function, intrahepatic lipid, and calcium levels were determined. Hepatic histology was examined using hematoxylin/eosin, Masson’s trichrome, and Oil Red O staining. Oxidative stress was assessed by measuring hepatic malondialdehyde (MDA) and F2α-isoprostane content. Expression of nuclear factor-erythroid-2-related factor 2 (Nrf2) and downstream target genes was analyzed using quantitative RT-PCR. 1,25(OH)₂D₃ treatment improved the serum lipid profile, reduced intrahepatic lipid levels, and attenuated hepatic steatosis and inflammation in HFD rats. Furthermore, MDA and F2α-isoprostane levels in liver tissue were reduced by 1,25(OH)₂D₃ administration. Although 1,25(OH)₂D₃ did not regulate the expression of Nrf2 mRNA, it did induce Nrf2 nuclear translocation. The expression of Nrf2 target genes, including Gclc, Nqo1, Sod2, and Cat, was up-regulated by 1,25(OH)₂D₃. We conclude that 1,25(OH)₂D₃ protects against HFD-induced NAFLD by attenuating oxidative stress, inducing NRF2 nuclear translocation, and up-regulating the expression of genes encoding antioxidant enzymes.

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Diagnostic delay of tumor induced osteomalacia (TIO) is common in clinic practice. To investigate the diagnostic condition of TIO in China and raise clinicians’ awareness of TIO, we retrospectively analyzed clinical manifestations, biochemical features, and specially evaluated missed diagnoses and misdiagnoses among 144 TIO patients from Peking Union Medical College Hospital during December 1982 to December 2014. Clinical presentations of TIO mainly included bone pain, difficulty in walking, pathological fractures, muscle weakness, and height loss. TIO patients demonstrated hypophosphatemia (0.48±0.13 mmol/L), elevated serum alkaline phosphatase (277.9±152.6 U/L), reduced tubular maximum for phosphorus/glomerular filtration rate (0.39±0.14) and markedly elevated serum fibroblast growth factor 23 (FGF23) (median level 302.9 pg/mL). The average time from onset to a correct diagnosis was 2.9±2.3 years while the mean duration from onset to tumor resection was 5.4±4.2 years. The initial misdiagnosis rate was 95.1% (137/144) and 240 case-times of misdiagnoses occurred among the 144 cases. The most frequent misdiagnoses were intervertebral disc herniation, spondyloarthritis (including ankylosing spondylitis) and osteoporosis. A total of 43.1% (62/144) cases with hypophosphatemia presented on their laboratory sheets were neglected and missed diagnosed. Our study showed that TIO was frequently misdiagnosed and missed diagnosed due to its rarity, insidious onset, nonspecific clinical manifestations and clinicians’ poor recognition. It is necessary to test serum phosphorus in patients with musculoskeletal symptoms and difficulty in walking. The measurement of serum FGF23 is rather valuable. Once hypophosphatemia is discovered, TIO should be suspected and it is highly recommended to search for tumors and perform curative surgery.

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To explore the role of NF-κB activation in the development of insulin resistance and investigate whether or not that the inhibition of NF-κB activation by PDTC will improve the insulin resistance of L6 cells exposed to H₂O₂. L6 cells were treated with H₂O₂, PDTC or both H₂O₂ and PDTC for 4 hours. The uptake of glucose with stimulation of insulin, the expression of P38-MAPK, p- P38-MAPK, NF-κBp65, p- NF-κBp65, IRS-1, IRS-2, p-IRS-2, PI3K, IκBα, p- IκBα, caspase-8 and GLUT4, the production of ROS, TNF-α, IL-6 and IL-1β as well as the apoptosis rate of L6 cells were determined and compared in L6 treated with H₂O₂ alone or both H₂O₂ and PDTC. Compared with the L6 cells treated with H₂O₂ alone, the L6 cells treated with both H₂O₂ and PDTC showed (1) significantly lower production of ROS, TNF-α, IL-6 and IL-1β; (2) significantly decreased expression of P38-MAPK, p- P38-MAPK and NF-κBp65, p- NF-κBp65, p- IκBα and caspase-8; (3) significantly lower rate of apoptosis; (4) significantly higher expression of IRS-2, p-IRS-2 (Tyr 612), PI3K and GLUT4; (5) significantly higher uptake of glucose with stimulation of insulin; (6) significantly increased expression of Bcl2 and decreased ratio of Bax to Bcl2. Based on the findings of the present study, inhibition of NF-κB activation by PDTC would improve the insulin resistance of L6 cells exposed to H₂O₂.

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The prognosis for autoimmune thyroid diseases (AITDs), such as Hashimoto’s disease (HD) and Graves’ disease (GD), varies among patients. Interleukin (IL)-12 and IL-18 also induce Th1 differentiation, and SOCS1 (Suppressor of cytokine signaling 1) and TIM-3 (T cell immunoglobulin and mucin domain-3) are known to be negative regulators of Th1 cells. To clarify the association of functional polymorphisms in the IL12, IL12Rβ1, IL18, SOCS1 and TIM3 genes with the intractability and severity of autoimmune thyroid disease (AITD), we genotyped these polymorphisms in 151 GD patients, including 61 patients with intractable GD and 51 patients with GD in remission, in 140 HD patients, including 59 patients with severe HD and 55 patients with mild HD, and in 74 healthy controls. The frequency of the IL18 -607CC genotype which correlates with a high production of IL-18, was significantly higher in patients with GD in remission than in those with intractable GD (p=0.0178). The -607C allele was significantly higher in patients with severe HD than in those with mild HD (p=0.0050). The -607CC genotype in IL18 gene may be protective against the intractability of GD, and the -607C allele may enhance the severity of HD.

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In Japan, premixed insulins are commonly used as starter insulin for type 2 diabetes. This subpopulation analysis assessed the efficacy and safety of twice-daily LM25 (25% insulin lispro/75% insulin lispro protamine) and LM50 (50% insulin lispro/50% insulin lispro protamine) as starter insulin in Japanese subjects, and compared these results with the whole-trial populations of East Asian subjects. In this subpopulation analysis of an open-label, phase 4, randomized trial (CLASSIFY), Japanese subjects received LM25 (n = 88) or LM50 (n = 84) twice-daily for 26 weeks. The primary outcome was change from baseline at Week 26 in glycated hemoglobin (HbA1c). Results for Japanese subjects were generally similar to those for the whole-trial population. Similar changes from baseline in HbA1c were observed for LM25 and LM50 groups (least squares [LS] mean difference [95% confidence interval] of LM25 - LM50 = 0.13 [-0.16, 0.41]%, 1.42 [-1.75, 4.48] mmol/mol, p = 0.388). More LM50-treated subjects than LM25-treated subjects achieved HbA1c targets of <7.0% (59.5% versus 43.2%; p = 0.034) or ≤6.5% (45.2% versus 28.4%; p = 0.027). The reduction in postprandial blood glucose concentrations after morning and evening meals was statistically significantly greater for LM50 than for LM25. The incidence of both hypoglycemia and treatment-emergent adverse events were similar between treatment groups. Both LM25 and LM50 twice daily appear to be effective and well tolerated as starter insulin, although LM50 might be more effective for Japanese type 2 diabetes patients.

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Non-islet cell tumor hypoglycemia (NICTH) is one of the causes of spontaneous hypoglycemia. The pathogenesis of NICTH is thought to be an excessive production by tumors of big insulin-like growth factor (IGF)-II. This study investigated the levels of glucose-regulatory hormones in patients with NICTH with high serum levels of big IGF-II (big IGF-II group) and compared these with profiles of patients with spontaneous hypoglycemia with normal IGF-II (normal IGF-II group). Circulating IRI, CPR, ACTH, cortisol, GH, and IGF-I levels measured during hypoglycemic episodes were examined retrospectively in 37 patients with big IGF-II producing NICTH and 6 hypoglycemic patients with normal IGF-II. The hormone profile data of 15 patients with NICTH from published case reports were reviewed and included in the analyses. Mean plasma glucose levels (36 vs. 29 mg/dL), serum IRI (0.53 vs. 0.37 μIU/mL), CPR (0.15 vs. 0.20 ng/mL), IGF-I SDS (-3.55 vs. -3.18 SD) and ACTH levels (27.3 vs. 33.8 pg/mL) were not significantly different between the big and normal IGF-II groups. However, mean serum GH (0.85 vs. 9.62 ng/mL) and plasma cortisol levels (16.2 vs. 34.5 μg/dL) were significantly lower in the big IGF-II group than in the normal IGF-II group (both p<0.05). In conclusion, although the magnitude of the decrease in insulin and IGF-I levels did not differ between spontaneous hypoglycemic patients caused by other etiologies, patients with NICTH tended to have low basal GH levels during hypoglycemic episodes. These differences in hormone profile may be helpful for selecting patients who require analysis of IGF-II.

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Diabetes mellitus is associated with an increased risk of falls, which increases the incidence of osteoporotic fractures and accordingly decreases quality of life. However, the association between fall risk and diabetic complications is not completely understood. Therefore, the aim of this study was to examine the association between fall risk and osteoporotic fractures in patients with type 2 diabetes mellitus (T2DM). We enrolled 194 Japanese patients with T2DM and assessed their fall risk using a brief interview form that included five items covering physical and social aspects of functioning and environmental factors. We examined the associations between fall risk and the presence of diabetic complications, such as neuropathy, retinopathy, nephropathy, cardiovascular disease, cerebrovascular disease, peripheral artery disease (PAD), and osteoporotic fractures (including any fracture and vertebral fractures only). In the multivariate logistic regression analysis, a longer history of T2DM, the presence of neuropathy and PAD, and a history of any fractures were significantly and positively associated with the risk of falls. On the other hand, a lower body mass index, the presence of neuropathy, and the risk of falls were independently and positively associated with the risk of any fracture. When fractures were limited to vertebral fractures only, the association with the risk of falls remained significant. We found that the risk of falls and osteoporotic fractures were associated in patients with T2DM and that a brief screening test of the risk of falls was useful for assessing the risk of osteoporotic fractures.

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A multicenter, open-label, phase 2 study was conducted to investigate the efficacy and safety of long-acting pasireotide formulation in Japanese patients with acromegaly or pituitary gigantism. Medically naïve or inadequately controlled patients (on somatostatin analogues or dopamine agonists) were included. Primary end point was the proportion of all patients who achieved biochemical control (mean growth hormone [GH] levels<2.5μg/L and normalized insulin-like growth factor-1 [IGF-1]) at month 3. Thirty-three patients (acromegaly, n=32; pituitary gigantism, n=1) were enrolled and randomized 1:1:1 to receive open-label pasireotide 20mg, 40mg, or 60mg. The median age was 52 years (range, 31-79) and 20 patients were males. At month 3, 18.2% of patients (6/33; 90% confidence interval: 8.2%, 32.8%) had biochemical control (21.2% [7/33] when including a patient with mean GH<2.5μg/L and IGF-1< lower limit of normal). Reductions in the median GH and IGF-1 levels observed at month 3 were maintained up to month 12; the median percent change from baseline to month 12 in GH and IGF-1 levels were -74.71% and -59.33%, respectively. Twenty-nine patients completed the 12-month core phase, 1 withdrew consent, and 3 discontinued treatment due to adverse events (AEs; diabetes mellitus, hyperglycemia, liver function abnormality, n=1 each). Almost all patients (97%; 32/33) experienced AEs; the most common AEs were nasopharyngitis (48.5%), hyperglycemia (42.4%), diabetes mellitus (24.2%), constipation (18.2%), and hypoglycemia (15.2%). Serious AEs were reported in 7 patients with the most common being hyperglycemia (n=2). Long-acting pasireotide demonstrated clinically relevant efficacy and was well tolerated in Japanese patients with acromegaly or pituitary gigantism.

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Subclinical hypothyroidism (SCH) patients have normal thyroid hormone levels but increased thyroid stimulating hormone (TSH) level in serum. It has been reported that high TSH is related to abnormal skeletal development in mice with hypothyroidism. However, the cellular mechanism is not fully understood. In the present study, we aim to investigate the direct effects of TSH stimulation on chondrocytes, and the putative role of autophagy in this process. By using EdU incorporation assay and flow cytometry for mitochondrial membrane potential assay, we demonstrated deceased proliferation and promoted apoptosis in TSH stimulated primary mouse chondrocytes. And the balance of Bcl-2 and BAX expression on protein level was broken. More interestingly, the expression of autophagic markers Beclin-1 and LC3II was reduced in TSH stimulated chondrocytes, accompanied by less autophagosomes and accumulated p62 protein, indicating an impaired autophagic flux. More interestingly, mTOR was upregulated and AMPK activity was decreased in TSH stimulated PMCs, suggesting that mTOR/AMPK pathway is get involved in the regulation of TSH on autophagy in PMCs. Collectively, we found an increased apoptosis and suppressed autophagy in TSH stimulated primary chondrocytes, which is meaningful in understanding the effects of increased TSH level on articular cartilage and the role of autophagy in this process, and thus provide a potential novel therapeutic target in related cartilage damages.

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