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Thyroid hormones are critical for the development of opsins involved in color vision. Hypothyroid mice show delayed M-opsin development and expanded distribution of S-opsin on the retina. However, the effects of maternal hypothyroidism on opsin development remain unknown. This study investigates the effects of congenital central hypothyroidism and maternal hypothyroidism on opsin development in thyrotropin-releasing hormone knockout (TRH−/−) mice. We examined the mRNA expression and protein distribution of S/M-opsin on postnatal days (P)12 and 17, as well as mRNA expression of type 2 and 3 iodothyronine deiodinase (DIO2 and DIO3, respectively) in the retina and type 1 iodothyronine deiodinase (DIO1) in the liver at P12 in TRH+/− mice born to TRH+/− or TRH−/− dams, and conducted S/M-opsin analysis in TRH+/+ or TRH−/− mice born to TRH+/− dams at P12, P17, and P30. M-opsin expression was lower in TRH+/− mice born to TRH−/− dams than in those born to TRH+/− dams, whereas S-opsin expression did not significantly differ between them. DIO1, DIO2, and DIO3 mRNA expression levels were not significantly different between the two groups; therefore, thyroid function in peripheral tissues in the pups was similar. S/M-opsin expression did not significantly differ between the TRH+/+ and TRH−/− mice born to TRH+/− dams on any postnatal day. These results demonstrate that maternal hypothyroidism causes M-opsin developmental delay during the early developmental stages of neonatal mice, and TRH−/− mice, a model of congenital central hypothyroidism, born to a euthyroid dam do not have delayed opsin development.

A 35-year-old man experienced general fatigue and could not eat solid food because of nausea and vomiting. His weight abruptly decreased from 49 to 45 kg after 2 weeks. A detailed examination indicated superior mesenteric artery syndrome (SMAS) accompanied by acute-onset type 1 diabetes complicated by Graves' disease, referred to as autoimmune polyglandular syndrome type 3A (APS3A). Although SMAS has a good prognosis, some cases require emergency surgery, especially when complicated by gastric perforation. In our case, APS3A and SMAS developed rapidly and at approximately the same time, resulting in a cycle of mutual exacerbation.

The purpose of this article is to introduce the unit-structured diagram and a professional development workshop using the diagram. The diagram consists of three areas, including objectives, content...

Background Hypoglycemia due to non-insulin-producing tumors is referred to as non-islet cell tumor hypoglycemia (NICTH). As NICTH is a rare lesion, the natural course of NICTH is not well understood. We report a case of NICTH that was observed 30 years before the onset of hypoglycemia. Case summary A 50-year-old man was diagnosed with an abnormal right chest shadow during a routine X-ray examination, but no further examination was undertaken because the lesion appeared benign. Thirty years after the tumor discovery, the patient was admitted to the hospital with symptoms of severe hypoglycemia, which was diagnosed as NICTH based on a complete examination. The tumor was resected and found to be a solitary fibrous mass (15.6 cm × 13.7 cm × 10.4 cm); thereafter, the patient's blood glucose levels normalized and he completely recovered. Conclusion NICTH can have an acute onset, even if the tumor has been present and asymptomatic over a long time period.

Achieving the optimal glucose level time in range (TIR), as recently proposed by the "International Consensus on Time in Range," is challenging. We retrospectively analyzed data from 192 patients, including 58 with type 1 diabetes, using the FreeStyle Libre Pro system. This device was used by physicians for continuous glucose monitoring (CGM) and for making therapeutic decisions based on unbiased data, as the patients were blinded to their blood glucose levels during monitoring. The desired 70% TIR among patients with type 2 diabetes corresponded to an HbA1c of 7.7%. Importantly, however, a 70% TIR for patients with type 1 diabetes corresponded to an HbA1c of 6.9%, which diverged markedly from the HbA1c of 7.9% that corresponded to the desired 4% time below range (TBR). Moreover, these dissociations were observed more in patients with type 1 diabetes with a higher % coefficient of variation (> 36%). Hence, while the TIR is strongly correlated with HbA1c, it is difficult to coordinate with the TBR in Japanese patients with type 1 diabetes. As these metrics (which are critical indicators in clinical practice) are rapidly gaining popularity globally, including in Japan, our data strongly support the cautious use of new CGM metrics such as TIR and TBR/time above range, and emphasize the importance of individualized treatment in achieving the optimal TIR and TBR, especially in patients with type 1 diabetes.

Sarcopenia is an important element that impairs daily activity. Sarcopenia is also linked to insulin resistance, and the number of diabetic patients also presenting sarcopenia is increasing. In recent years, autophagy has been identified as one of the novel mechanisms associated with sarcopenia. We previously reported that Fyn not only participates in the metabolic syndrome but also that autophagy-regulating sarcopenia was decreased in muscle specific Fyn transgenic mice through STAT3 regulation (Cell metabolism 2010, Cell Rep. 2012). More recently, we revealed Fyn-dependent STAT3 phosphorylation by IL6, which is involved in chronic inflammation and metabolic syndrome, using mouse C2C12 myotube cells expressing shRNA for Fyn. Furthermore, using WT mice with both the denervated and the hind limb suspension (HS) that promotes disuse atrophy by suspending the hind limb, not only both Fyn and IL6 gene expressions were increased but the expression and phosphorylation levels of STAT3 were also augmented, while the autophagic activity was decreased. To confirm those regulations are Fyn dependent, we took advantage of Fyn null mice (FynKO) with HS. Compare to WT mice with HS, all the muscles of FynKO were resistant for the loss of muscle mass induced by HS. The expressions of bothatrogin-1 and muRF-1,the key muscle specific E3 ubiquitin ligases as well as the markers for sarcopenia, were not changed in the muscles of FynKO with HS. Moreover, the STAT3 phosphorylation on tyrosine 705 was decreased in the muscle of FynKO compared to WT mice after hind limb suspension, while expression levels of STAT3 were not changed. IL-6mRNA expression levels were increased in the HS muscle of control mice, but were not changed in FynKO HS muscle. Finally, the autophagic activity, examined by both LC3-2 protein levels after intraperitoneal administration of colchicine andSQSTM1/p62 immunofluorescence in muscles, was retained in FynKO after HS. These results strongly suggest that Fyn is involved not only in the metabolic syndrome but also in the pathogenesis of sarcopenia, and may lead to a better understanding of the pathology of sarcopenia-associated obesity and the development of therapeutic methods. Presentation: No date and time listed

Objectives There is a little evidence for the TRH test criteria in the diagnosis of Central Hypothyroidism (CeH). Therefore, we investigated the significance of the TRH test for Central Hypothyroidism due to Non-Functional Pituitary Adenoma. Methods 107 cases of Non-functional pituitary adenoma (NFPA) in Gunma University Hospital Neurosurgery and Toranomon Hospital Intercerebral Pituitary Surgery, between 2007 to 2020 are studied. Subjects divided into CeH group (n = 19) with FT4 below the reference value and a normal group (n = 88). Serum TSH level was determined before (basal-TSH value) and 30, 60, 120 minutes after TRH administration. Peak-TSH value, delayed and prolonged responses were analyzed. A peak-TSH occurring at 60 minutes or later was considered as a delayed response. If 120-minutes TSH value to peak-TSH value ratio is equal to or higher than 0.6 was considered as a prolonged response. Results The basal-TSH was higher in the CeH group than in the normal group (median 2.7 vs. 1.5μIU/mL) (p Conclusion In central hypothyroidism due to Non-Functional Pituitary Adenoma, the basal-TSH value does not usually decrease, but rather be higher value within the reference range. 30-minute value or peak value was not useful in diagnosis, yet the prolonged response was more significant. Central Hypothyroidism in Non-Functional Pituitary Adenoma, can be diagnosed with sensitivity of 79% and specificity of 78% when the 120-minute value to peak value ratio is equal to or lower than 0.65. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Background Myeloid / Lymphoid or Mixed-lineage leukemia gene (MLL) is translocated to chromosome 11 long arm q23 region (11q23) and the MLL fusion gene expressed as a result of translocation reconstruction plays an important role in MLL-related leukemia development. It has also been reported that MLL and MLL protein play an important role in tumor development as a Menin-binding protein in Multiple Endocrine Neoplasia Type I (MEN1). More recently, normal MLL protein has been shown to have histone H3 lysine 4-methylation (H3K4-HMT) activity and to be an epigenetic transcriptional regulator. In addition, the function of MLL protein as a histone methylase has been reported in the gene region involved in metabolism regions. Here, we analyzed the involvement of MLL in glucose metabolism in the pancreas using MLL knockout mice. Methods Glucose metabolism in MLL knockout mice and the function of MLL in cultured cells were analyzed. Result: Since the homozygotes of MLL knockout mice are embryonic lethal, we analyzed them using Heterozygous mice. MLL heterozygous mice showed significantly weight loss compared to the wild type mice. MLL heterozygous mice showed no difference in food intake compared to wild type mice. IPGTT showed impaired glucose tolerance in MLL heterozygous mice. However, ITT showed no insulin resistance and decreased insulin secretion during glucose loading. In GSIS tests, Islets isolated from heterozygous mice pancreas have been observed to decrease insulin secretion in the response to glucose stimulation. In comprehensive gene analysis using Microarray analysis of mRNA extracted from mice islet, the gene expression changes related insulin secretion and apoptosis have been revealed in MLL heterozygous mice. Histological search showed no decrease in β-cell number, and immunohistological search showed no difference in insulin, glucagon, and TUNEL staining between heterozygous and wild type mice. And also, MLL knockdown was performed in a cultured cell line. Insulin secretion was decreased to glucose stimulation in MLL knockdown cell line same as in MLL knockout mice. In addition, RNA microarrays were performed to these cell lines, several same genes that have confirmed in MLL mouse islets were observed in MLL knockdown cell. In common to both MLL knockout mice and MLL knockdown cell line, the expression levels of GLUT1 and GLUT2 were decreased. In conclusion, MLL knockout mice showed decreased insulin secretion. It was suggested that MLL may be involved in insulin secretion through decreased expression of the GULT1 gene and GLUT2 genes in islets. Presentation: No date and time listed

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic triglycerides (TG) and hyperglycemia arising due to persistent insulin resistance, and is profoundly linked to obesity. However, there is currently no established treatment for NAFLD in obese human subjects. We previously isolated Helz2, the expression of which was upregulated in human and mouse NAFLD, and its deletion activated the hepatic expression of functional leptin receptor long form (Leprb) and suppressed NAFLD development and body weight (BW) gain in obese mice. A high-throughput assay of small-molecule drugs revealed that guanabenz acetate (Ga), originally used to treat hypertension, possesses a high affinity constant against HELZ2, and its administration activates LEPRB expression in HepG2 cells in vitro. The chronic oral administration of Ga shows the selective leptin sensitization in the liver via upregulation of hepatic Leprb expression, which affects expression of genes involved in lipogenesis and fatty acid β-oxidation and diminishes hepatocyte hypertrophy with droplets enriched in TG in high-fat diet-induced obese mice. This activity significantly improves insulin resistance to decrease hyperglycemia and hepatocyte and adipocyte weights, resulting in BW reduction without reducing food intake. Regarding drug repositioning, Ga has the potential to effectively treat NAFLD and hyperglycemia in obese patients.

The Abbott FreeStyle Libre flash glucose monitoring system (FGM) is a recently introduced, but widespread continuous glucose monitoring system. While its mean absolute relative difference (MARD) value indicating its accuracy is acceptable with reference to the self-monitoring of blood glucose (SMBG) levels, few reports have examined the MARD in sensor glucose values of FGM (FGM-SG) with reference to plasma glucose (PG) levels and the factors determining it. We performed oral glucose tolerance tests (OGTTs) in 25 Japanese subjects without diabetes. Parkes error grid analyses showed that FGM-SG with either SMBG or PG levels as a reference met International Organization for Standardization criteria. The MARD in FGM-SG with reference to SMBG levels was 10.9 ± 4.1% during OGTTs. Surprisingly, the MARD in FGM-SG with reference to PG levels was 20.3 ± 10.3% during OGTTs, revealing a discrepancy in the accuracy of FGM-SG compared with that of PG levels; moreover, the MARD showed negative correlations with fasting blood sugar level, homeostasis model assessment insulin resistance index, and body mass index (BMI). Multiple regression analyses revealed that BMI contributed the most to the MARD when FGM-SG and PG level were compared, as lean individuals have a greater MARD regardless of glucose levels. Inaccurate FGM data could potentially increase the risk of inappropriate treatment; consideration of such factors is critical to ensure reliable FGM values.

Background: Critical limb ischemia (CLI) patients have high risk for major adverse cerebrovascular and cardiovascular events. This study investigated the risk factors of cerebrovascular or cardiovascular death in CLI patients with concomitant coronary artery disease (CAD). Methods and Results: The association between baseline characteristics and cerebrovascular or cardiovascular death ≤2 years after revascularization for CLI was investigated in 137 CLI patients who previously underwent successful revascularization for CAD before treatment for CLI. Twenty-three patients (17%) died. Geriatric nutritional risk index (GNRI) in the deceased group (DG) was significantly lower than in the surviving group (SG). On Cox proportional hazard multivariate analysis, hemodialysis (HD) and malnutrition (defined as GNRI

Continuous intravenous infusion of prostaglandin I2 (PGI2) analog, epoprostenol, has improved the survival rate for severe pulmonary hypertension, but longer treatment with PGI2 sometimes occurs hyperthyroidism. For the hyperthyroidism during PGI2 treatment, two molecular mechanisms are speculated; the direct effect of PGI2 on thyroid follicular cells via PGI2 receptor which is coupled with G-protein alpha subunit like TSH receptor, and the indirect effect of PGI2 on activated T helper 17 cells which are associated with autoimmune disease (1). Here, we experienced three different cases of hyperthyroidism during PGI2 treatment in pulmonary hypertension. In case 1, epoprostenol had been administered intravenously for about ten months before the onset of hyperthyroidism. TSAb became positive (591%) and technetium uptake was elevated (4.7%), which were similar to the typical observations in Grave's disease. Total thyroidectomy was needed to control the thyroid function in case 1. In case 2, no thyroid antibody was detected and technetium uptake was almost vanished, as in the destructive thyroiditis. The thyroid function eventually normalized without any intervention. In case 3, hyperthyroidism occurred during oral PGI2 analog selexipag administration, but no evidence of Grave's disease or destructive thyroiditis was observed. Hyperthyroidism was declined when the dose of selexipag was reduced. To investigate the molecular mechanism underlying each case, we added the drugs which were used in each case on a thyroid follicular cell line, FRTL5. The thyroid tissue which was resected in case 1 and FRTL5 cells expressed PGI2 receptors in immunohistochemistry and immunofluorescence study. Human thyrotropin alpha (TSH) and epoprostenol elevated the intracellular cyclic AMP (cAMP) in FRTL5 (1.33 fold and 1.20 fold each, P Presentation: No date and time listed

This report details the case of a 41-year-old woman who was diagnosed with insulinoma. As the patient developed severe life-threatening hypoglycemia, we introduced Dexcom G4 Platinum (DG4P), a modern continuous glucose-monitoring system (CGM). The algorithm of the sensor glucose (SG) values of CGM is based on patients with diabThis report details the case of a 41-year-old woman who was diagnosed with insulinoma. As the patient developed severe life-threatening hypoglycemia, we introduced Dexcom G4 Platinum (DG4P), a modern continuous glucose-monitoring system (CGM). The algorithm of the sensor glucose (SG) values of CGM is based on patients with diabetes; therefore, we evaluated the accuracy of DG4P in this patient. The mean absolute relative differences and absolute differences between SG of DG4P and self-monitoring of blood sugar values were 10.8%±8.3% and 6.8±5.7 mg/dL, respectively, in the hypoglycemic region, which verifies DG4P's accuracy. DG4P was found to be useful for monitoring hypoglycemia not only in patients with diabetes but also in those with insulinoma.etes; therefore, we evaluated the accuracy of DG4P in this patient. The mean absolute relative differences and absolute differences between SG of DG4P and self-monitoring of blood sugar values were 10.8%±8.3% and 6.8±5.7 mg/dL, respectively, in the hypoglycemic region, which verifies DG4P's accuracy. DG4P was found to be useful for monitoring hypoglycemia not only in patients with diabetes but also in those with insulinoma.

ContextThe most frequent cause of central hypothyroidism (CeH) is pituitary adenomas, but the mechanisms remain unclear.ObjectiveWe investigated serum thyroid levels and GH/IGF-1 in central hypothyroidism in untreated patients with pituitary nonfunctioning and GH-secreting adenomas.DesignThis was a retrospective cross-sectional study of cases collected from Gunma University and Toranomon Hospitals between 2007 and 2016.PatientsOne-hundred thirty-nine cases of nonfunctioning pituitary adenoma (NFPA) and 150 cases of GH-secreting pituitary adenoma (GHPA) were analyzed.Main Outcome MeasuresThe correlations between thyroid levels, several clinicopathological parameters, and GH/IGF-1 were examined.ResultsTwenty-four percent of NFPA patients had CeH. The severity did not correlate with tumor size, age, or sex, and all cases had normal TSH levels. In contrast, only 8.7% of GHPA patients had CeH; approximately half had normal TSH levels and approximately half had low TSH levels. Serum TSH levels in GHPA patients were significantly lower and free T4 (FT4) and free T3 levels were higher than those in patients with NFPA. Furthermore, approximately one-fourth of GHPA patients had normal FT4 and low TSH levels. In addition, serum FT4 levels and serum TSH levels were positively and negatively correlated, respectively, with serum IGF-1 levels. Furthermore, IGF-1 levels in patients with GHPA decreased with age.Conclusions(i) NFPA patients with CeH had TSH levels within a normal range. (ii) GHPA patients had a low incidence of CeH, which may be a result of stimulated thyroid function by GH/IGF-1. (iii) We found an age-dependent decrease in serum IGF-1 levels in patients with GHPA.

Aim In this study, we aim to examine the clinical meaning of low-density lipoprotein cholesterol (LDL-C) ＜70 mg/dL as assessed by Friedewald equation [LDL-C (F)] and Martin method [LDL-C (M)] and non-high-density lipoprotein cholesterol (HDL-C) ＜100 mg/dL on the occurrence of new lesions among Japanese patients with stable angina who underwent percutaneous coronary intervention (PCI) and were prescribed with strong statins. Methods Among the 537 consecutive stable angina patients who had underwent PCI and had been prescribed with strong statins, the association between the occurrence of new lesions with myocardial ischemia at the 9-month follow-up coronary angiography and ≤ 2 years after PCI and baseline characteristics were assessed. Results New lesions appeared 9 months and ≤ 2 years after PCI in 31 and 90 patients, respectively. Multivariate logistic regression analysis revealed diabetes mellitus (DM) was significantly associated with the occurrence of new lesions ≤ 2 years after PCI [odds ratio (OR) 1.71, 95 % confidence interval (CI) 1.06-2.83, p=0.031], and only non-HDL-C ≥ 100 mg/dL was associated with the occurrence of new lesions both at 9 months and ≤ 2 years after PCI [OR 1.80, 95 % CI 1.10-3.00, p=0.021 and OR 1.85, 95 % CI 1.13-3.07, p=0.016]. Conclusions Non-HDL-C ≥ 100 mg/dL was determined to be the independent risk factor for the occurrence of new lesions 9 months and ≤ 2 years after PCI among stable angina patients with strong statins. Residual risk after PCI should be considered by assessing not only DM but also non-HDL-C beyond the scope of LDL-C-lowering therapy with strong statins.

To evaluate retrospectively the satisfaction of continuous subcutaneous insulin infusion (CSII) compared to multiple daily infusions in Japanese women with diabetes mellitus (DM) during pregnancy, we examined 27 women with type 1 (n = 20) or type 2 (n = 6) diabetes mellitus or gestational diabetes (n = 1) who previously used CSII. Among these patients, 19 had used CSII during pregnancy, which accounted for 30 births. Questionnaires were retrospectively administered. The mean age of patients was 36.5 ± 7.0 years. The average birth weight was 3.1 ± 0.6 kg, with 62% of babies exhibiting complications. The satisfaction level of CSII for patients during pregnancy was 3.95 ± 0.26, whereas it was 1.84 ± 0.26 for multiple daily infusions (P

Aim: The Friedewald equation is the standard method for estimating low-density lipoprotein cholesterol (LDL-C) levels [LDL-C(F)] and fixes the ratio of triglyceride (TG) to very LDL-C at 5. However, this has been reported to underestimate LDL-C, particularly in patients with LDL-C < 70 mg/dL. A novel method for LDL-C estimation [LDL-C(M)] using an adjustable factor instead of a fixed value of 5 has recently been proposed. The purpose of this study was to validate LDL-C(M) in Japanese patients with cardiovascular disease (CVD) treated with statins. Methods: In 385 consecutive CVD patients treated with statins, LDL-C(M) and LDL-C(F) levels were compared with directly measured LDL-C [LDL-C(D)]. Results: Mean LDL-C(D), LDL-C(F), and LDL-C(M) were 81.7 ± 25.5, 76.4 ± 24.6, and 79.9 ± 24.5 mg/dL, respectively. In all patients, both LDL-C(F) and LDL-C(M) were significantly correlated with LDL-C(D) [LDL-C(F) vs. LDL-C(D): R = 0.974, p < 0.001; LDL-C(M) vs. LDL-C(D): R = 0.987, p < 0.001]. In patients with LDL-C(D) < 70 mg/dL, LDL-C(M) showed a better correlation with LDL-C(D) compared with LDL-C(F) [LDL-C(M) vs. LDL-C(D): R = 0.935, p < 0.001; LDL-C(F) vs. LDL-C(D): R = 0.868, p < 0.001]. In contrast, the correlation of LDL-C(D) with LDL-C(M) or LDL-C(F) was similar in patients with LDL-C(D) ≥ 70 mg/dL. Conclusions: In Japanese patients with CVD treated with statins, LDL-C level estimated by this novel method might be more accurate than those estimated using the Friedewald equation for LDL-C levels < 70 mg/dL.

Background) Myeloid / Lymphoid or Mixed-lineage leukemia gene (MLL) is translocated to chromosome 11 long arm q23 region (11q23) and the MLL fusion gene expressed as a result of translocation reconstruction plays an important role in MLL-related leukemia development. It has also been reported that MLL and MLL protein play an important role in tumor development as a Menin-binding protein in Multiple Endocrine Neoplasia Type I (MEN1). More recently, normal MLL protein has been shown to have histone H3 lysine 4-methylation (H3K4-HMT) activity and to be an epigenetic transcriptional regulator. In addition, the function of MLL protein as a histone methylase has been reported in the gene region involved in metabolism regions. Here, we analyzed the involvement of MLL in glucose metabolism in the pancreas using MLL knockout mice. Methods:) Glucose metabolism in MLL knockout mice and the function of MLL in cultured cells were analyzed. Result) Since the homozygotes of MLL knockout mice are embryonic lethal, we analyzed them using Heterozygous mice. MLL heterozygous mice showed significantly weight loss compared to the wild type mice. MLL heterozygous mice showed no difference in food intake compared to wild type mice. IPGTT showed impaired glucose tolerance in MLL heterozygous mice. However, ITT showed no insulin resistance and decreased insulin secretion during glucose loading. In GSIS tests, Islets isolated from heterozygous mice pancreas have been observed to decrease insulin secretion in the response to glucose stimulation. In comprehensive gene analysis using Microarray analysis of mRNA extracted from mice islet, the gene expression changes related insulin secretion and apoptosis have been revealed in MLL heterozygous mice. Histological search showed no decrease in β-cell number, and immunohistological search showed no difference in insulin, glucagon, and TUNEL staining between heterozygous and wild type mice. And also, MLL knockdown was performed in a cultured cell line. Insulin secretion was decreased to glucose stimulation in MLL knockdown cell line same as in MLL knockout mice. In addition, RNA microarrays were performed to these cell lines, several same genes that have confirmed in MLL mouse islets were observed in MLL knockdown cell. In conclusion, MLL knockout mice showed decreased insulin secretion. It was suggested that MLL may be involved in insulin secretion in islets.

Introduction: Retinal cone photoreceptor cells contain short (S) and medium (M) wavelength opsins, which are light-sensitive substances involved in color vision and visual acuity by sensing lights of different wavelengths. Thyroid hormones promote M-opsin expression and suppress S-opsin expression during the differentiation of cone photoreceptors. It was previously reported that M-opsin expression was delayed and S-opsin expression increased in TSH receptor-deficient mice and methimazole-induced hypothyroid mice. In addition, no M-opsin expression and increased S-opsin expression were observed in thyroid hormone receptor (TR) β2-deficient mice (Ng L et al, Nature Genetics. 2001; 27(1): 94-98.). This suggested that impaired thyroid function affects opsin development. We therefore examined retinal development in TRH-deficient mice, which are a model of central hypothyroidism established in our laboratory. Methods: We performed HE staining of the retina at postnatal 30 days and electroretinography at postnatal 10 weeks using TRH-/- and wild-type (WT) mice. We also examined expression levels of S/M opsin mRNA in WT, TRH-/- and TRH-/- pups born from TRH-/- dams at postnatal 12,17 and 30 days, and TRβΔ337T knock-in mice (TRβmut/mut) at postnatal 30 days. Furthermore, we performed immunohistochemistry to examine S/M opsin protein expression in these mice. Results: The retinal structures by HE staining and retinal functions by electroretinography in TRH-/- mice were unchanged compared with those in WT mice. Although M-opsin expression was not detected and S-opsin expression was higher in TRβmut/mut mice than in WT mice, the mRNA and protein expression levels of S/M-opsin did not significantly differ between TRH-/- pups born from TRH+/- dams and WT pups at all postnatal days. TRH-/- pups born from TRH-/- dams exposed to maternal hypothyroidism had similar serum total T4 levels to TRH-/- pups born from TRH+/- with normal maternal thyroid function. In contrast, the mRNA expression level of M-opsin was significantly lower (1.00±0.06 vs 0.64±0.05: mean ± SE, p

Lymphocytic hypophysitis is a rare immune-mediated inflammatory disorder that causes pituitary dysfunction. It has been reported that lymphocytic hypophysitis onset during pregnancy rarely relapses or exacerbates in subsequent pregnancies. We herein report a patient with relapse of lymphocytic hypophysitis triggered by the pregnancy of the second child. Case Presentation: At the age of 34, at 28 weeks of gestation of the first child, she became aware of left visual field disorder and was diagnosed as an upper left visual field defect. An MRI scan revealed an enlargement of the pituitary gland and the thickening of the stalk. She was referred to our hospital for diagnosis and treatment. Laboratory data showed central adrenocortical dysfunction and central hypothyroidism. Based on the course of the disease, MRI findings and laboratory data, we diagnosed her as lymphocytic hypophysitis occurred during pregnancy. With a replacement dose of hydrocortisone and levothyroxine, she gave birth by cesarean section at 38 weeks of gestation. We performed detailed assessment of anterior pituitary functions with hypothalamic hormone challenges after giving birth. It showed panhypopituitarism without diabetes insipidus. An MRI scan found the compression of the optic chiasm remained after childbirth, the patient underwent steroid pulse therapy. After that, visual field defect improved rapidly, and the patient continued to receive oral prednisolone with gradually reduced amount. An MRI scan performed over time and found the pituitary swelling gradually improved. The pituitary was completely intact 3 years after the onset of disease. At the age of 38, the patient became pregnant with her second child, showed no signs of hypopituitarism at the time of pregnancy. She still had been administrated with 3.5mg/day prednisolone. At the 21 weeks of pregnancy, she became aware of blurred vision and was diagnosed as a left paracenter scotoma. Laboratory data showed a decrease in blood glucose and neutrophil count, suggesting the occurrence of central adrenocortical insufficiency. Therefore, we suspected the relapse of hypophysitis due to second pregnancy. We started hydrocortisone supplementation in addition to prednisolone. No MRI scan was performed during pregnancy, since no progression of visual impairment was observed. She gave birth at 37 weeks of gestation, and postpartum MRI scan showed mild thickening of the stalk. Steroid pulse therapy was not performed because the visual field abnormality was spontaneously improved. Lymphocytic hypophysitis has a diverse course, and there is currently no confirmed risk factor for recurrence. In this case, hypophysitis recurred due to pregnancy despite the continuation of prednisolone administration, and the pathogenic mechanism may be different from the previously reported cases of recurrence of hypophysitis.

An 84-year-old woman was admitted to our hospital because of congestive heart failure, rapid atrial fibrillation, and ischemic heart disease. Percutaneous coronary intervention (PCI) via the left radial artery was performed, and a stent was deployed successfully into left anterior descending coronary artery (LAD). She got into shock state one hour after PCI. Chest X-ray and computed tomography scan revealed increase of soft tissue around the left axilla and implied the existence of hematoma. Hemoglobin level decreased from 13.3 g/dL to 8.2 g/dL and hemorrhagic shock was suspected. Angiography of the left axillary artery demonstrated contrast extravasation, and selective angiography using a micro-catheter identified bleeding from a branch of the superior thoracic artery. Hemostasis was performed successfully by embolization using a gelatin sponge, and improvement of the general condition was obtained. Aberration of 0.025-in. angle tipped guidewire was considered to induce arterial perforation during sheath insertion.

Somatic mutations in KCNJ5 gene have been identified in patients with adrenal aldosterone-producing adenomas (APAs). We previously reported that Japanese patients with APAs had distinct characteristics from patients in Western countries; i.e. they had a high frequency of KCNJ5 mutations and exhibited a frequent association with cortisol co-secretion. Therefore, APAs among Japanese patients may have different features from those in Western countries. We added recent cases, examined 47 cases (43% male) of APAs, including clinicopathological features, KCNJ5 mutations, and the mRNA levels of several steroidogenic enzymes, and compared the results obtained to those reported in other countries. While the prevalence of KCNJ5 mutations is approximately 40% in Western countries, 37 APA cases (78.7%) showed mutations: 26 with p.G151R and 11 with p.L168R. Although a significant gender difference has been reported in the frequency of KCNJ5 mutations in Europe, we did not find any gender difference. However, the phenotypes of Japanese patients with mutations were similar to those of patients in Western countries; patients were younger and had higher plasma aldosterone levels, lower potassium levels, and higher diastolic blood pressure. Reflecting these phenotypes, APAs with mutations had higher CYP11B2 mRNA levels. However, in contrast to APAs in Western countries, Japanese APAs with mutations showed lower CYP11B1, CYP17A1, and CYP11A1 mRNA levels. These findings demonstrated that Japanese APA patients may have distinct features including a higher prevalence of KCNJ5 mutations, no gender difference in the frequency of these mutations, and characteristics similar to the zona glomerulosa.

PM20D1 is a candidate thermogenic enzyme in mouse fat, with its expression cold-induced and enriched in brown versus white adipocytes. Thiazolidinedione (TZD) antidiabetic drugs, which activate the peroxisome proliferator-activated receptor-γ (PPARγ) nuclear receptor, are potent stimuli for adipocyte browning yet fail to induce Pm20d1 expression in mouse adipocytes. In contrast, PM20D1 is one of the most strongly TZD-induced transcripts in human adipocytes, although not in cells from all individuals. Two putative PPARγ binding sites exist near the gene’s transcription start site (TSS) in human but not mouse adipocytes. The −4 kb upstream site falls in a segmental duplication of a nearly identical intronic region +2.5 kb downstream of the TSS, and this duplication occurred in the primate lineage and not in other mammals, like mice. PPARγ binding and gene activation occur via this upstream duplicated site, thus explaining the species difference. Furthermore, this functional upstream PPARγ site exhibits genetic variation among people, with 1 SNP allele disrupting a PPAR response element and giving less activation by PPARγ and TZDs. In addition to this upstream variant that determines PPARγ regulation of PM20D1 in adipocytes, distinct variants downstream of the TSS have strong effects on PM20D1 expression in human fat as well as other tissues. A haplotype of 7 tightly linked downstream SNP alleles is associated with very low PMD201 expression and correspondingly high DNA methylation at the TSS. These PM20D1 low-expression variants may account for human genetic associations in this region with obesity as well as neurodegenerative diseases.

Background Malnutrition is the important factor to cause frailty and sarcopenia which affect the prognosis of cardiovascular diseases. However, the effect of malnutrition on prognosis of coronary artery disease (CAD) patients with myocardial damage is still uncertain. Purpose The aim of the present study was to investigate the effect of malnutrition on prognosis of CAD patients with myocardial damage who received percutaneous coronary intervention (PCI). Methods The subjects were 241 CAD patients with myocardial damage due to myocardial ischemia by coronary artery stenosis or occlusion. These patients underwent successful revascularization for CAD by PCI using second-generation drug eluting stents and discharged. Geriatric Nutritional Risk Index (GNRI) was used to assess nutritional status in this study, and patients with GNRI Results The mean follow-up period was 546±310 days, with a maximum follow-up duration of 1092 days. MACCE within 3 years after PCI were 42 cases (17%) and malnutrition group had high rate of MACCE (38 vs. 11%, P92+HD: HR 1.26, 95% CI: 0.65–2.47, p=0.493). Conclusions In CAD patients with myocardial damage, malnutrition (GNRI

Background: The Abbott FreeStyle Libre Flash glucose monitoring system (FGM) is one of the recently introduced personal continuous glucose monitoring systems. While FGM use has spread widely, few reports have examined the factors that determine its accuracy. Methods: We performed oral glucose tolerance tests (OGTTs) in 25 Japanese subjects without diabetes. Results: The mean absolute relative difference (MARD) in sensor glucose values of FGM (FGM-SG) with reference to self-monitoring of blood glucose (SMBG) levels was 10.9±4.1% during OGTTs. However, surprisingly, the MARD in FGM-SG with reference to plasma glucose (PG) levels was 20.3±10.3% during OGTTs, demonstrating the problems in accuracy of FGM-SG compared with that of PG levels in our study setting; however, this issue was not observed on comparison with accuracy of SMBG levels. Parkes error grid analyses showed that FGM-SG with either SMBG or PG levels as reference met the criteria of the International Organization for Standardization. Moreover, the MARD showed negative correlations with fasting blood sugar, homeostasis model assessment insulin resistance index, area under curve (AUC)-PG, and body mass index (BMI); multiple regression analyses revealed that BMI was the most contributing factor to the MARD between FGM-SG and PG levels. In other words, lean people showed more MARDs. Conclusions: Inaccurate FGM data could potentially increase the risk of inappropriate treatment. Consideration of such factors might be critical while using FGM. Disclosure S. Yoshino: None. E. Yamada: None. S. Okada: None. T. Saito: None. M. Yamada: None.

Thermogenesis by brown and beige adipocytes is a potential avenue to increased energy expenditure and thus management of obesity and metabolic syndrome. In mice, Pm20d1 has been previously identified as a candidate thermogenic gene, with its mRNA levels cold-induced and enriched in brown and beige versus white adipocytes, and with the potential mechanism of generating a novel uncoupling metabolite. Thiazolidinedione (TZD) antidiabetic drugs, which activate the PPARγ nuclear receptor, are potent stimuli for adipocyte browning, yet they fail to induce Pm20d1 expression mouse adipocytes or adipose tissue. In contrast, we show here that PM20D1 is one of the most strongly TZD-induced transcripts in human adipocytes, though not in samples from all individuals. Two putative PPARγ binding sites were identified near the gene’s transcription start site (TSS) in human but not mouse adipocytes. The ~4kb upstream binding site falls in a segmental duplication of a nearly identical intronic region ~2.5kb downstream of the TSS, and this duplication event occurred in the primate lineage and is absent in other mammals like mice. We demonstrate by chromatin immunoprecipitation and reporter assays that PPARγ binding and gene activation occur via this upstream duplicated site, thus explaining the species difference. Furthermore, this functional upstream PPARγ site has genetic variation in the human population, with one single nucleotide polymorphism (SNP) allele disrupting a PPAR response element. We show that this allele gives less activation by PPARγ and TZDs in reporter assays and reduced TZD activation of PM20D1 in patient-derived cultured adipocytes. In addition to this upstream variant that determines PPARγ regulation of PM20D1 in adipocytes, genotype at a distinct and unlinked variant >40kb downstream of the TSS strongly correlates with overall levels of PM20D1 expression in human fat as well as multiple other tissues. Seven tightly linked downstream SNP alleles correlate with very low PMD201 expression and correspondingly high DNA methylation at the TSS. These low PM20D1 expression variants may have phenotypic consequences, accounting for human genetic associations in this region with metabolic and neurodegenerative diseases. Overall, human PM20D1 expression is genetically variable at two levels, with genotype at downstream SNPs correlating with overall PM20D1 expression across tissues (an “on/off switch”), while the upstream PPARγ site SNP determines PPARγ and TZD regulation in adipose tissue (a “rheostat”). This human genetic variation in PM20D1 expression may ultimately inform precision medicine approaches. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Background: The most frequent cause of central hypothyroidism (CeH) is pituitary adenomas, but the mechanisms remain unclear. We investigated thyroid status and GH/IGF-1 in CeH in untreated patients with pituitary non-functioning and GH-secreting adenomas. Methods: This was a retrospective cross-sectional study of cases collected from two Hospitals between 2007 and 2016. One hundred-thirty-nine cases of non-functioning (NFPA) and 150 cases of GH-secreting pituitary adenoma (GHPA) were analyzed. The correlations between the thyroid status, several clinicopathological parameters, and GH/IGF-1 were examined. Findings: Twenty-four percent of NFPA patients had CeH. The severity did not correlate with tumor size and age, and all cases had normal TSH levels. In contrast, only 8.7% of GHPA patients had CeH; about half had normal TSH levels and about half had low TSH levels. Serum TSH levels in GHPA patients were significantly lower and free T4 (FT4) and free T3 levels were higher than those in NFPA patients. One-fourth of GHPA patients had normal FT4 levels and low TSH levels. In addition, serum FT4 levels and serum TSH levels were positively and negatively correlated, respectively, with serum IGF-1 levels. Furthermore, IGF-1 levels in patients with GHPA decreased with age. Interpretation: 1) NFPA patients with CeH had TSH levels within a normal range. 2) GHPA patients were resistant to CeH, which may be a result of stimulated thyroid function by GH/IGF-1. 3) We found an age-dependent decrease in serum IGF-1 levels in a large cohort of GHPAs. Funding Statement: This work was supported by JSPS KAKENHI Grants 16K15493, 23591345, and 20591087 (to M.Y.) and 16K19551 (to K.H.). This work was partially supported by the Advancing Care of Hypothalamic-Pituitary Dysfunction in Japan Study (to M.Y.) from the Japan Agency for Medical Research and Development, and the Research on Rare and Intractable Disease, Health and Labour Sciences Research Grants (to M.Y.). Declaration of Interests: The authors state: "The authors have nothing to disclose." Ethics Approval Statement: The studies were conducted in accordance with the principles of the Declaration of Helsinki and were approved by the Ethics Committee on human research of Gunma University (Approval number 535: Gunma University Human Genome Ethics Committee).

In type 2 diabetes, pancreatic beta cells are gradually ‘exhausted’ and fall into beta cell dysfunction, which proceeds more severe insulin dependence. Among the proposed mechanisms of beta cell dysfunction such as endoplasmic reticulum stress and oxidative stress, the beta cell heterogeneity has attracted the researcher’s interest recently. In 2012, Talchai et al. revealed that the beta cells were dedifferentiated in diabetic mice model, and nowadays it is considered as one form of the beta cell heterogeneity and is observed broadly among diabetic animal models and human patients. Previously we showed that food restriction had the best effect to restore beta cell gene expression in obese diabetic model mice, among the known diabetic treatments which we tested. In the current study, we aimed to unveil the molecular basis in the improvement of beta cell dedifferentiation during the calorie restriction. First, we utilized the high-fat/low carbohydrate diet (HF) or low-fat/high carbohydrate (HC) diet, to determine whether fat restriction or sugar restriction reduces the beta cell dedifferentiation in obese mice. When calorie intake was restricted evenly, both HF diet and HC diet decreased the body weight and hyperglycemia in db/db mice equally. Albeit the same metabolic profile, db/db group fed with HC diet had more enlarged islets and more dedifferentiated beta cell features than db/dbs fed with HF diet, which indicated the compensatory beta cell response in HC diet group. Moreover, HC diet group showed more severe fatty liver than HF diet group, along with the elevated synthesis and accumulation of triglycerides and cholesterol in liver. It is speculated that the insulin resistance in liver might impact on the beta cell dedifferentiation. Next, we analyzed the effect of glucagon-like peptide 1 (GLP-1) on beta cell dedifferentiation, since GLP-1 is secreted more from intestine by protein and fat intake, rather than by sugar intake. Also, increasing number of reports have suggested the improving effect of GLP-1 on beta cell dysfunction and fatty liver. Indeed, GLP-1 administration altered the reduced beta cell/alpha cell ratio in db/db mice, which indicated the restoration of beta cell heterogeneity. We are now investigating if GLP-1 administration reimburse the beta cell dedifferentiation in db/db mice fed with HC diet, to illuminate the role of incretins in beta cell dedifferentiation induced by unbalanced nutrition during diet. Also, we will present the RNA sequencing data of the liver in db/db mice fed with HF and HC diet, to elucidate the key molecules and genes which connect the beta cell function and metabolic state in liver.

AIM The amount of contrast media and renal atheroemboli are risk factors for acute kidney injury after percutaneous coronary intervention (PCI). However, the chronic kidney injury after PCI has not been fully characterized. The purpose of this study was to investigate factors affecting renal function in the late phase after PCI by measuring serum Cystatin C (CysC). METHODS In 143 consecutive patients who underwent elective PCI, CysC was evaluated at baseline and at 9 months after PCI, and the percent change in CysC (%CysC) was calculated. The association between %CysC and baseline characteristics, including medication use, was assessed. RESULTS Of 143 patients, 86 had worsening renal function (WRF; %CysC ≥0), and 57 did not (non-WRF; %CysC

Activating mutations in the KCNJ5 gene are responsible for the significant number of aldosterone-producing adenomas. To elucidate the molecular mechanisms underlying KCNJ5 expression, we characterized the entire human KCNJ5 gene. The gene spanned approximately 29.8 kb and contained three exons and two introns. The strongest expression of KCNJ5 mRNA was observed in the adrenal gland. The promoter region contained a putative binding site for SF-1 at −1782 bp. A construct containing −2444 bp of the promoter region exhibited the strongest promoter activity in adrenal H295R cells, and the introduction of a mutation in the SF-1 binding site almost completely abolished promoter activity. Furthermore, deletion mutation, EMSA, and knockdown analyses revealed that SF-1 bound to this element and was functional. Immunochemistry showed that KCNJ5 was predominantly expressed in the zona glomerulosa, while SF-1 was ubiquitously expressed in the adrenal cortex. These results demonstrated that SF-1 mediates the expression of human KCNJ5 in the adrenal cortex.

Brief refeeding times (~60 min) enhanced hepatic Angptl8 expression in fasted mice. We cloned the mouse Angptl8 promoter region to characterise this rapid refeeding-induced increase in hepatic Angptl8 expression. Deletion of the −309/−60 promoter region significantly attenuated basal promoter activity in hepatocytes. A computational motif search revealed a potential binding motif for hepatocyte nuclear factor 1α/1β (HNF-1α/β) at −84/−68 bp of the promoter. Mutation of the HNF-1 binding site significantly decreased the promoter activity in hepatocytes, and the promoter carrying the mutated HNF-1 site was not transactivated by co-transfection of HNF-1 in a non-hepatic cell line. Silencing Hnf-1 in hepatoma cells and mouse primary hepatocytes reduced Angptl8 protein levels. Electrophoretic mobility-shift assays confirmed direct binding of Hnf-1 to its Angptl8 promoter binding motif. Hnf-1α expression levels increased after short-term refeeding, paralleling the enhanced in vivo expression of the Angptl8 protein. Chromatin immunoprecipitation (ChIP) confirmed the recruitment of endogenous Hnf-1 to the Angptl8 promoter region. Insulin-treated primary hepatocytes showed increased expression of Angptl8 protein, but knockdown of Hnf-1 completely abolished this enhancement. HNF-1 appears to play essential roles in the rapid refeeding-induced increases in Angptl8 expression. HNF-1α may therefore represent a primary medical target for ANGPTL8-related metabolic abnormalities. The study revealed the transcriptional regulation of the mouse hepatic Angptl8 gene by HNF-1.

Mutations in TBL1X, a component of the nuclear receptor co-repressor (N-CoR) and silencing mediator of retinoic acid and thyroid hormone receptor co-repressor complexes, have recently been implicated in isolated central hypothyroidism (CeH). However, the mechanisms by which TBL1X mutations affect negative feedback regulation in the hypothalamus-pituitary-thyroid axis remain unclear. N-CoR was previously reported to paradoxically enhance the ligand-independent stimulation of TRH and TSHβ gene promoters by thyroid hormone receptors (TR) in cell culture systems. We herein investigated whether TBL1X affects the unliganded TR-mediated stimulation of the promoter activities of genes negatively regulated by T3 in cooperation with N-CoR. In a hypothalamic neuronal cell line, the unliganded TR-mediated stimulation of the TRH gene promoter was significantly enhanced by co-transfected TBL1X, and the co-transfection of TBL1X with N-CoR further enhanced promoter activity. In contrast, the knockdown of endogenous Tbl1x using short interfering RNA significantly attenuated the N-CoR-mediated enhancement of promoter activity in the presence of unliganded TR. The co-transfection of N365Y or Y458C, TBL1X mutants identified in CeH patients, showed impaired co-activation with N-CoR for the ligand-independent stimulation of the TRH promoter by TR. In the absence of T3, similar or impaired enhancement of the TSHβ gene promoter by the wild type or TBL1X mutants, respectively, was observed in the presence of co-transfected TR and N-CoR in CV-1 cells. These results suggest that TBL1X is needed for the full activation of TRH and TSHβ gene promoters by unliganded TR. Mutations in TBL1X may cause CeH due to the impaired up-regulation of TRH and/or TSHβ gene transcription despite low T3 levels.

Patients with adrenal insufficiency require appropriate glucocorticoid replacement therapy; however, reliable biological parameters for optimizing glucocorticoid supplementation are limited. The physician has to rely primarily on clinical judgment, carefully taking into account signs and symptoms potentially suggestive of over- or under-replacement. We have found that some patients who are viewed as receiving sufficient doses of glucocorticoids occasionally exhibit morning headache or morning discomfort, which may be caused by unrecognized nocturnal hypoglycemia. Our aim in this study was to evaluate the usefulness of continuous glucose monitoring (CGM) for detecting unrecognized hypoglycemia and optimizing glucocorticoid replacement therapy in adult patients with central hypoadrenalism. Six patients with central hypoadrenalism of various etiologies were included in this study. All patients exhibited occasional morning headache or discomfort. We performed CGM to measure plasma glucose levels in all patients, and CGM identified unrecognized hypoglycemia episodes at midnight and early in the morning in five patients (83%). The CGM findings were used to fine-tune the dosing and regimens of glucocorticoid replacement and to re-evaluate glucose levels to avoid further unrecognized hypoglycemic events. This optimization of hydrocortisone supplementation prevented additional nocturnal hypoglycemia incidences in all cases. The addition of L-thyroxine with hydrocortisone continued to provide favorable glycemic control. Occasional symptoms also improved after maintenance in all patients. These findings demonstrated that CGM may represent a powerful tool for identifying unrecognized hypoglycemia and for optimizing supplementary hormones in patients with central hypoadrenalism, thereby improving their quality of life.

Sirolimus-eluting stents (SES), especially those deployed at distal sites, cause more coronary vasospasm and endothelial dysfunction in the chronic phase compared to bare-metal stents (BMS). In comparison, endothelial dysfunction is less frequently induced by the Biolimus-A9 eluting stent (BES). A 75-year-old man with effort-induced angina pectoris previously underwent a total of three SES implantations in the left anterior descending coronary artery (LAD) and right coronary artery (RCA) in 2010 and 2011. He was referred to our hospital for the management of chest discomfort at rest in August 2014. We diagnosed this patient with coronary spastic angina (CSA) and coronary endothelial dysfunction (CED) induced by the SES, together with an atherosclerotic lesion in the left main coronary artery (LMCA). Adequate medication for CSA and CED and intervention for the atherosclerotic lesion contributed to improvement of vascular function and disappearance of his symptoms.

A 69-year-old man with effort angina pectoris previously underwent a total of 4 drug-eluting stent implantations in the left main trunk (LMT) to left anterior descending coronary artery (LAD), and a biolimus A9–eluting stent (BES) was deployed in the LMT. He was referred to our hospital for follow