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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.

This study aimed to investigate whether persistently high 1-h postchallenge glucose (PG) levels in a 75 g oral glucose tolerance test (75 g OGTT), as well as persistently low 1-h PG levels, are a risk factor for reclassification from normal glucose tolerance (NGT) into impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) among participants continually observed for 11 years. This single-center retrospective study used the electronic records of all participants undergoing Ningen Dock (health checkup) at Kiryu Kosei General Hospital between 2008 and 2018. In 2008, 361 of 523 participants who received Ningen Dock had NGT. Of the 361 participants, 109 received 75 g OGTT yearly for 11 years (2008–2018), and 72 of these 109 participants showed either persistently high 1-h PG (> 155 mg/dL) or persistently low 1-h PG (

Background: Previously, AF-956, which contains S356 of FAM83G and an N-terminal antenna peptide for entry into colon cancer cells, is markedly antiproliferative compared to a control peptide (AF-859), which lacks the N-terminal antenna peptide, by inducing apoptosis via the inhibition of HSP27 phosphorylation at residues S15 and S82. Objective: Because FAM83G-derived peptides are promising lead compounds for colon cancer treatment, we reanalyzed the effect of AG-066, which contains S356 of FAM83G and an N-terminal antenna peptide for entry into the liver cancer cells. Methods: HepG2 liver cancer cells were incubated with either AF-859 or AG-066 at a concentration of 54 μM at 37 °C for 24, 48, and 72 h. The effects of AF-859 and AG-066 on the cultured HepG2 cells were estimated using an inverted light microscope. Furthermore, the DNA ladder method and the dead cell assay were performed by applying Live/Dead Cell Staining Kit II. Erk phosphorylation was estimated by western blotting. Results: Treatment with AG-066 markedly reduced HepG2 viable cell counts compared to the AF- 859-treated HepG2 cells, as evident from the significantly increased number of dead cells in the culture medium. Additionally, AG-066 treatment increased cellular DNA laddering. We found no difference in Erk phosphorylation status between the AG-066- and AF-859-treated groups. Conclusion: This study illustrated that the peptide with a structure based on FAM83G functions as a spontaneous apoptosis inducer for liver cancer cells. Hence, it is a promising lead compound for the treatment of liver cancer.

Exocyst complex component 3-like 1 (EXOC3L1), which regulates insulin secretion, is ubiquitously present in heart, lung, liver, spleen, kidney, muscle, cerebellum, pituitary, adrenal grand, and pancreatic islets. Its deduced amino acid sequence has 31% identity and 53% similarity with Sec6, so they are considered isoforms. Since Sec6 suppresses apoptosis via HSP27, we investigated the involvement of EXOC3L1 expression in apoptosis. We found that overexpressed EXOC3L1 in Chinese hamster ovary cells significantly reduced cultured cell numbers. It also significantly increased apoptotic DNA ladder, caspase 3 activity, and cleavage of caspase 3 compared with the control. Thus, although Sec6 reduces apoptosis by increasing HSP27 phosphorylation, overexpressed EXOC3L1 alone can spontaneously induce apoptosis without apoptotic stimulators or inducers.

Objective: Because patients with diabetes mellitus (DM) were forced to stay indoors during the state of emergency, resulting in stress and a lack of physical activity, concerns about their glycemic control were raised. Patients and Methods: The 165 patients' glycated hemoglobin (HbA1c) levels were compared during the following periods: the 4 months that were selected as a representative condition 1 year before the COVID-19 pandemic (May 2018, March 2019, June 2019, and July 2019) and the latter 3 months as a 1-year follow-up during the COVID-19 pandemic (May 2019, March 2020, June 2020, and July 2020). Results: The patients' HbA1c levels were 7.32 ± 1.23, 7.44 ± 1.20, 7.16 ± 1.06, 7.01 ± 1.05, 7.23 ± 1.06, 7.45 ± 1.18, 7.15 ± 10.7, and 7.11 ± 1.17 in May 2018, March 2019, June 2019, July 2019, May 2019, March 2020, June 2020, and July 2020, respectively (expressed as mean ± standard deviation). Conclusion: The analysis showed that HbA1c levels did not worsen during the self-restraint period.

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

Triiodothyronine reduces sodium glucose cotransporter 2 expression in the kidney and increased glucose excretion in urine of alloxan-induced diabetic rats. Free thyroxine is also negatively associated with islet beta-cell function in euthyroid subjects. However, the influence of sodium glucose cotransporter 2 inhibitor on thyroid function in patients with type 2 diabetes mellitus has not been established.We investigated thyroid function in patients with type 2 diabetes mellitus in the presence or absence of sodium glucose cotransporter 2 inhibitor in a multicenter retrospective study conducted between 2019 and 2021. All participants visited the hospital monthly for type 2 diabetes mellitus treatment and plasma glucose and glycated hemoglobin level measurements. Furthermore, thyroid-stimulating hormone, free triiodothyronine, and free thyroxine levels were measured annually.Free triiodothyronine level and the free triiodothyronine:free thyroxine ratio in the group treated with sodium glucose cotransporter 2 inhibitor were significantly higher than the levels in the group not treated with sodium glucose cotransporter 2 inhibitor. Free triiodothyronine levels in the group treated with sodium glucose cotransporter 2 inhibitor were significantly higher than the levels in the group not treated with sodium glucose cotransporter 2 inhibitor (p = 0.040). Free thyroxine levels in the group treated with sodium glucose cotransporter 2 inhibitor were significantly lower than the levels in the group not treated with sodium glucose cotransporter 2 inhibitor (p = 0.002). Thyroid-stimulating hormone levels did not differ significantly between the two groups.Our findings show that sodium glucose cotransporter 2 inhibitor affects free triiodothyronine levels free thyroxine levels, and the free triiodothyronine:free thyroxine ratio.

A 79-year old Japanese woman was diagnosed with coronavirus disease (COVID-19), caused by SARS coronavirus 2 (SARS-CoV-2), based on a positive reverse transcription-PCR (RT-PCR) test result. Chest computed tomography revealed mild interstitial pneumonia. She had intermittent persistent inflammatory reactions with fever. Laboratory findings and RT-PCR test results showed SARS-CoV-2 positivity for more than 70 days. To the best of our knowledge, this relatively mild case has the longest duration of viral shedding recorded, as confirmed by RT-PCR analysis. This case demonstrates that the viral shedding in COVID-19 can be prolonged, even in mild disease, and highlights the difficulties in distinguishing viral shedding from SARS-CoV-2 infectivity.

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.

In this study, we compared the efficacy of a dipeptidyl peptidase-4 inhibitor (DPP4i) to improve glucose control in patients with type 2 diabetes mellitus (T2DM) with or without Hashimoto's thyroiditis (HT). First, we compared the change in glycated hemoglobin (HbA1c) between the hypothyroid condition (before levothyroxine sodium hydrate [LT4] treatment) and euthyroid condition (after LT4 treatment when patients had achieved euthyroidism for at least six months) in patients with T2DM and HT. Next, we compared the change in HbA1c levels before and six months of DPP4i treatment in patients with T2DM with and without HT. In hypothyroid condition the change in HbA1c after six months of DPP4i treatment was 0.13% ± 0.86%. The change in HbA1c levels from when patients first achieved euthyroidism to after six months in the euthyroid condition was 0.26% ± 0.90%. DPP4i efficacy in patients with T2DM and HT was reduced compared to patients with T2DM but without HT (-0.40 ± 0.90 vs. -0.99 ± 0.5, p = 0.0032). These data suggest that hypothyroidism does not impact on DPP4i efficacy. However, the effect of DPP4i in patients with T2DM and HT was reduced compared to that in T2DM patients without HT. An estimation of thyroid function before prescribing DPP4i may be useful tool for predicting the efficacy of DPP4i, allowing the ruling out complications from HT.

Free triiodothyronine/free thyroxine (FT3/FT4) ratio is considered as an index of the activities of iodothyronine deiodinase types 1 and 2 (DIO1 and DIO2, respectively) and is reportedly associated with insulin resistance in euthyroid adults. Euthyroid women with polycystic ovary syndrome accompanied with insulin resistance have lesser deiodinase activities. Correspondingly, the serum insulin level in a fasted condition positively correlates with the FT3/FT4 ratio, and insulin depletion decreases the DIO2 activity in mice. Selected genetic variants in DIO1 are also associated with insulin resistance measures. Therefore, if insulin positively regulates DIO1 and DIO2, the FT3/FT4 ratio should decrease under impaired insulin action, and the casual insulin level and FT3/FT4 ratio should be negatively correlated. To evaluate this hypothesis, we conducted a single-center retrospective study between 2018 and 2021. All participants visited the selected hospitals monthly for type 2 diabetes mellitus treatment and casual plasma glucose and HbA1c level measurements. Furthermore, their casual serum insulin levels were measured annually. Meanwhile, we excluded patients treated with insulin injection. Ultimately, we evaluated 71 patients, which all exhibited euthyroid conditions. The FT3/FT4 ratio was independently associated with thyroid-stimulating hormone, casual plasma glucose, and casual insulin levels. In terms of the regression coefficients of the univariate linear regression analysis, the FT3/FT4 ratio negatively correlated with the casual serum insulin levels. Therefore, the risk of FT3/FT4 ratio underestimation should be considered when diagnosing Graves' disease, which is often accompanied with insulin resistance.

Case Presentation: We report a case of a male patient with rheumatoid arthritis (RA) diagnosed during treatment with a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist (once-weekly dulaglutide injection). At 3 months after dulaglutide initiation, he began experiencing left shoulder pain that continued despite treatment by an acupuncturist, indicating that the pain was not due to periarthritis scapulohumeralis. His HbA1c level was 7.3% at the 3-month follow-up. At the 6-month follow-up visit, the HbA1c level was 8.2%, the low-density lipoprotein cholesterol level was 132 mg/dL, and he expressed right shoulder pain. After 3 months, the HbA1c level was 9.0%, and his bilateral shoulder pain worsened, due to which he could not use his arms well. Routine laboratory testing revealed no other abnormalities at that time. However, several inflammatory and serological RA markers were detected, including an erythrocyte sedimentation rate of 73 (normal range, Discussion: Thus, this case report suggests an association between RA and GLP-1. Based on a literature search in PubMed, we believe that this case report is the first to demonstrate that a patient with type 2 diabetes mellitus treated with a long-acting GLP-1 receptor agonist had RA. However, further research is needed to determine whether RA is one of the adverse effects of long-acting GLP-1 receptor agonists. Conclusion: During treatment with long-acting GLP-1 receptor agonists, it is necessary to consider the possibility of RA as a differential diagnosis when patients complain of persistent joint pain.

Only a few studies of continuous glucose monitoring (CGM) in patients with steroid diabetes have been published. Therefore, we investigated all patients with type 2 diabetes (n = 121) and steroid diabetes (n = 40) who used the FreeStyle Libre Pro® device (Abbott Japan) at Gunma University Hospital between 2017 and 2019. Glycated hemoglobin (HbA1c), mean sensor glucose (SG), and glucose management indicator values were similar in both groups. However, the indices for glycemic variabilities, expressed as standard deviations and percent coefficients of variation, were higher in patients with steroid diabetes than in those with type 2 diabetes. The associations between HbA1c, mean SG, and time in range (TIR) when glucose values were 70-180, 180 mg/dL were assessed using Pearson's product-moment correlation coefficient, which demonstrated good correlations in both patient groups. However, patients with steroid diabetes had a higher SG and lower TIR than did counterparts with type 2 diabetes who had similar HbA1c levels. To examine the effect of prednisolone on CGM data, we divided patients with steroid diabetes into 2 subgroups according to prednisolone dose (≤5 and >5 mg), and found that the dose of this steroid impacted the associations between HbA1c and CGM data, mean SG, and TIR. In summary, our data highlight the importance of cautiously interpreting CGM data and the optimal HbA1c level in patients with steroid diabetes to prevent diabetes-related complications. Further analyses using other CGM devices are necessary to further validate our findings.

Evaluation of residual beta cell function is indispensable in patients with type 2 diabetes as it informs not only diagnoses but also appropriate treatment modalities. However, there is a lack of convenient biomarkers for residual beta cell function. Therefore, we evaluated endogenous insulin level as a biomarker in outpatients who were being treated with insulin therapy and in patients who were introduced to insulin therapy after 4 years.Data of 174 outpatients with type 2 diabetes (50% male) whose glycemia was moderately controlled (glycated A1c 7.3% [5.2%-14.8%]) were reviewed. Twenty patients whose estimated glomerular filtration rate was lower than 30 ml/min/1.73 mC-CPI and UCPCR were significantly lower in the insulin-treated patients than in the insulin-untreated patients (0.9 vs. 2.2, p0.0001; 24.7 vs. 75.5, p = 0.0003, respectively). Moreover, C-CPI were significantly lower in the insulin-requiring patients for 4 years than in the insulin-unrequiring patients (1.0 vs. 1.7, p = 0.0184). The multivariate logistic regression analysis revealed that both indicators of insulin secretion influenced the requirement for insulin therapy, but C-CPI could serve as the most convenient and useful biomarker for not only current insulin therapy requirements (p = 0.0002) but also the subsequent requirement for insulin therapy (p = 0.0008).C-CPI could be determined easily, and it was found to be a more practical marker for outpatients; therefore, our findings would have critical implications for primary care.背景: 对2型糖尿病患者残余β细胞功能的评估是必不可少的, 因为它不仅指导诊断, 而且指导适当的治疗方式。然而, 尚缺乏方便评估残余β细胞功能的生物标志物。因此, 我们评估了正在接受胰岛素治疗的门诊患者和在4年后接受胰岛素治疗的患者内源性胰岛素水平。 方法: 回顾174例门诊2型糖尿病患者(男性占50%), 血糖得到适度控制(HbA1c:7.3%, 5.2%~14.8%)。20例肾小球滤过率低于30mL/min/1.73m

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.

Diabetic kidney disease (DKD) is one of the major diabetic complications and the leading cause of the end stage renal disease. Recently autophagy was shown to regulate DKD. Previously we reported that Fyn regulates muscle mass by suppressing autophagy through Fyn-STAT3 signaling pathway. More recently, we demonstrated that Fyn also inhibits autophagy in HK2 cells, in vitro cell model of renal proximal tubular epithelial cells (RPTC). Moreover, we found Y369 of Tgm2, a known inhibitor of autophagy, is directory phosphorylated by Fyn both in vitro and in cells and Fyn-dependent phosphorylation of Tgm2 regulates autophagy in RPTC. It has been reported that Tgm2 forms complexes with p53 and p62 (a known autophagy regulator) to mediate the degradation of p53 at autophagosomes in cancer cells. To note is that p53 could function as a DKD inducer. We found that p53 expression was decreased in Tgm2 knock-downed HK2 cells, suggesting that Tgm2-p62-p53 complex also modulates autophagy in RPTC. Since these were only in vitro studies, we proceeded with those in vivo. In HFD fed mice, diet-induced rodent models of metabolic disorders, we found that protein expression of p53 was increased due to decreased levels of autophagy implicated by decreased p62 punctuations in RPTC. To confirm the role of Fyn in autophagy and p53 expression we took advantage of a diabetic mouse model of FynKO mice induced by Streptozocin(STZ). While p53 was increased in the kidney of diabetic WT mice induced by STZ, it was not the case in the kidney of diabetic FynKO, indicating that Fyn could regulate autophagic activity and p53 expression. Taken together, these data suggest that the metabolic status may regulate Fyn to phosphorylate Tgm2 and modulate Tgm2-p62-p53 complex leading to the development of DKD. This regulatory mechanism is not mediated by blood glucose and may lead to the new therapeutic targets for diabetic kidney disease regardless of control of diabetes. 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.

Overexpressed TBC1D8B, a GTPase-activating protein, significantly reduced cultured HCT116 human colon cancer cell number. We tested N-terminal TBC1D8B, which is identical to wild type TBC1D8B from amino acid positions 1 to 427 and possesses a modified sequence from position 428 to 435 (ECGGLFLL) because of the introduction of a premature stop codon at position 436 to narrow down the minimum requirement element. The N-terminal TBC1D8B contains two GRAM domains but not the TBC domain essential for Rab-GTPase activity. The N-terminal TBC1D8B overexpression significantly reduced the cultured HCT116 cell number. When we tested C-terminal TBC1D8B, containing the portion of TBC1D8B absent in the N-terminal TBC1D8B, the cell number reduction was not observed. The N-terminal TBC1D8B overexpression significantly increased the coronin 1B expression and reduced the phosphorylation of serine 51 in eIF2α, respective markers of apoptosis and cell death/survival. Also, caspase 3 and poly ADP-ribose polymerase increased cleavage in suspended cells overexpressing the N-terminal TBC1D8B. Taken together, it is not the TBC domain for Rab-GTPase activity, but amino acids 1 to 435, including the two GRAM domains, that is enough for TBC1D8B to cause spontaneous apoptosis. TBC1D8B could be a potential anticancer therapeutic molecule.

The new type 2 diabetes drug, dapagliflozin, reduces blood glucose levels and body weight by inhibiting sodium glucose transporter 2 (SGLT2) in proximal tubular cells. SGLT2 inhibitors might modulate glucose influx into renal tubular cells, thereby regulating the metabolic conditions that cause endoplasmic reticulum (ER) stress in the cells. In this study, we examined the effect of dapagliflozin on ER stress in the HK-2 proximal tubular cell line and in the kidney of db/db mice to characterise its function in diabetic nephropathy (DN). We found that dapagliflozin regulated ER stress-mediated apoptosis in vitro and in vivo. Only the elf2α-ATF4-CHOP pathway was regulated under these conditions. Notably, the drug rescued C2 ceramide-induced ER stress-mediated apoptosis and ER stress-mediated apoptosis, which might occur in DN, in db/db mice. Our study shows a novel role for dapagliflozin as an inhibitor of ER stress and suggests that dapagliflozin might be useful for the prevention of DN.

Introduction Previously, we reported that the renal threshold for glucose reabsorption can be measured as the lowest plasma glucose level that correlates with the first detectable appearance of urine glucose. These data revealed significant variations among patients with type 2 diabetes mellitus (T2DM), and there was a significant negative correlation between the renal threshold for glucose reabsorption and HbA1c levels following treatment with the sodium-glucose co-transporter 2 (SGLT2) inhibitor ipragliflozin. Recently approved SGLT inhibitors may not show the same efficacy in patients with T1DM as in those with T2DM unless the renal threshold for glucose reabsorption shows similar levels between the two groups. SGLT2 inhibitors improve plasma glucose control in patients with T2DM by reducing glucose reabsorption via the epithelial cells of the proximal tubule. Methods The renal threshold for glucose reabsorption was defined as the minimum blood glucose concentration that results in the presence of measurable glycosuria in at least 12 measurements. Results The renal threshold for glucose reabsorption in patients with T2DM [n = 64; 201.8 ± 33.6 (range 121–268) mg/dL] was significantly higher than that in patients with T1DM [n = 33; 171.0 ± 33.0 (range 76–259) mg/dL; p = 0.00022]. Conclusion The renal threshold for glucose reabsorption in patients with T1DM was near the normal range and significantly lower than that in patients with T2DM. The efficacy of the SGLT2 inhibitor was better in patients with a higher renal threshold for glucose reabsorption. Thus, these results indicate that it is advisable to estimate the renal threshold for glucose reabsorption prior to initiating SGLT2 inhibitor therapy in patients with T1DM.