Human TMEM2 is not a catalytic hyaluronidase, but a regulator of hyaluronan metabolism via HYBID (KIAA1199/CEMIP) and HAS2 expression.

Cutaneous hyaluronan (HA) is depolymerized to intermediate sizes in the extracellular matrix, and further fragmented in the regional lymph nodes. Previously, we showed that the HA-binding protein involved in HA depolymerization (HYBID), also known as KIAA1199/CEMIP, is responsible for the first step of HA depolymerization. Recently, mouse transmembrane 2 (mTMEM2) with high structural similarity to HYBID was proposed to be a membrane-bound hyaluronidase. However, we showed that the knockdown of human TMEM2 (hTMEM2) conversely promoted HA depolymerization in normal human dermal fibroblasts (NHDFs). Therefore, we examined the HA-degrading activity and function of hTMEM2 using HEK293T cells. We found that human HYBID and mTMEM2, but not hTMEM2, degraded extracellular HA, indicating that hTMEM2 does not function as a catalytic hyaluronidase. Analysis of the HA-degrading activity of chimeric TMEM2 in HEK293T cells suggested the importance of the mouse GG domain. Therefore, we focused on the amino acid residues that are conserved in active mouse and human HYBID and mTMEM2 but are substituted in hTMEM2. The HA-degrading activity of mTMEM2 was abolished when its His248 and Ala303 were simultaneously replaced by the corresponding residues of inactive hTMEM2 (Asn248 and Phe303). In NHDFs, enhancement of hTMEM2 expression by proinflammatory cytokines decreased HYBID expression and increased hyaluronan synthase 2-dependent HA production. The effects of proinflammatory cytokines were abrogated by hTMEM2 knockdown. A decreased HYBID expression by interleukin-1ß and transforming growth factor-ß was canceled by hTMEM2 knockdown. In conclusion, these results indicate that hTMEM2 is not a catalytic hyaluronidase, but a regulator of HA metabolism.

Pro-inflammatory cytokines suppress HYBID (hyaluronan (HA) -binding protein involved in HA depolymerization/KIAA1199/CEMIP) -mediated HA metabolism in human skin fibroblasts.

In the skin, the metabolism of hyaluronan (HA) is highly regulated. Aging leads to chronic low-grade inflammation, which is characterized by elevated levels of pro-inflammatory cytokines; however, the relationship between inflammation and HA metabolism is not clear. Herein, we investigated the effects of a mixture of pro-inflammatory cytokines containing TNF-α, IL-1ß, and IL-6 on HA metabolism in human skin fibroblasts. Treatment with the cytokine mixture for 24 h suppressed HA depolymerization via downregulation of HYBID (HA-binding protein involved in HA depolymerization/KIAA1199/CEMIP) and promoted HA synthesis via upregulation of HAS2 in human skin fibroblasts. Moreover, HAS2-dependent HA synthesis was driven mainly by IL-1ß with partial contribution from TNF-α. Transmembrane protein 2 (TMEM2/CEMIP2), which was previously reported as a candidate hyaluronidase, was upregulated by the cytokine mixture, suggesting that TMEM2 might not function as a hyaluronidase in human skin fibroblasts. Furthermore, the effects of the cytokine mixture on HA metabolism were observed in fibroblasts after 8 days of treatment with cytokines during three passages. Thus, we have shown that HYBID-mediated HA metabolism is negatively regulated by the pro-inflammatory cytokine mixture, providing novel insights into the relationship between inflammation and HA metabolism in the skin.

A Case of Marine-Lenhart Syndrome with Predominance of Plummer Disease.

A 74-year-old woman with a left neck mass and thyrotoxicosis was referred to our hospital, and was later diagnosed with Marine-Lenhart syndrome based on positivity for thyroid autoantibodies, ultrasonographically evident left lobe thyroid nodule with increased blood flow, and scintigraphically identified not only increased tumor-like accumulation but also diffused uptake. Disease control was difficult despite administration of antithyroid drugs, so subtotal thyroidectomy was performed. No hyperplastic changes or histopathological findings characteristic of Graves disease were evident on histopathology, so Plummer disease was considered to be dominant. In case of hot in low type which showed higher uptake in the nodule and lower uptake in the extranodular part on scintigraphy, there is a possibility of relapse in drug treatment.

Glycemic Profiling in Patients with Drug-Naïve Type 2 Diabetes by Continuous Glucose Monitoring.

The purpose of this study was to determine the glycemic profiles of drug-naïve type 2 diabetes patients according to hemoglobin A1c (HbA1c) level using continuous glucose monitoring. We aimed to clarify factors associated with HbA1c and average blood glucose level. Patients were divided into three groups according to their HbA1c level (< 7.0% n=23, 7.0% ≤ HbA1c < 8.0% n=17 and ≥ 8.0% n=31), and the factors associated with HbA1c and average glucose of each group were evaluated. Pre-meal glucose levels were the highest before lunch, and the 2 hour postprandial blood glucose level was the lowest after lunch. The pre-meal and postprandial blood glucose levels increased after each meal with increases in HbA1c. Average glucose level was the most significant determinant of HbA1c, whereas pre-meal glucose level at dinner was the most significant determinant of average glucose level, and the range of increase in glucose from pre-meal at dinner was the most significant determinant of standard deviation (SD) of 24 hour glucose levels. HbA1c subgroup analysis indicated that pre-meal glucose level at lunch significantly correlated with average glucose level in the HbA1c < 8.0% group, while pre-meal glucose level at dinner significantly correlated with average glucose level in the HbA1c ≥ 8.0% group. The range of increase in glucose from pre-meal in the morning significantly correlated with SD of 24 hour glucose levels in the HbA1c < 8.0% group, and the postprandial peak glucose level at lunch significantly correlated with SD of 24 hour glucose levels in the HbA1c ≥ 8.0% group. The results suggest that improvement of the average glucose level is necessary to improve the HbA1c levels. For patients with HbA1c < 7.0%, it is important to improve blood glucose level after breakfast and before lunch to decrease the average glucose level. For patients with 7.0% ≤ HbA1c < 8.0%, it is important to improve blood glucose level before lunch and after dinner to decrease the average glucose level. For patients with HbA1c ≥ 8.0%, it is important to improve blood glucose levels after lunch and before dinner to decrease the average glucose level.

Twenty-four-hour variations in blood glucose level in Japanese type 2 diabetes patients based on continuous glucose monitoring.

AIMS/INTRODUCTION: High fluctuations in blood glucose are associated with various complications. The correlation between glycated hemoglobin (HbA1c) level and fluctuations in blood glucose level has not been studied in Japanese patients with type 2 diabetes. In the present study, blood glucose profile stratified by HbA1c level was evaluated by continuous glucose monitoring (CGM) in Japanese type 2 diabetes patients. MATERIALS AND METHODS: Our retrospective study included 294 patients with type 2 diabetes who were divided by HbA1c level into five groups (≥6.0 to <7.0%, ≥7.0 to <8.0%, ≥8.0 to <9.0%, ≥9.0 to <10.0% and ≥10%). The correlation between HbA1c level and CGM data was analyzed. The primary end-point was the difference in blood glucose fluctuations among the HbA1c groups. RESULTS: The mean blood glucose level increased significantly with increasing HbA1c (Ptrend  < 0.01). The standard deviation increased with increases in HbA1c (Ptrend  < 0.01). The mean amplitude of glycemic excursions did not vary significantly with HbA1c. The levels of maximum blood glucose, minimum blood glucose, each preprandial blood glucose, each postprandial maximum blood glucose, range of increase in postprandial glucose from pre-meal to after breakfast, the area under the blood concentration-time curve >180 mg/dL and percentage of the area under the blood concentration-time curve >180 mg/dL were higher with higher HbA1c. Mean glucose level and pre-breakfast blood glucose level were significant and independent determinants of HbA1c. CONCLUSIONS: In Japanese patients treated for type 2 diabetes, the mean amplitude of glycemic excursions did not correlate with HbA1c, making it difficult to assess blood glucose fluctuations using HbA1c. Parameters other than HbA1c are required to evaluate fluctuations in blood glucose level in patients receiving treatment for type 2 diabetes.

Comparative analysis of the effects of alogliptin and vildagliptin on glucose metabolism in type 2 diabetes mellitus.

The aim of this 24-week, prospective randomized open-label study was to compare the effects of alogliptin and vildagliptin on glucose control, renal function, and lipid metabolism. In Study 1, DPP-4 inhibitor-naive type 2 diabetes (T2DM) were randomly assigned to alogliptin 25 mg/day or vildagliptin 50 mg twice daily. In Study 2, T2DM on treatment with 50 mg/day sitagliptin were switched to either 25 mg/day alogliptin or 50 mg twice daily vildagliptin. The primary endpoint was change in glycosylated hemoglobin (HbA1c) level at 24 weeks, while the secondary endpoints were changes in urinary albumin excretion and low-density lipoprotein cholesterol (LDL-C) levels at 24 weeks. In Study 1, HbA1c levels changed at 24-week by -0.5±0.7% in the alogliptin group (p=0.002, relative to baseline) and -0.7±0.9% in the vildagliptin group (p=0.001, relative to baseline), and the extent of these changes were comparable between the two groups (p=0.219). The decrease in log urinary albumin excretion was more significant in the vildagliptin group (p=0.008). In Study 2, HbA1c levels at 24-week changed by 0.2±0.7% in the switch-to-alogliptin group (p=0.007) and 0.0±0.6% in the switch-to-vildagliptin group (p=0.188), indicating a significant difference between the groups (p=0.003). In both studies, the changes in LDL-C levels were comparable between the two groups. The two drugs had comparable glucose-lowering effects in DPP-4 inhibitor-naive patients but the effect was more pronounced for vildagliptin in patients switched from sitagliptin. The results may point to subtle yet important differences between the two DPP-4 inhibitors. This trial was registered with UMIN (no. #000019022).

Correlation between the physicochemical property of some nonsteroidal anti-inflammatory drugs and changes in adenosine triphosphate, glutathione and hemoglobin in rat erythrocytes.

This study was conducted to explore the relationship between physicochemical property and toxic effectiveness using rat red blood cells (RBCs). The toxic effectiveness of acid nonsteroidal anti-inflammatory drugs (NSAIDs) was systemically examined by the depletion of intracorpuscular adenosine triphosphate (ATP), glutathione (GSH), and hemoglobin (Hb) at various doses, increased every 5 fmol/RBC. When the RBCs were incubated with NSAIDs, the drugs attained maximum levels within RBC, and the levels were then reduced. The ATP depletion seemed to be observed on the excretion of the drugs prior to the depletions of GSH and Hb. The physicochemical properties of NSAIDs were obtained from QMPRPlus, SMILES code, and CS ChemRaw Ultra. Correlation between their physicochemical properties and their doses for the depletions of ATP, GSH and Hb was performed in comparison with those of the membrane bound enzyme (MBE) inhibiting- and methemoglobin (MHb)-generating drugs. The ATP depletion by NSAIDs was correlated with the GSH depletion and intracorpuscular levels of the drugs, but not with the Hb depletion. The GSH depletion was correlated with the Hb depletion and participated in the lipophilicity of the drugs.