Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Glucagon stimulation test (GST) is often employed to assess the insulin reserve of the pancreatic beta cells in diabetic subjects. The clinical significance of the increment of plasma glucose (Δglucose) by exogenous glucagon during GST has not been elucidated. We investigated the relationship between Δglucose and clinical parameters including the liver and renal function in type 2 diabetic subjects, since we hypothesized that Δglucose is associated with the liver and renal function reflecting the capacity for gluconeogenesis in the organs. METHODS: A total of 209 subjects with type 2 diabetes who underwent GST during admission were included in this cross-sectional study. We defined the difference between plasma glucose at fasting and 6 min after intravenous injection of 1 mg glucagon as Δglucose. We assessed correlations between Δglucose and clinical parameters such as diabetic duration, BMI, HbA1c, beta cell function, serum free fatty acids (FFA) which is known to stimulate gluconeogenesis, liver function, the indices of liver function, renal function, and urinary albumin excretion (UAE). RESULTS: In correlation analysis, Δglucose positively correlated to FFA and estimated glomerular filtration rate (eGFR), but inversely to serum creatinine and cystatin C, although Δglucose showed no correlation with both liver function and the indices of residual liver function. Multiple regression analysis revealed that Δglucose was an independent determinant for the eGFR after 1 year, equally BMI, HbA1c, serum lipids, and UAE, which are known as the predictors for the development of chronic kidney disease. CONCLUSION: Our results suggest that Δglucose during GST might be related to gluconeogenesis in the kidney and could be the determinant of future renal function in type 2 diabetes.

DOI： 10.1186/s12902-019-0428-6

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

症例は43歳女性。若年時より難聴あり。頭痛と嘔気を主訴に前医を受診。糖尿病ケトアシドーシスの診断で、当院紹介入院となった。インスリン分泌能は著明に低下し、強化インスリン療法を要した。母系の糖尿病家族歴に感音性難聴を伴い、白血球におけるm.3243A>G変異を認め、ミトコンドリア糖尿病(mitochondrial diabetes mellitus:MDM)と診断。細小血管症は認められなかったが、中枢神経病変を合併していた。41歳の妹にも難聴あり。34歳時に糖尿病の診断となり、経口薬で加療中であったが、姉の診断を契機に当院紹介。姉と同様にm.3243A>G変異を認め、MDMと診断した。姉とは異なり、腎障害と心筋症を合併していた。ミトコンドリア病では正常と異常ミトコンドリアDNAへのヘテロプラスミーの程度により症状は多彩となる。臨床経過及び、合併症が異なるMDMの同胞例を経験したので報告する。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00926&link_issn=&doc_id=20190415430003&doc_link_id=10.11213%2Ftonyobyo.62.162&url=https%3A%2F%2Fdoi.org%2F10.11213%2Ftonyobyo.62.162&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Language：Japanese   Publisher：(一社)日本糖尿病・妊娠学会  

症例は30代女性。5経妊3経産。過去に耐糖能異常を指摘されたことはない。第4子を自然妊娠。妊娠25週に尿糖陽性を認め、29週の75g OGTTで血糖値125mg/dL(0分)、344mg/dL(60分)、306mg/dL(120分)を認め当科紹介。HbA1c 7.9%にて妊娠中の明らかな糖尿病と診断。加療目的に入院、強化インスリン療法を開始した。一方、満月様顔貌、中心性肥満、低K血症、ACTHの抑制、cortisolの日内変動消失を認めたほか、MRIで右副腎に30mm大、左副腎に15mm大の腺腫を認め、副腎性Cushing症候群が疑われた。妊娠継続を困難にする症候はなく、慎重に経過観察する方針としたが、妊娠35週に胎児発育不全の診断で緊急入院。第2病日に胎児機能不全のため緊急帝王切開で女児を分娩した。児は1715gのSFD児で、Apgar scoreは1分/8点、5分/9点であった。分娩後においてもACTHの抑制、cortisol日内変動の消失を認め、1mg・8mgのデキサメタゾン抑制試験でcortisol抑制の消失を認めた。アドステロールシンチグラフィで右副腎に限局した集積を認め、右副腎腫瘍によるCushing症候群と診断した。分娩後6ヵ月で腹腔鏡下右副腎摘出術が行われ、以後hydrocortisoneの補充療法中である。Cushing症候群は無月経や不妊の原因となり、合併妊娠の報告は少ないが、母児の周産期合併症リスクが高く、見逃してはならない疾患である。妊娠中に顕在化した耐糖能異常の鑑別として、Cushing症候群も念頭に置く必要がある。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J03986&link_issn=&doc_id=20190329410008&doc_link_id=%2Few4touny%2F2019%2F001901%2F008%2F0048-0053%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Few4touny%2F2019%2F001901%2F008%2F0048-0053%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Diabetes Society  

A 43-year-old deaf woman who presented with headache and nausea was referred to our department to undergo treatment for diabetic ketoacidosis. She needed basal-bolus insulin treatment because her insulin secretory reserve was severely reduced. Mitochondrial diabetes mellitus (MDM) was suspect based on her sensorineural deafness and a maternal family history of diabetes. Because a mitochondrial DNA 3243 A&gt
G mutation was detected in her blood leukocytes, she was diagnosed with MDM. Although there was no evidence of diabetic microangiopathy, she exhibited atrophy of both the occipital lobe of the cerebrum and cerebellum associated with an m.3243A&gt
G mutation. Her 41-year-old younger sister was also deaf and was previously diagnosed with diabetes. The younger sister's treatment course differed in that she was treated with oral glucose-lowering agents. She also had an m.3243A&gt
G mutation and was diagnosed with MDM. Her manifestations were differed from her sister's in that she had renal dysfunction and cardiomyopathy. The clinical manifestations in patients with mitochondrial disease vary because heteroplasmy levels of m.3243A&gt
G mutation are divergent in organs and tissues. We report sibling cases of MDM that presented with distinct clinical manifestations.

DOI： 10.11213/tonyobyo.62.162

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Recent large-scale clinical studies demonstrate that sodium-glucose cotransporter 2 (SGLT2) inhibitors protect the diabetic kidney. However, clinical and animal studies have not shown the changes of the total glomeruli in the whole kidney treated with SGLT2 inhibitors. METHODS: We performed computed tomography (CT) imaging on mice using synchrotron radiation to investigate the impact of luseogliflozin, a SGLT2 inhibitor, on the number and volume of glomeruli in the whole kidney. FINDINGS: We did not observe a significant difference in the total glomerular number (Nglom) among mice. Luseogliflozin redistributed the number of glomeruli in different regions, accompanied by the normalization of diabetes-augmented renal volume (Vkidney). Diabetic db/db mice had a larger glomerular volume in the mid-cortex than did control db/m mice, and luseogliflozin increased the glomerular volume in all renal cortical zones of the whole kidney in db/db mice. According to the multivariate regression analysis, hemoglobin A1c level was the most relevant determinant of Vkidney, not Nglom or mean glomerular volume (Vglom), indicating that hyperglycemia induced renal (tubular) hypertrophy, but not glomerular enlargement. Luseogliflozin increased hypoxia in the juxtamedullary region, sustained upregulated renal renin expression and plasma renin activity, and failed to decrease albuminuria by downregulating megalin in db/db mice. INTERPRETATION: Based on our findings, SGLT2 inhibitors may alter glomerular distribution and size in addition to their glucose-lowering effects, presumably by affecting oxygen metabolism and humoral factors. FUND: Funding for this research was provided by The Japan Society for the Promotion of Science, the Japan Diabetes Foundation, and Asahikawa Medical University.

File： PIIS2352396418304079.pdf

DOI： 10.1016/j.ebiom.2018.09.048

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Objective: Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) possess multiple bioactive isoforms that are rendered non-insulinotropic by the enzyme dipeptidyl peptidase-4 (DPP-4). Recently, some ELISA kits have been developed to specifically measure " active" GIP and GLP-1, but it is unclear if these kits can accurately quantify all bioactive forms. Therefore, it remains uncertain to what extent treatment with a DPP-4 inhibitor boosts levels of biologically active GIP and GLP-1. Thus, we evaluated our novel receptor-mediated incretin bioassays in comparison to commercially available ELISA kits using plasma samples from healthy subjects before and after DPP-4 inhibitor administration.
Methods: We utilized cell lines stably co-transfected with human GIP or GLP-1 receptors and a cAMP-inducible luciferase expression construct for the bioassays and commercially available ELISA kits. Assays were tested with synthetic GIP and GLP-1 receptor agonists and plasma samples collected from subjects during a 75 g oral glucose tolerance test (OGTT) performed before or following 3-day administration of a DPP-4 inhibitor.
Results: A GIP isoform GIP(1e30) NH2 increased luciferase activity similarly to GIP(1e42) in the GIP bioassay but was not detectable by either a total or active GIP ELISA kit. During an OGTT, total GIP levels measured by ELISA rapidly increased from 0 min to 15 min, subsequently reaching a peak of 59.2 +/- 8.3 pmol/l at 120 min. In contrast, active GIP levels measured by the bioassay peaked at 15 min (43.4 +/- 6.4 pmol/l) and then progressively diminished at all subsequent time points. Strikingly, at 15 min, active GIP levels as determined by the bioassay reached levels approximately 20-fold higher after the DPP-4 inhibitor treatment, while total and active GIP levels determined by ELISA were increased just 1.5 and 2.1-fold, respectively. In the absence of DPP-4 inhibition, total GLP-1 levels measured by ELISA gradually increased up to 90 min, reaching 23.5 +/- 2.4 pmol/l, and active GLP-1 levels determined by the bioassay did not show any apparent peak. Following administration of a DPP-4 inhibitor there was an observable peak of active GLP-1 levels as determined by the bioassay at 15 min after oral glucose load, reaching 11.0 +/- 0.62 pmol/l, 1.4-fold greater than levels obtained without DPP-4 inhibitor treatment. In contrast, total GLP-1 levels determined by ELISA were decreased after DPP-4 inhibitor treatment.
Conclusion: Our results using bioassays indicate that there is a greater increase in plasma levels of bioactive GIP than GLP-1 in subjects treated with DPP-4 inhibitors, which may be unappreciated using conventional ELISAs. (C) 2016 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

DOI： 10.1016/j.molmet.2016.12.009

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

A low carbohydrate diet (LCHD) as well as sodium glucose cotransporter 2 inhibitors (SGLT2i) may reduce glucose utilization and improve metabolic disorders. However, it is not clear how different or similar the effects of LCHD and SGLT2i are on metabolic parameters such as insulin sensitivity, fat accumulation, and especially gluconeogenesis in the kidney and the liver. We conducted an 8-week study using non-diabetic mice, which were fed ad-libitum with LCHD or a normal carbohydrate diet (NCHD) and treated with/without the SGLT-2 inhibitor, ipragliflozin. We compared metabolic parameters, gene expression for transcripts related to glucose and fat metabolism, and glycogen content in the kidney and the liver among the groups. SGLT2i but not LCHD improved glucose excursion after an oral glucose load compared to NCHD, although all groups presented comparable non-fasted glycemia. Both the LCHD and SGLT2i treatments increased calorie-intake, whereas only the LCHD increased body weight compared to the NCHD, epididimal fat mass and developed insulin resistance. Gene expression of certain gluconeogenic enzymes was simultaneously upregulated in the kidney of SGLT2i treated group, as well as in the liver of the LCHD treated group. The SGLT2i treated groups showed markedly lower glycogen content in the liver, but induced glycogen accumulation in the kidney. We conclude that LCHD induces deleterious metabolic changes in the non-diabetic mice. Our results suggest that SGLT2i induced gluconeogenesis mainly in the kidney, whereas for LCHD it was predominantly in the liver.

DOI： 10.1371/journal.pone.0157672

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Glucose-dependent insulinotropic polypepide (GIP) was first extracted from porcine gut mucosa and identified as incretin decades ago. Though early studies have shown the possible GIP isoforms by gel filtration profiles from porcine or human intestinal extracts analyzed by radioimmunoassay (RIA), GIP is currently believed to consist of 42 amino acids (GIP1-42), which are released from gut K-cells and promote postprandial insulin release. In fact, GIP1-42 is usually processed from proGIP by the action of prohormone convertase (PC) 1/3 in the gut. GIP expression is occasionally found in the intestinal glucagon-like peptide-1-secreting cells, suggesting gene expression of both GIP and proglucagon can co-exist in identical cells. However, GIP1-42 immunoreactivity is rarely found in -cells or other pancreatic endocrine cells of wild-type mammals. Interestingly, we found that short-form GIP1-30 is expressed in and released from pancreatic -cells and a subset of enteroendocrine cells through proGIP processing by PC2. GIP1-30 is also insulinotropic and modulates glucose-stimulated insulin secretion in a paracrine manner. It is also suggested that short-form GIP1-30 possibly plays a crucial role for the islet development. It has not been well elucidated whether expression of GIP1-30 is modulated in the diabetic status, and whether GIP1-30 might have therapeutic potentials. Our preliminary data suggest that short-form GIP1-30 might play important roles in glucose metabolism.

DOI： 10.1111/jdi.12445

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Tubular injury is one of the important determinants of progressive renal failure in diabetic nephropathy (DN), and TGF-beta 1 has been implicated in the pathogenesis of tubulointerstitial disease that characterizes proteinuric renal disease. The aim of this study was to identify novel therapeutic target molecules that play a role in the tubule damage of DN. We used an LC-MS/MS-based proteomic technique and human renal proximal epithelial cells (HRPTECs). Urine samples from Japanese patients with type 2 diabetes (n = 46) were used to quantify the candidate protein. Several proteins in HRPTECs in cultured media were observed to be driven by TGF-beta 1, one of which was 33-kDa IGFBP7, which is a member of IGFBP family. TGF-beta 1 up-regulated the expressions of IGFBP7 mRNA and protein in a dose-and time-dependent fashion via Smad2 and 4, but not MAPK pathways in HRPTECs. In addition, the knockdown of IGFBP7 restored the TGF-beta 1-induced epithelial to mesenchymal transition (EMT). In the immunohistochemical analysis, IGFBP7 was localized to the cytoplasm of tubular cells but not that of glomerular cells in diabetic kidney. Urinary IGFBP7 levels were significantly higher in the patients with macroalbuminuria and were correlated with age (r = 0.308, p = 0.037), eGFR (r = -0.376, p = 0.01), urinary beta(2)-microglobulin (r = 0.385, p = 0.008), and urinary N-acetyl-beta-D-glucosaminidase (NAG) (r = 0.502, p = 0.000). A multivariate regression analysis identified urinary NAG and age as determinants associated with urinary IGFBP7 levels. In conclusion, our data suggest that TGF-beta 1 enhances IGFBP7 via Smad2/4 pathways, and that IGFBP7 might be involved in the TGF-beta 1-induced tubular injury in DN.

DOI： 10.1371/journal.pone.0150897

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Aims/hypothesis Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone released from gut K cells. While the predominant form is GIP(1-42), a shorter form, GIP(1-30), is produced by pancreatic alpha cells and promotes insulin secretion in a paracrine manner. Here, we elucidated whether GIP(1-30) expression is modulated in mouse models of diabetes. We then investigated whether PEGylated GIP(1-30) can improve islet function and morphology as well as suppress the progression to hyperglycaemia in mice treated with low-dose streptozotocin (LD-STZ).
Methods We examined pancreatic GIP immunoreactivity in rodent diabetic models. We synthesised [D-Ala(2)]GIP(1-30) and modified the C-terminus with polyethylene glycol (PEG) to produce a dipeptidyl peptidase-4 (DPP-4)-resistant long-acting GIP analogue, [D-Ala(2)]GIP(1-30)-PEG. We performed i.p.GTT and immunohistochemical analysis in nondiabetic and LD-STZ diabetic mice, with or without administration of [D-Ala(2)]GIP(1-30)-PEG.
Results Pancreatic GIP expression was concomitantly enhanced with alpha cell expansion in rodent models of diabetes. Treatment with DPP-4 inhibitor decreased both the GIP-and glucagon-positive areas and preserved the insulin-positive area in LD-STZ diabetic mice. Body weight was not affected by [D-Ala(2)]GIP(1-30)-PEG in LD-STZ or non-diabetic mice. Treatment with GIP significantly ameliorated chronic hyperglycaemia and improved glucose excursions in LD-STZ mice. Treatment with GIP also reduced alpha cell expansion in the islets and suppressed plasma glucagon levels compared with non-treated LD-STZ mice. Additionally, [D-Ala2] GIP(1-30)-PEG preserved beta cell area via inhibition of apoptosis in LD-STZ mice.
Conclusions/interpretation Our data suggest that GIP(1-30) expression is upregulated in diabetes, and PEGylated GIP(1-30) can suppress the progression to STZ-induced hyperglycaemia by inhibiting beta cell apoptosis and alpha cell expansion.

DOI： 10.1007/s00125-015-3842-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Promyelocytic leukaemia zinc finger (PLZF) is a transcriptional repressor that was originally isolated from a patient with promyelocytic leukaemia. PLZF also affects key elements for cell cycle progression, such as cyclin A, and can affect the tumourigenicity of various cancers. Thus far, the behaviour of PLZF in thyroid carcinoma remains unclear.
Methods: We analysed the expression profile of PLZF in different types of benign and malignant thyroid lesions as well as in normal thyroid tissue. Specifically, we examined PLZF expression in normal thyroid (N; n = 4), adenomatous lesion (AL; n = 5), follicular adenoma (FA; n = 2), papillary thyroid carcinoma (PTC; n = 20), and anaplastic thyroid carcinoma (ATC; n = 3) samples. PLZF expression was estimated by western blotting and immunohistochemical (IHC) staining.
Results: PLZF was expressed in all samples of thyroid lesions examined. In N, AL, and FA, PLZF was mainly localized in the nucleus. In contrast, in PTC and ATC, PLZF was mainly expressed in the cytosol with high intensity. In more detail, the cytoplasmic IHC scores in PTC with capsular invasion (CI) and lymph node (LN) metastasis were higher than those in PTC without CI and LN metastasis.
Conclusions: PLZF shows different subcellular localizations among PTC, ATC, and other thyroid lesions. Furthermore, high cytoplasmic expression of PLZF may be correlated with CI and LN metastasis in thyroid carcinoma. The present report is the first to describe the implications of intracellular PLZF expression in thyroid carcinomas.

DOI： 10.1186/1472-6823-14-52

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：HINDAWI PUBLISHING CORPORATION  

Diabetic nephropathy (DN) is now a leading cause of end-stage renal disease. In addition, DN accounts for the increased mortality in type 1 and type 2 diabetes, and then patients without DN achieve long-term survival compatible with general population. Hypoxia represents an early event in the development and progression of DN, and hypoxia-inducible factor-(HIF-) 1 mediates the metabolic responses to renal hypoxia. Diabetes induces the "fraternal twins" of hypoxia, that is, pseudohypoxia and hypoxia. The kidneys are susceptible to hyperoxia because they accept 20% of the cardiac output. Therefore, the kidneys have specific vasculature to avoid hyperoxia, that is, AV oxygen shunting. The NAD-dependent histone deacetylases (HDACs) sirtuins are seven mammalian proteins, SIRTs 1-7, which are known to modulate longevity and metabolism. Recent studies demonstrated that some isoforms of sirtuins inhibit the activation of HIF by deacetylation or noncatalyzing effects. The kidneys, which have a vascular system that protects them against hyperoxia, unfortunately experience extraordinary hypernutrition today. Then, an unexpected overload of glucose augments the oxygen consumption, which ironically results in hypoxia. This review highlights the primary role of HIF in diabetic kidneys for the metabolic adaptation to diabetes-induced hypoxia.

DOI： 10.1155/2014/837421

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (bulletin of university, research institution)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Incretins stimulate insulin secretion in a glucose-dependent manner but also promote pancreatic beta cell protection. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new glucose-lowering treatment that blocks incretin degradation by DPP-4. We assessed whether DPP-4 inhibition suppresses the progression to hyperglycaemia in a low-dose streptozotocin (STZ)-induced diabetic mouse model, and then investigated how DPP-4 inhibition affects islet function and morphology.
The DPP-4 inhibitor, des-fluoro-sitagliptin (SITA), was administered to mice during and after STZ injections, and in some mice also before STZ.
In control mice, STZ resulted in hyperglycaemia associated with impaired insulin secretion and excess glucagon secretion. In SITA-treated STZ mice, these metabolic abnormalities were improved, particularly when SITA administration was initiated before STZ injections. We observed beta cell loss and dramatic alpha cell expansion associated with decreased insulin content and increased glucagon content after STZ administration. In SITA-treated mice, islet architecture and insulin content were preserved, and no significant increase in glucagon content was observed. After STZ exposure, beta cell apoptosis increased before hyperglycaemia, and SITA treatment reduced the number of apoptotic beta cells. Interestingly, alpha cell proliferation was observed in non-treated mice after STZ injection, but the proliferation was not observed in SITA-treated mice.
Our results suggest that the ability of DPP-4 inhibition to suppress the progression to STZ-induced hyperglycaemia involves both alleviation of beta cell death and alpha cell proliferation.

DOI： 10.1007/s00125-011-2365-4

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本内分泌学会  

67歳男。44歳より糖尿病、高血圧症、高脂血症で治療中であった。66歳時、腹部CT検査にて、径20mm大の右副腎腫瘍を認めた。下垂体病変は認められず、コルチゾール、ACTH分泌の日内変動は消失しているが、デキサメサゾン試験により抑制が認められ、経過観察となった。右副腎腫瘍に対する第2回目精査目的で入院した。内分泌学的検査結果より、クッシング病に特徴的な身体徴候を欠如している下垂体病変によるプレクリニカルクッシニング病が疑われた。131I-アドステロール副腎シンチグラムにおいては、第1、2回の精査目的入院時とも腫瘍側に有意な集積を認め、右副腎機能腺腫の合併が疑われた。下垂体微小腺腫に対して手術の同意が得られず、経過観察となった。その後も、クッシング徴候は出現せず、画像検査では下垂体腫瘍性病変の大きさに変化はないが、両側副腎病変の増大傾向を認めている。

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER DIABETES ASSOC  

OBJECTIVE-Chronic hypoxia has been recognized as a key regulator in renal tubulointerstitial fibrosis, as seen in diabetic nephropathy, which is associated with the activation of hypoxia-inducible factor (HIF)-1 alpha. We assess here the effects of the biguanide, metformin, on the expression of HIF-1 alpha in diabetic nephropathy using renal proximal tubular cells and type 2 diabetic rats.
RESEARCH DESIGN AND METHODS-We explored the effects of metformin on the expression of HIF-1 alpha using human renal proximal tubular epithelial cells (HRPTECs). Male Zucker diabetic fatty (ZDF; Gmi-fa/fa) rats were treated from 9 to 39 weeks with metformin (250 mg kg(-1) . day(-1)) or insulin.
RESULTS- Metformin inhibited hypoxia-induced HIF-1 alpha accumulation and the expression of HIF-1-targeted genes in HRPTECs. Although metformin activated the downstream pathways of AMP-activated protein kinase (AMPK), neither the AMPK activator, AICAR, nor the mTOR inhibitor, rapamycin, suppressed hypoxia-induced HIF-1 alpha expression. In addition, knockdown of AMPK-a did not abolish the inhibitory effects of metformin on HIF-1 alpha expression. The proteasome inhibitor, MG-132, completely eradicated the suppression of hypoxia-induced HIF-1 alpha accumulation by metformin. The inhibitors of mitochondrial respiration similarly suppressed hypoxia-induced HIF-1 alpha expression. Metformin significantly decreased ATP production and oxygen consumption rates, which subsequently led to increased cellular oxygen tension. Finally, metformin, but not insulin, attenuated tubular HIF-1 alpha expression and pimonidazole staining and ameliorated tubular injury in ZDF rats.
CONCLUSIONS-Our data suggest that hypoxia-induced HIF-1 alpha accumulation in diabetic nephropathy could be suppressed by the antidiabetes drug, metformin, through the repression of oxygen consumption. Diabetes 60:981-992, 2011

DOI： 10.2337/db10-0655

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (bulletin of university, research institution)  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Aim: In order to clarify the importance of Interleukin (IL)-18 in the development of diabetic nephropathy (DN), we evaluated the expressions of IL-18 in diabetic kidney.
Methods: We per-formed immmunohistochemical analysis of IL-18 and IL-18 receptor (IL-18 R) in human kidney tissue derived from 12 subjects with type 2 diabetes and overt nephropathy, and compared with those in 7 subjects with minimal change nephrotic syndrome (MCNS). In addition, we examined the regulation of IL-18 expression using human renal proximal tubular epithelial cells (HRPTECs) in culture.
Results: IL-18 expression in tubular cells was observed in higher rate (83%) in patients with diabetes, whereas one positive specimen (14.3%) for IL-18 in patients with MCNS. In contrast, IL-18 R was expressed in glomerular mesangial cells and endothelial cells as well as tubular cells, similarly in almost of both groups. Exposure to transforming growth factor beta (TGF-beta(1)) led to two-fold increase in IL-18 gene expression in HRPTECs, and mitogen-activated protein kinases (MAPK) inhibitors abolished TGF-beta(1)-induced IL-18 mRNA expression. Western blot analysis showed the IL-18 protein in HRPTECs.
Conclusion: The present data indicate that IL-18 is overexpressed in human tubular epithelial cells in diabetic nephropathy, probably through the activation of MAPK pathways induced by TGF-beta(1). (C) 2008 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.diabres.2008.11.018

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (bulletin of university, research institution)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Dendritic cells (DCs) are considered to be the most powerful antigen -presenting cells (APCs). DCs are thought to be associated with Th1 or Th2 polarization and with polarization-induced disease such as atopic dermatitis, asthma and allergic rhinitis, but its mechanism is not well known. In this study, we analyzed the mRNA expression of DCs between birch pollen allergic rhinitis and healthy controls by using cDNA array. We found that the expressions of CCL22/ macrophage-derived chemokine (MDC) differed significantly. We also revealed that CCL22/MDC production was higher in patients than in healthy donors. By chemotaxis assay, CCL22/MDC can enhance the migration of patient's T cells rather than those of healthy controls. Surface marker analysis of migrated cells revealed that the most of migrated cells expressed CCR4, which were considered to be Th2 cells. Furthermore, CD1a(+) CD83(+) cells Located in the nasal mucosa expressed CCL22/MDC in vivo. To the best of our knowledge, this is the first report clearly indicating the rote of CCL22/MDC in allergic rhinitis. (c) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.clim.2007.08.002

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 73-year-old man who had been diagnosed as having type 2 diabetes mellitus over 30 years previously was detected to have overt proteinuria since 1999. The urinary albumin excretion (U-alb) was 1,604 mg/gCre in January 2002. When he was admitted to another hospital leg edema, the urinary protein excretion was 1.2 g/day and the creatinine clearance (Ccr) was 68 ml/min. He was started on treatment with oral hypoglycemic agents and an angiotensin II receptor blocker, however, both glycemic control and blood pressure control remained poor. In October 2001, when he visited our department for the first time, the U-alb was 773 mg/gCre, and he was detected to have both neuropathy and proliferative retinophathy as complications of diabetes mellitus. In May 2002, he was admitted to our hospital with acute myocardial infarction. The U-alb was 167 mg/gCre and the Ccr was 71 ml/min at this time. Insulin therapy and aggressive intensive antihypertensive therapy were started, and antiplatelet agents and a statin were also given. Thereafter, the hemoglobin Aie value was maintained at about 7% during ambulatory care. One year later, the U-alb was 50 mg/gCre, and two years later, it had decreased to 12 mg/gCre. The multifactorial treatment successfully converted overt proteinuira to normoalbumiuria in a patient with multiple diabetic vascular complications.

Scopus

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ENDOCRINE SOC  

Retinoid X receptors (RXRs) are ligand-inducible transcription factors that belong to the superfamily of nuclear hormone receptors. Because RXRs heterodimerize with thyroid hormone receptor, retinoic acid receptor, vitamin D(3) receptor, and peroxisome proliferator-activated receptor, they play central roles in regulating a number of signaling pathways. To understand the roles of RXRs in human thyroid carcinogenesis, we have investigated the immunohistochemical expression of RXRs in normal and neoplastic thyroid tissues. Whereas nontumorous human thyroid cells exhibited distinct nuclear staining for the RXRs, thyroid carcinomas showed decreased nuclear expression of all three RXR isoforms. In particular, some thyroid carcinoma cells showed intense RXR-alpha cytoplasmic staining accompanied by decreased immunoreactivity in their nuclei. This subcellular localization of RXR-alpha was confirmed by Western blot analysis, which showed both lower nuclear expression levels of RXR-alpha and a cytosolic presence of RXR-related protein in neoplastic regions. We present here, for the first time, the histological distribution of each RXR protein (alpha, beta, and gamma) in human thyroid follicular cells. In addition, we found that the nuclear expression of RXRs was lower in thyroid carcinomas than in normal tissue. The differential expressions of these RXRs in thyroid carcinomas might be implicated in the pathogenesis of thyroid cancers.

DOI： 10.1210/jc.2003-032036

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Visinin-like protein-3, which is one of the neuronal calcium sensors, has been shown to be mainly expressed in cerebellar Purkinje cells, but cellular function of this protein has not yet been elucidated. We examined the tissue distribution of murine visinin-like protein-3 transcripts using real-time reverse transcription-PCR. Visinin-like protein-3 mRNA was found to be expressed in peripheral tissues. Particularly, the expression of the transcript in the thymus was significantly higher than in other peripheral tissues. In addition, B6RVTC1 thymoma cells robustly expressed visinin-like protein-3 mRNA. To identify a target protein of visinin-like protein-3, we performed a pull-down experiment using glutathione S-transferase-tagged visinin-like protein-3 and two-dimensional electrophoresis. We demonstrated that microsomal cytochrome b(5) was a Ca2+-dependent binding partner of visinin-like protein-3. In a co-immunoprecipitation experiment, it was observed that hippocalcin, as well as visinin-like protein-3, could interact with cytochrome b(5). Furthermore, we confirmed that the sequence Val(114)-Tyr(127) at the C-terminal tail of cytochrome b(5) is the minimal structural requirement for binding to visinin-like protein-3. In addition, the loop His(19)-His(25) at the N terminus of visinin-like protein-3 is essential for binding to cytochrome b(5). Microsomal cytochrome b(5) was also shown to be a potential activator of cytochrome P450. The present findings raise the possibility that visinin-like protein-3 may link Ca2+ signaling to the machinery of microsomal monooxygenase complex composed of cytochrome b5, cytochrome P450, and some reductases. This report provides the first evidence of an interaction between visinin-like protein-3 and microsomal cytochrome b(5).

DOI： 10.1074/jbc.M312766200

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC  

DAP12 (also known as KARAP) is a novel ITAM-bearing transmembrane adapter molecule that is expressed on the cell surface of natural killer cells, monocytes, dendritic cells, and macrophages. Several myeloid cell-specific DAP12-associating receptors, such as TREM receptor family, SIRP-beta1, and MDL-1 have been identified. The in vivo function of DAP12 and its associating molecules in inflammation has remained primarily unknown. To investigate DAP12 signaling during chronic inflammation, we constructed two adenoviral gene transfer vectors to express FLAG/DAP12 (Ad-FDAP12) and the extracellular domain of mouse TREM-1 and the Fc portion of human IgG1 (Ad-TREM-1 Ig), respectively, and observed their modulatory activities in a mouse model of hepatic granulomatous inflammation elicited by zymosan A. Mice were injected with zymosan A intravenously and 24 hours after zymosan A, they were injected with Ad-FDAP12 or Ad-TREM-1 Ig. Zymosan A-induced hepatic granuloma formation peaked at day 7 and markedly declined by day 10. Although adenoviral-mediated DAP12 gene transfer did not enhance granuloma formation by day 7, it sustained and enhanced granuloma formation beyond day 7. However, an anti-FLAG monoclonal antibody used to potentiate the signaling of adenoviral-derived DAP12, enhanced granuloma formation at day 7. In sharp contrast to the effect by Ad-FDAP12, transgene expression in the liver of soluble form of extracellular domain of TREM-1 as an antagonist of DAP12 signaling, remarkably inhibited zymosan A-induced granuloma formation at all time points examined. Our findings thus suggest that both DAP12 and TREM-1 are involved in the development of granulomatous responses in the liver.

DOI： 10.1016/S0002-9440(10)63915-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT INC PUBL  

Interleukin (IL)-18 is a cloned cytokine that was identified originally as a factor having potent interferon (IFN)-inducing activity on Kupffer cells. First, we analyzed IL-18 gene expression by reverse transcription-polymerase chain reaction (RT-PCR) in rat thyroid FRTL-5 cells and human thyroid tissue samples. The expression of IL-18 mRNA in FRTL-5 cells was enhanced by thryoid-stimulating hormone (TSH) in a dose-dependent manner. 8-Bromo-cyclic adenosine monophosphate (cAMP) also increased in IL-18 mRNA levels. Furthermore, TGCT clones that exhibited an increase in intracellular cAMP accumulation showed an increased IL-18 mRNA signal when compared to controls. Taken together, these data suggested that the effect of TSH on IL-18 gene expression was mediated by activating protein kinase A. Treatment of FRTL-5 cells with the antithyroid drug, methimazole (MMI), suppressed this stimulatory action of TSH on IL-18 gene expression. Next, we examined IL-18 expression in human thyroid tissue derived from patients with autoimmune thyroid diseases (ATD). RTPCR and immunohistology demonstrated that human thyroid follicular cells expressed IL-18. Especially in thyroid tissue from a patient with Hashimoto's thyroiditis, expression was more diffuse and extensive, generally observed in close relation to a lyrphocytic infiltrate. Also, IL-18 protein was distributed in the same follicles that express Fas-L and HLA-DR. This study is the first to demonstrate the detection of IL-18 in the thyroid gland. The frequent expression of IL-18 in thyrocytes suggests that IL-18 itself might be a secreted immunomodulator in ATD.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

DAP12. is a recently cloned, immunoreceptor tyrosine-based activation motif-bearing transmembrane adapter molecule that is associated with the NK-activating receptors, Previous reports showed that the DAP12 message could be detected not only in NK cells but also in granulocytes, monocytes, dendritic cells, and macrophages, In this study we found a significant level of DAP12 protein expression in macrophage-related cell lines and organs. Additionally, we observed increased expression of DAP12, after LPS-induced differentiation of M1 cells into macrophages, To examine the role of DAP12 in the myeloid cell lineage, we established M1 FLAG-DAP12 transfectants (FDAP-M1) and demonstrated the marked;morphological changes in FDAP-M1 cells caused by signaling through DAP12 Cell surface phenotypic analysis showed up-regulation of macrophage markers CD11b, 2,4G2, and adhesion molecule B7-2, Additionally, after stimulation through DAP12, phosphorylated FLAG -DAP12 could be immunoprecipitated using anti-phosphotyrosine mAbs, Collectively, these findings indicate that direct DAP12 signaling has an important role in macrophage differentiation.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ENDOCRINE SOC  

Follicular and Hurthle cell carcinomas of the thyroid cannot be differentiated from adenomas by either preoperative fine needle aspiration or intraoperative frozen section examination, and yet there exist potentially significant differences in the recommended surgical management. We examined, by PCR-based microsatellite polymorphism analysis, DNA obtained from 83 thyroid neoplasms [22 follicular adenomas, 29 follicular carcinomas, 20 Hurthle cell adenomas (HA), and 12 Hurthle cell carcinomas (HC)] to determine whether a pattern of allelic alteration exists that could help distinguish benign from malignant lesions. Alterations were found in only 7.5% of informative PCR reactions from follicular neoplasms, whereas they were found in 23.3% of reactions from Hurthle cell neoplasms. Although there were no significant differences between follicular adenoma and follicular carcinoma, HC demonstrated a significantly greater percentage of allelic alteration than HA on chromosomal arms 1q (P < 0.001) and 2p (P < 0.05) by Fisher's exact test. The documentation of an alteration on either 1q or 2p was 100% sensitive and 65% specific in the detection of HC (P < 0.0005, by McNemar's test).
In conclusion, PCR-based microsatellite polymorphism analysis maybe a useful technique in distinguishing HC from HA. Potentially, the application of this technique to aspirated material may allow this distinction preoperatively and thus facilitate more optimal surgical management. Consistent regions of allelic alteration may also indicate the locations of critical genes, such as tumor suppressor genes or oncogenes, that are important in the progression from adenoma to carcinoma. Finally, this study demonstrates that Hurthle cell neoplasms, now considered variants of follicular neoplasms, differ significantly from follicular neoplasms on a molecular level.

DOI： 10.1210/jc.83.6.2036

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/jjco/28.10.590

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT INC PUBL  

Fine-needle aspiration (FNA) of the thyroid is the sine qua non in the preoperative evaluation of thyroid nodules. Despite this, cytological examination of FNA cannot differentiate malignant from benign Hurthle cell neoplasms. We have previously shown that Hurthle cell carcinomas harbor more genetic alterations on chromosomal arms 1q and 2p than Hurthle cell adenomas, and that all Hurthle cell neoplasms have a significantly higher frequency of alterations on chromosomal arm 1p compared with normal thyroid. To determine if these genetic alterations could be detected in FNA samples, we examined DNA from FNAs that were available from eight Hurthle cell neoplasms. Polymerase chain reaction (PCR) amplification of DNA demonstrated either direct correlation with alterations seen in the tumor samples or in some instances, additional chromosomal alterations. We conclude that PCR-based microsatellite DNA analysis of preoperative FNA samples from Hurthle cell neoplasms can potentially distinguish Hurthle cell carcinomas from adenomas and that with further validation and perfection, this technique may allow more optimal surgical management of patients with these lesions.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ENDOCRINE SOC  

Thyroid cell growth and function are regulated by hormones and growth factors binding to cell surface receptors that are coupled via G proteins, Gs and Gq, to the adenylyl cyclase and phospholipase C signal transduction systems, respectively. Activating mutations of the TSH receptor and Gas have been documented in subsets of thyroid neoplasms. To test the oncogenic potential of activated Gels in transgenic mice, we used the cholera toxin Al subunit that constitutively activates G alpha s and used the rat thyroglobulin gene promoter for targeting this transgene (TGCT) to thyroid follicular cells. Three (M1392, F1358, and F1286) of six founders identified were able to transmit the transgene to their offspring and thyroid glands from these mice contained elevated levels of cAMP. Concentrations of serum thyroxine were elevated as early as 2 months of age (M 1392 and F 1286). F1358 mice were euthyroid until 8 months of age, at which time they developed hyperthyroidism. All three TGCT lines developed thyroid hyperplasia independent of their thyroxine levels. DNA image analysis of thyroid follicular cells from both the hyper and euthyroid mice showed that DNA index and ''S+G2/M'' phase were increased compared with normal, changes similar to that seen in poor prognosis human carcinomas. These data suggest that the Gas-adenylyl cyclase-cAMP pathway has an important role in thyroid hyperplasia and the transgenic mouse models reported herein will allow further examination of the role of this pathway in thyroid oncogenesis.

DOI： 10.1210/en.138.8.3133

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-YEAR BOOK INC  

Background. Patients with thyroid carcinoma experience excellent long-term survival; however, up to 16% will die of their disease. We have transformed a rat thyroid follicular cell line (FRTL-5) with a gene (TGCT) that mimics a Known mutation associated with thyroid neoplasms. These cells form subcutaneous tumors that metastasize to lung in nude mice.
Methods, In anticipation of developing gene therapy against this thyroid carcinoma model, we (1) tested whether adenovirus containing the beta-galactosidase gene could infect FRTL-5 cells and. neonatal rat thyroid and (2) evaluated the ability to kill FRTL-5 cells by transfecting them with a transgene in which the thyroglobulin promoter (TG) directed the expression of herpes simplex virus type I thymidine Kinase (HSV1TK) and treating TG-HSV1TK-transfected cells with 5 mu g/ml ganciclovir.
Results, Nearly 100% of the TG-HSV1TK but only 5% of control cells were killed by addition of ganciclovir. Histochemical staining for beta-galactosidase activity demonstrated infection of FRTL-5 cells and neonatal rat thyroid tissue by adenovirus beta-galactosidase.
Conclusions, These data demonstrate the feasibility of using adenovirus as vector to infect thyroid cells in vivo and provide a rationale for development of gene therapy for treatment of thyroid cancer.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT INC PUBL  

The effects of bile acids on iodide uptake and DNA synthesis were studied in cultured porcine thyroid cells. All five bile acids, which are commonly found in serum, chenodeoxycholic acid (CDCA), cholic acid (CA), deoxycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA) dose-dependently inhibited both basal and TSH-induced iodide uptake at concentrations of 25-250 mu M. Since CDCA is one of the two major primary endogenous bile acids, we studied mainly the effects of CDCA. The inhibitory effect of CDCA was detected after 24 h treatment of thyroid cells, and was dependent on the time of exposure up to 72 h. Treatment of thyroid cells with CDCA for 72 h inhibited cAMP production stimulated by 50 mU/L TSH or 0.5 mg/L forskolin and also inhibited iodide uptake induced by 0.5 mM 8-bromo cAMP or 0.5 mg/L forskolin. These results suggest that CDCA inhibits iodide uptake by decreasing cAMP production as well as post-cAMP generation. Bile acids except LCA stimulated [H-3]thymidine incorporation into the thyroid cells by itself, indicating that the inhibitory effect of bile acids on iodide uptake is not due to cytotoxic effect. In conclusion, these findings suggest that the direct inhibition of thyroid function by bile acids might cause hypothyroidism in chronic liver disease.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ENDOCRINE SOC  

The effects of hydrocortisone on iodide uptake and DNA synthesis were studied in porcine thyroid cells cultured in phenol red-free medium supplemented with low concentrations (0-1%) of charcoal-stripped fetal calf serum. Hydrocortisone dose-dependently stimulated TSH-induced iodide uptake at physiological concentrations (1-1000 nM), and the minimum detectable dose was 33 nM hydrocortisone. Treatment of thyroid cells with hydrocortisone for 72 h increased cAMP production stimulated by TSH. In addition, this stimulatory effect of hydrocortisone was observed when iodide uptake was induced with 0.25 mM 8-bromo-cAMP. These results suggest that hydrocortisone stimulates iodide uptake, influencing cAMP production and post-cAMP pathways. The synthetic glucocorticoid antagonist RU486 alone had no effect on iodide uptake in porcine thyroid cells; however, along with TSH, RU486 a weak agonist activity. As a glucocorticoid antagonist, RU486 inhibited the stimulatory actions of hydrocortisone on iodide uptake in combination with TSH and also with 8-bromo-cAMP, suggesting a specific effect of hydrocortisone mediated by a glucocorticoid receptor. The effect of hydrocortisone on thyroid cell multiplication was also studied. Hydrocortisone decreased [H-3]thymidine incorporation into DNA slightly but not significantly when the cells were treated with 100 ng/ml insulin-like growth factor-I and hydrocortisone.
In summary, it has been demonstrated that hydrocortisone directly stimulated the function of porcine thyroid cells at physiological concentrations, by using a glucocorticoid receptor and by affecting cAMP pathways. The data that RU486 inhibited iodide uptake induced by hydrocortisone and TSH propose that monitoring of thyroid function may be necessary if RU486 is been used for a long time.

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DOI： 10.1507/endocrj1954.39.477

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DOI： 10.1210/endo-126-1-460

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：科学評論社  

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DOI： 10.2337/db20-1845-P

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J-GLOBAL

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J-GLOBAL

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)   Publisher：株式会社メディカルレビュー社  

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：株式会社ライフメディコム  

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J-GLOBAL

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER DIABETES ASSOC  

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：日本臨床  

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J-GLOBAL

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：医学出版  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SPRINGER  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER DIABETES ASSOC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER DIABETES ASSOC  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：日本臨床  

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)   Publisher：医学出版  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER DIABETES ASSOC  

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Authorship：Lead author   Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER DIABETES ASSOC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER DIABETES ASSOC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：JAPAN ENDOCRINE SOC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：JAPAN ENDOCRINE SOC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER DIABETES ASSOC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER DIABETES ASSOC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER DIABETES ASSOC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER DIABETES ASSOC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER DIABETES ASSOC  

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：医学の世界社  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：FEDERATION AMER SOC EXP BIOL  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：FEDERATION AMER SOC EXP BIOL  

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Event date： 2023.10

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Venue：神戸  

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Event date： 2019.11 - 2019.12

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Venue：岡山市  

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Venue：高知市  

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Venue：SAN FRANCISCO  

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Venue：東京  

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Venue：Berlin, Germany  

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Venue：Orlando, FL, USA  

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Venue：東京  

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Venue：Lisbon, Portugal  

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Venue：San Diego, CA, USA  

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Venue：東京  

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Venue：札幌  

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Event date： 2016.11

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Venue：札幌  

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Event date： 2016.10

Language：English   Presentation type：Oral presentation (invited, special)  

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Event date： 2016.10

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：仙台  

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Event date： 2016.6

Language：English   Presentation type：Poster presentation  

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Event date： 2016.5

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2015.12

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2015.11

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

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Event date： 2015.11

Language：English   Presentation type：Poster presentation  

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Event date： 2015.10 - 2015.11

Language：English   Presentation type：Oral presentation (invited, special)  

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Event date： 2015.6

Language：English   Presentation type：Poster presentation  

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Event date： 2015.5

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2014.12

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2014.11

Language：English   Presentation type：Symposium, workshop panel (public)  

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Event date： 2014.11

Language：English   Presentation type：Poster presentation  

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Event date： 2014.9

Language：English   Presentation type：Symposium, workshop panel (nominated)  

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Event date： 2014.9

Language：English   Presentation type：Poster presentation  

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Event date： 2014.6

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

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Event date： 2014.6

Language：English   Presentation type：Poster presentation  

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Event date： 2014.5

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2013.12

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：東京  

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Event date： 2013.11

Language：English   Presentation type：Poster presentation  

Venue：Atlanta, GA  

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Event date： 2013.9

Language：English   Presentation type：Oral presentation (general)  

Venue：Barcelona, Spain  

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Event date： 2013.9

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

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Event date： 2013.9

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

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Event date： 2013.9

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Venue：旭川  

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Event date： 2013.9

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2013.7

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

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Event date： 2013.7

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

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Event date： 2013.6

Language：English   Presentation type：Poster presentation  

Venue：Chicago, IL  

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Event date： 2013.5

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2013.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：熊本  

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Event date： 2013.5

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2012.12

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2012.11

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2012.11

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2012.6

Language：English   Presentation type：Poster presentation  

Venue：Philadelphia, PA, USA  

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Event date： 2012.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：横浜  

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Event date： 2012.2

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Venue：愛知県  

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Event date： 2011.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京  

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Event date： 2011.11

Language：English   Presentation type：Poster presentation  

Venue：Philadelphia, PA, USA  

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Event date： 2011.10

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：埼玉県さいたま市 大宮  

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Event date： 2011.6

Language：English   Presentation type：Poster presentation  

Venue：San Diego, CA, USA  

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Event date： 2011.1

Language：Japanese   Presentation type：Poster presentation  

Venue：札幌  

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Event date： 2010.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：札幌  

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Event date： 2010.6

Language：English   Presentation type：Poster presentation  

Venue：Orlando, FL  

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Event date： 2010.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：岡山  

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Event date： 2010.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：岡山  

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Event date： 2010.4

Language：English   Presentation type：Poster presentation  

Venue：Kyoto, Japan  

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Event date： 2010.3

Language：English   Presentation type：Poster presentation  

Venue：Kyoto, Japan  

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Event date： 2010.3

Language：English   Presentation type：Symposium, workshop panel (nominated)  

Venue：Kyoto, Japan  

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Event date： 2009.10

Language：English   Presentation type：Poster presentation  

Venue：San Diego, LA.  

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Event date： 2009.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：岡山  

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Event date： 2009.6

Language：English   Presentation type：Poster presentation  

Venue：New Orleans, LA  

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Event date： 2009.5

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：大阪  

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Event date： 2009.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大阪  

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Event date： 2009.4

Language：Japanese   Presentation type：Poster presentation  

Venue：前橋  

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Event date： 2008.11

Language：Japanese   Presentation type：Poster presentation  

Venue：前橋  

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Event date： 2008.11

Language：English   Presentation type：Poster presentation  

Venue：Philadelphia, PA  

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Event date： 2008.9

Language：English   Presentation type：Poster presentation  

Venue：Roma, Italy  

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Event date： 2008.6

Language：English   Presentation type：Poster presentation  

Venue：San Francisco, CA  

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Event date： 2008.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京  

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Event date： 2007.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京  

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Event date： 2007.11

Language：Japanese   Presentation type：Poster presentation  

Venue：神戸  

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Event date： 2007.10 - 2007.11

Language：English   Presentation type：Poster presentation  

Venue：San Francisco, CA  

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Event date： 2007.10

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Venue：つくば  

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Event date： 2007.10

Language：English   Presentation type：Poster presentation  

Venue：New York, NY.  

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Event date： 2007.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：仙台  

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Event date： 2006.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：高松  

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Event date： 2006.10

Language：English   Presentation type：Poster presentation  

Venue：Phoenix, AZ  

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Event date： 2006.6

Language：English   Presentation type：Poster presentation  

Venue：Washington, DC, MD  

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Event date： 2005.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京  

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Event date： 2005.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京  

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Event date： 2005.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：神戸.  

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Event date： 2004.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：前橋  

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Event date： 2004.9 - 2004.10

Language：English   Presentation type：Poster presentation  

Venue：Vancouver, Canada  

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Event date： 2004.6

Language：Japanese   Presentation type：Poster presentation  

Venue：京都  

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Event date： 2004.6

Language：Japanese   Presentation type：Poster presentation  

Venue：札幌  

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Language：Japanese   Presentation type：Oral presentation (general)  

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幹事

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会長

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【教員評価対象外項目：地方学会】

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【教員評価対象外項目：地方学会】

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【教員評価対象外項目：地方学会】

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