小川 渉 | ![]() |
オガワ ワタル | |
大学院医学研究科 医科学専攻 | |
教授 | |
医学 |
AIMS/INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve blood glucose control, as well as reducing bodyweight by promoting urinary glucose excretion. The weight loss is less than expected from urinary glucose loss, however, likely because of an increase in food intake. To investigate whether SGLT-2 inhibitors might increase appetite by affecting related hormones, we examined the effects of the SGLT-2 inhibitor, ipragliflozin, including those on appetite-regulating hormones, in individuals with suboptimally controlled type 2 diabetes. MATERIALS AND METHODS: The present prospective, multicenter, open-label study was carried out with 96 patients with a body mass index of ≥22 kg/m2 who were treated with ipragliflozin (50 mg/day) for 16 weeks. Parameters including glycated hemoglobin level, bodyweight, circulating leptin and active ghrelin concentrations, and appetite as assessed with a visual analog scale were measured before and during treatment. RESULTS: Both glycated hemoglobin level (from 7.9 ± 0.8 to 7.1 ± 0.7%) and bodyweight (from 75.2 ± 12.6 to 72.6 ± 12.4 kg) were significantly decreased after treatment for 16 weeks. The fasting serum leptin level was significantly decreased after 2 weeks (from 19.5 ± 13.1 to 18.1 ± 12.4 ng/mL) and remained decreased up to 16 weeks, even after adjustment for bodyweight, whereas the plasma active ghrelin level showed no significant change. The visual analog scale score for hunger was significantly increased at 2 and 8 weeks. CONCLUSIONS: The present results suggest that ipragliflozin improved glycemic control and reduced bodyweight, but also reduced serum leptin levels and might thereby have increased appetite.
2019年09月, Journal of diabetes investigation, 10 (5), 1254 - 1261, 英語, 国内誌[査読有り]
研究論文(学術雑誌)
Here, we report phenotypic differences and similarities of monozygotic twins with maturity-onset diabetes of the young type 5 harboring a partial deletion of chromosome 17q12. The proband and her twin sister manifested complete aplasia and marked hypoplasia, respectively, of the body and tail of the pancreas. Whereas both twins showed marked hypoplasia of the right kidney and multiple cysts in both kidneys, only the proband's sister showed hydronephrosis in the left kidney. The proband had profound defects in insulin and glucagon secretion, as well as mild renal dysfunction, whereas her sister had pronounced renal dysfunction accompanied by mild defects in insulin and glucagon secretion. Both twins manifested hypomagnesemia and hyperuricemia, but no apparent liver dysfunction or intellectual disability. The severity of renal and pancreatic defects differed between monozygotic twins with maturity-onset diabetes of the young type 5, suggesting that the phenotypes of this condition are determined not solely by genetic factors.
2019年07月, Journal of diabetes investigation, 10 (4), 1112 - 1115, 英語, 国内誌[査読有り]
研究論文(学術雑誌)
PURPOSE: Hypoglycemia is a common and life-threatening complication in type 1 diabetes mellitus (T1DM) patients. Current guidelines recommend glucagon for treating hypoglycemia in out-of-hospital settings; however, glucagon is reportedly underused in such patients. We conducted a doctor-oriented, questionnaire-based survey of pediatricians and physicians to determine the glucagon prescription rate and identify the reason(s) for its underuse in T1DM patients. METHODS: A questionnaire was mailed to 415 pediatricians and 200 physicians employed at 66 facilities with >100 general wards throughout Hyogo, Japan. The following variables were surveyed: doctor's specialty, glucagon prescription rate, familiarity with glucagon use guidelines, barriers to prescribing glucagon, and attitude changes after education. RESULTS: After 16 doctors were found to have retired, 599 doctors were enrolled; 305 (187 pediatricians and 118 physicians) returned a completed questionnaire. In all, 45 pediatricians and 104 physicians were treating T1DM patients, of whom 24% and 28% reported prescribing glucagon, respectively. The guideline familiarity rate among pediatricians was lower than that among physicians. The major barrier to prescribing glucagon was the complex preparation procedure required by patients/caregivers. More than half of the doctors who did not prescribe glucagon began doing so after being educated about the guidelines. CONCLUSION: The glucagon prescription rate was low among both pediatricians and physicians in Japan.
2019年05月, Endocrine, 64 (2), 233 - 238, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
PURPOSE: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are categorized as short- or long-acting types, but information regarding differences in the effects of these two types on postprandial glucose disposal has been limited. We have now investigated the effects of exenatide and liraglutide (short- and long-acting GLP-1RAs, respectively) on glucose disposal during an oral glucose tolerance test (OGTT). METHODS: Fourteen healthy volunteers with normal glucose tolerance underwent three OGTTs, which were performed without pharmacological intervention or after a single administration of exenatide or liraglutide at 30 min and 10 h, respectively, before test initiation. The three OGTTs were performed with intervals of at least 7 days between successive tests and within a period of 2 months. RESULTS: Exenatide, but not liraglutide, markedly decelerated the peak of both plasma glucose and serum insulin levels during the OGTT, with the peaks of both glucose and insulin concentrations occurring at 150 min after test initiation with exenatide compared with 30 min in the control condition or with liraglutide. Exenatide and liraglutide reduced the area under the curve for plasma glucose levels during the OGTT by similar extents, whereas that for serum insulin levels was reduced only by exenatide. CONCLUSIONS: Our results suggest that exenatide decelerates the increase in plasma glucose levels through inhibition of glucose absorption and that it exerts an insulin-sparing action after glucose challenge.
2019年04月, Endocrine, 64 (1), 43 - 47, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
AIMS/INTRODUCTION: Fat-specific protein 27 (FSP27) α is the major isoform of FSP27 in white adipose tissue (WAT), and is essential for large unilocular lipid droplet (LD) formation in white adipocytes. In contrast, FSP27β is abundantly expressed in brown adipose tissue (BAT), and plays an important role in small multilocular LD formation. In FSP27 KO mice in which FSP27α and β are both depleted, WAT is characterized by multilocular LD formation, and by increased mitochondrial abundance and energy expenditure, whereas BAT conversely manifests large oligolocular LDs and reduced energy expenditure. MATERIALS AND METHODS: We investigated the effects of autophagy in WAT and BAT of wild type (WT) and FSP27 knockout (KO) mice. In addition, we examined the effects of FSP27α and FSP27β to the induction of autophagy in COS cells. RESULTS: Food deprivation induced autophagy in BAT of WT mice, as well as in WAT of FSP27 KO mice, suggesting that enhanced autophagy is characteristic of adipocytes with small multilocular LDs. Pharmacological inhibition of autophagy attenuated the fasting-induced loss of LD area in adipocytes with small multilocular LDs (BAT of WT mice and WAT of FSP27 KO mice), without affecting that in adipocytes with large unilocular or oligolocular LDs (WAT of WT mice or in BAT of FSP27 KO mice). Overexpression of FSP27α inhibited autophagy induction by serum deprivation in COS cells, whereas that of FSP27β had no such effect. CONCLUSIONS: The present results thus showed that FSP27α inhibits autophagy and might thereby contribute to the energy-storage function of WAT.
2019年03月, J Diabetes Investig, 10 (6), 1419 - 1429, 英語, 国内誌[査読有り]
研究論文(学術雑誌)
BACKGROUND: Insulinoma represents hypoglycemia as a predominant symptom; the autonomic symptoms may be resolved by chronically recurrent hypoglycemia resulting in the persistence of non-specific symptoms alone. Therefore, it has been estimated that there are many patients in whom the disease takes longer to diagnose and has remained undiagnosed. Although some parameters exist for the definitive diagnosis of the disease, there are currently no indices for early screening. Indices of glycemic control, hemoglobin A1c (HbA1c), and glycated albumin (GA) may be useful for the screening of patients with insulinoma having chronic hypoglycemia because the values become low in such a condition. Because there are no articles that have reported the point, we examine the effective cutoff values of HbA1c and GA for the diagnosis of insulinoma in the present study. METHODS: In a multicenter cross-sectional study, 31 patients with insulinoma were included for comparison with 120 control subjects with normal glucose tolerance based on 75 g oral glucose tolerance tests whose characteristics were matched to the patients. The primary outcomes were optimal cutoff values of HbA1c and GA for the screening of insulinoma. RESULTS: HbA1c was significantly lower in the insulinoma group at 4.7 ± 0.4% compared to the healthy control group at 5.7 ± 0.3% (p < 0.001), and GA was significantly lower in the insulinoma group at 11.6 ± 1.8% compared to the healthy control group at 14.5 ± 1.0% (p < 0.001). According to a receiver operating characteristic (ROC) analysis, optimal cutoff values of HbA1c and GA for the diagnosis of insulinoma were 5.0 and 12.4%, respectively. Area under the curve values of HbA1c and GA were 0.970 and 0.929, respectively, showing no significant difference (p = 0.399). CONCLUSIONS: In the present study, HbA1c and GA values in patients with insulinoma were significantly lower compared to the healthy controls, and effective cutoff values for screening were shown in the diagnosis of insulinoma for the first time. HbA1c and GA can be useful indices for insulinoma screening. Because malignant insulinoma have a similar diagnostic process to that of benign insulinoma, these could be useful for malignant insulinoma.
2019年02月26日, BMC cancer, 19 (1), 174 - 174, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
© 2019, Springer Science+Business Media, LLC, part of Springer Nature. Purpose: IgG4-related disease involves various organs including the pituitary and pancreas. The prevalence of IgG4-related hypophysitis is relatively rare compared with IgG4-related pancreatitis (autoimmune pancreatitis). Although several cases demonstrating both autoimmune pancreatitis and hypophysitis have been reported, the prevalence of IgG4-related hypophysitis in patients with autoimmune pancreatitis remains unknown. This study aimed at screening for IgG4-related hypophysitis to accurately determine its prevalence in patients with autoimmune pancreatitis. Methods: In this cohort study, we screened IgG4-related hypophysitis via pituitary magnetic resonance imaging (MRI) and endocrinological examination in 27 patients who were undergoing follow-up for autoimmune pancreatitis at Kobe University Hospital between 2014 and 2018. Results: Among 27 patients with autoimmune pancreatitis, 5 patients exhibited morphological abnormalities in the pituitary (18.5%). Among them, one patient (3.7%) met the criteria for hypophysitis with an enlarged pituitary and stalk concomitant with hypopituitarism. After glucocorticoid treatment, the enlarged pituitary shrank and became empty sella during the clinical course. Four patients (14.8%) revealed empty sella without obvious pituitary dysfunction. Four of 5 patients with morphological pituitary abnormalities showed multiple organ involvement in addition to pancreatic and pituitary involvement. Accordingly, multiple organ involvement was more prevalent in patients with morphological pituitary abnormalities (80%) compared to those without (48%). Conclusions: Although a large-scale study is necessary to validate these results, these data suggest that the prevalence of hypophysitis in patients with autoimmune pancreatitis may be underestimated. Based on our findings, we recommend screening for hypophysitis, especially in patients with multiple organ involvement.
2019年02月15日, Pituitary, 22 (1), 54 - 61, 英語[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
BACKGROUND: Gut microbiome composition or circulating microbiome-related metabolites in patients with heart failure (HF) have not been investigated at different time points (i.e., in the decompensated (Decomp) and compensated (Comp) phases). Methods and Results: We prospectively enrolled 22 patients admitted for HF and 11 age-, sex-, and comorbidity-matched hospitalized control subjects without a history of HF. Gut flora and plasma microbiome-related metabolites were evaluated by amplicon sequencing of the bacterial 16S ribosomal RNA gene and capillary electrophoresis time-of-flight mass spectrometry, respectively. HF patients were evaluated in both the Decomp and Comp phases during hospitalization. The phylum Actinobacteria was enriched in HF patients compared with control subjects. At the genus level, Bifiodobacterium was abundant while Megamonas was depleted in HF patients. Meanwhile, plasma concentration of trimethylamine N-oxide (TMAO), a gut microbiome-derived metabolite, was increased in HF patients (Decomp HF vs. control, P=0.003; Comp HF vs. control, P=0.004). A correlation analysis revealed positive correlations between the abundance of the genus Escherichia/Shigella and levels of TMAO and indoxyl sulfate (IS, a microbe-dependent uremic toxin) in Comp HF (TMAO: r=0.62, P=0.002; IS: r=0.63, P=0.002). Escherichia/Shigella was more abundant in Decomp than in Comp HF (P=0.030). CONCLUSIONS: Our results suggest that gut microbiome composition and microbiome-related metabolites are altered in HF patients.
2018年12月25日, Circulation journal : official journal of the Japanese Circulation Society, 83 (1), 182 - 192, 英語, 国内誌[査読有り]
研究論文(学術雑誌)
INTRODUCTION: Administered basal insulin markedly influences the fasting plasma glucose (FPG) level of individuals with type 1 diabetes. Insulin degludec (IDeg) and insulin glargine U300 (IGlar U300) are now available as ultra-long-acting insulin formulations, but whether or how their glucose-stabilizing effects differ remains unclear. We will compare the effects of these basal insulins on parameters related to blood glucose control, with a focus on day-to-day glycemic variability, in individuals with type 1 diabetes treated with multiple daily injections. METHODS: A multicenter, randomized, open-label, crossover, comparative study (Kobe Best Basal Insulin Study 2) will be performed at 13 participating institutions in Japan. A total of 46 C-peptide-negative adult outpatients with type 1 diabetes will be randomly assigned 1:1 by a centralized allocation process to IGlar U300 (first period)/IDeg (second period) or IDeg (first period)/IGlar U300 (second period) groups, in which subjects will be treated with the corresponding basal insulin for consecutive 4-week periods. The basal insulin will be titrated to achieve an FPG of less than 130 mg/dL initially and then less than 110 mg/dL if feasible. In the last week of each period, plasma glucose will be determined seven times a day by self-monitoring of blood glucose (SMBG) and intraday and day-to-day glucose excursions will be determined by flash glucose monitoring (FGM). The primary end point is comparison of day-to-day glycemic variability as evaluated by the standard deviation (SD) of FPG during the last week of each treatment period. Secondary end points include the coefficient of variance of FPG, the frequency of severe hypoglycemia as evaluated by SMBG, the duration of hypoglycemia as evaluated by FGM, intraday glycemic variability calculated from both SMBG and FGM data, and the administered insulin dose. PLANNED OUTCOMES: The results of the study will be submitted for publication in a peer-reviewed journal to report differences in the effects of two ultra-long-acting basal insulins, IDeg and IGlar U300. CONCLUSION: This head-to-head comparison will be the first study to compare the effects of IDeg and IGlar U300 on day-to-day FPG variability in C-peptide-negative individuals with type 1 diabetes. TRIAL REGISTRATION: Registered in University Hospital Medical Information Network (UMIN) Clinical Trials Registry as 000029630 on 20 June 2017. FUNDING: Novo Nordisk Pharma Ltd.
2018年12月, Diabetes therapy : research, treatment and education of diabetes and related disorders, 9 (6), 2399 - 2406, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
BACKGROUND: It is increasingly recognized that gut microbiota play a pivotal role in the development of atherosclerotic cardiovascular disease. Previously, we have reported that the abundance of genus Bacteroides is lower in patients with coronary artery disease (CAD) than in patients without CAD with coronary risk factors or in healthy volunteers. However, it remains unclear which and how specific gut bacteria contribute to the progression of atherosclerosis. METHODS: We recruited patients with CAD patients and controls without CAD with coronary risk factors. We then compared gut microbial composition using 16S ribosomal RNA gene sequencing in fecal samples to detect species with differential abundance between 2 groups. Subsequently, we used atherosclerosis-prone mice to study the mechanisms underlying the relationship between such species and atherosclerosis. RESULTS: Human fecal 16S ribosomal RNA gene sequencing revealed a significantly lower abundance of Bacteroides vulgatus and Bacteroides dorei in patients with CAD. This significant differential abundance was confirmed by quantitative polymerase chain reaction. Gavage with live B. vulgatus and B. dorei attenuated atherosclerotic lesion formation in atherosclerosis-prone mice, markedly ameliorating endotoxemia followed by decreasing gut microbial lipopolysaccharide production, effectively suppressing proinflammatory immune responses. Furthermore, fecal lipopolysaccharide levels in patients with CAD were significantly higher and negatively correlated with the abundance of B. vulgatus and B. dorei. CONCLUSIONS: Our translational research findings identify a previously unknown link between specific gut bacteria and atherosclerosis. Treatment with live B. vulgatus and B. dorei may help prevent CAD. CLINICAL TRIAL REGISTRATION: URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000018051 . Unique identifier: UMIN000015703.
2018年11月27日, Circulation, 138 (22), 2486 - 2498, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
[査読有り][招待有り]
研究論文(学術雑誌)
Thiazolidinediones exert their antidiabetic effect in part by ameliorating chronic inflammation in adipose tissue. However, the precise mechanism of this anti-inflammatory action has remained unclear. We here investigated the effects of the TZD pioglitazone on the lipid mediator profile of adipose tissue in obese diabetic KKAy mice by metabololipidomics analysis based on liquid chromatography and tandem mass spectrometry. Pioglitazone treatment increased the amounts of pro-resolving lipid mediators including lipoxin B4 (LXB4), resolvin E2, and eicosapentaenoic acid as well as reduced those of prostaglandin E2 and 4-hydroxydocosahexaenoic acid in epididymal adipose tissue of KKAy mice. These effects were accompanied by increased expression of genes for the anti-inflammatory proteins arginase 1, interleukin (IL)-13, and IL-10 in this tissue. Pioglitazone also increased LXB4 production in cultured 3T3-L1 adipocytes. Finally, LXB4 increased IL-10 gene expression in adipose tissue explants from KKAy mice. Together, our results suggest that up-regulation of LXB4 may contribute to the anti-inflammatory effect of pioglitazone in obese adipose tissue.
2018年10月20日, Biochemical and biophysical research communications, 505 (1), 29 - 35, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
PURPOSE: In isolated adrenocorticoropic hormone (ACTH) deficiency (IAD), autoimmunity against corticotrophs has been suggested; however, the pathogenesis remains largely unknown. Large cell neuroendocrine carcinoma (LCNEC) of the lung is a pulmonary tumor of high-grade malignant neuroendocrine tumor and it reportedly caused paraneoplastic syndrome by autoimmunity in several cases. METHODS: A 42-year-old woman with isolated adrenocorticotropic (ACTH) hormone deficiency (IAD) was diagnosed with large cell neuroendocrine carcinoma (LCNEC) 3 years after being diagnosed with IAD. We hypothesized that the LCNEC played a causal role in the development of IAD as a paraneoplastic syndrome and analyzed the autoimmunity. We also analyzed another case of ectopic ACTH syndrome to prove this hypothesis. RESULTS: The LCNEC tissue revealed an ectopic ACTH expression and lymphocyte infiltration. Interestingly, autoantibody against the proopiomelanocortin (POMC) protein was detected in the peripheral blood. Although, patient's serum did not show any effects on cell viability, proliferation, nor pomc expression in a corticotroph cell line, AtT20 cells, patient's lymphocytes in the peripheral blood specifically reacted toward POMC protein, indicating a presence of cytotoxic T lymphocytes (CTLs). In addition, the analysis of another case of ectopic ACTH syndrome showed lymphocyte infiltration not only in the metastatic liver tumors but also in the pituitary. Moreover, most CD8-positive cells resided adjacent to corticotrophs. CONCLUSIONS: These data indicate that the ectopic ACTH expression in the tumor evoked the autoimmunity to corticotrophs and caused IAD as a form of paraneoplastic syndrome.
2018年10月, Pituitary, 21 (5), 480 - 489, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
[査読有り]
研究論文(学術雑誌)
AIMS/INTRODUCTION: The preservation of pancreatic β-cell mass is an essential factor in the onset and development of type 2 diabetes mellitus. Recently, sodium-glucose cotransporter 2 inhibitors have been launched as antihyperglycemic agents, and their organ-protective effects are attracting attention. They are also reported to have favorable effects on the preservation of pancreatic β-cell mass, but the appropriate timing for the administration of sodium-glucose cotransporter 2 inhibitors is obscure. MATERIALS AND METHODS: In the present study, we administered a sodium-glucose cotransporter 2 inhibitor, dapagliflozin, to an animal model of type 2 diabetes mellitus, db/db mice, and investigated the adequate timing and duration for its administration. We also carried out microarray analysis using pancreatic islets from db/db mice. RESULTS: We found that dapagliflozin preserved pancreatic β-cell mass depending on the duration of administration and markedly improved blood glucose levels. If the duration was the same, the earlier administration of dapagliflozin was more effective in preserving pancreatic β-cell mass, increasing serum insulin levels and improving blood glucose levels. From microarray analysis, we discovered that the expression of Agr2, Tff2 and Gkn3 was significantly upregulated after the early administration of dapagliflozin. This upregulated gene expression might provide a legacy effect for the preservation of pancreatic β-cell mass. CONCLUSIONS: We expect that the early administration of dapagliflozin would provide a long-lasting effect in preserving pancreatic β-cell mass.
2018年10月, J Diabetes Investig, 10 (3), 577 - 590, 英語, 国内誌[査読有り]
研究論文(学術雑誌)
INTRODUCTION: We comprehensively evaluated the effects of combination therapy with insulin glargine and the incretin-based drugs lixisenatide or vildagliptin in Japanese patients with type 2 diabetes. METHODS: In this 12-week, randomized, open-label, parallel-group, multicenter study (GLP-ONE Kobe), the incretin-based drug sitagliptin was randomly switched to lixisenatide (20 μg/day, n = 18) or vildagliptin (100 mg/day, n = 20) in patients with inadequate glycemic control despite combination therapy with insulin glargine and sitagliptin. The dose of insulin glargine was titrated after the switch to maintain fasting blood glucose at approximately 110 mg/dL. The primary end points of the study were the change in glycosylated hemoglobin (HbA1c) level between before and 12 weeks after the treatment switch, the proportion of patients achieving an HbA1c level below 7.0%, and the postprandial increase in glucose concentration as assessed by self-monitoring of blood glucose. RESULTS: The change in HbA1c level from baseline to 12 weeks did not differ significantly between the lixisenatide and vildagliptin groups (- 0.6 ± 0.7% and - 0.6 ± 1.2%, respectively, P = 0.920). Neither the proportion of patients achieving an HbA1c level below 7.0% nor the postprandial increase in glucose concentration was different between two groups. Body weight and serum low density lipoprotein (LDL) cholesterol level decreased significantly in the lixisenatide and vildagliptin groups, respectively. Both drugs were associated with mild gastrointestinal symptoms but not with severe hypoglycemia. Vildagliptin was associated with elevation of serum aspartate transaminase. Treatment satisfaction as assessed with the Diabetes Treatment Satisfaction Questionnaire did not differ significantly between the two groups. CONCLUSION: The combinations of basal insulin and either lixisenatide or vildagliptin have similar efficacies with regard to improvement of glycemic control. TRIAL REGISTRATION: This trial has been registered with UMIN (No. 000010769).
2018年10月, Diabetes therapy : research, treatment and education of diabetes and related disorders, 9 (5), 2067 - 2079, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
AIM: To examine the association between treatment-achieved HbA1c values and incidence of both coronary artery disease (CAD) and severe eye disease with different diabetes treatments. METHODS: Associations of treatment-achieved HbA1c were investigated in various treatment groups [diet only; insulin; sulphonylurea (SU) alone; SU with glinides; and antihyperglycaemic agents other than glinides, SU or insulin] taken from a nationwide claims database of 14,633 Japanese diabetes patients. Cox's regression analysis examined risks over a 5.1-year follow-up. RESULTS: A significant linear trend was associated with HbA1c levels and CAD events in the diet-only group, and CAD risks were significantly higher in insulin and SU groups with HbA1c ≤ 7.0% and > 8.0% than in the diet-only group with HbA1c ≤ 7.0%. In contrast to CAD, a linear association was observed regardless of treatment modality between achieved HbA1c levels and risk of severe diabetic eye disease, but with no significant difference in eye disease risk between groups with HbA1c ≤ 7.0% and 7.1-8.0% in those treated with either SU alone, SU with glinides, or insulin. CONCLUSION: These findings suggest that the relationship between treatment-achieved HbA1c and incidence of both CAD and severe diabetic eye disease differed according to treatment, based on a large-scale real-life database. More research is now needed to confirm these findings and to further investigate the underlying mechanisms.
2018年09月10日, Diabetes & metabolism, 46 (4), 331 - 334, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
Endoplasmic reticulum (ER) stress leads to peripheral insulin resistance and the progression of pancreatic beta cell failure in type 2 diabetes. Although ER stress plays an important role in the pathogenesis of diabetes, it is indispensable for cellular activity. Therefore, when assessing the pathological significance of ER stress, it is important to monitor and quantify ER stress levels. Here, we have established a novel system to monitor ER stress levels quickly and sensitively, and using this method, we have clarified the effect of differences in glucose concentration and various fatty acids on the ER of pancreatic β cells. First, we developed a cell system that secretes Gaussia luciferase in culture medium depending on the activation of the GRP78 promoter. This system could sensitively monitor ER stress levels that could not be detected with real-time RT-PCR and immunoblotting. This system revealed that hyperglycemia does not induce unfolded protein response (UPR) in a short period of time in MIN6 cells, a mouse pancreatic β cell line. Physiological concentrations of palmitic acid, a saturated fatty acid, induced ER stress quickly, while physiological concentrations of oleic acid, an unsaturated fatty acid, did not. Docosahexaenoic acid, an n-3 unsaturated fatty acid, inhibited palmitic acid-induced ER stress. In this study, we have established a system that can sensitively detect ER stress levels of living cells in a short period of time. This system can be used to monitor the state of the ER in living cells and lead to the investigation of the significance of physiological or pathological ER stress levels.
2018年09月, Kobe J Med Sci, 64 (2), E43 - E55, 英語, 国内誌[査読有り]
研究論文(大学,研究機関等紀要)
Aims: Evidence suggests that sensor augmented pump (SAP) therapy is superior to conventional continuous subcutaneous insulin infusion (CSII) for achieving glycemic control in patients with type 1 diabetes. However, the clinical benefit of SAP therapy in East Asians has not yet been demonstrated. Methods: The effect of switching from conventional CSII to SAP therapy on glycemic profile was examined in 18 Japanese patients with type 1 diabetes. The glycemic profile of the patients was determined by retrospective continuous glucose monitoring (CGM) within 1 month before the treatment switch, whereas that at 6 and 12 months after the switch was evaluated with the CGM function of the SAP device. Hemoglobin A1c levels were also measured before and after the switch to SAP therapy. Results: The duration of hypoglycemia was significantly decreased at both 6 and 12 months after the change in treatment (6.6 ± 4.5, 3.2 ± 4.1, and 3.0 ± 2.8 min/h for before and 6 and 12 months, respectively), as was the HbA1c level at 12 months (7.8 ± 1.0 and 7.4 ± 0.9%, respectively). The duration of hyperglycemia did not differ between before and after the treatment switch. The decline in HbA1c level at 12 months after the switch to SAP was negatively correlated with age. Conclusion: Switching from conventional CSII to SAP therapy was associated with a decrease in both the duration of hypoglycemia and the level of HbA1c in Japanese patients with type 1 diabetes.
2018年07月, Diabetology international, 9 (3), 201 - 207, 英語, 国内誌[査読有り]
研究論文(学術雑誌)
Oxytocin neurons in the paraventricular nucleus (PVN) of hypothalamus regulate energy metabolism and reproduction. Plasma oxytocin concentration is reduced in obese subjects with insulin resistance. These findings prompted us to hypothesize that insulin serves to promote oxytocin release. This study examined whether insulin activates oxytocin neurons in the PVN, and explored the underlying signaling. We generated the mice deficient of 3-phosphoinositide-dependent protein kinase-1 (PDK1), a major signaling molecule particularly for insulin, specifically in oxytocin neurons (Oxy Pdk1 KO). Insulin increased cytosolic calcium concentration ([Ca2+]i) in oxytocin neurons with larger (≧25 μm) and smaller (<25 μm) diameters isolated from PVN in C57BL/6 mice. In PDK1 Oxy Pdk1 KO mice, in contrast, this effect of insulin to increase [Ca2+]i was markedly diminished in the larger-sized oxytocin neurons, while it was intact in the smaller-sized oxytocin neurons. Furthermore, intracerebroventricular insulin administration induced oxytocin release into plasma in Oxy Cre but not Oxy Pdk1 KO mice. These results demonstrate that insulin PDK1-dependently preferentially activates PVN magnocellular oxytocin neurons to release oxytocin into circulation, possibly serving as a mechanism for the interaction between metabolism and perinatal functions.
2018年07月, Sci Rep, 8 (1), 10415 - 10415, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
In the hypothalamic arcuate nucleus (ARC), orexigenic agouti-related peptide (AgRP) neurons regulate feeding behavior and energy homeostasis. The 3-phosphoinositide-dependent protein kinase-1 (PDK1) in AgRP neurons serves as a major signaling molecule for leptin and insulin, the hormones regulating feeding behavior, energy homeostasis and circulation. However, it is unclear whether PDK1 in AGRP neurons is also involved in regulation of blood pressure. This study explored it by generating and analyzing AgRP neuron-specific PDK1 knockout (Agrp-Pdk1flox/flox) mice and effect of high salt diet on blood pressure in KO and WT mice was analyzed. Under high salt diet feeding, systolic blood pressure (SBP) of Agrp-Pdk1flox/flox mice was significantly elevated compared to Agrp-Cre mice. When the high salt diet was switched to control low salt diet, SBP of Agrp-Pdk1flox/flox mice returned to the basal level observed in Agrp-Cre mice within 1 week. In Agrp-Pdk1flox/flox mice, urinary noradrenalin excretion and NUCB2 mRNA expression in hypothalamic paraventricular nucleus (PVN) were markedly upregulated. Moreover, silencing of NUCB2 in the PVN counteracted the rises in urinary noradrenalin excretions and SBP. These results demonstrate a novel role of PDK1 in AgRP neurons to counteract the high salt diet-induced hypertension by preventing hyperactivation of PVN nesfatin-1 neurons.
2018年06月12日, Biochemical and biophysical research communications, 500 (4), 910 - 916, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
Data presented in this article are supplementary material to our research article entitled "Impact of CD14++CD16+ monocytes on coronary plaque vulnerability assessed by optical coherence tomography in coronary artery disease patients" [1]. This article contains the data of study population, diagnostic ability of CD14++CD16+ monocytes to identify thin-cap fibroatheromas, and association between laboratory variables and plaque properties.
2018年06月, Data in brief, 18, 172 - 175, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
症例は89歳男性で、全身倦怠感・呼吸苦を主訴とした。主訴にて近医を受診し、血液検査で温式自己免疫性溶血性貧血(AIHA)と診断された他、同時期に低Ca血症、高P血症、高PTH血症を認め、偽性副甲状腺機能低下症(PHP)が疑われた。遺伝子検査ではGNAS遺伝子の変異は認めず、Ellsworth-Howard試験で尿中c-AMPの増加反応は正常であったが、尿中P排泄の増加を認めないことからPHP II型と考えられた。発症様式、頭部CTで頭蓋内石灰化を認めない点、これまで低Ca血症による明らかな症状を認めなかった点から後天性にPHPを発症したことが強く示唆され、AIHAに対するステロイド治療と同時にPTHに対するビタミンDの補充量が明らかに減量・中止できたことから、PHPがAIHAと関連して自己免疫機序で発症した可能性が示唆された。
(一社)日本内分泌学会, 2018年06月, 日本内分泌学会雑誌, 94 (Suppl.Update), 32 - 34, 日本語[査読有り]
研究論文(学術雑誌)
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研究論文(学術雑誌)
Insulin plays a central role in glucose homeostasis, and impairment of insulin action causes glucose intolerance and leads to type 2 diabetes mellitus (T2DM). A decrease in the transient peak and sustained increase of circulating insulin following an infusion of glucose accompany T2DM pathogenesis. However, the mechanism underlying this abnormal temporal pattern of circulating insulin concentration remains unknown. Here we show that changes in opposite direction of hepatic and peripheral insulin clearance characterize this abnormal temporal pattern of circulating insulin concentration observed in T2DM. We developed a mathematical model using a hyperglycemic and hyperinsulinemic-euglycemic clamp in 111 subjects, including healthy normoglycemic and diabetic subjects. The hepatic and peripheral insulin clearance significantly increase and decrease, respectively, from healthy to borderline type and T2DM. The increased hepatic insulin clearance reduces the amplitude of circulating insulin concentration, whereas the decreased peripheral insulin clearance changes the temporal patterns of circulating insulin concentration from transient to sustained. These results provide further insight into the pathogenesis of T2DM, and thus may contribute to develop better treatment of this condition.
2018年03月, NPJ Syst Biol Appl, 4, 14 - 14, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
During the development of type 2 diabetes, endoplasmic reticulum (ER) stress leads to pancreatic β cell failure. CCAAT/enhancer-binding protein (C/EBP) β is highly induced by ER stress and AMP-activated protein kinase (AMPK) suppression in pancreatic β cells, and its accumulation reduces pancreatic β cell mass. We investigated the phosphorylation state of C/EBPβ under these conditions. Casein kinase 2 (CK2) was found to co-localize with C/EBPβ in MIN6 cells. It phosphorylated S222 of C/EBPβ a previously unidentified phosphorylation site. We found that C/EBPβ is phosphorylated by CK2 under AMPK suppression and ER stress, which are important from the viewpoint of the worsening pathological condition of type 2 diabetes, such as decreased insulin secretion and apoptosis of pancreatic β cells.
Elsevier B.V., 2018年02月26日, Biochem. Biophys. Res. Commun., 497 (1), 451 - 456, 英語[査読有り]
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Thrombospondin 1 (TSP-1) is abundantly expressed in visceral adipose tissue and this expression is up-regulated in obese humans and rodents. Recent studies showed that genetic deletion of TSP-1 protects mice from diet-induced insulin resistance. However, the molecular mechanism is largely unknown. In this study, we examined the effect of recombinant TSP-1 on insulin signaling in cultured cells from insulin sensitive tissues to investigate whether TSP-1 could act as an adipokine. Here we show that treatment with recombinant TSP-1 suppressed insulin signaling in cultured muscle cells, which was accompanied by the activation of stress signaling such as JNK, p38, and IKK. These results suggest that TSP-1 acts as an adipokine which is involved in the pathogenesis of obesity-induced insulin resistance. Thus, TSP-1 could be a potential target for the treatment of insulin resistance and metabolic disease related to insulin resistance.
Kobe University School of Medicine, 2016年, Kobe Journal of Medical Sciences, 62 (1), E13 - E18, 英語研究論文(学術雑誌)
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INTRODUCTION: Immunoglobulin (Ig) G4-related hypophysitis is an emerging clinical entity, which is characterized by an elevated serum IgG4 concentration and infiltration of IgG4-positive plasma cells in the pituitary. Although some criteria for its diagnosis have been proposed, they have not been fully established. In particular, differential diagnosis from secondary chronic inflammation including granulomatosis with polyangiitis (GPA) is difficult in some cases. We describe central diabetes insipidus with pituitary swelling exhibiting infiltration of IgG4-positive cells. PATIENT: A 43-year-old woman in the remission stage of GPA presented with sudden-onset polyuria and polydipsia. Pituitary magnetic resonance imaging revealed swelling of the anterior and posterior pituitary and stalk, with heterogeneous gadolinium enhancement and disappearance of the high signal intensity of the posterior pituitary. Evaluation of biochemical markers for GPA suggested that the disease activity was well-controlled. Endocrinological examination revealed the presence of central diabetes insipidus and growth hormone deficiency. Pituitary biopsy specimen showed IgG4-positive cells, with a 43% IgG4(+)/IgG(+) ratio, which met the criteria for IgG4-related hypophysitis. However, substantial infiltration of polymorphonuclear neutrophils with giant cells was also noted, resulting in a final diagnosis of pituitary involvement of GPA. CONCLUSION: These results suggest that pituitary involvement of GPA should be taken into account for the differential diagnosis of IgG4-related hypophysitis.
2015年10月, Pituitary, 18 (5), 722 - 30, 英語, 国際誌[査読有り]
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68歳男。約20年の経過で増大した29mm大の右副腎腫瘍の精査目的で当科紹介となった。染色体検査で45,X/46,XX/47,XXXのモザイクを認め、モザイク型Turner症候群と診断した。また、尿中ステロイドプロファイルで17OH progesterone・21-deoxycortisone・11OH androstenedione代謝物の著明な高値を認めた。ACTH高値、コルチゾール低値、血中17-OHPの基礎値およびrapid ACTH試験での高値も認め、21水酸化酵素欠損症と診断した。右副腎腫瘍は、MRIのT1強調像で腫瘍内部がin phaseからout of phaseにかけ信号低下を認め、脂肪成分が主体で、先天性副腎皮質の過形成よりも画像上は皮質腺腫の可能性が高いと考えられた。内分泌学的に機能性を示唆する所見はなく、非機能性腺腫として経過観察を行うこととした。MRIでは萎縮した卵巣、子宮を認めた。以上より、モザイク型Turner症候群と21水酸化酵素欠損症の合併と診断した。
(一社)日本内分泌学会, 2015年07月, 日本内分泌学会雑誌, 91 (Suppl.Update), 44 - 46, 日本語[査読有り]
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52歳男。50歳頃より間擦部に黄色隆起性病変の出現を認めていた。51歳時に突然に口渇、多飲、多尿が出現し、今回、尿崩症疑いで入院となった。入院時、眼瞼、頸部、腋窩、肘窩、鼠径部、膝窩部に、ほぼ左右対称性に表面平滑で半球状ないしは扁平に隆起した弾性硬、褐色の小結節が多発し、一部融合していた。皮疹の生検を行い、病理組織学的に播種状黄色腫と診断した。また、5%高張食塩水負荷試験ではADH分泌不全を、バゾプレシン負荷試験では尿浸透圧は上昇し血漿浸透圧を上回り反応を認めた。下垂体MRIではT1強調像で後葉の高信号消失を認め、下垂体茎は肥厚し軽度造影された。デスモプレシン口腔内崩壊錠による治療を開始したところ、1日尿量、尿回数の減少、自覚症状の改善を認め退院となった。しかし、退院2ヵ月後より嗄声、嚥下障害が出現し、咽頭・声帯に黄色腫を疑う隆起性病変を認め、呼吸困難などの気道閉塞症状を認めないため外来にて経過観察中である。
(一社)日本内分泌学会, 2014年09月, 日本内分泌学会雑誌, 90 (Suppl.HPT), 83 - 85, 日本語[査読有り]
研究論文(学術雑誌)
71歳女。両股、膝、足関節の拘縮を主訴とした。股・膝関節の伸展障害、足関節の背屈障害を認め、膝蓋腱反射およびアキレス腱反射は消失し、大腿・下腿の筋硬直もあり、膝X線で関節裂隙の狭小化を認めた。血液検査でCK高値、FT4は感度以下、TSH低値を認め、レボチロキシン・ヒドロコルチゾン内服を開始し、内服下に行った下垂体MRIを含む内分泌学的検査所見よりempty sellaによる汎下垂体機能低下症と診断した。内服治療開始後、CK、足関節の可動性は速やかに改善し、数日後には股・膝関節の可動性も改善傾向となり歩行可能となった。治療開始20日には下腿の筋硬直も回復し、大腿の筋硬直も3ヵ月後には消失し、歩行困難も完全消失した。
(一社)日本内分泌学会, 2014年09月, 日本内分泌学会雑誌, 90 (Suppl.Update), 16 - 18, 日本語[査読有り]
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To estimate the carbohydrate-to-insulin ratio (CIR), a formula dividing a constant, usually 300-500, by the total daily dose (TDD) of insulin, is widely utilized. An appropriate CIR varies for each meal of the day, however. Here, we investigate diurnal variation of CIR in hospitalized Japanese type 1 diabetic patients treated with continuous subcutaneous insulin infusion. After optimization of the insulin dose, TDD and total basal insulin dose (TBD) were 34.9 ± 10.2 and 9.3 ± 2.8 units, respectively, with a percentage of TBD to TDD of 27.3 ± 6.0%. The products of CIR and TDD at breakfast, lunch and dinner were 311 ± 63, 530 ± 161, and 396 ± 63, respectively, suggesting that in the formula estimating CIR using TDD, the constant should vary for each meal of the day, and that 300, 500, and 400 are appropriate for breakfast, lunch, and dinner, respectively.
2014年02月12日, Journal of diabetes investigation, 5 (1), 48 - 50, 英語, 国内誌[査読有り]
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OBJECTIVE: The C-peptide index (CPI), a ratio of serum C-peptide to plasma glucose levels, is a readily measured index of β-cell function. The difference in the physiological features reflected by the index measured under fasting (F-CPI) or postprandial (PP-CPI) conditions has remained unclear, however. MATERIALS/METHODS: We investigated the relationship of the two CPIs to indexes of insulin secretion measured with an oral glucose tolerance test (OGTT) or with hyperglycemic and hyperinsulinemic-euglycemic clamp analyses as well as to disposition indexes (indexes of insulin secretion adjusted for insulin sensitivity) calculated from OGTT- or clamp-based analyses. We also examined the relationship between glucose tolerance and the clamp-based disposition index. RESULTS: The clamp-based disposition index declined progressively from normal glucose tolerance to impaired glucose tolerance to Type 2 diabetes, and it strongly correlated with the 2-h plasma glucose level during an OGTT. For patients with Type 2 diabetes, both F-CPI and PP-CPI correlated with indexes of insulin secretion including HOMA-β, the insulinogenic index, the ratio of the area under the insulin curve to that under the glucose curve during an OGTT, the serum C-peptide level after glucagon challenge, as well as early and total insulin secretion measured with a hyperglycemic clamp. PP-CPI, but not F-CPI, was significantly correlated with clamp-based and OGTT-based disposition indexes. CONCLUSIONS: F-CPI was correlated only with unadjusted indexes of insulin secretion, whereas PP-CPI was correlated with such indexes as well as with those adjusted for insulin sensitivity. The better clinical utility of PP-CPI might be attributable to these physiological characteristics.
2013年10月, Metabolism: clinical and experimental, 62 (10), 1470 - 6, 英語, 国際誌[査読有り]
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耐糖能異常をきたす内分泌疾患は多く存在するが、その病態評価をクランプ法で行った報告はみられない。そこで今回、原疾患未治療の先端巨大症11例(以下Acro群)と、ACTH非依存性Cushing症候群5例(CS群)、褐色細胞腫13例(Pheo群)、原発性アルドステロン症28例(PA群)について、75g経口ブドウ糖負荷試験とクランプ法を施行し、各疾患における耐糖能異常の頻度を調査した(以下;検討1)。また、耐糖能状態や、各種検査で算出したインスリン分泌指標、インスリン感受性指標について、健常人43例(対照群)のデータと比較検討した(以下;検討2)。検討1の結果、境界型と糖尿病型を合わせた耐糖能異常はAcro群で6例(55%)、CS群で4例(80%)、Pheo群で8例(62%)、PA群で14例(50%)に認められた。検討2では次のような結果が得られた。1)対照群に比べてAcro群は[Glucose infusion rate(GIR)]が有意に低く、[Insulinogenic index]が低値傾向にある。2)CS群では[GIR]が有意に低く、[HOMA-R]が高値傾向、[Composite index]が低値傾向にある。3)Pheo群では[HOMA-β]や[インスリン分泌第1相]が有意に低値。
(一社)日本内分泌学会, 2013年06月, 日本内分泌学会雑誌, 89 (Suppl.Update), 92 - 94, 日本語[査読有り]
研究論文(学術雑誌)
AIMS: We developed a system for measuring glucose area under the curve (AUC) using minimally invasive interstitial fluid extraction technology (MIET). Sweat contamination during interstitial fluid glucose (IG) extraction affects the accuracy of glucose AUC measurement, because this technology uses extracted sodium ion levels as an internal standard. Therefore, we developed a sweat monitoring patch to reduce this effect and investigated its efficacy in volunteers undergoing oral glucose tolerance tests (OGTTs). MATERIALS AND METHODS: Fifty diabetes mellitus inpatients and 10 healthy subjects undergoing the 75 g OGTT were included. Two sites on the forearm were pretreated with microneedle arrays, then hydrogels for interstitial fluid extraction were placed on the treated sites. Simultaneously, hydrogels for sweat monitoring were placed on untreated sites near the treated sites. Plasma glucose (PG) levels were measured every 30 min for 2 h to calculate reference AUC values. Using MIET, IG AUC was calculated from extracted glucose and sodium ion levels after attachment of the hydrogel for 2 h. RESULTS: Good correlation between IG AUC measurements using MIET and reference AUCs measured using PG levels was confirmed over a wide AUC range (202-610 mg/h/dl) after correction for the sweat-induced error detected by the hydrogel patches on the nonpretreated skin. Strong correlation between IG AUC and peak glucose levels indicates that glucose spikes can be easily detected by this system. CONCLUSION: We confirmed the effectiveness of a sweat monitoring patch for precise AUC measurement using MIET. This novel, easy-to-use system has potential for glucose excursion evaluation in daily clinical practice.
2013年05月01日, Journal of diabetes science and technology, 7 (3), 678 - 88, 英語, 国際誌[査読有り]
研究論文(学術雑誌)
Evaluating insulin secretion ability and sensitivity is essential to establish an appropriate treatment for patients with type 2 diabetes. The serum C-peptide response (CPR) level is used to evaluate the quantity of endogenous insulin secretion. However, the serum CPR level alone cannot indicate insulin-secretion ability or insulin sensitivity, because plasma glucose levels influence endogenous insulin secretion and vice versa. The CPR index, a ratio of serum CPR level to plasma glucose concentration when measured simultaneously, was previously reported to be a useful marker to determine the necessity of insulin treatment in patients with type 2 diabetes, but the reasons are unknown. The aim of this study was to clarify which factors affect the CPR index in patients with type 2 diabetes. Totally, 121 subjects were included in this study; all participants were hospitalized for type 2 diabetes. On the day after admission, we calculated the CPR index from each patient's fasting blood sample and a blood sample taken 2 hours after breakfast (the postprandial sample). A detailed medical history was taken from each patient to establish the disease duration. The degree of diabetic retinopathy judged by an ophthalmologist was obtained from patients' medical records. An oral glucose tolerance test and a glucagon load test were performed after the fasting plasma glucose level decreased to 130 mg/dl, and indices of insulin secretion and sensitivity were calculated. Fasting and postprandial CPR indices were moderately correlated with total endogenous insulin secretion after oral glucose load and with the CPR level after glucagon load, insulin sensitivity, composite index, and the reciprocal index of homeostasis model assessment (HOMA-R-1). Furthermore, there was a weak but significant correlation between the postprandial CPR index and the duration of diabetes. The postprandial CPR index was inversely correlated with the degree of diabetic retinopathy, which is known to be associated with the duration of hyperglycemia. Our data clearly shows that the CPR index is a useful parameter to reflect the degree of impaired glucose tolerance.
2013年04月18日, The Kobe journal of medical sciences, 59 (2), E44-53 - 53, 英語, 国内誌[査読有り]
研究論文(大学,研究機関等紀要)
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To elucidate the role of 3-phosphoinositide-dependent protein kinase-1 (PDK1) in cellular signaling, we constructed and expressed a pseudosubstrate of PDK1, designated as delta AL-PIF, and characterized its properties in cultured cells. delta AL-PIF consists of two fused proteins of the protein kinase C delta (delta PKC) activation loop (delta AL) and PDK1-interacting fragment (PIF). The phosphorylation of delta AL-PIF was detected with anti-delta PKC phospho-Thr(505)-specific antibody and was increased in proportion to the expression level of co-expressed GST-PDK1, indicating that it acts as a pseudosubstrate of PDK1. In cells expressing delta AL-PIF, basal phosphorylation level at the activation loop of PKB alpha, delta PKC and gamma PKC was reduced, compared with that in control cells, suggesting that delta AL-PIF functions as an inhibitory molecule for PDK1. delta AL-PIF affected the stability, translocation and endogenous activity of PKCs. These effects of delta AL-PIF on gamma PKC properties were confirmed by investigation using conditioned PDK1 knockout cells. Furthermore, apoptosis frequently occurred in cells expressing delta AL-PIF for 3 days. These findings revealed that delta AL-PIF served as an effective pseudosubstrate and an inhibitory molecule for PDK1, suggesting that this molecule can be used as a tool for investigating PDK-mediated cellular functions as well as being applicable for anti-cancer therapy.
BLACKWELL PUBLISHING, 2006年09月, GENES TO CELLS, 11 (9), 1051 - 1070, 英語研究論文(学術雑誌)
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For type 1 diabetes patients with inadequate glycemic control, one treatment option is to increase the insulin dose (scenario 1), which should not give rise to a "metabolic imbalance." A second option is additional treatment with a sodium-glucose cotransporter 2 inhibitor, which might lead to a "metabolic imbalance" (scenario 2). A reduction in insulin dose in addition to administration of a sodium-glucose cotransporter 2 inhibitor might further increase the "metabolic imbalance" (scenario 3).
2019年07月, Journal of diabetes investigation, 10 (4), 879 - 882, 英語, 国内誌[査読有り]
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Recent evidence suggests that metformin exerts glucose-lowering effects via its action in the gut. The accumulation in the colon of 18 F-labeled fluorodeoxyglucose (FDG), a nonmetabolizable derivative of glucose, is markedly augmented after metformin administration, indicating that metformin affects the handling of glucose in colon whereas the underlying mechanism and the significance to glucose metabolism of the finding remain to be determined.
2018年07月, J Diabetes Investig, 9 (4), 701 - 703, 英語, 国内誌[査読有り]
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