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Publications (28)69.2 Total impact

  • [Show abstract] [Hide abstract] ABSTRACT: Background: Diabetes therapy that not only lowers glucose levels but also lengthens life spans is required. We previously demonstrated that DPP-4 inhibition ameliorated β cell apoptosis and adipose tissue inflammation in β cell-specific glucokinase haploinsufficient mice fed a diet containing a combination of sucrose and linoleic acid (SL). Methods: In this study, we investigated the effects of DPP-4 inhibition in obese diabetic db/db mice fed an SL diet or a control diet containing sucrose and oleic acid (SO). We also examined the effects of DPP-4 inhibition in IRS-1-deficient mice fed an SL or SO diet as a model of insulin resistance. Results: DPP-4 inhibition efficiently increases the active GLP-1 levels in db/db mice. Unexpectedly, the SL diet, but not the SO diet, markedly increases mortality in the db/db mice. DPP-4 inhibition reduces the early lethality in SL-fed db/db mice. DPP-4 inhibition improves glucose tolerance, β cell function, and adipose tissue inflammation in db/db mice fed either diet. No significant changes in glycemic control or β cell mass were observed in any of the IRS-1-deficient mouse groups. Conclusions: A diet containing a combination of sucrose and linoleic acid causes early lethality in obese diabetic db/db mice, but not in lean and insulin resistant IRS-1 knockout mice. DPP-4 inhibition has protective effects against the diet-induced lethality in db/db mice.
    No preview · Article · Dec 2016 · Diabetology and Metabolic Syndrome
  • [Show abstract] [Hide abstract] ABSTRACT: We have previously reported that dehydroepiandrosterone (DHEA) suppresses the activity and mRNA expression of the hepatic gluconeogenic enzyme glucose-6-phosphatase (G6Pase), and hepatic glucose production in db/db mice. Tyrosine phosphorylation levels of Insulin receptor substrate (IRS)1 and IRS2 reportedly differ between the liver and muscle tissue and the effect of DHEA on insulin signaling has not been elucidated. Therefore, we examined DHEA’s effect on the liver and muscle tissue of IRS1−/− and IRS2−/− mice. Eight-week-old male C57BL6, IRS1−/−, and IRS2−/− mice were fed a high-fat diet (HFD), or an HFD containing 0.2% DHEA for 4 weeks. In a separate experiment, 8-week-old male C57BL6 mice were fed an HFD or an HFD containing 0.2% androstenedione for 4 weeks. In an insulin tolerance test, DHEA administration decreased the initial plasma glucose levels in the C57BL6, IRS1−/−, and IRS2−/− mice but did not decrease the ratios to the basal blood glucose level. Although DHEA administration increased Akt phosphorylation in the liver of the C57BL6, IRS1−/−, and IRS2−/− mice, androstenedione administration did not increase Akt phosphorylation in the liver of C57BL6 mice. DHEA administration did not increase Akt and PKCζ phosphorylation in the muscle tissue of C57BL6, IRS1−/−, or IRS2−/− mice. However, androstenedione administration increased Akt and PKCζ phosphorylation in the muscle tissue of C57BL6 mice. These findings suggest that the effect of DHEA on insulin action in the liver is self-mediated by DHEA or DHEA sulfate (DHEA-S) in the presence of IRS1, IRS2, or both.
    No preview · Article · Mar 2016 · The Journal of steroid biochemistry and molecular biology
  • [Show abstract] [Hide abstract] ABSTRACT: Objective: We compared the efficacy and safety of taking miglitol dissolved in water during a meal and taking a miglitol tablet just before a meal. Primary efficacy parameter is the area under the curve (AUC) of postprandial plasma glucose. Methods: Miglitol was administered according to three different intake schedules in each subject: intake schedule A, no miglitol; intake schedule B, administration of miglitol (50 mg) just before breakfast; intake schedule C, dissolving miglitol (50 mg) in water and taking it just before (1/3), during (1/3), and just after breakfast (1/3). Blood samples were collected at 0, 30, 60, 120, and 180 min after breakfast. Results: The AUCs for plasma glucose, insulin, and total glucose-dependent insulinotropic polypeptide (GIP) were significantly lower for intake schedules B and C, compared with those for intake schedule A. The AUC for total glucagon like peptide-1(GLP-1) was higher for intake schedule C than for intake schedule A. The coefficient of variation (CV) of plasma glucose was significantly lower for intake schedule C than for intake schedules A and B. Conclusion: Taking miglitol dissolved in water was equivalent to taking a miglitol tablet. The CV of plasma glucose was significantly lower for the dissolved-dose regimen.
    No preview · Article · Feb 2016 · Expert Opinion on Pharmacotherapy
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    [Show abstract] [Hide abstract] ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is associated with various metabolic disorders, and the therapeutic strategies for treating NAFLD and non-alcoholic steatohepatitis (NASH) have not been fully established. In the present study, we examined whether lipid-lowering agents inhibited the progression of NAFLD and tumorigenesis in a non-alcoholic steatohepatitis-derived hepatocellular carcinoma model mouse (STAM mice) generated by streptozotocin injection and a high-fat diet. Seven-week-old STAM mice were divided into groups fed a high-fat diet (Ctl) or a high-fat diet supplemented with ezetimibe (Ez), fenofibrate (Ff), rosuvastatin (Rs), ezetimibe plus fenofibrate (EF), or ezetimibe plus rosuvastatin (ER) for 4 weeks. At the end of the experiments, an oral glucose tolerance test, an insulin tolerance test, biochemical analyses using serum and liver, and a histological analysis of liver were performed in 11-week-old STAM mice. The lipid-lowering agents did not affect the body weight or the casual blood glucose levels in any of the groups. The serum triglyceride level was significantly decreased by Ff, Rs, and EF. Glucose tolerance was improved by Ez and Ff, but none of these agents improved insulin sensitivity. A histochemical analysis revealed that the lipid-lowering agents, with the exception of Rs, significantly inhibited the progression of hepatic steatosis. Nonetheless, no significant changes in the incidence of hepatic tumors were observed in any of the groups. Lipid-lowering agents inhibited the progression of hepatic steatosis without suppressing tumorigenesis in STAM mice. Our data has implications for the mechanism underlying steatosis-independent hepatic tumorigenesis in mice.
    Full-text · Article · Dec 2015 · European journal of pharmacology
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    [Show abstract] [Hide abstract] ABSTRACT: Diazoxide is a non-diuretic benzothiadiazine derivative, one of a group of substances introduced into clinical practice in the 1950s for the treatment of hypertension. Fajans reported the use of diazoxide for the treatment of insulinoma in 1979. Although patients with hyperinsulinemic hypoglycemia worldwide have been treated with diazoxide for more than 30 years, there are no recent reports about the adverse effects of this drug in Asian patients, including Japanese patients. Herein, we report the results of our retrospective clinical record review of 6 Japanese patients (3 females and 3 males, ranging in age from 58 to 91 years) with hyperinsulinemic hypoglycemia and inoperable insulinoma treated with diazoxide. Diazoxide improved control of hypoglycemic symptoms and maintained normoglycemia in 5 of the 6 patients, and was ineffective in one patient. Surprisingly, although all 6 patients received diazoxide according to the treatment strategy recommended in Western patients, 5 of the 6 patients developed edema and two developed congestive heart failure. Thus, when starting treatment with diazoxide in Japanese patients, the symptoms and signs of fluid retention should be evaluated carefully. Also, appropriate protocols for treatment with diazoxide should be evaluated by means of clinical trials in Japanese patients with hyperinsulinemic hypoglycemia.
    Full-text · Article · Nov 2015 · Endocrine Journal
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    [Show abstract] [Hide abstract] ABSTRACT: We investigated the role of insulin receptor substrate (Irs)-1 for diethylnitrosamine (DEN) plus high-fat (HF) diet-induced hepatic tumorigenesis in mice. We gave DEN by intraperitoneal injection at the dose of 80 mg/kg to 18-week-old wild-type (WT) and Irs1-knockout (Irs1−/−) mice, which were fed a HF diet from 8 weeks-of-age until they were killed (52 weeks). The Irs1−/− mice showed significantly lower plasma alanine aminotransferase levels, triglyceride contents in the liver and also lower expression levels of the genes encoding inflammatory cytokines than the WT mice. The incidence of DEN plus HF diet-induced hepatic tumors was 71.4% in the WT mice, whereas it was just 14.3% in the Irs1−/− mice. The present study showed that Irs1 played an important role in DEN plus HF diet-induced hepatic tumorigenesis.
    Full-text · Article · Feb 2014
  • [Show abstract] [Hide abstract] ABSTRACT: The glucokinase-induced upregulation of insulin receptor substrate 2 (IRS-2) plays an important role in β cell adaptive proliferation in response to high-fat diet-induced insulin resistance. This study aimed to investigate the role of IRS-2 in the proliferation of β cells following a 60% partial pancreatectomy. IRS-2 deficient (IRS-2(-/-)) mice or wild-type (WT) mice were subjected to a pancreatectomy (60% partial pancreatectomy) or a sham operation (Sham). The β cell proliferation and gene expression profiles of the islets were then assessed. Gene expression in islets from pancreatectomized and sham-operated C57BL/6J male mice was analyzed using a cDNA microarray analysis. To compare with β cell proliferation induced by a high-fat diet, Gck(+/-) mice subjected to a pancreatectomy were also analyzed. The IRS-2(-/-) mice exhibited β cell expansion and a significant increase in β cell proliferation after the pancreatectomy, compared with the Sham group. Although glucose stimulated insulin secretion from islets was not impaired, IRS-2(-/-) mice manifested severe hyperglycemia after the pancreatectomy. The expression levels of Aurora kinase B (AurkB), Cyclin A, and Cyclin B1 in the pancreatectomized islets were also enhanced in the IRS-2(-/-) mice. A gene set enrichment analysis (GSEA) suggested an association between the genes that were upregulated in the pancreatectomized islets and those involved in M phase progression in the cell cycle. β cell proliferation after a pancreatectomy was observed even in the Gck(+/-) mice. In conclusion, IRS-2 was not required for β cell proliferation, but might be needed for functional β cell mass, after a pancreatectomy. A partial pancreatectomy in mice may be an attractive model for the development of new strategy for exploring the unique nature of β cell proliferation.
    No preview · Article · Feb 2014 · Endocrinology
  • [Show abstract] [Hide abstract] ABSTRACT: We previously reported that combination therapy with an α-glucosidase inhibitor (αGI) and a dipeptidyl peptidase-4 (DPP-4) inhibitor increased active glucagon-like peptide-1 (GLP-1) levels and decreased total glucose-dependent insulinotropic polypeptide (GIP) levels, compared with monotherapy, in non-diabetic men. However, the peptide YY (PYY), cholecystokinin (CCK), ghrelin, and obestatin levels in patients receiving a combination of αGIs and DPP-4 inhibitors have not been previously reported. We evaluated the effect of miglitol, vildagliptin, or their combination on these parameters. Miglitol and/or vildagliptin were administered according to four different intake schedules in eleven non-diabetic men (C: no drug, M: miglitol; V: vildagliptin, M+V: miglitol+vildagliptin). Blood samples were collected at 0, 30, 60, and 120 min after the start of breakfast. The plasma glucose, serum insulin, serum total PYY (PYY1-36 and PYY3-36), plasma CCK, plasma active ghrelin, and plasma obestatin levels were measured. The area under the curve (AUC) of the serum total PYY level in the M group was significantly greater than that in the C group, and the AUC of the serum total PYY level in the M+V group was significantly lower than that in the M group. The combination therapy did not change the AUC of the plasma CCK, plasma active ghrelin, plasma obestatin, and ghrelin/obestatin levels, compared with the control. The results of our study suggested that combination therapy with miglitol and vildagliptin had no effect on appetite regulation hormones, such as total PYY, CCK, active ghrelin, and obestatin, compared with the levels in the control group.
    No preview · Article · Dec 2013 · Endocrine Journal
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    [Show abstract] [Hide abstract] ABSTRACT: The prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is increasing with the growing epidemics of obesity and diabetes. NAFLD encompasses a clinicopathologic spectrum of disease ranging from isolated hepatic steatosis to NASH, which is a more aggressive form of fatty liver disease, to cirrhosis and finally, hepatocellular carcinoma (HCC). The exact mechanism behind the development of HCC in NASH remains unclear; however it has been established that hepatic steatosis is the important risk factor in the development of HCC. Metformin has recently drawn attention because of its potential antitumor effect. Here, we investigated the effects of metformin on high-fat diet (HFD)-induced liver tumorigenesis using a mouse model of NASH and liver tumor. Metformin prevented long-term HFD-induced liver tumorigenesis in C57Bl/6 mice. Of note, metformin failed to protect against liver tumorigenesis in mice that had already begun to develop NAFLD. Metformin improved short-term HFD-induced fat accumulation in the liver, associated with the suppression of adipose tissue inflammation. Collectively, these results suggest that metformin may prevent liver tumorigenesis via suppression of liver fat accumulation in the early stage, before the onset of NAFLD, which seems to be associated with a delay in the development of inflammation of the adipose tissue.
    Full-text · Article · Aug 2013 · AJP Endocrinology and Metabolism
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    [Show abstract] [Hide abstract] ABSTRACT: The derangement of endoplasmic reticulum (ER) homeostasis triggers β-cell apoptosis, leading to diabetes. Glucokinase up-regulates IRS-2 expression in β cell, but the role of glucokinase and IRS-2 in ER stress has been unclear. In this study, we investigated the impact of glucokinase activation by glucokinase activator (GKA) on ER stress in β cells. GKA administration improved β-cell apoptosis in Akita mice, a model of ER stress-mediated diabetes. GKA increased the expression of IRS-2 in β cells, even under ER stress. Both glucokinase-deficient Akita mice and IRS-2-deficient Akita mice exhibited an increase in β-cell apoptosis, compared with Akita mice. β-cell-specific IRS-2-overexpressing (βIRS2Tg) Akita mice showed less β-cell apoptosis than Akita mice. IRS-2-deficient islets were vulnerable, but βIRS2Tg islets were resistant to ER stress-induced apoptosis. Meanwhile, GKA regulated the expressions of CHOP and other ER stress-related genes in an IRS-2-independent fashion in islets. GKA suppressed the expressions of CHOP and Bax and protected against β-cell apoptosis under ER stress in an ERK1/2-dependent, IRS-2-independent manner. Taken together, GKA ameliorated ER stress-mediated apoptosis by harmonizing IRS-2 upregulation and the IRS-2-independent control of apoptosis in β cells.
    Full-text · Article · Jun 2013 · Diabetes
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    Dataset: Figure S5
    [Show abstract] [Hide abstract] ABSTRACT: The effect of glucokinase activator on the protein expression of the incretin receptors under a low glucose concentration. Isolated islets were incubated with DMSO (ctl) or GKA (G: 30 µM compound A) in the presence of 2.8 mM glucose for 24 hours. Total cell extracts from the isolated islets were subjected to immunoblotting for p-AMPKα (Thr172), AMPKα, anti-GLP1R antibody, anti-GIPR antibody, and GAPDH (n = 3). (TIF)
    Full-text · Dataset · May 2013
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    [Show abstract] [Hide abstract] ABSTRACT: The precise role of AMP-activated protein kinase (AMPK), a target of metformin, in pancreatic β cells remains controversial, even though metformin was recently shown to enhance the expression of incretin receptors (GLP-1 and GIP receptors) in pancreatic β cells. In this study, we investigated the effect of AMPK in the regulation of incretin receptors expression in pancreatic islets. The phosphorylation of AMPK in the mouse islets was decreased by increasing glucose concentrations. We showed the expression of incretin receptors in bell-shaped response to glucose; Expression of the incretin receptors in the isolated islets showed higher levels under a medium glucose concentration (11.1 mM) than that under a low glucose concentration (2.8 mM), but was suppressed under a high glucose concentration (22.2 mM). Both treatment with an AMPK inhibitor and DN-AMPK expression produced a significant increase of the incretin receptors expression under a low glucose concentration. By contrast, in hyperglycemic db/db islets, the enhancing effect of the AMPK inhibitor on the expression of incretin receptors was diminished under a low glucose concentration. Taken together, AMPK is involved in the regulation of incretin receptors expression in pancreatic islets under a low glucose concentration.
    Full-text · Article · May 2013 · PLoS ONE
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    Dataset: Figure S9
    [Show abstract] [Hide abstract] ABSTRACT: The impact of pharmacologic modulation of AMPK phosphorylation on the protein expressions of the incretin receptors in db/db mice. Isolated islets from 7-week-old db/+ and db/db mice were pre-treated for 15 min with vehicle (Veh; DMSO) or an AMPK inhibitor (AMPKi; 40 µM compound C) in the presence of 2.8 mM glucose, or with vehicle (Veh; DMSO) in the presence of 11.1 mM glucose, followed by the addition of vehicle (Veh; water) for an additional 24 h. Total cell extracts from the isolated islets were subjected to immunoblotting for p-AMPKα (Thr172), AMPKα, anti-GLP1R antibody, anti-GIPR antibody, and GAPDH. (TIF)
    Full-text · Dataset · May 2013
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    Dataset: Figure S1
    [Show abstract] [Hide abstract] ABSTRACT: The effect of adenoviral infection on the apoptosis in islets. Trypsinized islet cells of indicated groups were subjected to a TUNEL assay. Insulin is stained green and TUNEL-positive nuclei are stained red. DAPI (blue) and differential interference contrast (DIC) images were also merged. TUNEL staining was performed using the ApopTag In Situ Detection Kit (Chemicon). For TUNEL staining, at least 40 islets per trypsinized islets group attached to poly-L-lysine coated coverslips (Falcon) were analyzed using the FLUOVIEW FV 1000-D confocal laser scanning microscope (OLYMPUS) to assess the proportion of immunostained nuclei among the insulin-positive cells. (TIF)
    Full-text · Dataset · May 2013
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    Dataset: Figure S7
    [Show abstract] [Hide abstract] ABSTRACT: The effect of pharmacologic modulation of AMPK phosphorylation on the protein expressions of the incretin receptors under a low glucose concentration. Isolated islets were treated for 24 h with vehicle (Veh; DMSO) or the AMPK inhibitor (AMPKi; 40 µM compound C) in the presence of 2.8 mM glucose. Total cell extracts from the isolated islets were subjected to immunoblotting for p-AMPKα (Thr172), AMPKα, anti-GLP1R antibody, anti-GIPR antibody, and GAPDH (n = 3). (TIF)
    Full-text · Dataset · May 2013
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    Dataset: Figure S4
    [Show abstract] [Hide abstract] ABSTRACT: The effect of glucose signal on the protein expression of the incretin receptors in islets. Isolated islets were incubated for 24 h in the presence of 2.8, 5.6, 11.1 or 22.2 mM glucose. Total cell extracts from the isolated islets were subjected to immunoblotting for p-AMPKα (Thr172), AMPKα, anti-GLP1R antibody, anti-GIPR antibody, and GAPDH. (TIF)
    Full-text · Dataset · May 2013
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    Dataset: Figure S8
    [Show abstract] [Hide abstract] ABSTRACT: The effect of pharmacologic modulation of AMPK phosphorylation on the protein expression of the incretin receptors under a medium glucose concentration. Isolated islets were treated for 24 h with vehicle (V, water) or AICAR (A, 1 mM) in the presence of 11.1 mM glucose. Total cell extracts from the isolated islets were subjected to immunoblotting for p-AMPKα (Thr172), AMPKα, anti-GLP1R antibody, anti-GIPR antibody, and GAPDH (n = 4) (TIF)
    Full-text · Dataset · May 2013
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    Dataset: Figure S2
    [Show abstract] [Hide abstract] ABSTRACT: The impact of treatment with metformin on the phosphorylation level of AMPK and the expressions of the incretin receptors in islets in vitro. A), B) Isolated islets were incubated with or without 1 mM metformin (Dainippon Sumitomo Pharma, Osaka, Japan) for 24 h in the presence of 2.8 or 11.1 mM glucose. A) The Glp1, Gip receptor and Pparα expressions in the islets were determined by real-time quantitative RT-PCR and normalized to the expression level of β actin mRNA and to the vehicle-treated control samples at 2.8 mM glucose (n = 7–8). *P<0.05. B) Insulin secretion by the islets treated with metformin or vehicle (ctl) in the presence of 11.1 mM glucose for 24 h with or without addition of 10 nM GLP-1 or 10 nM GIP. The results are expressed in ng of insulin/10 islets/90 min (n = 4). * P<0.05 and ** P<0.01. C), D) Isolated islets were incubated with or without 1 mM metformin for 24 h in the presence of 11.1 mM glucose. C) Islet morphology of the vehicle- and metformin-treated islets. D) The insulin content in the islets was determined after acid ethanol extraction (n = 3). White bars, vehicle; Black bars; metformin. E) Total islet extracts from the isolated islets were subjected to immunoblotting for p-AMPKα (Thr172) and AMPKα. The intensities of the signals were quantified by densitometry and normalized to the vehicle-treated control samples at 2.8 mM glucose (n = 3). The results shown are the means of three independent experiments. F) Total cell extracts from the isolated islets were subjected to immunoblotting for p-AMPKα (Thr172), AMPKα, anti-GLP1R antibody, and β actin. (TIF)
    Full-text · Dataset · May 2013
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    Dataset: Figure S3
    [Show abstract] [Hide abstract] ABSTRACT: The impact of treatment with metformin on the phosphorylation level of AMPK and the expressions of the incretin receptors in islets in vivo. Mice were given metformin in drinking water at 300 mg/kg daily or standard drinking water for 48 hours. Four hours prior to the islet isolation, the food was removed from the cages and the mice were orally administrated metformin (75 mg/kg) or vehicle (water) [14]. A) The Glp1, Gip receptor and Pparα expressions in the islets were determined by real-time quantitative RT-PCR and normalized to the expression level of β actin mRNA and to the samples in vehicle-treated mice (n = 6–7). Experiments were performed on mice treated with metformin or vehicle (ctl). *P<0.05 and ** P<0.01. B) Insulin secretion from the islets of mice treated with metformin or vehicle (ctl) in the presence of 2.8 mM or 11.1 mM glucose, with or without addition of 10 nM GLP-1 or 10 nM GIP. The results are expressed as ng of insulin/10 islets/90 min (n = 4). * P<0.05 and ** P<0.01. C) Freshly isolated total islets, the extracted liver and skeletal muscle tissues from the vehicle or metformin-treated mice were subjected to immunoblotting for p-AMPKα (Thr172) and AMPKα. The intensities of the signals were quantified by densitometry and normalized to the samples in vehicle-treated mice (n = 3). The results shown are the means of three independent experiments. D) Total cell extracts from the isolated islets were subjected to immunoblotting for p-AMPKα (Thr172), AMPKα, anti-GLP1R antibody, and β actin (n = 3). (TIF)
    Full-text · Dataset · May 2013
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    Dataset: Figure S6
    [Show abstract] [Hide abstract] ABSTRACT: The effect of glucokinase activator on the protein expression of the incretin receptors under a medium glucose concentration. Isolated islets were incubated with DMSO (ctl) or GKA (G: 30 µM compound A) in the presence of 11.1 mM glucose for 24 hours. Total cell extracts from the isolated islets were subjected to immunoblotting for p-AMPKα (Thr172), AMPKα, anti-GLP1R antibody, anti-GIPR antibody, and GAPDH (n = 3). (TIF)
    Full-text · Dataset · May 2013