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Masahiro Takihata,
Akinobu Nakamura, Kazuki Tajima,
Takaharu Inazumi,
Yumiko Komatsu,
Haruka Tamura,
Syunsuke Yamazaki,
Yoshinobu Kondo,
Masayo Yamada,
Mari Kimura,
Yasuo Terauchi
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ABSTRACT: AIMS: To compare the efficacy and safety of these two agents and the presence of surrogate markers related to diabetic complications in Japanese type 2 diabetic patients. MATERIALS AND METHODS: In a multicenter, open-label trial, 130 patients whose diabetes had been inadequately controlled (HbA1c, 6.9%-9.5%) with metformin and/or sulfonylurea were randomly assigned to a sitagliptin group (50 mg/day) or a pioglitazone group (15 mg/day) and were followed up for 24 weeks. At 16 weeks, if the patient's HbA1c level was ≥ 6.5%, the dose of sitagliptin or pioglitazone was increased up to 100 mg/day or 30 mg/day, respectively. Main outcome measure was the difference in the mean changes in the HbA1c level from baseline at 24 weeks between these two groups. RESULTS: Of the 130 patients who were enrolled, 115 subjects (sitagliptin group: 58 patients, pioglitazone group: 57 patients) completed this trial. At 0 weeks, the mean HbA1c level was 7.47 ± 0.66% in the sitagliptin group and 7.40 ± 0.61% in the pioglitazone group. At 24 weeks, the mean changes in the HbA1c level from baseline were -0.86 ± 0.63% vs. -0.58 ± 0.68% (P = 0.024). Hypoglycemia (2 patients, 3.4% vs. 2 patients, 3.5%), gastrointestinal symptoms (3 patients, 5.2% vs. 1 patient, 1.8%), and pretibial edema (0 patients, 0% vs. 39 patients, 68.4%, P < 0.001) were observed for 24 weeks. CONCLUSIONS: Sitagliptin was not only more tolerable, but more effective than pioglitazone in Japanese type 2 diabetic patients who had been treated with metformin and/or sulfonylurea.
Diabetes Obesity and Metabolism 12/2012; · 3.38 Impact Factor
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Kazuki Orime,
Jun Shirakawa,
Yu Togashi, Kazuki Tajima,
Hideaki Inoue,
Yuzuru Ito,
Koichiro Sato,
Akinobu Nakamura,
Kazutaka Aoki,
Yoshio Goshima,
Yasuo Terauchi
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ABSTRACT: Decreased β-cell mass is a hallmark of type 2 diabetes, and therapeutic approaches to increase the pancreatic β-cell mass have been expected. In recent years, gastrointestinal incretin peptides have been shown to exert a cell-proliferative effect in pancreatic β-cells. Trefoil factor 2 (TFF2), which is predominantly expressed in the surface epithelium of the stomach, plays a role in antiapoptosis, migration, and proliferation. The TFF family is expressed in pancreatic β-cells, whereas the role of TFF2 in pancreatic β-cells has been obscure. In this study, we investigated the mechanism by which TFF2 enhances pancreatic β-cell proliferation. The effects of TFF2 on cell proliferation were evaluated in INS-1 cells, MIN6 cells, and mouse islets using an adenovirus vector containing TFF2 or a recombinant TFF2 peptide. The forced expression of TFF2 led to an increase in bromodeoxyuridine (BrdU) incorporation in both INS-1 cells and islets, without any alteration in insulin secretion. TFF2 significantly increased the mRNA expression of cyclin A2, D1, D2, D3, and E1 in islets. TFF2 peptide increased ERK1/2 phosphorylation and BrdU incorporation in MIN6 cells. A MAPK kinase inhibitor (U0126) abrogated the TFF2 peptide-mediated proliferation of MIN6 cells. A CX-chemokine receptor-4 antagonist also prevented the TFF2 peptide-mediated increase in ERK1/2 phosphorylation and BrdU incorporation in MIN6 cells. These results indicated that TFF2 is involved in β-cell proliferation at least partially via CX-chemokine receptor-4-mediated ERK1/2 phosphorylation, suggesting TFF2 may be a novel target for inducing β-cell proliferation.
Endocrinology 11/2012; · 4.46 Impact Factor
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ABSTRACT: The glucagon-like peptide-1 receptor agonist liraglutide is used to treat diabetes. A hallmark of liraglutide is the glucose-dependent facilitation of insulin secretion from pancreatic β-cells. In β-cells, the glycolytic enzyme glucokinase plays a pivotal role as a glucose sensor. However, the role of glucokinase in the glucose-dependent action of liraglutide remains unknown. We first examined the effects of liraglutide on glucokinase haploinsufficient (Gck(+/-)) mice. Single administration of liraglutide significantly improved glucose tolerance in Gck(+/-) mice without increase of insulin secretion. We also assessed the effects of liraglutide on the survival rates, metabolic parameters, and histology of liver or pancreas of β-cell-specific glucokinase-deficient (Gck(-/-)) newborn mice. Liraglutide reduced the blood glucose levels in Gck(-/-) neonates but failed to prolong survival, and all the mice died within 1 wk. Furthermore, liraglutide did not improve glucose-induced insulin secretion in isolated islets from Gck(-/-) neonates. Liraglutide initially prevented increases in alanine aminotransferase, free fatty acids, and triglycerides in Gck(-/-) neonates but not at 4 d after birth. Liraglutide transiently prevented liver steatosis, with reduced triglyceride contents and elevated glycogen contents in Gck(-/-) neonate livers at 2 d after birth. Liraglutide also protected against reductions in β-cells in Gck(-/-) neonates at 4 d after birth. Taken together, β-cell glucokinase appears to be essential for liraglutide-mediated insulin secretion, but liraglutide may improve glycemic control, steatosis, and β-cell death in a glucokinase-independent fashion.
Endocrinology 05/2012; 153(7):3066-75. · 4.46 Impact Factor
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ABSTRACT: We investigated a possible association between serum plasminogen activator inhibitor-1 (PAI-1) levels and renal dysfunction in 124 type 2 diabetes patients. Multiple linear regression analyses indicated that the PAI-1 levels were significantly inversely correlated with estimated glomerular filtration rate (eGFR) independent of albuminuria, BMI, LDL-C, and triglyceride.
Diabetes research and clinical practice 04/2012; 97(1):e9-12. · 2.16 Impact Factor
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Jun Shirakawa,
Kikuko Amo,
Hirokazu Ohminami,
Kazuki Orime,
Yu Togashi,
Yuzuru Ito, Kazuki Tajima,
Megumi Koganei,
Hajime Sasaki,
Eiji Takeda,
Yasuo Terauchi
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ABSTRACT: Chronic exposure to high glucose and fatty acid levels caused by dietary sugar and fat intake induces β cell apoptosis, leading to the exacerbation of type 2 diabetes. Oleic acid and linoleic acid are two major dietary fatty acids, but their effects in diabetes are unclear. We challenged β cell-specific glucokinase haploinsufficient (Gck(+/-)) mice with a diet containing sucrose and oleic acid (SO) or sucrose and linoleic acid (SL) and analyzed β cell apoptosis. In Gck(+/-) but not wild-type mice, SL significantly decreased the β cell mass and β cell proportion in islet cells arising from increased apoptosis to a greater degree than did SO. The mRNA expression of SREBP-1c was significantly higher, and that of E-cadherin was significantly lower in the islets of Gck(+/-) mice fed SL compared with mice fed SO. We next evaluated monotherapy with desfluorositagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in these mouse groups. DPP-4 inhibitor protected against β cell apoptosis, restored the β cell mass, and normalized islet morphology in Gck(+/-) mice fed SL. DPP-4 inhibition normalized the changes in the islet expression of SREBP-1c and E-cadherin mRNA induced by the SL diet. Furthermore, linoleic acid induced β cell apoptosis to a greater degree in the presence of high glucose levels than in the presence of low glucose levels in vitro in islets and MIN6 cells, whereas a GLP-1 receptor agonist prevented apoptosis. In conclusion, SL exacerbated β cell apoptosis in diabetic Gck(+/-) mice but not in euglycemic wild-type mice, and DPP-4 inhibition protected against these effects.
Journal of Biological Chemistry 05/2011; 286(29):25467-76. · 4.77 Impact Factor
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Jun Shirakawa,
Kikuko Amo,
Hirokazu Ohminami,
Kazuki Orime,
Yu Togashi,
Yuzuru Ito, Kazuki Tajima,
Megumi Koganei,
Hajime Sasaki,
Eiji Takeda,
Yasuo Terauchi
[show abstract]
[hide abstract]
ABSTRACT: Chronic exposure to high glucose and fatty acid levels caused by dietary sugar and fat intake induces β cell apoptosis, leading
to the exacerbation of type 2 diabetes. Oleic acid and linoleic acid are two major dietary fatty acids, but their effects
in diabetes are unclear. We challenged β cell-specific glucokinase haploinsufficient (Gck+/-) mice with a diet containing
sucrose and oleic acid (SO) or sucrose and linoleic acid (SL) and analyzed β cell apoptosis. In Gck+/-, but not wild-type,
mice, SL significantly decreased the β cell mass and β cell proportion in islet cells arising from increased apoptosis to
a greater degree than SO. The mRNA expression of SREBP-1c was significantly higher and that of E-cadherin was significantly
lower in the islets of Gck+/- mice fed SL, compared with mice fed SO. We next evaluated monotherapy with des-fluoro-sitagliptin,
a dipeptidyl peptidase-4 (DPP-4) inhibitor, for them. DPP-4 inhibitor protected against β cell apoptosis, restored the β cell
mass, and normalized islet morphology in Gck+/- mice fed SL. DPP-4 inhibition normalized the changes in the islet expression
of SREBP-1c and E-cadherin mRNA induced by the SL diet. Furthermore, linoleic acid induced β cell apoptosis to a greater degree
in the presence of high glucose levels than in the presence of low glucose levels in vitro in islets and MIN6 cells, whereas
a GLP-1 receptor agonist prevented apoptosis. In conclusion, SL exacerbated β cell apoptosis in diabetic Gck+/- mice but not
in euglycemic wild-type mice, and DPP-4 inhibition protected against these effects.
Journal of Biological Chemistry 05/2011; · 4.77 Impact Factor
