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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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Kaori Kikuchi,
Uru Nezu,
Koji Inazumi,
Takashi Miyazaki,
Kanako Ono,
Kazuki Orime, Jun Shirakawa,
Koichiro Sato,
Hirofumi Koike,
Tadashi Wakasugi,
Misako Sato,
Chihiro Kawakami,
Shinichiro Watanabe,
Tadashi Yamakawa,
Yasuo Terauchi
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ABSTRACT: Aim: Ezetimibe selectively blocks intestinal cholesterol absorption by inhibiting Niemann-Pick C1-like 1 (NPC1L1) and reducing LDL cholesterol (LDL-C). In animals, ezetimibe reversed diet-induced obesity, liver steatosis, and insulin resistance. In humans, its potential effects on liver steatosis and insulin resistance have been suggested. We investigated the effects of ezetimibe on postprandial hyperlipidaemia and hyperglycaemia in obese subjects with dyslipidaemia in a double-blind randomized crossover trial.Methods: Twenty obese men with hypertriglyceridaemia were assigned randomly to an ezetimibe- or a placebo-precedence-treated group. Subjects in the ezetimibe group were treated with ezetimibe (10 mg/day) for the first 4 weeks, followed by a 4-week interval and then treated with placebo for another 4 weeks. The placebo group received these treatments in reverse order. Subjects were requested to fast for at least 12 hours and then received a standard meal. Blood samples were collected at 0, 30, 60, 120, 240, 360 and 480 minutes after the meal on Days 0, 28, 56 and 84 and were used to measure the lipid and glucose metabolism markers.Results: Ezetimibe significantly decreased the postprandial serum triglyceride excursion (p=0.01) and fasting serum LDL-C, remnant-like particles(RLP) and ApoB48 levels (p<0.05). Postprandial glucose excursion, serum insulin levels, serum glucose-dependent insulinotropic polypeptide (GIP) and active glucagon-like peptide-1 (GLP-1) were not significantly affected by ezetimibe treatment.Conclusion: Ezetimibe restored the postprandial dysregulation of lipid but did not affect glucose metabolism in a double-blind randomized crossover trial.
Journal of atherosclerosis and thrombosis 08/2012; · 2.69 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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Nippon rinsho. Japanese journal of clinical medicine 05/2012; 70 Suppl 3:721-7.
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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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ABSTRACT: Type 2 diabetes is characterized by diminished pancreatic β-cell mass and function. Glucagon-like peptide-1 has been reported to increase islet cell proliferation and reduce apoptosis of β-cells in rodents. In this study, we explored the effect of chronic administration of the dipeptidyl peptidase-4 inhibitor vildagliptin on glucose tolerance, β-cell function, and β-cell mass in Irs2-knockout (Irs2(-/-)) mice. Wild-type and Irs2(-/-) mice were fed a high-fat diet for 20 wk, with or without vildagliptin. In both genotypes of mice, vildagliptin significantly decreased the area under the curve (0-120 min) of blood glucose and increased the insulin response to glucose during the oral glucose tolerance test. In the oral glucose tolerance test performed 1 d after discontinuation of vildagliptin administration, the area under the curve (0-120 min) of blood glucose was still significantly decreased and the insulin response to glucose was significantly increased in the Irs2(-/-) mice treated with vildagliptin as compared with the values in the mice not treated with vildagliptin. Histochemical analysis of the pancreatic islets revealed significant increase of the β-cell mass and decrease in the proportion of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive β-cells but no significant increase of the bromodeoxyuridine incorporation in Irs2(-/-) mice treated with vildagliptin. Our results suggest that vildagliptin improved glucose tolerance and increased the β-cell mass by reducing β-cell apoptosis in the Irs2(-/-) mice, and that the reduction of β-cell apoptosis by vildagliptin was independent of the Irs2 expression in the cells.
Endocrinology 03/2012; 153(3):1093-102. · 4.46 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
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Jun Shirakawa,
Hideki Fujii,
Kei Ohnuma,
Koichiro Sato,
Yuzuru Ito,
Mitsuyo Kaji,
Eri Sakamoto,
Megumi Koganei,
Hajime Sasaki,
Yoji Nagashima,
Kikuko Amo,
Kazutaka Aoki,
Chikao Morimoto,
Eiji Takeda,
Yasuo Terauchi
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ABSTRACT: Diet composition alters the metabolic states of adipocytes and hepatocytes in diabetes. The effects of dipeptidyl peptidase-4 (DPP-4) inhibition on adipose tissue inflammation and fatty liver have been obscure. We investigated the extrapancreatic effects of DPP-4 inhibition on visceral fat and the liver.
We investigated diet-induced metabolic changes in β-cell-specific glucokinase haploinsufficient (Gck(+/-)) diabetic mice. We challenged animals with a diet containing a combination of sucrose and oleic acid (SO) or sucrose and linoleic acid (SL). Next, we assessed the effects of a DPP-4 inhibitor, des-fluoro-sitagliptin, on adipose tissue inflammation and hepatic steatosis.
The epididymal fat weight and serum leptin level were significantly higher in Gck(+/-) mice fed SL than in mice fed SO, although no significant differences in body weight or adipocyte size were noted. Compared with SO, SL increased the numbers of CD11c(+) M1 macrophages and CD8(+) T-cells in visceral adipose tissue and the expression of E-selectin, P-selectin, and plasminogen activator inhibitor-1 (PAI-1). DPP-4 inhibition significantly prevented adipose tissue infiltration by CD8(+) T-cells and M1 macrophages and decreased the expression of PAI-1. The production of cytokines by activated T-cells was not affected by DPP-4 inhibition. Furthermore, DPP-4 inhibition prevented fatty liver in both wild-type and Gck(+/-) mice. DPP-4 inhibition also decreased the expressions of sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase-1, and fatty acid synthase, and increased the expression of peroxisome proliferator-activated receptor-α in the liver.
Our findings indicated that DPP-4 inhibition has extrapancreatic protective effects against diet-induced adipose tissue inflammation and hepatic steatosis.
Diabetes 02/2011; 60(4):1246-57. · 8.29 Impact Factor
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ABSTRACT: Studies from overseas have indicated that postprandial glucose excursions are predominant in subjects with moderate hyperglycemia, while fasting hyperglycemia become the predominant abnormality with worsening of hyperglycemia; however, few studies have yet investigated the correlation between HbA1c and fasting and/or postprandial hyperglycemia in Japanese subjects. We investigated the correlation between fasting and postprandial hyperglycemia and the overall diabetic status, as assessed by measurement of HbA1c, in Japanese patients with type 2 diabetes. Blood glucose (BG) concentrations were determined in the fasting state (8:00 A.M.), during the postprandial phases (at 10:30 A.M., 2:30 P.M. and 8:30 P.M.) and during the postabsorptive periods (at 11:30 A.M. and 17:30 P.M.) in 66 patients with type 2 diabetes who were not being treated with prandial/premixed insulins or alpha-glucosidase inhibitors. The areas under the curve above the fasting BG concentrations (AUC1) and over 110 mg/dl (AUC2) were calculated for further evaluation of the correlations of the postprandial (AUC1) and fasting (AUC2 - AUC1) BG increments to the overall diurnal hyperglycemic status. Subjects were separated into two groups using the HbA1c cutoff value of 8%. The fasting BG was not correlated with the HbA1c in the group with a HbA1c values of less than 8% (r = 0.125, p = 0.473). On the other hand, fasting hyperglycemia was strongly correlated with the HbA1c level in the group with HbA1c values of over 8.0% (r = 0.406, p = 0.023). Furthermore, postprandial hyperglycemia was strongly correlated with the HbA1c in the group with HbA1c levels less than 8.0% (r = 0.524, p = 0.001). Thus, there existed a progressive shift in the contribution of fasting and postprandial hyperglycemia to the overall hyperglycemic status with progression from moderate to severe diabetes mellitus in Japanese type 2 diabetic patients.
Endocrine Journal 01/2010; 57(3):259-66. · 2.03 Impact Factor
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ABSTRACT: A 53-year-old man was hospitalized with general fatigue, headache, dizziness and polyuria. The laboratory findings revealed anterior hypopituitarism and central diabetes insipidus. He also showed eye movement disorder and facial sensory impairment. These symptoms were treated successfully with conservative medical treatment. Concurrently, abnormal pituitary MR imaging findings were revealed. Pituitary abscess was primarily suspected on MR imaging findings, although it was difficult to differentiate pituitary apoplexy by MR imaging findings, alone. In this report, we propose a new diagnostic approach of pituitary abscess, using a combination of CT, MR imaging and clinical manifestations, without either pituitary surgery or pituitary biopsy.
Internal Medicine 02/2009; 48(6):441-6. · 0.94 Impact Factor
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Kazutaka Aoki,
Yuzuru Ito,
Kaori Saito, Jun Shirakawa,
Yu Togashi,
Kouichiro Satoh,
Tomonori Muraoka,
Kazuaki Shinoda,
Kiyomi Masuda,
Mari Kimura,
Yasuo Terauchi
Diabetes research and clinical practice 01/2009; 83(2):e31-2. · 2.16 Impact Factor
