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  • 1
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    2150-P: Single Cell RNA-Sequencing Dissects Proliferation of Pancreatic Beta Cells
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Background: The decreasing pancreatic beta cell mass in patients with type 2 diabetes mellitus is a critical problem and increasing the beta cell mass would be one of the strategies for its treatment. However, little is known about the mechanism of beta cell proliferation in adult. In addition, since pancreatic beta cells are heterogeneous and proliferating beta cells are in a small population, the analysis using bulk pancreatic islets has limitations. To clarify the further molecular mechanism of beta cell proliferation, we addressed the gene regulation of proliferating beta cells at single cell level. Methods: Young (8 weeks) and old (1 year) C57BL/6 mice were performed partial pancreatectomy (PPTx), and conducted 3 analyses; 1) immunohistochemistry for proliferating beta cells with BrdU staining, 2) conventional bulk RNA-sequencing (bulk RNA-seq) of isolated pancreatic islets from young or old mice with PPTx or without PPTx (control) to examine the impact of aging and stimulation by resection, 3) single cell RNA-seq to highlight gene expression profiles of proliferating beta cells. Results: In young mice, the proliferation of beta cells was highly induced by PPTx. On the contrary, the proliferation in old PPTx mice was much less than young PPTx. The bulk RNA-seq followed by gene ontology analysis demonstrated that genes related to DNA replication and cell cycle regulation were specifically up-regulated in young PPTx. The scRNA-seq could sort beta cells with Ins1 and Ins2 expression from the other endocrine cells like alpha, delta and PP cells, and identified the cells with high expressions of Pcna and Ccnb1 in the beta cells. By the motif analysis, we further identified candidate transcription factors that activate genes specific for the proliferating cells. Conclusion: We found genes specific for proliferating beta cells and identified candidate regulators to activate the proliferation of beta cells. Disclosure H. Tatsuoka: None. D. Yabe: Advisory Panel; Self; Abbott. Research Support; Self; Astellas Pharma Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. S. Sakamoto: None. A. Watanabe: None. R. Usui: None. S. Tokumoto: None. A. Botagarova: None. D. Ootani: None. H. Goto: None. M. Fauzi: None. M. Ogura: Research Support; Self; Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kyowa Hakko Kirin Co., Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited. N. Inagaki: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Japan Tobacco Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-2150-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 2
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    Macrophage Scavenger Receptor-A–Deficient Mice Are Resistant Against Diabetic Nephropathy Through Amelioration of Microinflammation
    American Diabetes Association ; 2007
    In:  Diabetes Vol. 56, No. 2 ( 2007-02-01), p. 363-372
    Details
    In: Diabetes, American Diabetes Association, Vol. 56, No. 2 ( 2007-02-01), p. 363-372
    Abstract: Microinflammation is a common major mechanism in the pathogenesis of diabetic vascular complications, including diabetic nephropathy. Macrophage scavenger receptor-A (SR-A) is a multifunctional receptor expressed on macrophages. This study aimed to determine the role of SR-A in diabetic nephropathy using SR-A–deficient (SR-A−/−) mice. Diabetes was induced in SR-A−/− and wild-type (SR-A+/+) mice by streptozotocin injection. Diabetic SR-A+/+ mice presented characteristic features of diabetic nephropathy: albuminuria, glomerular hypertrophy, mesangial matrix expansion, and overexpression of transforming growth factor-β at 6 months after induction of diabetes. These changes were markedly diminished in diabetic SR-A−/− mice, without differences in blood glucose and blood pressure levels. Interestingly, macrophage infiltration in the kidneys was dramatically decreased in diabetic SR-A−/− mice compared with diabetic SR-A+/+ mice. DNA microarray revealed that proinflammatory genes were overexpressed in renal cortex of diabetic SR-A+/+ mice and suppressed in diabetic SR-A−/− mice. Moreover, anti–SR-A antibody blocked the attachment of monocytes to type IV collagen substratum but not to endothelial cells. Our results suggest that SR-A promotes macrophage migration into diabetic kidneys by accelerating the attachment to renal extracellular matrices. SR-A may be a key molecule for the inflammatory process in pathogenesis of diabetic nephropathy and a novel therapeutic target for diabetic vascular complications.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db06-0359
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2007
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  • 3
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    Deterioration of HbA1c-Lowering Effects in Dipeptidyl-Peptidase Inhibitor and Dietary Habits in Japanese Type 2 Diabetes—Comparison with That of Metformin
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: Aims: This study was designed to assess the possible relationship between deterioration of HbA1c-lowering effects with dipeptidyl peptidase-4 inhibitor (DPP-4i) or metformin (MET) treatment and macronutrient intake among patients with type 2 diabetes. Methods: Medical records of individuals visiting Kansai Electric Power Hospital during the period between September 20and June 2017 were retrospectively analyzed, based on predefined criteria, for initiation and continuation of DPP-4i or MET without any prescription change as well as HbA1c, bodyweight and macro-nutrient intake. Identified patients were stratified into two groups based on changes in HbA1c from 0.5 to 1 year (δHbA1c [1-0.5 year]) as previously described: Group A, patients whose HbA1c was maintained 1 year after initiation of DPP-4i or MET (δHbA1c [1-0.5 year] & lt;0.4%), and group B, patients whose HbA1c was increased (δHbA1c [1-0.5 year] ≥0.4%). Results: Screening of 65,323 individuals’ medical records identified 63 DPP-4i patients (Groups A and B: n=53 and 10; age 65.2±1.6 and 58.2±4.2 years; BMI 24.6±1.6 and 25.3±1.2 kg/m2) and 35 MET patients (Groups A and B: n=27 and 8; age 52.6±11.7 and 53.9±2.4 years; BMI 30.7±7.4 and 30.2±2.7 kg/m2). In the DPP-4i patients, group B had significantly higher total energy intake and fat intake while the two groups had similar carbohydrate and protein intake. Group B also had significantly higher intake of saturated and monounsaturated fats but not polyunsaturated fats. A stepwise multiple regression analysis showed that δHbA1c (1-0.5 year) was independently correlated with saturated fat intake (B=0.032, SE=0.010, p & lt; 0.01). In the MET patients, the two groups had similar intake of total energy, carbohydrate, protein and fat. Conclusion: The current findings show a novel association between deterioration of the HbA1c-lowering effects in DPP-4i-treated, but not in MET-treated patients, and dietary saturated fat intake. Disclosure S. Okamoto: None. H. Kuwata: None. D. Yabe: Speaker's Bureau; Self; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd.. Research Support; Self; Nippon Boehringer Ingelheim Co. Ltd., Eli Lilly and Company, MSD K.K., Ono Pharmaceutical Co., Ltd., Arkray, Inc., Taisho Toyama Pharmaceutical Co., Ltd., Novo Vordisk Pharma Ltd., Takeda Pharamaceutical Co., Ltd.. K. Murotani: None. Y. Seino: None. R. Usui: None. H. Tatsuoka: None. Y. Hamamoto: None. T. Kurose: Consultant; Self; Sanofi, Ono Pharmaceutical Co., Ltd.. Other Relationship; Self; Abbott. Consultant; Self; Taisho Pharmaceutical Co., Ltd.. Other Relationship; Self; Takeda Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Novartis Pharma K.K. Y. Seino: Speaker's Bureau; Self; MSD K.K., Kao Corporation, Taisho Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Taisho Toyama Pharamceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Nippon Becton Dickinson Co., Ltd., Novo Nordisk Pharma Ltd.. Research Support; Self; Terumo Medical Corporation, Bayer Yakuhin, Ltd., Boehringer Ingelheim GmbH, Arkray, Inc., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Novo Nordisk Pharma Ltd..
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-2306-PUB
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 4
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    Generation and Characterization of a Novel Mouse Model That Allows Spatiotemporal Quantification of Pancreatic β-Cell Proliferation
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. 11 ( 2020-11-01), p. 2340-2351
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. 11 ( 2020-11-01), p. 2340-2351
    Abstract: Pancreatic β-cell proliferation has been gaining much attention as a therapeutic target for the prevention and treatment of diabetes. In order to evaluate potential β-cell mitogens, accurate and reliable methods for the detection and quantification of the β-cell proliferation rate are indispensable. In this study, we developed a novel tool that specifically labels replicating β-cells as mVenus+ cells by using RIP-Cre; R26Fucci2aR mice expressing the fluorescent ubiquitination-based cell cycle indicator Fucci2a in β-cells. In response to β-cell proliferation stimuli, such as insulin receptor antagonist S961 and diet-induced obesity (DIO), the number of 5-ethynyl-2′-deoxyuridine-positive insulin+ cells per insulin+ cells and the number of mVenus+ cells per mCherry+ mVenus− cells + mCherry− mVenus+ cells were similarly increased in these mice. Three-dimensional imaging of optically cleared pancreas tissue from these mice enabled quantification of replicating β-cells in the islets and morphometric analysis of the islets after known mitogenic interventions such as S961, DIO, pregnancy, and partial pancreatectomy. Thus, this novel mouse line is a powerful tool for spatiotemporal analysis and quantification of β-cell proliferation in response to mitogenic stimulation.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-0290
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 5
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    41-OR: Store-Operated Ca2+ Entry Activated by STIM1 Plays an Essential Role in GPR40-Mediated GIIS Potentiation
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Background: Store-operated Ca2+ entry (SOCE) is activated by endoplasmic reticulum (ER) Ca2+ sensor STIM1 which senses depletion of Ca2+ from the ER, and induces extracellular Ca2+ influx through Orai1 to the cytosol to maintain intracellular Ca2+ homeostasis in various cell types, however the role of SOCE in pancreatic β-cells remains largely unknown. GPR40 plays an important role in potentiation of glucose-induced insulin secretion (GIIS) by long-chain fatty acids and its activation enhances Ca2+-release from ER by activating inositol 1,4,5-triphosphate (IP3) receptor. Therefore, we hypothesized that SOCE contributed to GPR40-mediated GIIS potentiation. To test the hypothesis, we examined the role of SOCE modulator, STIM1 in MIN6 cells and β-cell specific STIM1-deficient mice (βSTIM1 cKO). Methods: Fasiglifam(fas) was used for GPR40 agonist. STIM1 or Orai1 knockdowned (KD) MIN6 cells were analyzed for insulin secretion or intracellular Ca2+-dynamics. MIN6 cells were also transfected with pEX-SP-YFP-STIM1(23-685) and Orai1-CFP to analyze intracellular trafficking of STIM1 in response to fas. Insulin secretion from βSTIM1 cKO islets and OGTT was also analyzed to reveal physiological role of STIM1. Results: STIM1 or Orai1 KD MIN6 cells and islets from βSTIM1 cKO similarly abolished fas-mediated potentiation of GIIS and fas-induced elevation of intracellular Ca2+ levels, while there was little effect on GIIS itself. STIM1-YFP was rapidly translocated from the ER to the plasma membrane and merged with Orai1-CFP in response to fas which was cancelled by pretreatment of IP3 receptor antagonist, xestospongin C. In OGTT, blood glucose levels were similar in control mice and βSTIM1 cKO without fas administration, however fas-mediated glucose lowering and insulin increasing effect were significantly lower compared with control. Conclusion: GPR40 signal activates STIM1 and SOCE activated by STIM1 is essential for GPR40-mediated potentiation of GIIS. Disclosure R. Usui: None. D. Yabe: Advisory Panel; Self; Abbott. Research Support; Self; Astellas Pharma Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. M. Fauzi: None. A. Botagarova: None. H. Goto: None. S. Tokumoto: None. H. Tatsuoka: None. Y. Tahara: None. S. Kobayashi: None. T. Manabe: None. Y. Baba: None. T. Kurosaki: None. M. Ogura: Research Support; Self; Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kyowa Hakko Kirin Co., Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited. K. Nagashima: None. N. Inagaki: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Japan Tobacco Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Japan Society for the Promotion of Science; Japan Association for Diabetes Education and Care
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-41-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 6
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    110-OR: Generation of a Novel Mouse Model to Study ß-Cell Proliferation
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Background and Aims: The induction of β-cell proliferation could relieve the progression of diabetes. Many factors have been claimed to be potential β-cell mitogens, but their impacts on β-cell replication have been poorly reproduced and validated due to unstandardized β-cell proliferation assay and lack of alternative methods. In this study, we aimed to generate a novel mouse model that enables more accurate quantification of β-cell proliferation by using a cell cycle monitoring biosensor (Fucci2a). imaging of the pancreas from this mouse model. Next, 3D images of optically cleared pancreas samples were obtained for the analysis of replicating β-cell number and morphometric data per islet following the mitogenic intervention of insulin receptor antagonist (S961). Moreover, in order to examine whether glucose mediates S961-induced β-cell proliferation, we compared the β-cell proliferation rate between the hyperglycemic S961 monotherapy group and the normoglycemic S961 group with coadministration of SGLT2i (S961 + SGLT2i group). vivo Materials and Methods: We established a novel mouse line in which the Fucci2a reporter is specifically expressed in β-cells (RIP-Cre; Fucci2aR). We performed real-time 3D in Results: We succeeded in real-time visualization of cell cycle progression of β-cells. A strong correlation between replicating β-cell number per islet and islet size was found in both S961 (r = 0.87, p & lt;0.01) and vehicle groups (r = 0.77, p & lt;0.01). While hyperglycemia induced by S961 treatment was normalized in the S961 + SGLT2i group, there was no significant difference in β-cell proliferation rate between the S961 monotherapy and S961 + SGLT2i groups. Conclusion: Here we present the first in vivo 4D images of cell cycle phase transition of β-cells. The strong correlation between islet size and its proliferative capacity suggests stochastic replication of β-cells. S961-induced β-cell replication was not mediated by glucose. Thus, this novel mouse could be a powerful tool for β-cell proliferation assessment. Disclosure S. Tokumoto: None. D. Yabe: Advisory Panel; Self; Abbott. Research Support; Self; Astellas Pharma Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. H. Tatsuoka: None. R. Usui: None. M. Fauzi: None. H. Goto: None. M. Ogura: Research Support; Self; Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kyowa Hakko Kirin Co., Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited. N. Inagaki: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Japan Tobacco Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-110-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 7
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    Intercellular Adhesion Molecule-1–Deficient Mice Are Resistant Against Renal Injury After Induction of Diabetes
    American Diabetes Association ; 2003
    In:  Diabetes Vol. 52, No. 10 ( 2003-10-01), p. 2586-2593
    Details
    In: Diabetes, American Diabetes Association, Vol. 52, No. 10 ( 2003-10-01), p. 2586-2593
    Abstract: Diabetic nephropathy is a leading cause of end-stage renal failure. Several mechanisms, including activation of protein kinase C, advanced glycation end products, and overexpression of transforming growth factor (TGF)-β, are believed to be involved in the pathogenesis of diabetic nephropathy. However, the significance of inflammatory processes in the pathogenesis of diabetic microvascular complications is poorly understood. Accumulation of macrophages and overexpression of leukocyte adhesion molecules and chemokines are prominent in diabetic human kidney tissues. We previously demonstrated that intercellular adhesion molecule (ICAM)-1 mediates macrophage infiltration into the diabetic kidney. In the present study, to investigate the role of ICAM-1 in diabetic nephropathy, we induced diabetes in ICAM-1–deficient (ICAM-1−/−) mice and ICAM-1+/+ mice with streptozotocin and examined the renal pathology over a period of 6 months. The infiltration of macrophages was markedly suppressed in diabetic ICAM-1−/− mice compared with that of ICAM-1+/+ mice. Urinary albumin excretion, glomerular hypertrophy, and mesangial matrix expansion were significantly lower in diabetic ICAM-1−/− mice than in diabetic ICAM-1+/+ mice. Moreover, expressions of TGF-β and type IV collagen in glomeruli were also suppressed in diabetic ICAM-1−/− mice. These results suggest that ICAM-1 is critically involved in the pathogenesis of diabetic nephropathy.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.52.10.2586
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2003
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  • 8
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    P-Selectin Glycoprotein Ligand-1 Deficiency Is Protective Against Obesity-Related Insulin Resistance
    American Diabetes Association ; 2011
    In:  Diabetes Vol. 60, No. 1 ( 2011-01-01), p. 189-199
    Details
    In: Diabetes, American Diabetes Association, Vol. 60, No. 1 ( 2011-01-01), p. 189-199
    Abstract: An inflammatory process is involved in the mechanism of obesity-related insulin resistance. Recent studies indicate that monocyte chemoattractant protein-1 (MCP-1) is a major chemokine that promotes monocyte infiltration into adipose tissues; however, the adhesion pathway in adipose tissues remains unclear. We aimed to clarify the adhesion molecules that mediate monocyte infiltration into adipose tissue. RESEARCH DESIGN AND METHODS We used a DNA microarray to compare the gene expression profiles in epididymal white adipose tissues (eWAT) between db/db mice and C57/BL6 mice each fed a high-fat diet (HFD) or a low-fat diet (LFD). We investigated the change of insulin resistance and inflammation in eWAT in P-selectin glycoprotein ligand-1 (PSGL-1) homozygous knockout (PSGL-1−/−) mice compared with wild-type (WT) mice fed HFD. RESULTS DNA microarray analysis revealed that PSGL-1, a major ligand for selectins, is upregulated in eWAT from both db/db mice and WT mice fed HFD. Quantitative real-time RT-PCR and immunohistochemistry showed that PSGL-1 is expressed on both endothelial cells and macrophages in eWAT of obese mice. PSGL-1−/− mice fed HFD showed a remarkable reduction of macrophage accumulation and expression of proinflammatory genes, including MCP-1 in eWAT. Moreover, adipocyte hypertrophy, insulin resistance, lipid metabolism, and hepatic fatty change were improved in PSGL-1−/− mice compared with WT mice fed HFD. CONCLUSIONS These results indicate that PSGL-1 is a crucial adhesion molecule for the recruitment of monocytes into adipose tissues in obese mice, making it a candidate for a novel therapeutic target for the prevention of obesity-related insulin resistance.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db09-1894
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2011
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  • 9
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    Cholecystokinin Plays a Novel Protective Role in Diabetic Kidney Through Anti-inflammatory Actions on Macrophage
    American Diabetes Association ; 2012
    In:  Diabetes Vol. 61, No. 4 ( 2012-04-01), p. 897-907
    Details
    In: Diabetes, American Diabetes Association, Vol. 61, No. 4 ( 2012-04-01), p. 897-907
    Abstract: Inflammatory process is involved in the pathogenesis of diabetic nephropathy. In this article, we show that cholecystokinin (CCK) is expressed in the kidney and exerts renoprotective effects through its anti-inflammatory actions. DNA microarray showed that CCK was upregulated in the kidney of diabetic wild-type (WT) mice but not in diabetic intracellular adhesion molecule-1 knockout mice. We induced diabetes in CCK-1 receptor (CCK-1R) and CCK-2R double-knockout (CCK-1R−/−,-2R−/−) mice, and furthermore, we performed a bone marrow transplantation study using CCK-1R−/− mice to determine the role of CCK-1R on macrophages in the diabetic kidney. Diabetic CCK-1R−/−,-2R−/− mice revealed enhanced albuminuria and inflammation in the kidney compared with diabetic WT mice. In addition, diabetic WT mice with CCK-1R−/− bone marrow–derived cells developed more albuminuria than diabetic CCK-1R−/− mice with WT bone marrow–derived cells. Administration of sulfated cholecystokinin octapeptide (CCK-8S) ameliorated albuminuria, podocyte loss, expression of proinflammatory genes, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, CCK-8S inhibited both expression of tumor necrosis factor-α and chemotaxis in cultured THP-1 cells. These results suggest that CCK suppresses the activation of macrophage and expression of proinflammatory genes in diabetic kidney. Our findings may provide a novel strategy of therapy for the early stage of diabetic nephropathy.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db11-0402
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2012
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