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Dpp fibrosis

Mark M Smits, Lennart Tonneijck, Marcel H A Muskiet, Mark H H Kramer, Petra J W Pouwels, Indra C Pieters-van den Bos, Trynke Hoekstra, Michaela Diamant, Daniël H van Raalte, Djuna L Cahen
AIMS/HYPOTHESIS: Glucagon-like peptide (GLP)-1-based therapies have been suggested to improve hepatic steatosis. We assessed the effects of the GLP-1 receptor agonist liraglutide and the dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin on hepatic steatosis and fibrosis in patients with type 2 diabetes. METHODS: In this 12 week, parallel, randomised, placebo-controlled trial, performed at the VU University Medical Center between July 2013 and August 2015, 52 overweight patients with type 2 diabetes treated with metformin and/or sulphonylurea agent ([mean ± SD] age 62...
September 15, 2016: Diabetologia
Satoru Takashima, Hiroki Fujita, Hiromi Fujishima, Tatsunori Shimizu, Takehiro Sato, Tsukasa Morii, Katsushi Tsukiyama, Takuma Narita, Takamune Takahashi, Daniel J Drucker, Yutaka Seino, Yuichiro Yamada
The role of stromal cell-derived factor-1 (SDF-1) in the pathogenesis of diabetic nephropathy and its modification by dipeptidyl peptidase-4 (DPP-4) inhibition are uncertain. Therefore, we studied this independent of glucagon-like peptide-1 receptor (GLP-1R) signaling using two Akita diabetic mouse models, the diabetic-resistant C57BL/6-Akita and diabetic-prone KK/Ta-Akita. Increased SDF-1 expression was found in glomerular podocytes and distal nephrons in the diabetic-prone mice, but not in kidneys from diabetic-resistant mice...
October 2016: Kidney International
Teruo Jojima, Takanori Tomotsune, Toshie Iijima, Kazumi Akimoto, Kunihiro Suzuki, Yoshimasa Aso
BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are new oral antidiabetic drugs that reduce hyperglycemia by promoting urinary glucose excretion. Glycosuria produced by SGLT2 inhibitors is associated with weight loss, mainly due to reduced fat volume. We investigated the effects of empagliflozin (selective SGLT2 inhibitor) and linagliptin (DPP-4 inhibitor) on steatohepatitis and fibrosis in a mouse model of non-alcoholic steatohepatitis (NASH) with diabetes. METHODS: A novel NASH model was generated by administration of streptozotocin to C57BL/6J mice at 2 days old, with a high-fat diet from 4 weeks...
2016: Diabetology & Metabolic Syndrome
Xiaoling Pang, Akio Shimizu, Souichi Kurita, Dimitar P Zankov, Keisuke Takeuchi, Mako Yasuda-Yamahara, Shinji Kume, Tetsuo Ishida, Hisakazu Ogita
Dipeptidyl peptidase III (DPP III) cleaves dipeptide residues from the N terminus of polypeptides ranging from 3 to 10 amino acids in length and is implicated in pathophysiological processes through the breakdown of certain oligopeptides or their fragments. In this study, we newly identified the biochemical properties of DPP III for angiotensin II (Ang II), which consists of 8 amino acids. DPP III quickly and effectively digested Ang II with Km = 3.7×10(-6) mol/L. In the in vivo experiments, DPP III remarkably reduced blood pressure in Ang II-infused hypertensive mice without alteration of heart rate...
September 2016: Hypertension
Swayam Prakash Srivastava, Sen Shi, Megumi Kanasaki, Takako Nagai, Munehiro Kitada, Jianhua He, Yuka Nakamura, Yasuhito Ishigaki, Keizo Kanasaki, Daisuke Koya
N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous antifibrotic peptide. We found that suppression of AcSDKP and induction of dipeptidyl peptidase-4 (DPP-4), which is associated with insufficient levels of antifibrotic microRNA (miR)s in kidneys, were imperative to understand the mechanisms of fibrosis in the diabetic kidneys. Analyzing streptozotocin (STZ)-induced diabetic mouse strains, diabetic CD-1 mice with fibrotic kidneys could be differentiated from less-fibrotic diabetic 129Sv mice by suppressing AcSDKP and antifibrotic miRs (miR-29s and miR-let-7s), as well as by the prominent induction of DPP-4 protein expression/activity and endothelial to mesenchymal transition...
2016: Scientific Reports
Camila Manrique, Javad Habibi, Annayya R Aroor, James R Sowers, Guanghong Jia, Melvin R Hayden, Mona Garro, Luis A Martinez-Lemus, Francisco I Ramirez-Perez, Thomas Klein, Gerald A Meininger, Vincent G DeMarco
BACKGROUND: Vascular stiffening, a risk factor for cardiovascular disease, is accelerated, particularly in women with obesity and type 2 diabetes. Preclinical evidence suggests that dipeptidylpeptidase-4 (DPP-4) inhibitors may have cardiovascular benefits independent of glycemic lowering effects. Recent studies show that consumption of a western diet (WD) high in fat and simple sugars induces aortic stiffening in female C57BL/6J mice in advance of increasing blood pressure. The aims of this study were to determine whether administration of the DPP-4 inhibitor, linagliptin (LGT), prevents the development of aortic and endothelial stiffness induced by a WD in female mice...
2016: Cardiovascular Diabetology
Lin-Lin Kang, Dong-Mei Zhang, Chun-Hua Ma, Jian-Hua Zhang, Ke-Ke Jia, Jia-Hui Liu, Rong Wang, Ling-Dong Kong
Fructose consumption induces metabolic syndrome to increase cardiovascular disease risk. Cinnamaldehyde and allopurinol possess anti-oxidative and anti-inflammatory activity to relieve heart injury in metabolic syndrome. But the mechanisms of fructose-induced cardiac injury, and cardioprotective effects of cinnamaldehyde and allopurinol are not completely understood. In this study, fructose-fed rats displayed metabolic syndrome with elevated serum ox-LDL, cardiac oxidative stress, inflammation and fibrosis...
2016: Scientific Reports
Jeffrey Cui, Len Philo, Phirum Nguyen, Heather Hofflich, Carolyn Hernandez, Ricki Bettencourt, Lisa Richards, Joanie Salotti, Archana Bhatt, Jonathan Hooker, William Haufe, Catherine Hooker, David A Brenner, Claude B Sirlin, Rohit Loomba
BACKGROUND & AIMS: Uncontrolled studies show sitagliptin, an oral DPP-4 inhibitor, may improve alanine aminotransferase and liver histology in non-alcoholic fatty liver disease (NAFLD) patients. We aimed to compare sitagliptin vs. the efficacy of a placebo in reducing liver fat measured by MRI-derived proton density-fat fraction (MRI-PDFF). METHODS: This randomized, double-blind, allocation-concealed, placebo-controlled trial included 50 NAFLD patients with prediabetes or early diabetes randomized to sitagliptin orally 100mg/day or placebo for 24weeks...
August 2016: Journal of Hepatology
Noriyuki Hayami, Akiko Sekiguchi, Yu-Ki Iwasaki, Yuji Murakawa, Takeshi Yamashita
Chronic inflammation is known to occur in diabetes mellitus (DM) and contributes to atrial fibrosis, possible substrates for atrial fibrillation. We tested the hypothesis that dipeptidyl peptidase (DPP)-4 inhibitors prevent the formation of atrial fibrosis through their anti-inflammatory activity, beyond the effects of controlling blood glucose.DM models obtained by administration of streptozotocin (STZ) were divided into 3 groups: with PKF275-055, a DPP-4 inhibitor in group D, glibenclamide in group SU, and no additional drug in group P...
May 25, 2016: International Heart Journal
Gwon Soo Jung, Jae Han Jeon, Mi Sun Choe, Sung Woo Kim, In Kyu Lee, Mi Kyung Kim, Keun Gyu Park
BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in the treatment of patients with type 2 diabetes and have proven protective effects on diabetic kidney disease (DKD). Whether DPP-4 inhibitors have renoprotective effects on insulin-deficient type 1 diabetes has not been comprehensively examined. The aim of this study was to determine whether gemigliptin, a new DPP-4 inhibitor, has renoprotective effects in streptozotocin (STZ)-induced type 1 diabetic mice. METHODS: Diabetes was induced by intraperitoneal administration of a single dose of STZ...
June 2016: Diabetes & Metabolism Journal
Oleg Tsuprykov, Ryotaro Ando, Christoph Reichetzeder, Karoline von Websky, Viktoriia Antonenko, Yuliya Sharkovska, Lyubov Chaykovska, Jan Rahnenführer, Ahmed A Hasan, Harald Tammen, Markus Alter, Thomas Klein, Seiji Ueda, Sho-Ichi Yamagishi, Seiya Okuda, Berthold Hocher
Dipeptidyl peptidase (DPP)-4 inhibitors delay chronic kidney disease (CKD) progression in experimental diabetic nephropathy in a glucose-independent manner. Here we compared the effects of the DPP-4 inhibitor linagliptin versus telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. Animals were allocated to 1 of 4 groups: sham operated plus placebo; 5/6 nephrectomy plus placebo; 5/6 nephrectomy plus linagliptin; and 5/6 nephrectomy plus telmisartan. Interstitial fibrosis was significantly decreased by 48% with linagliptin but a non-significant 24% with telmisartan versus placebo...
May 2016: Kidney International
Masako Uchii, Naoya Kimoto, Mariko Sakai, Tetsuya Kitayama, Shunji Kunori
Although previous studies have shown an important role of renal dipeptidyl peptidase-4 (DPP-4) inhibition in ameliorating kidney injury in hypertensive rats, the renal distribution of DPP-4 and mechanisms of renoprotective action of DPP-4 inhibition remain unclear. In this study, we examined the effects of the DPP-4 inhibitor saxagliptin on DPP-4 activity in renal cells (using in situ DPP-4 staining) and on renal gene expression related to inflammation and fibrosis in the renal injury in hypertensive Dahl salt-sensitive (Dahl-S) rats...
July 15, 2016: European Journal of Pharmacology
Nattayaporn Apaijai, Tharnwimol Inthachai, Suree Lekawanvijit, Siriporn C Chattipakorn, Nipon Chattipakorn
Adverse cardiac remodeling after myocardial infarction (MI) leads to progressive heart failure. Obese-insulin resistance increases risks of MI and heart failure. Although dipeptidyl peptidase-4 (DPP4) inhibitor is known to exert cardioprotection, its effects on adverse remodeling after MI in obese-insulin-resistant rats are unclear. We hypothesized that DPP4 inhibitor reduces adverse left ventricular (LV) remodeling and LV dysfunction in obese-insulin-resistant rats with MI. Rats were fed either normal diet (ND) or high-fat diet (HFD) for 12 weeks to induce obese-insulin resistance, followed by left anterior descending coronary artery ligation to induce MI...
June 2016: Journal of Endocrinology
Ju-Young Moon, Jong Shin Woo, Jung-Woo Seo, Arah Lee, Dong Jin Kim, Yang-Gyun Kim, Se-Yeun Kim, Kyung Hye Lee, Sung-Jig Lim, Xian Wu Cheng, Sang-Ho Lee, Weon Kim
OBJECTIVE: Although dipeptidyl peptidase-4 (DPP-4) inhibitors have been suggested to have a non-glucoregulatory protective effect in various tissues, the effects of long-term inhibition of DPP-4 on the micro- and macro-vascular complications of type 2 diabetes remain uncertain. The aim of the present study was to investigate the organ-specific protective effects of DPP-4 inhibitor in rodent model of type 2 diabetes. METHODS: Eight-week-old diabetic and obese db/db mice and controls (db/m mice) received vehicle or one of two doses of gemigliptin (0...
2016: PloS One
Sen Shi, Daisuke Koya, Keizo Kanasaki
Diabetic nephropathy (DN) is the most common cause of end-stage kidney disease worldwide and is associated with increased morbidity and mortality in patients with both type 1 and type 2 diabetes. Recent evidence revealed that dipeptidyl peptidase-4 (DPP-4) inhibitors may exhibit a protective effect against DN. In fact, the kidney is the organ where the DPP-4 activity is the highest level per organ weight. A preclinical analysis revealed that DPP-4 inhibitors also ameliorated kidney fibrosis. In this review, we analyzed recent reports in this field and explore the renoprotective effects and possible mechanism of the DPP-4 inhibitors...
2016: Fibrogenesis & Tissue Repair
Sen Shi, Keizo Kanasaki, Daisuke Koya
Dipeptidyl peptidase (DPP)-4 plays an important role in endothelial cell biology. We have shown that the DPP-4 inhibitor Linagliptin can inhibit the endothelial-mesenchymal transition (EndMT) and ameliorate diabetic kidney fibrosis associated with the suppression of DPP-4 protein levels via the induction of miR-29. The current study demonstrated that such effects of Linagliptin on endothelial cell profibrotic programs were drug-specific but not class effects. In the cell-free system, both Linagliptin and Sitagliptin inhibited recombinant DPP-4 activity in a concentration-dependent manner...
February 26, 2016: Biochemical and Biophysical Research Communications
Yuki Tanaka, Shinji Kume, Masami Chin-Kanasaki, Hisazumi Araki, Shin-ichi Araki, Satoshi Ugi, Takeshi Sugaya, Takashi Uzu, Hiroshi Maegawa
Dipeptidyl peptidase (DPP)-4 inhibitors, a new class of antidiabetic agent, have recently been suggested to exert pleiotropic effects beyond glucose lowering. Renal prognosis in patients with diabetic nephropathy depends on the severity of tubulointerstitial injury induced by massive proteinuria. We thus examined the renoprotective effect of DPP-4 inhibitors on inflammation in cultured mouse proximal tubular cells stimulated with free fatty acid (FFA)-bound albumin. Linagliptin and higher concentrations of sitagliptin, vildagliptin, and alogliptin all inhibited FFA-bound albumin-induced increases in mRNA expression of MCP-1 in cultured mouse proximal tubular cells...
February 12, 2016: Biochemical and Biophysical Research Communications
Chiung-Huei Peng, Charng-Cherng Chyau, Chau-Jong Wang, Huei-Ting Lin, Chien-Ning Huang, Yaw-Bee Ker
Although Abelmoschus esculentus (AE) is known for anti-hyperglycemia, few reports have addressed its target. Our recent studies have focused on diabetic renal epithelial to mesenchymal transition (EMT), which plays a critical role in fibrosis that accompanies increasing vimentin and suggested signals DPP-4/AT-1/TGF-β1. This study aimed to investigate whether AE is useful for preventing diabetic renal EMT. We used a succession of extractions and obtained the corresponding fractions F1-F5, each with its own individual properties: F1 inhibits high glucose-stimulated vimentin, AT-1, TGF-β1, and DPP-4, and recovers E-cadherin in tubular cells; F2 decreases high glucose-induced vimentin, AT-1 and DPP-4; F3-F5 do not reduce the expression of vimentin...
February 2016: Food & Function
Md Ashraful Alam, Mohammed Riaz Hasan Chowdhury, Preeti Jain, Md Abu Taher Sagor, Hasan Mahmud Reza
BACKGROUND: Hyperglycemia and insulin resistance often develop cardiovascular and nephrological dysfunction in diabetic patients. Sitagliptin is used to treat diabetes and showed potential benefit in lowering increased blood glucose level in diabetes. This investigation reports the effect of sitagliptin treatment on oxidative stress in kidney and heart of 2K1C rats. METHODS: Male Long Evans rats underwent unilateral surgical stenosis of the renal artery [2-kidney-1-clip (2K1C) method]...
2015: Diabetology & Metabolic Syndrome
Kyoko Kohashi, Munenori Hiromura, Yusaku Mori, Michishige Terasaki, Takuya Watanabe, Hideki Kushima, Kyoko Shinmura, Masako Tomoyasu, Masaharu Nagashima, Tsutomu Hirano
AIM: The main pathophysiology of abdominal aortic aneurysm (AAA) considerably overlaps with that of atherosclerosis. We reported that incretins [glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP)] or a dipeptidyl peptidase-4 inhibitor (DPP-4I) suppressed atherosclerosis in apolipoprotein E-null (Apoe-/-) mice. Here we investigated the effects of incretin-related agents on AAA in a mouse model. METHODS: Apoe-/- mice maintained on an atherogenic diet were subcutaneously infused with saline, Ang II (2000 ng/kg/min), Ang II, and native GLP-1 (2...
2016: Journal of Atherosclerosis and Thrombosis
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