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A novel strategy for production of liraglutide precursor peptide and development of a new long-acting incretin mimic. PLoS One 2022; 17:e0266833. [PMID: 35500009 PMCID: PMC9060347 DOI: 10.1371/journal.pone.0266833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 03/29/2022] [Indexed: 11/27/2022] Open
Abstract
Nowadays, a small number of incretin mimics are used to treat type 2 diabetes mellitus (T2DM) due to their longer half-life. The present study aimed to introduce a novel method for producing the liraglutide precursor peptide (LPP) and developing a potentially new incretin mimic. Here, human αB-crystallin (αB-Cry) was ligated to the LPP at the gene level, and the gene construct was expressed in Escherichia coli with a relatively good efficiency. The hybrid protein (αB-lir) was then purified by a precipitation method followed by anion exchange chromatography. After that, the peptide was released from the carrier protein by a chemical cleavage method yielding about 70%. The LPP was then purified by gel filtration chromatography, and HPLC estimated its purity to be about 98%. Also, the molecular mass of the purified peptide was finally confirmed by mass spectroscopy analysis. Assessment of the secondary structures suggested a dominant α-helical structure for the LPP and a β-sheet rich structure for the hybrid protein. The subcutaneous injection of the LPP and the αB-lir hybrid protein significantly reduced the blood sugar levels in healthy and diabetic mice and stimulated insulin secretion. Also, the hybrid protein exerts its bioactivities more effectively than the LPP over a relatively longer period of time. The results of this study suggested a novel method for the easy and cost-effective production of the LPP and introduced a new long-acting incretin mimic that can be potentially used for the treatment of T2DM patients.
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Ji J, Petropavlovskaia M, Khatchadourian A, Patapas J, Makhlin J, Rosenberg L, Maysinger D. Type 2 diabetes is associated with suppression of autophagy and lipid accumulation in β-cells. J Cell Mol Med 2019; 23:2890-2900. [PMID: 30710421 PMCID: PMC6433726 DOI: 10.1111/jcmm.14172] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 12/14/2018] [Accepted: 12/29/2018] [Indexed: 01/05/2023] Open
Abstract
Both type 2 diabetes (T2D) and obesity are characterized by excessive hyperlipidaemia and subsequent lipid droplet (LD) accumulation in adipose tissue. To investigate whether LDs also accumulate in β-cells of T2D patients, we assessed the expression of PLIN2, a LD-associated protein, in non-diabetic (ND) and T2D pancreata. We observed an up-regulation of PLIN2 mRNA and protein in β-cells of T2D patients, along with significant changes in the expression of lipid metabolism, apoptosis and oxidative stress genes. The increased LD buildup in T2D β-cells was accompanied by inhibition of nuclear translocation of TFEB, a master regulator of autophagy and by down-regulation of lysosomal biomarker LAMP2. To investigate whether LD accumulation and autophagy were influenced by diabetic conditions, we used rat INS-1 cells to model the effects of hyperglycaemia and hyperlipidaemia on autophagy and metabolic gene expression. Consistent with human tissue, both LD formation and PLIN2 expression were enhanced in INS-1 cells under hyperglycaemia, whereas TFEB activation and autophagy gene expression were significantly reduced. Collectively, these results suggest that lipid clearance and overall homeostasis is markedly disrupted in β-cells under hyperglycaemic conditions and interventions ameliorating lipid clearance could be beneficial in reducing functional impairments in islets caused by glucolipotoxicity.
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Affiliation(s)
- Jeff Ji
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada
| | | | - Armen Khatchadourian
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada
| | - Jason Patapas
- Department of Surgery, McGill University, Montreal, QC, Canada
| | - Julia Makhlin
- Department of Surgery, McGill University, Montreal, QC, Canada
| | | | - Dusica Maysinger
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada
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Elekofehinti OO, Ariyo EO, Akinjiyan MO, Olayeriju OS, Lawal AO, Adanlawo IG, Rocha JBT. Potential use of bitter melon (Momordica charantia) derived compounds as antidiabetics: In silico and in vivo studies. ACTA ACUST UNITED AC 2018; 25:327-333. [PMID: 29764719 DOI: 10.1016/j.pathophys.2018.05.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 05/09/2018] [Accepted: 05/10/2018] [Indexed: 02/06/2023]
Abstract
Momordica charantia (bitter lemon) belongs to the cucurbitaceae family which has been extensively used in traditional medicines for the cure of various ailments such as cancer and diabetes. The underlying mechanism of M. charantia to maintain glycemic control was investigated. GLP-1 and DPP-4 gene modulation by M. charantia (5-20% inclusion in rats diet) was investigated in vivo by RT-PCR and possible compounds responsible for diabetic action predicted through in silico approach. Phytochemicalss previously characterized from M. charantia were docked into glucacon like peptide-1 receptor (GLP-1r), dipeptidyl peptidase (DPP4) and Takeda-G-protein-receptor-5 (TGR5) predicted using Autodock Vina. The results of the in silico suggests momordicosides D (ligand for TGR5), cucurbitacin (ligand for GLP-1r) and charantin (ligand for DPP-4) as the major antidiabetic compounds in bitter lemon leaf. M. charantia increased the expression of GLP-1 by about 295.7% with concomitant decreased in expression of DPP-4 by 87.2% with 20% inclusion in rat's diet. This study suggests that the mechanism underlying the action of these compounds is through activation of TGR5 and GLP-1 receptor with concurrent inhibition of DPP4. This study confirmed the use of this plant in diabetes management and the possible bioactive compounds responsible for its antidiabetic property are charantin, cucurbitacin and momordicoside D and all belong to the class of saponins.
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Affiliation(s)
- Olusola Olalekan Elekofehinti
- Bioinformatics and Molecular Biology Units, Department of Biochemistry, Federal University of Technology, Akure, Nigeria.
| | - Esther Opeyemi Ariyo
- Bioinformatics and Molecular Biology Units, Department of Biochemistry, Federal University of Technology, Akure, Nigeria
| | - Moses Orimoloye Akinjiyan
- Bioinformatics and Molecular Biology Units, Department of Biochemistry, Federal University of Technology, Akure, Nigeria
| | - Olanrewaju Sam Olayeriju
- Bioinformatics and Molecular Biology Units, Department of Biochemistry, Federal University of Technology, Akure, Nigeria
| | - Akeem Olalekan Lawal
- Bioinformatics and Molecular Biology Units, Department of Biochemistry, Federal University of Technology, Akure, Nigeria
| | | | - Joao Batista Teixeira Rocha
- Bioquimica Toxicologia, Departmento de Quimica, CCNE, Universidade Federal de Santa Maria, RS, 97105-900 Brazil
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Campbell RK. Diabetes: Rationale for Dipeptidyl Peptidase 4 Inhibitors: A New Class of Oral Agents for the Treatment of Type 2 Diabetes Mellitus. Ann Pharmacother 2016; 41:51-60. [PMID: 17190843 DOI: 10.1345/aph.1h459] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Objective: To review advances in understanding the pathophysiologic basis of type 2 diabetes mellitus and the pharmacology and mechanism of action of dipeptidyl peptidase 4 (DPP-4) inhibition in correcting the underlying defects in glycemic control. Data Sources: Articles were identified through MEDLINE for the period 1966 through November 2006. Abstracts and presentations from the American Diabetes Association Scientific Sessions and the European Association for the Study of Diabetes (2002–2006) were also searched for scientific reports on DPP-4 inhibitors. Study Selection And Data Extraction: Abstracts, original clinical and preclinical research reports, and review articles published in the English language were identified for review. Literature discussing glucose regulation, incretin hormones, type 2 diabetes pathophysiology, and DPP-4 inhibition were evaluated and selected based on consideration of their support for the proof of concept, mechanistic and in vivo findings, and timeliness. Data Synthesis: The search for new and effective therapies for type 2 diabetes has led to the identification of a novel therapeutic target, the incretin hormones, which play a role in mediating glucose homeostasis via effects on glucagon and insulin secretion from pancreatic islet α- and β-cells, respectively. The incretins' glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide are rapidly inactivated by the enzyme DPP-4. DPP-4 inhibitor agents act by blocking the active site of DPP-4, thereby preventing inactivation of and prolonging the duration of action of incretins, which in turn helps to correct the defective insulin and glucagon secretion that marks type 2 diabetes. Clinical studies to date indicate that DPP-4 inhibitors effectively stimulate insulin secretion, suppress glucagon release, and improve glucose control in patients with type 2 diabetes. These agents are well tolerated and have a low incidence of adverse effects. Conclusions: The DPP-4 inhibitors are novel agents for the treatment of type 2 diabetes. Compounds under development in this new class of oral antidiabetic drugs may be free of the limitations of current therapies.
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Affiliation(s)
- R Keith Campbell
- College of Pharmacy, Wegner Hall #147, PO Box 646510, Washington State University, Pullman, WA 99164, USA.
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Mechanisms by which cocoa flavanols improve metabolic syndrome and related disorders. J Nutr Biochem 2016; 35:1-21. [PMID: 27560446 DOI: 10.1016/j.jnutbio.2015.12.008] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Revised: 12/17/2015] [Accepted: 12/18/2015] [Indexed: 12/24/2022]
Abstract
Dietary administration of cocoa flavanols may be an effective complementary strategy for alleviation or prevention of metabolic syndrome, particularly glucose intolerance. The complex flavanol composition of cocoa provides the ability to interact with a variety of molecules, thus allowing numerous opportunities to ameliorate metabolic diseases. These interactions likely occur primarily in the gastrointestinal tract, where native cocoa flavanol concentration is high. Flavanols may antagonize digestive enzymes and glucose transporters, causing a reduction in glucose excursion, which helps patients with metabolic disorders maintain glucose homeostasis. Unabsorbed flavanols, and ones that undergo enterohepatic recycling, will proceed to the colon where they can exert prebiotic effects on the gut microbiota. Interactions with the gut microbiota may improve gut barrier function, resulting in attenuated endotoxin absorption. Cocoa may also positively influence insulin signaling, possibly by relieving insulin-signaling pathways from oxidative stress and inflammation and/or via a heightened incretin response. The purpose of this review is to explore the mechanisms that underlie these outcomes, critically review the current body of literature related to those mechanisms, explore the implications of these mechanisms for therapeutic utility, and identify emerging or needed areas of research that could advance our understanding of the mechanisms of action and therapeutic potential of cocoa flavanols.
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Connelly KA, Advani A, Zhang Y, Advani SL, Kabir G, Abadeh A, Desjardins JF, Mitchell M, Thai K, Gilbert RE. Dipeptidyl peptidase-4 inhibition improves cardiac function in experimental myocardial infarction: Role of stromal cell-derived factor-1α. J Diabetes 2016; 8:63-75. [PMID: 25565455 DOI: 10.1111/1753-0407.12258] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 11/21/2014] [Accepted: 12/11/2014] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND In addition to degrading glucagon-like peptide-1 (GLP-1), dipeptidyl peptidase-4 (DPP-4) inactivates several chemokines, including stromal cell-derived factor-1α (SDF-1α), a pro-angiogenic and cardiomyocyte protective protein. We hypothesized that DPP-4 inhibition may confer benefit following myocardial infarction (MI) in the diabetic setting as a consequence of enhanced SDF-1α availability rather than potentiating GLP-1. To test this we compared the effects of saxagliptin with those of liraglutide and used the SDF-1α receptor (CXCR4) antagonist plerixafor. METHODS Studies were conducted in streptozotocin-diabetic rats. Rats were randomized to receive saxagliptin (10 mg/kg per day), liraglutide (0.2 mg/kg, s.c., b.i.d.), plerixafor (1 mg/kg per day, s.c.), saxagliptin plus plerixafor or vehicle (1% phosphate-buffered saline). Two weeks later, rats underwent experimental MI, with cardiac function examined 4 weeks after MI. RESULTS Glycemic control and MI size were similar in all groups. Four weeks after MI, mortality was reduced in saxagliptin-treated rats compared with vehicle treatment (P < 0.05). Furthermore, rats receiving saxagliptin had improved cardiac function compared with vehicle-treated rats (P < 0.05). Antagonism of CXCR4 prevented the improvement in cardiac function in saxagliptin-treated rats and was associated with increased mortality (P < 0.05). CONCLUSION Saxagliptin-mediated DPP-4 inhibition, but not liraglutide-mediated GLP-1R agonism, improved cardiac function after MI independent of glucose lowering. These findings suggest that non-GLP-1 actions of DPP-4 inhibition, such as SDF-1α potentiation, mediate biological effects.
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Affiliation(s)
- Kim A Connelly
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada
| | - Andrew Advani
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada
| | - Yanling Zhang
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada
| | - Suzanne L Advani
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada
| | - Golam Kabir
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada
| | - Armin Abadeh
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada
| | - Jean-Francois Desjardins
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada
| | - Melissa Mitchell
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada
| | - Kerri Thai
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada
| | - Richard E Gilbert
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada
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Gault VA, Lennox R, Flatt PR. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, improves recognition memory, oxidative stress and hippocampal neurogenesis and upregulates key genes involved in cognitive decline. Diabetes Obes Metab 2015; 17:403-13. [PMID: 25580570 DOI: 10.1111/dom.12432] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2014] [Revised: 12/17/2014] [Accepted: 12/31/2014] [Indexed: 12/25/2022]
Abstract
AIM To examine whether prolonged dipeptidyl peptidase-4 (DPP-4) inhibition can reverse learning and memory impairment in high-fat-fed mice. METHODS High-fat-fed mice received oral sitagliptin (50 mg/kg body weight) once daily or saline vehicle over 21 days. An additional group of mice on standard chow received saline vehicle. Energy intake, body weight, glucose and insulin concentrations were measured at regular intervals. Glucose tolerance, insulin sensitivity, novel object recognition, DPP-4 activity, hormone analysis, hippocampal gene expression and histology were performed. RESULTS Sitagliptin decreased circulating DPP-4 activity and improved glucose tolerance, glucose-stimulated insulin secretion and insulin sensitivity, and reduced plasma triglycerides and cholesterol levels. DPP-4 inhibition improved recognition memory (1.2-fold increase) without affecting hypermoteric activity or anxiety levels. Improvement in memory and learning was linked to reduced immunostaining for 8-oxoguanine and increased doublecortin staining in the hippocampus, which were indicative of reduced brain oxidative stress and increased hippocampal neurogenesis, respectively. These effects were associated with significant upregulation of hippocampal gene expression of glucagon-like peptide-1 (GLP-1) receptor, glucose-dependent insulinotropic polypeptide receptor, synaptophysin, sirtuin 1, glycogen synthase kinase 3β, superdioxide mutase 2, nuclear factor (erythroid-derived 2)-like 2 and vascular endothelial growth factor. Total plasma and brain GLP-1 concentrations were significantly increased after sitagliptin therapy, whereas DPP-4 activity in brain tissue was not altered. CONCLUSION These studies show that sitagliptin can reverse memory impairment in high-fat-fed mice and is also associated with improved insulin sensitivity, enhanced hippocampal neurogenesis and reduced oxidative stress. DPP-4 inhibitors may therefore exhibit dual benefits by improving metabolic control and reducing the decline in cognitive function.
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Affiliation(s)
- V A Gault
- Diabetes Research Group, School of Biomedical Sciences, University of Ulster, Coleraine, UK
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Cai Y, Lydic TA, Turkette T, Reid GE, Olson LK. Impact of alogliptin and pioglitazone on lipid metabolism in islets of prediabetic and diabetic Zucker Diabetic Fatty rats. Biochem Pharmacol 2015; 95:46-57. [PMID: 25801003 DOI: 10.1016/j.bcp.2015.03.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Accepted: 03/13/2015] [Indexed: 12/30/2022]
Abstract
Prolonged exposure of pancreatic beta (β) cells to elevated glucose and free fatty acids (FFA) as occurs in type 2 diabetes results in loss of β cell function and survival. In Zucker Diabetic Fatty (ZDF) rats, β cell failure is associated with increased triacylglyceride (TAG) synthesis and disruption of the glycerolipid/FFA (GL/FFA) cycle, a critical arm of glucose-stimulated insulin secretion (GSIS). The aim of this study was to determine the impact of activation of PPARγ and increased incretin action via dipeptidyl-peptidase inhibition using pioglitazone and/or alogliptin, respectively, on islet lipid metabolism in prediabetic and diabetic ZDF rats. Transition of control prediabetic ZDF rats to diabetes was associated with reduced plasma insulin levels, reduced islet insulin content and GSIS, reduced stearoyl-CoA desaturase 2 (SCD 2) expression, and increased islet TAG, diacylglyceride (DAG) and ceramides species containing saturated FA. Treatment of prediabetic ZDF rats with a combination of pioglitazone and alogliptin, but not individually, prevented the transition to diabetes and was associated with marked lowering of islet TAG and DAG levels. Pioglitazone and alogliptin, however, did not restore SCD2 expression, the degree of FA saturation in TAG, DAG or ceramides, islet insulin content, or lower ceramide levels. These findings are consistent with activation of PPARγ and increased incretin action working in concert to restore GL/FFA cycle in β cells of ZDF rats. Restoration of the GL/FFA cycle without correcting islet FA desaturation, production of islet ceramides, and/or insulin sensitivity, however, may place these islets at risk for β cell failure.
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Affiliation(s)
- Ying Cai
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
| | - Todd A Lydic
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA.
| | - Thomas Turkette
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
| | - Gavin E Reid
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA; Department of Chemistry, Michigan State University, East Lansing, MI 48824 USA.
| | - L Karl Olson
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
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Papaetis GS. Incretin-based therapies in prediabetes: Current evidence and future perspectives. World J Diabetes 2014; 5:817-834. [PMID: 25512784 PMCID: PMC4265868 DOI: 10.4239/wjd.v5.i6.817] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2014] [Revised: 09/10/2014] [Accepted: 11/10/2014] [Indexed: 02/05/2023] Open
Abstract
The prevalence of type 2 diabetes (T2D) is evolving globally at an alarming rate. Prediabetes is an intermediate state of glucose metabolism that exists between normal glucose tolerance (NGT) and the clinical entity of T2D. Relentless β-cell decline and failure is responsible for the progression from NGT to prediabetes and eventually T2D. The huge burden resulting from the complications of T2D created the need of therapeutic strategies in an effort to prevent or delay its development. The beneficial effects of incretin-based therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, on β-cell function in patients with T2D, together with their strictly glucose-depended mechanism of action, suggested their possible use in individuals with prediabetes when greater β-cell mass and function are preserved and the possibility of β-cell salvage is higher. The present paper summarizes the main molecular intracellular mechanisms through which GLP-1 exerts its activity on β-cells. It also explores the current evidence of incretin based therapies when administered in a prediabetic state, both in animal models and in humans. Finally it discusses the safety of incretin-based therapies as well as their possible role in order to delay or prevent T2D.
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Ahmadieh H, Azar ST. The role of incretin-based therapies in prediabetes: a review. Prim Care Diabetes 2014; 8:286-294. [PMID: 24666932 DOI: 10.1016/j.pcd.2014.02.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 02/20/2014] [Accepted: 02/24/2014] [Indexed: 12/25/2022]
Abstract
Prediabetes, a high-risk state for future development of diabetes, is prevalent globally. Abnormalities in the incretin axis are important in the progression of B-cell failure in type 2 diabetes. Incretin based therapy was found to improve B cell mass and glycaemic control in addition to having multiple beneficial effects on the systolic and diastolic blood pressure, weight loss in addition to their other beneficial effects on the liver and cardiovascular system. In prediabetes, several well-designed preventive trials have shown that lifestyle and pharmacologic interventions such as metformin, thiazolidinediones (TZD), acarbose and, nateglinide and orlistat, are effective in reducing diabetes development. In recent small studies, incretin based therapy (DPP IV inhibitors and GLP-1 agonists) have also been extended to patients with prediabetes since it was shown to better preserve B-cell function and mass in animal studies and in clinical trials and it was also shown to help maintain good long term metabolic control. Because of the limited studies and clinical experience, their side effects and costs currently guidelines do not recommend incretin-based therapies as an option for treatment in patients with prediabetes. With future clinical trials and studies they may be recommended for patients with impaired fasting glucose or impaired glucose tolerance.
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Affiliation(s)
- Hala Ahmadieh
- Department of Internal Medicine, Division of Endocrinology and Metabolism, American University of Beirut-Medical Center, 3 Dag Hammarskjold Plaza, 8th Floor, New York, NY 10017, United States.
| | - Sami T Azar
- Department of Internal Medicine, Division of Endocrinology and Metabolism, American University of Beirut-Medical Center, 3 Dag Hammarskjold Plaza, 8th Floor, New York, NY 10017, United States.
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Sharma R, Soman SS. Design and synthesis of sulfonamide derivatives of pyrrolidine and piperidine as anti-diabetic agents. Eur J Med Chem 2014; 90:342-50. [PMID: 25437620 DOI: 10.1016/j.ejmech.2014.11.041] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Revised: 10/20/2014] [Accepted: 11/21/2014] [Indexed: 11/16/2022]
Abstract
Type 2 diabetes (T2D) is a lifestyle disease affecting millions of people worldwide. Various therapies are available for the management of T2D and dipeptidyl peptidase-IV (DPP-IV) inhibition has emerged as a promising therapy for the treatment of type 2 diabetes (T2D). Here we report design, synthesis and in vitro efficacy of sulfonamide derivatives of pyrrolidine and piperidine as anti-diabetic agents. Amongst all the compounds synthesized in this series, 9a, is the most potent (IC50 = 41.17 nM).
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Affiliation(s)
- Radhika Sharma
- Department of Chemistry, Faculty of Science, The M. S. University of Baroda, Vadodara, Gujarat 390 002, India
| | - Shubhangi S Soman
- Department of Chemistry, Faculty of Science, The M. S. University of Baroda, Vadodara, Gujarat 390 002, India.
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Daniele G, Abdul-Ghani M, DeFronzo RA. What are the pharmacotherapy options for treating prediabetes? Expert Opin Pharmacother 2014; 15:2003-18. [PMID: 25139488 DOI: 10.1517/14656566.2014.944160] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION The incidence of type 2 diabetes mellitus (T2DM) has risen to epidemic proportions, and this is associated with enormous cost. T2DM is preceded by 'prediabetes', and the diagnosis of impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) provides an opportunity for targeted intervention. Prediabetic subjects manifest both core defects characteristic of T2DM, that is, insulin resistance and β-cell dysfunction. Interventions which improve insulin sensitivity and/or preserve β-cell function are logical strategies to delay the conversion of IGT/IFG to T2DM or revert glucose tolerance to normal. AREAS COVERED The authors examine pharmacologic agents that have proven to decrease the conversion of IGT to T2DM and represent potential treatment options in prediabetes. EXPERT OPINION Weight loss improves whole body insulin sensitivity, preserves β-cell function and decreases progression of prediabetes to T2DM. In real life long-term weight loss is the exception and, even if successful, 40 - 50% of IGT individuals still progress to T2DM. Pharmacotherapy provides an alternative strategy to improve insulin sensitivity and preserve β-cell function. Thiazolidinediones (TZDs) are highly effective in T2DM prevention. Long-acting glucagon-like peptide-1 (GLP-1) analogs, because they augment β-cell function and promote weight loss, are effective in preventing IGT progression to T2DM. Metformin is considerably less effective than TZDs or GLP-1 analogs.
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Affiliation(s)
- Giuseppe Daniele
- University of Texas Health Science Center at San Antonio, Division of Diabetes , 7703 Floyd Curve Dr, San Antonio, TX, 78229 , USA +1 210 567 6691 ; +1 210 567 6554 ;
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One-Step Purification of a Fusion Protein of Glucagon-Like Peptide-1 and Human Serum Albumin Expressed inPichia pastorisby an Immunomagnetic Separation Technique. Biosci Biotechnol Biochem 2014; 71:2655-62. [DOI: 10.1271/bbb.70190] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Masuda T, Fu Y, Eguchi A, Czogalla J, Rose MA, Kuczkowski A, Gerasimova M, Feldstein AE, Scadeng M, Vallon V. Dipeptidyl peptidase IV inhibitor lowers PPARγ agonist-induced body weight gain by affecting food intake, fat mass, and beige/brown fat but not fluid retention. Am J Physiol Endocrinol Metab 2014; 306:E388-98. [PMID: 24347054 PMCID: PMC3923087 DOI: 10.1152/ajpendo.00124.2013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Peroxisome proliferator-activated receptor-γ (PPARγ) agonists like pioglitazone (PGZ) are effective antidiabetic drugs, but they induce fluid retention and body weight (BW) gain. Dipeptidyl peptidase IV (DPP IV) inhibitors are antidiabetic drugs that enhance renal Na(+) and fluid excretion. Therefore, we examined whether the DPP IV inhibitor alogliptin (ALG) ameliorates PGZ-induced BW gain. Male Sv129 mice were treated with vehicle (repelleted diet), PGZ (220 mg/kg diet), ALG (300 mg/kg diet), or a combination of PGZ and ALG (PGZ + ALG) for 14 days. PGZ + ALG prevented the increase in BW observed with PGZ but did not attenuate the increase in body fluid content determined by bioimpedance spectroscopy (BIS). BIS revealed that ALG alone had no effect on fat mass (FM) but enhanced the FM-lowering effect of PGZ; MRI analysis confirmed the latter and showed reductions in visceral and inguinal subcutaneous (sc) white adipose tissue (WAT). ALG but not PGZ decreased food intake and plasma free fatty acid concentrations. Conversely, PGZ but not ALG increased mRNA expression of thermogenesis mediator uncoupling protein 1 in epididymal WAT. Adding ALG to PGZ treatment increased the abundance of multilocular cell islets in sc WAT, and PGZ + ALG increased the expression of brown-fat-like "beige" cell marker TMEM26 in sc WAT and interscapular brown adipose tissue and increased rectal temperature vs. vehicle. In summary, DPP IV inhibition did not attenuate PPARγ agonist-induced fluid retention but prevented BW gain by reducing FM. This involved ALG inhibition of food intake and was associated with food intake-independent synergistic effects of PPARγ agonism and DPP-IV inhibition on beige/brown fat cells and thermogenesis.
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Hsu T, Chen CT, Tsai TY, Cheng JH, Wu SY, Chang CN, Chien CH, Yeh KC, Huang YW, Huang CL, Huang CY, Wu SH, Chiang YK, Wang MH, Chao YS, Chen X, Jiaang WT. (1,3-Diphenyl-1H-Pyrazol-4-yl)-Methylamine Analogues as Inhibitors of Dipeptidyl Peptidases. J CHIN CHEM SOC-TAIP 2013. [DOI: 10.1002/jccs.200900152] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Malin SK, Huang H, Mulya A, Kashyap SR, Kirwan JP. Lower dipeptidyl peptidase-4 following exercise training plus weight loss is related to increased insulin sensitivity in adults with metabolic syndrome. Peptides 2013; 47:142-7. [PMID: 23872069 PMCID: PMC3825405 DOI: 10.1016/j.peptides.2013.07.008] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2013] [Revised: 07/09/2013] [Accepted: 07/09/2013] [Indexed: 12/29/2022]
Abstract
Dipeptidyl peptidase-4 (DPP-4) is a circulating glycoprotein that impairs insulin-stimulated glucose uptake and is linked to obesity and metabolic syndrome. However, the effect of exercise on plasma DPP-4 in adults with metabolic syndrome is unknown. Therefore, we determined the effect of exercise on DPP-4 and its role in explaining exercise-induced improvements in insulin sensitivity. Fourteen obese adults (67.9±1.2 years, BMI: 34.2±1.1kg/m(2)) with metabolic syndrome (ATP III criteria) underwent a 12-week supervised exercise intervention (60min/day for 5 days/week at ∼85% HRmax). Plasma DPP-4 was analyzed using an enzyme-linked immunosorbent assay. Insulin sensitivity was measured using the euglycemic-hyperinsulinemic clamp (40mU/m(2)/min) and estimated by HOMA-IR. Visceral fat (computerized tomography), 2-h glucose levels (75g oral glucose tolerance), and basal fat oxidation as well as aerobic fitness (indirect calorimetry) were also determined before and after exercise. The intervention reduced visceral fat, lowered blood pressure, glucose and lipids, and increased aerobic fitness (P<0.05). Exercise improved clamp-derived insulin sensitivity by 75% (P<0.001) and decreased HOMA-IR by 15% (P<0.05). Training decreased plasma DPP-4 by 10% (421.8±30.1 vs. 378.3±32.5ng/ml; P<0.04), and the decrease in DPP-4 was associated with clamp-derived insulin sensitivity (r=-0.59; P<0.04), HOMA-IR (r=0.59; P<0.04) and fat oxidation (r=-0.54; P<0.05). Increased fat oxidation also correlated with lower 2-h glucose levels (r=-0.64; P<0.02). Exercise training reduces plasma DPP-4, which may be linked to elevated insulin sensitivity and fat oxidation. Maintaining low plasma DPP-4 concentrations is a potential mechanism whereby exercise plus weight loss prevents/delays the onset of type 2 diabetes in adults with metabolic syndrome.
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Affiliation(s)
- Steven K. Malin
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
- Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH
| | - Hazel Huang
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Anny Mulya
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Sangeeta R. Kashyap
- Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic, Cleveland, OH
- Metabolic Translational Research Center, Endocrine and Metabolism Institute, Cleveland Clinic, Cleveland, OH
| | - John P. Kirwan
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
- Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH
- Metabolic Translational Research Center, Endocrine and Metabolism Institute, Cleveland Clinic, Cleveland, OH
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Kim HS, Hong SH, Oh SH, Kim JH, Lee MS, Lee MK. Activin A, exendin-4, and glucose stimulate differentiation of human pancreatic ductal cells. J Endocrinol 2013; 217:241-52. [PMID: 23503774 DOI: 10.1530/joe-12-0474] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Islet transplantation is one treatment option for diabetes mellitus. However, novel sources of pancreatic islets or insulin-producing cells are required because the amount of donor tissue available is severely limited. Pancreatic ductal cells are an alternative source of β-cells because they have the potential to differentiate into insulin-producing cells. We investigated whether treatment of human pancreatic ductal cells with activin A (ActA) and exendin-4 (EX-4) stimulated transdifferentiation of the cells, both in vitro and in vivo. We treated human pancreatic ductal cells with ActA and EX-4 in high-glucose media to induce differentiation into insulin-producing cells and transplanted the cells into streptozotocin-induced diabetic nude mice. Co-treatment of mice with ActA and EX-4 promoted cell proliferation, induced expression of pancreatic β-cell-specific markers, and caused glucose-induced insulin secretion compared with the ActA or EX-4 mono-treatment groups respectively. When pancreatic ductal cells treated with ActA and EX-4 in high-glucose media were transplanted into diabetic nude mice, their blood glucose levels normalized and insulin was detected in the graft. These findings suggest that pancreatic ductal cells have a potential to replace pancreatic islets for the treatment of diabetes mellitus when the ductal cells are co-treated with ActA, EX-4, and glucose to promote their differentiation into functional insulin-producing cells.
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Affiliation(s)
- Hyo-Sup Kim
- Division of Endocrinology and Metabolism, Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Samsung Medical Center, #50 Ilwon-dong, Kangnam-ku, Seoul 135-710, Republic of Korea Korea
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Gowda N, Dandu A, Singh J, Biswas S, Raghav V, Lakshmi MN, Shilpa PC, Sunil V, Reddy A, Sadasivuni M, Aparna K, Verma MK, Moolemath Y, Anup MO, Venkataranganna MV, Somesh BP, Jagannath MR. Treatment with CNX-011-67, a novel GPR40 agonist, delays onset and progression of diabetes and improves beta cell preservation and function in male ZDF rats. BMC Pharmacol Toxicol 2013; 14:28. [PMID: 23692921 PMCID: PMC3668190 DOI: 10.1186/2050-6511-14-28] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2013] [Accepted: 05/15/2013] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The role of G protein-coupled receptor (GPR40), which is highly expressed in pancreatic beta cells, has been studied extensively in the amelioration of beta cell dysfunction in T2D using rat and mouse islets, beta cell lines and in animal models of diabetes. But its potential as a therapeutic target has not been fully explored. This aim of the study is to evaluate the therapeutic potential of CNX-011-67, a highly selective, potent and orally bioavailable GPR40 agonist, in controlling diabetes and other metabolic parameters. METHODS Seven week old male ZDF rats were treated with either vehicle or CNX-011-67, 5 mg/kg twice daily, for seven weeks. The animals were subjected to oral glucose tolerance and insulin tolerance tests. Plasma glucose, insulin, triglyceride, HbA1c, fructosamine and free fatty acids were measured at selected time points. Pancreas from control and treated animals were subjected to insulin and pancreatic and duodenal homeobox 1 (PDX1) immunohistochemistry and were also evaluated by electron microscopy. Also the potential impact of CNX-011-67 on islet insulin secretion, content, ATP levels and markers of both glucose oxidation, beta cell health in rat islets under chronic glucolipotoxic conditions was evaluated. RESULTS Treatment of male ZDF rats with CNX-011-67 for 7 weeks significantly enhanced insulin secretion in response to oral glucose load, delayed the onset of fasting hyperglycemia by 3 weeks, reduced nonfasting glucose excursions, fasting free fatty acids and triglyceride levels. A significant increase in PDX1 expression and insulin content and reduction in plasma fructosamine, HOMA-IR, and beta cell apoptosis were observed. CNX-011-67 improves glucose mediated insulin secretion, insulin gene transcription and islet insulin content in cultured rat islets under chronic glucolipotoxic condition. Also enhanced glucose oxidation in the form of increased islet ATP content and overall improvement in beta cell health in the form of reduced expression of stress markers (TXNIP and CHOP mRNA) were observed. CONCLUSIONS These findings, suggest that long-term oral therapy with CNX-011-67 could be of clinical value to provide good glycemic control and improve islet beta cell function.
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Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors have recently emerged as a new class of antidiabetic that show favorable results in improving glycemic control with a minimal risk of hypoglycemia and weight gain. Teneligliptin, a novel DPP-4 inhibitor, exhibits a unique structure characterized by five consecutive rings, which produce a potent and long-lasting effect. Teneligliptin is currently used in cases showing insufficient improvement in glycemic control even after diet control and exercise or a combination of diet control, exercise, and sulfonylurea- or thiazolidine-class drugs. In adults, teneligliptin is orally administered at a dosage of 20 mg once daily, which can be increased up to 40 mg per day. Because the metabolites of this drug are eliminated via renal and hepatic excretion, no dose adjustment is necessary in patients with renal impairment. The safety profile of teneligliptin is similar to those of other available DPP-4 inhibitors. However, caution needs to be exercised when administering teneligliptin to patients who are prone to QT prolongation. One study has reported that the postprandial blood glucose-lowering effects of teneligliptin administered prior to breakfast were sustained throughout the day, and the effects observed after dinner were similar to those observed after breakfast or lunch. Thus, although clinical data for this new drug are limited, this drug shows promise in stabilizing glycemic fluctuations throughout the day and consequently suppressing the progression of diabetic complications. However, continued evaluation in long-term studies and clinical trials is required to evaluate the efficacy and safety of the drug as well as to identify additional indications for its clinical use.
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Affiliation(s)
- Miyako Kishimoto
- Department of Diabetes and Metabolic Medicine, Center Hospital, Tokyo, Japan; Diabetes and Metabolism Information Center, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
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Ávila DDL, Araújo GRD, Silva M, Miranda PHDA, Diniz MF, Pedrosa ML, Silva ME, Lima WGD, Costa DC. Vildagliptin Ameliorates Oxidative Stress and Pancreatic Beta Cell Destruction in Type 1 Diabetic Rats. Arch Med Res 2013; 44:194-202. [DOI: 10.1016/j.arcmed.2013.03.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2012] [Accepted: 03/05/2013] [Indexed: 01/09/2023]
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Holst JJ, Deacon CF. Is there a place for incretin therapies in obesity and prediabetes? Trends Endocrinol Metab 2013; 24:145-52. [PMID: 23415157 DOI: 10.1016/j.tem.2013.01.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2012] [Revised: 01/05/2013] [Accepted: 01/10/2013] [Indexed: 02/07/2023]
Abstract
Incretin-based therapies exploit the insulinotropic actions of the gut hormones gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1) for the treatment of diabetes and include GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase-4 (DPP-4), the enzyme that inactivates the incretin hormones in the body. Both drug classes improve metabolic control in type 2 diabetes (T2DM), with GLP-1 receptor agonists also lowering body weight. Pharmacotherapy using DPP-4 inhibitors has few side effects and is weight neutral. Animal studies support their use in prediabetes; however, human data are scarce. GLP-1 receptor agonist effects are also apparent in non-diabetic obese individuals. Therefore, incretin-based therapies, if safe, may be effective in preventing progression of prediabetes; and GLP-1 receptor agonists may have potential for use in the treatment of obesity.
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Affiliation(s)
- Jens Juul Holst
- The NNF Center for Basic Metabolic Research, Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
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Wang Y, Landheer S, van Gilst WH, van Amerongen A, Hammes HP, Henning RH, Deelman LE, Buikema H. Attenuation of renovascular damage in Zucker diabetic fatty rat by NWT-03, an egg protein hydrolysate with ACE- and DPP4-inhibitory Activity. PLoS One 2012; 7:e46781. [PMID: 23071636 PMCID: PMC3468629 DOI: 10.1371/journal.pone.0046781] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2012] [Accepted: 09/06/2012] [Indexed: 12/15/2022] Open
Abstract
Background Dipeptidyl peptidase 4 (DPP4) and angiotensin-converting enzyme (ACE) are important target enzymes in glycemic control and renovascular protection. Here, we studied the effect of NWT-03, an egg protein hydrolysate with DPP4- and ACE-inhibitory activity, on renovascular damage in Zucker diabetic fatty (ZDF) rats. Comparisons were made to rats treated with vildagliptin (VIL), included as a positive control for the effect of DPP4 inhibition. Methods ZDF rats received NWT-03 (1 g/kg/day) or VIL (3 mg/kg/day) from 10 to 25 weeks of age. Metabolic and renal functions were assessed; the kidney was removed for histological analysis of glomerulosclerosis and expression of pro-inflammatory/fibrotic markers (RT-PCR and Western blotting); and the aorta was removed for studies of endothelium-dependent relaxation (EDR). Findings Hyperinsulinemic ZDF rats typically developed signs of type-2 diabetes and renovascular damage, as evidenced by albuminuria, glomerulosclerosis, and impaired EDR. Neither NWT-03 nor VIL improved metabolic parameters; for VIL, this was despite a 5-fold increase in glucagon-like peptide (GLP)-1 levels. NWT-03 and VIL both reduced renal interleukin (Il)-1β/Il-13 mRNA expression and glomerulosclerosis. However, only NWT-03 additionally decreased renal tumor necrosis factor (TNF)-α mRNA and P22phox protein expression, reduced albuminuria, and restored aortic EDR. Indomethacin added to the organ bath instantly improved aortic EDR, indicating a role for cyclooxygenase (COX)-derived contractile prostanoids in opposing relaxation in ZDF rats. This indomethacin effect was reduced by NWT-03, but not by VIL, and coincided with decreased renal COX-1/2 protein expression. Conclusion and Interpretation Long-term supplementation with the egg protein hydrolysate NWT-03 attenuated renovascular damage in this preclinical rat model of type 2 diabetes. A comparison to the DPP4-inhibitor VIL suggests that the effects of NWT-03 were related to both ACE- and DPP4-inhibitory properties. The development of protein hydrolysates with a multiple-targeting strategy may be of benefit to functional food formulations.
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Affiliation(s)
- Yumei Wang
- 5th Medical Department, Section of Endocrinology, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany
| | - Sjoerd Landheer
- Departments of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Wiek H. van Gilst
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Aart van Amerongen
- Food and Biobased Research, Wageningen University and Research Center, Wageningen, The Netherlands
| | - Hans-Peter Hammes
- 5th Medical Department, Section of Endocrinology, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany
| | - Robert H. Henning
- Departments of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Leo E. Deelman
- Departments of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Hendrik Buikema
- Departments of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- * E-mail:
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Fukuda-Tsuru S, Anabuki J, Abe Y, Yoshida K, Ishii S. A novel, potent, and long-lasting dipeptidyl peptidase-4 inhibitor, teneligliptin, improves postprandial hyperglycemia and dyslipidemia after single and repeated administrations. Eur J Pharmacol 2012; 696:194-202. [PMID: 23022337 DOI: 10.1016/j.ejphar.2012.09.024] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2012] [Revised: 09/03/2012] [Accepted: 09/17/2012] [Indexed: 11/16/2022]
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors have been demonstrated to improve glycemic control, in particular postprandial hyperglycemic control, in patients with type 2 diabetes. Teneligliptin is a novel chemotype prolylthiazolidine-based DPP-4 inhibitor. The present study aimed to characterize the pharmacological profiles of teneligliptin in vitro and in vivo. Teneligliptin competitively inhibited human plasma, rat plasma, and human recombinant DPP-4 in vitro, with IC(50) values of approximately 1 nmol/l. Oral administration of teneligliptin in Wistar rats resulted in the inhibition of plasma DPP-4 with an ED(50) of 0.41 mg/kg. Plasma DPP-4 inhibition was sustained even at 24h after administration of teneligliptin. An oral carbohydrate-loading test in Zucker fatty rats showed that teneligliptin at ≥ 0.1mg/kg increased the maximum increase in plasma glucagon-like peptide-1 and insulin levels, and reduced glucose excursions. This effect was observed over 12h after a dose of 1mg/kg. An oral fat-loading test in Zucker fatty rats also showed that teneligliptin at 1mg/kg reduced triglyceride and free fatty acid excursions. In Zucker fatty rats, repeated administration of teneligliptin for two weeks reduced glucose excursions in the oral carbohydrate-loading test and decreased the plasma levels of triglycerides and free fatty acids under non-fasting conditions. The present studies indicate that teneligliptin is a potent, competitive, and long-lasting DPP-4 inhibitor that improves postprandial hyperglycemia and dyslipidemia by both single and repeated administrations.
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Affiliation(s)
- Sayaka Fukuda-Tsuru
- Department I, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan.
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Inaba W, Mizukami H, Kamata K, Takahashi K, Tsuboi K, Yagihashi S. Effects of long-term treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin on islet endocrine cells in non-obese type 2 diabetic Goto-Kakizaki rats. Eur J Pharmacol 2012; 691:297-306. [PMID: 22820107 DOI: 10.1016/j.ejphar.2012.07.030] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2012] [Revised: 06/25/2012] [Accepted: 07/10/2012] [Indexed: 01/09/2023]
Abstract
Reduced β cell mass is a characteristic feature of type 2 diabetes and incretin therapy is expected to prevent this condition. However, it is unknown whether dipeptidyl peptidase-4 inhibitors influence β and α cell mass in animal models of diabetes that can be translated to humans. Therefore, we examined the long-term effects of treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin on islet morphology in Goto-Kakizaki (GK) rats, a spontaneous, non-obese model of type 2 diabetes, and explored the underlying mechanisms. Four-week-old GK rats were orally administered with vildagliptin (15 mg/kg) twice daily for 18 weeks. Glucose tolerance was monitored during the study. After 18 weeks, β and α cell morphology and the expression of molecules involved in cell proliferation and cell death were examined by immunohistochemistry and morphometric analysis. We found that vildagliptin improved glucose tolerance and insulin secretion, and suppressed hyperglucagonemia by increasing plasma active glucagon-like peptide-1 concentrations. β cell mass was reduced in GK rats to 40% of that in Wistar rats, but was restored to 80% by vildagliptin. Vildagliptin enhanced β and α cell proliferation, and increased the number of small neogenetic islets. Vildagliptin also reduced the number of 8-hydroxy-2'-deoxyguanosine-positive cells and forkhead box protein O1 expression, inhibited macrophage infiltration, and enhanced S6 ribosomal protein, molecule of target of rapamycin, and pancreatic duodenal homeobox 1 expression. These results indicate that starting vildagliptin treatment from an early age improved glucose tolerance and preserved islet β cell mass in GK rats by facilitating the proliferation of islet endocrine cells.
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Affiliation(s)
- Wataru Inaba
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan
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Ovais S, Bashir R, Yaseen S, Rathore P, Samim M, Javed K. Synthesis and pharmacological evaluation of some novel 2-pyrazolines bearing benzenesulfonamide as anti-inflammatory and blood glucose lowering agents. Med Chem Res 2012. [DOI: 10.1007/s00044-012-0130-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Takeda Y, Fujita Y, Honjo J, Yanagimachi T, Sakagami H, Takiyama Y, Makino Y, Abiko A, Kieffer TJ, Haneda M. Reduction of both beta cell death and alpha cell proliferation by dipeptidyl peptidase-4 inhibition in a streptozotocin-induced model of diabetes in mice. Diabetologia 2012; 55:404-12. [PMID: 22072158 DOI: 10.1007/s00125-011-2365-4] [Citation(s) in RCA: 97] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2011] [Accepted: 10/12/2011] [Indexed: 12/25/2022]
Abstract
AIMS/HYPOTHESIS Incretins stimulate insulin secretion in a glucose-dependent manner but also promote pancreatic beta cell protection. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new glucose-lowering treatment that blocks incretin degradation by DPP-4. We assessed whether DPP-4 inhibition suppresses the progression to hyperglycaemia in a low-dose streptozotocin (STZ)-induced diabetic mouse model, and then investigated how DPP-4 inhibition affects islet function and morphology. METHODS The DPP-4 inhibitor, des-fluoro-sitagliptin (SITA), was administered to mice during and after STZ injections, and in some mice also before STZ. RESULTS In control mice, STZ resulted in hyperglycaemia associated with impaired insulin secretion and excess glucagon secretion. In SITA-treated STZ mice, these metabolic abnormalities were improved, particularly when SITA administration was initiated before STZ injections. We observed beta cell loss and dramatic alpha cell expansion associated with decreased insulin content and increased glucagon content after STZ administration. In SITA-treated mice, islet architecture and insulin content were preserved, and no significant increase in glucagon content was observed. After STZ exposure, beta cell apoptosis increased before hyperglycaemia, and SITA treatment reduced the number of apoptotic beta cells. Interestingly, alpha cell proliferation was observed in non-treated mice after STZ injection, but the proliferation was not observed in SITA-treated mice. CONCLUSIONS/INTERPRETATION Our results suggest that the ability of DPP-4 inhibition to suppress the progression to STZ-induced hyperglycaemia involves both alleviation of beta cell death and alpha cell proliferation.
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Affiliation(s)
- Y Takeda
- Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka Higashi, Asahikawa 078-8510, Japan
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Uenishi H, Kabuki T, Seto Y, Serizawa A, Nakajima H. Isolation and identification of casein-derived dipeptidyl-peptidase 4 (DPP-4)-inhibitory peptide LPQNIPPL from gouda-type cheese and its effect on plasma glucose in rats. Int Dairy J 2012. [DOI: 10.1016/j.idairyj.2011.08.002] [Citation(s) in RCA: 140] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Mega C, Teixeira de Lemos E, Vala H, Fernandes R, Oliveira J, Mascarenhas-Melo F, Teixeira F, Reis F. Diabetic nephropathy amelioration by a low-dose sitagliptin in an animal model of type 2 diabetes (Zucker diabetic fatty rat). EXPERIMENTAL DIABETES RESEARCH 2011; 2011:162092. [PMID: 22203828 PMCID: PMC3235777 DOI: 10.1155/2011/162092] [Citation(s) in RCA: 119] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2011] [Revised: 08/21/2011] [Accepted: 08/29/2011] [Indexed: 11/17/2022]
Abstract
This study was performed to assess the effect of chronic low-dose sitagliptin, a dipeptidyl peptidase 4 inhibitor, on metabolic profile and on renal lesions aggravation in a rat model of type-2 diabetic nephropathy, the Zucker diabetic fatty (ZDF) rat. Diabetic and obese ZDF (fa/fa) rats and their controls ZDF (+/+) were treated for 6 weeks with vehicle (control) or sitagliptin (10 mg/kg/bw). Blood/serum glucose, HbA1c, insulin, Total-c, TGs, urea, and creatinine were assessed, as well as kidney glomerular and tubulointerstitial lesions (interstitial fibrosis/tubular atrophy), using a semiquantitative rating from 0 (absent/normal) to 3 (severe and extensive damage). Vascular lesions were scored from 0-2. Sitagliptin in the diabetic rats promoted an amelioration of glycemia, HbA1c, Total-c, and TGs, accompanied by a partial prevention of insulinopenia. Furthermore, together with urea increment prevention, renal lesions were ameliorated in the diabetic rats, including glomerular, tubulointerstitial, and vascular lesions, accompanied by reduced lipid peroxidation. In conclusion, chronic low-dose sitagliptin treatment was able to ameliorate diabetic nephropathy, which might represent a key step forward in the management of T2DM and this serious complication.
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Affiliation(s)
- Cristina Mega
- Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Research on Light and Image (IBILI), Medicine Faculty, Coimbra University, 3000-548 Coimbra, Portugal
- Agrarian School of Viseu, Polytechnic Institute of Viseu, 3500-606 Viseu, Portugal
- Educational, Technologies and Health Study Center, Polytechnic Institute of Viseu, 3504-510 Viseu, Portugal
| | - Edite Teixeira de Lemos
- Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Research on Light and Image (IBILI), Medicine Faculty, Coimbra University, 3000-548 Coimbra, Portugal
- Agrarian School of Viseu, Polytechnic Institute of Viseu, 3500-606 Viseu, Portugal
| | - Helena Vala
- Agrarian School of Viseu, Polytechnic Institute of Viseu, 3500-606 Viseu, Portugal
- Educational, Technologies and Health Study Center, Polytechnic Institute of Viseu, 3504-510 Viseu, Portugal
| | - Rosa Fernandes
- Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Research on Light and Image (IBILI), Medicine Faculty, Coimbra University, 3000-548 Coimbra, Portugal
| | - Jorge Oliveira
- Agrarian School of Viseu, Polytechnic Institute of Viseu, 3500-606 Viseu, Portugal
- Educational, Technologies and Health Study Center, Polytechnic Institute of Viseu, 3504-510 Viseu, Portugal
| | - Filipa Mascarenhas-Melo
- Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Research on Light and Image (IBILI), Medicine Faculty, Coimbra University, 3000-548 Coimbra, Portugal
| | - Frederico Teixeira
- Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Research on Light and Image (IBILI), Medicine Faculty, Coimbra University, 3000-548 Coimbra, Portugal
| | - Flávio Reis
- Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Research on Light and Image (IBILI), Medicine Faculty, Coimbra University, 3000-548 Coimbra, Portugal
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Kim MK, Chae YN, Kim HD, Yang EK, Cho EJ, Choi SH, Cheong YH, Kim HS, Kim HJ, Jo YW, Son MH, Kim SH, Shin CY. DA-1229, a novel and potent DPP4 inhibitor, improves insulin resistance and delays the onset of diabetes. Life Sci 2011; 90:21-9. [PMID: 22056373 DOI: 10.1016/j.lfs.2011.10.007] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2010] [Revised: 09/05/2011] [Accepted: 10/03/2011] [Indexed: 12/18/2022]
Abstract
AIM To characterize the pharmacodynamic profile of DA-1229, a novel dipeptidyl peptidase (DPP) 4 inhibitor. MAIN METHODS Enzyme inhibition assays against DPP4, DPP8 and DPP9. Antidiabetic effects of DA-1229 in HF-DIO mice and young db/db mice. KEY FINDINGS DA-1229 was shown to potently inhibit the DPP4 enzyme in human and murine soluble forms and the human membrane-bound form with IC(50) values of 0.98, 3.59 and 1.26 nM, respectively. As a reversible and competitive inhibitor, DA-1229 was more selective to human DPP4 (6000-fold) than to human DPP8 and DPP9. DA-1229 (0.1-3mg/kg) dose-dependently inhibited plasma DPP4 activity, leading to increased levels of plasma GLP-1 and insulin, and thereby lowering blood glucose levels in mice. In high fat diet-fed (HF) mice, a single oral dose of 100mg/kg of DA-1229 reduced plasma DPP4 activity by over 80% during a 24h period. Long-term treatment with DA-1229 for 8 weeks revealed significant improvements in glucose intolerance and insulin resistance, accompanied by significant body weight reduction. However, it remains unclear whether there is a direct causal relationship between DPP4 inhibition and body weight reduction. In young db/db mice, the DA-1229 treatment significantly reduced blood glucose excursions for the first 2 weeks, resulting in significantly lower levels of HbA1c at the end of the study. Furthermore, the pancreatic insulin content of the treatment group was significantly higher than that of the db/db control. SIGNIFICANCE DA-1229 as a novel and selective DPP4 inhibitor improves the insulin sensitivity in HF mice and delays the onset of diabetes in young db/db mice.
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Affiliation(s)
- Mi-Kyung Kim
- Dong-A Pharm. Research Center, 47-5 Sanggal-dong, Giheung-gu, Yongin-si, Gyeonggi-do, 446-905, Republic of Korea
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Lamers D, Famulla S, Wronkowitz N, Hartwig S, Lehr S, Ouwens DM, Eckardt K, Kaufman JM, Ryden M, Müller S, Hanisch FG, Ruige J, Arner P, Sell H, Eckel J. Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes 2011; 60:1917-25. [PMID: 21593202 PMCID: PMC3121429 DOI: 10.2337/db10-1707] [Citation(s) in RCA: 460] [Impact Index Per Article: 32.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Comprehensive proteomic profiling of the human adipocyte secretome identified dipeptidyl peptidase 4 (DPP4) as a novel adipokine. This study assessed the functional implications of the adipokine DPP4 and its association to the metabolic syndrome. RESEARCH DESIGN AND METHODS Human adipocytes and skeletal and smooth muscle cells were used to monitor DPP4 release and assess the effects of soluble DPP4 on insulin signaling. In lean and obese subjects, depot-specific expression of DPP4 and its release from adipose tissue explants were determined and correlated to parameters of the metabolic syndrome. RESULTS Fully differentiated adipocytes exhibit a substantially higher release of DPP4 compared with preadipocytes or macrophages. Direct addition of DPP4 to fat and skeletal and smooth muscle cells impairs insulin signaling. A fivefold higher level of DPP4 protein expression was seen in visceral compared with subcutaneous fat of obese patients, with no regional difference in lean subjects. DPP4 serum concentrations significantly correlated with adipocyte size. By using adipose tissue explants from lean and obese subjects, we observed a twofold increase in DPP4 release that strongly correlated with adipocyte volume and parameters of the metabolic syndrome and was decreased to the lean level after weight reduction. DPP4 released from adipose tissue correlated positively with an increasing risk score for the metabolic syndrome. CONCLUSIONS DPP4 is a novel adipokine that may impair insulin sensitivity in an autocrine and paracrine fashion. Furthermore, DPP4 release strongly correlates with adipocyte size, potentially representing an important source of DPP4 in obesity. Therefore, we suggest that DPP4 may be involved in linking adipose tissue and the metabolic syndrome.
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Affiliation(s)
- Daniela Lamers
- Paul-Langerhans-Group, German Diabetes Center, Duesseldorf, Germany
| | - Susanne Famulla
- Paul-Langerhans-Group, German Diabetes Center, Duesseldorf, Germany
| | - Nina Wronkowitz
- Paul-Langerhans-Group, German Diabetes Center, Duesseldorf, Germany
| | - Sonja Hartwig
- Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Duesseldorf, Germany
| | - Stefan Lehr
- Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Duesseldorf, Germany
| | - D. Margriet Ouwens
- Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Duesseldorf, Germany
| | - Kristin Eckardt
- Paul-Langerhans-Group, German Diabetes Center, Duesseldorf, Germany
| | - Jean M. Kaufman
- Department of Endocrinology, Ghent University Hospital, Ghent, Belgium
| | - Mikael Ryden
- Department of Medicine, Karolinska Institute at Karolinska Hospital, Stockholm, Sweden
| | - Stefan Müller
- Institute of Biochemistry II, Medical Faculty, University of Cologne, Cologne, Germany
| | - Franz-Georg Hanisch
- Institute of Biochemistry II, Medical Faculty, University of Cologne, Cologne, Germany
| | - Johannes Ruige
- Department of Endocrinology, Ghent University Hospital, Ghent, Belgium
| | - Peter Arner
- Department of Medicine, Karolinska Institute at Karolinska Hospital, Stockholm, Sweden
| | - Henrike Sell
- Paul-Langerhans-Group, German Diabetes Center, Duesseldorf, Germany
| | - Juergen Eckel
- Paul-Langerhans-Group, German Diabetes Center, Duesseldorf, Germany
- Corresponding author: Juergen Eckel,
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Slavkovsky R, Kohlerova R, Tkacova V, Jiroutova A, Tahmazoglu B, Velebny V, Rezačová M, Sobotka L, Kanta J. Zucker diabetic fatty rat: A new model of impaired cutaneous wound repair with type II diabetes mellitus and obesity. Wound Repair Regen 2011; 19:515-25. [DOI: 10.1111/j.1524-475x.2011.00703.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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6-Imino-2-thioxo-pyrimidinones as a new class of dipeptidyl peptidase IV inhibitors. Med Chem Res 2011. [DOI: 10.1007/s00044-010-9314-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Kshirsagar AD, Aggarwal AS, Harle UN, Deshpande AD. DPP IV inhibitors: successes, failures and future prospects. Diabetes Metab Syndr 2011; 5:105-112. [PMID: 22813415 DOI: 10.1016/j.dsx.2012.02.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The dipeptidyl peptidase IV (DPP IV) enzyme is a novel target for the treatment of type 2 diabetes. Several DPP IV inhibitors are in the clinical development, since they are safe and tolerable with no increased risk of adverse events compared to placebo and have a low risk of hypoglycemia. They are flourishing as monotherapy and also in combination with commonly prescribed antidiabetic agents and are appropriate for once-daily oral dosing. However, further studies are needed to validate both long-term β-cell preservation and the role of these agents in the management of diabetes. The present review gives an inside out of the DPP IV inhibitors for its success, failure and future prospects in the treatment of diabetes and associated complication.
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Affiliation(s)
- Ajay D Kshirsagar
- Department of Pharmacology, Padm. Dr. D.Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune 411018, Maharashtra, India.
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Tajima A, Yamamoto K, Kozakai A, Okumura-Kitajima L, Mita Y, Kitano K, Jingu S, Nakaike S. (2S,4S)-4-Fluoro-1-{[(2-hydroxy-1,1-dimethylethyl)amino]acetyl}-pyrrolidine-2-carbonitrile monobenzenesulfonate (TS-021) is a selective and reversible dipeptidyl peptidase IV inhibitor. Eur J Pharmacol 2011; 655:99-107. [PMID: 21262219 DOI: 10.1016/j.ejphar.2011.01.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2010] [Revised: 12/10/2010] [Accepted: 01/07/2011] [Indexed: 11/26/2022]
Abstract
The incretin hormone glucagon-like peptide-1 (GLP-1) has significant roles in the regulation of postprandial glucose metabolism, and the active form of GLP-1 is rapidly degraded by dipeptidyl peptidase (DPP)-IV. Therefore, DPP-IV inhibition is a promising approach for the treatment of type 2 diabetes. In the present study, we investigated the character of a DPP-IV inhibitor, TS-021, (2S, 4S)-4-fluoro-1-{[(2-hydroxy-1,1-dimethylethyl)amino]acetyl}-pyrrolidine-2-carbonitrile monobenzenesulfonate both in vitro and in vivo. TS-021 inhibits DPP-IV activity in human plasma with an IC(50) value of 5.34nM. In kinetics experiments, TS-021 had a relatively higher dissociation rate constant, with a k(off) value of 1.09×10(-3)s, despite exhibiting a potent human plasma DPP-IV inhibition activity with a K(i) value of 4.96nM. TS-021 exhibited significant inhibition selectivity against DPP-8 (>600 fold), DPP-9 (>1200 fold) and other peptidases examined (>15,000 fold). In normal rats, dogs and monkeys, a single oral dose of TS-021 exhibited favorable pharmacokinetic profiles. In Zucker fatty (fa/fa) rats, a rat model of obesity and impaired glucose tolerance, the oral administration of TS-021 resulted in the suppression of plasma DPP-IV activity and an increase in the active form of GLP-1. Furthermore, TS-021 exhibited a significant improvement in glucose tolerance by increasing the plasma insulin level during oral glucose tolerance tests at doses of 0.02-0.5mg/kg. These results suggest that TS-021 is a selective and reversible dipeptidyl peptidase IV inhibitor and has excellent characteristics as an oral anti-diabetic agent for postprandial hyperglycemia in patients with impaired glucose tolerance or type 2 diabetes.
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Affiliation(s)
- Atsushi Tajima
- Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
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Ferreira L, Teixeira-de-Lemos E, Pinto F, Parada B, Mega C, Vala H, Pinto R, Garrido P, Sereno J, Fernandes R, Santos P, Velada I, Melo A, Nunes S, Teixeira F, Reis F. Effects of sitagliptin treatment on dysmetabolism, inflammation, and oxidative stress in an animal model of type 2 diabetes (ZDF rat). Mediators Inflamm 2010; 2010:592760. [PMID: 20652060 PMCID: PMC2905949 DOI: 10.1155/2010/592760] [Citation(s) in RCA: 127] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2010] [Revised: 04/17/2010] [Accepted: 04/28/2010] [Indexed: 11/17/2022] Open
Abstract
The purpose of this paper is to evaluate the chronic effect of sitagliptin on metabolic profile, inflammation, and redox status in the Zucker Diabetic Fatty (ZDF) rat, an animal model of obese type 2 diabetes. Diabetic and obese ZDF (fa/fa) rats and their controls (ZDF +/+) were treated during 6 weeks with vehicle (control) and sitagliptin (10 mg/kg/bw). Glucose, HbA1c, insulin, Total-c, TGs, IL-1beta, TNF-alpha, CRPhs, and adiponectin were assessed in serum and MDA and TAS in serum, pancreas, and heart. Pancreatic histology was also evaluated. Sitagliptin in diabetic rats promoted a decrease in glucose, HbA1c, Total-c, and TGs accompanied by a partial prevention of insulinopenia, together, with a decrease in CRPhs and IL-1beta. Sitagliptin also showed a positive impact on lipid peroxidation and hypertension prevention. In conclusion, chronic sitagliptin treatment corrected the glycaemic dysmetabolism, hypertriglyceridaemia, inflammation, and hypertension, reduced the severity of the histopathological lesions of pancreatic endocrine and exocrine tissues, together with a favourable redox status, which might be a further advantage in the management of diabetes and its proatherogenic comorbidities.
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Affiliation(s)
- Liliana Ferreira
- Institute of Pharmacology & Experimental Therapeutics, IBILI, Medicine Faculty, University of Coimbra, 3000-354 Coimbra, Portugal
| | - Edite Teixeira-de-Lemos
- Institute of Pharmacology & Experimental Therapeutics, IBILI, Medicine Faculty, University of Coimbra, 3000-354 Coimbra, Portugal
- ESAV, Polytechnic Institute of Viseu, 3500 Viseu, Portugal
| | - Filipa Pinto
- Institute of Pharmacology & Experimental Therapeutics, IBILI, Medicine Faculty, University of Coimbra, 3000-354 Coimbra, Portugal
| | - Belmiro Parada
- Institute of Pharmacology & Experimental Therapeutics, IBILI, Medicine Faculty, University of Coimbra, 3000-354 Coimbra, Portugal
| | - Cristina Mega
- ESAV, Polytechnic Institute of Viseu, 3500 Viseu, Portugal
| | - Helena Vala
- ESAV, Polytechnic Institute of Viseu, 3500 Viseu, Portugal
| | - Rui Pinto
- Pharmacology & Pharmacotoxicology Unit, Faculty of Pharmacy, Lisbon University, 1649-003 Lisboa, Portugal
| | - Patrícia Garrido
- Institute of Pharmacology & Experimental Therapeutics, IBILI, Medicine Faculty, University of Coimbra, 3000-354 Coimbra, Portugal
| | - José Sereno
- Institute of Pharmacology & Experimental Therapeutics, IBILI, Medicine Faculty, University of Coimbra, 3000-354 Coimbra, Portugal
| | - Rosa Fernandes
- Institute of Pharmacology & Experimental Therapeutics, IBILI, Medicine Faculty, University of Coimbra, 3000-354 Coimbra, Portugal
| | - Paulo Santos
- Functional Genomics Laboratory, Center of Histocompatibility of the Centre, 3001-301 Coimbra, Portugal
| | - Isabel Velada
- Functional Genomics Laboratory, Center of Histocompatibility of the Centre, 3001-301 Coimbra, Portugal
| | - Andreia Melo
- Institute of Pharmacology & Experimental Therapeutics, IBILI, Medicine Faculty, University of Coimbra, 3000-354 Coimbra, Portugal
| | - Sara Nunes
- Institute of Pharmacology & Experimental Therapeutics, IBILI, Medicine Faculty, University of Coimbra, 3000-354 Coimbra, Portugal
| | - Frederico Teixeira
- Institute of Pharmacology & Experimental Therapeutics, IBILI, Medicine Faculty, University of Coimbra, 3000-354 Coimbra, Portugal
- Institute for Molecular and Cellular Biology, Porto University, 4150 Porto, Portugal
| | - Flávio Reis
- Institute of Pharmacology & Experimental Therapeutics, IBILI, Medicine Faculty, University of Coimbra, 3000-354 Coimbra, Portugal
- Institute for Molecular and Cellular Biology, Porto University, 4150 Porto, Portugal
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Yeh TK, Tsai TY, Hsu T, Cheng JH, Chen X, Song JS, Shy HS, Chiou MC, Chien CH, Tseng YJ, Huang CY, Yeh KC, Huang YL, Huang CH, Huang YW, Wang MH, Tang HK, Chao YS, Chen CT, Jiaang WT. (2S,4S)-1-[2-(1,1-Dimethyl-3-oxo-3-pyrrolidin-1-yl-propylamino)acetyl]-4-fluoro-pyrrolidine-2-carbonitrile: A potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV. Bioorg Med Chem Lett 2010; 20:3596-600. [DOI: 10.1016/j.bmcl.2010.04.124] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2010] [Revised: 04/23/2010] [Accepted: 04/27/2010] [Indexed: 12/01/2022]
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Oeseburg H, de Boer RA, Buikema H, van der Harst P, van Gilst WH, Silljé HHW. Glucagon-like peptide 1 prevents reactive oxygen species-induced endothelial cell senescence through the activation of protein kinase A. Arterioscler Thromb Vasc Biol 2010; 30:1407-14. [PMID: 20448207 DOI: 10.1161/atvbaha.110.206425] [Citation(s) in RCA: 208] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
OBJECTIVE Endothelial cell senescence is an important contributor to vascular aging and is increased under diabetic conditions. Here we investigated whether the antidiabetic hormone glucagon-like peptide 1 (GLP-1) could prevent oxidative stress-induced cellular senescence in endothelial cells. METHODS AND RESULTS In Zucker diabetic fatty rats, a significant 2-fold higher level of vascular senescence was observed compared with control lean rats. Dipeptidyl-peptidase 4 (DPP-4) inhibition significantly increased GLP-1 levels in these animals and reduced senescence almost to lean animal levels. In vitro studies with human umbilical vein endothelial cells showed that GLP-1 had a direct protective effect on oxidative stress (H(2)O(2))-induced senescence and was able to attenuate oxidative stress-induced DNA damage and cellular senescence. The GLP-1 analogue exendin-4 provided similar results, whereas exendin fragment 9-39, a GLP-1 receptor antagonist, abolished this effect. Intracellular signaling by the phosphoinositide 3-kinase (PI3K)/Akt survival pathway did not appear to be involved. Further analysis revealed that GLP-1 activates the cAMP response element-binding (CREB) transcription factor in a cAMP/protein kinase A (PKA)-dependent manner, and inhibition of the cAMP/PKA pathway abolished the GLP-1 protective effect. Expression analysis revealed that GLP-1 can induce the oxidative defense genes HO-1 and NQO1. CONCLUSIONS Dipeptidyl-peptidase 4 inhibition protects against vascular senescence in a diabetic rat model. In vitro studies with human umbilical vein endothelial cells showed that reactive oxygen species-induced senescence was attenuated by GLP-1 in a receptor-dependent manner involving downstream PKA signaling and induction of antioxidant genes.
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Affiliation(s)
- Hisko Oeseburg
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713AV Groningen, the Netherlands
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Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes. Eur J Pharmacol 2009; 623:148-54. [PMID: 19765579 DOI: 10.1016/j.ejphar.2009.09.027] [Citation(s) in RCA: 111] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2009] [Revised: 08/30/2009] [Accepted: 09/08/2009] [Indexed: 11/24/2022]
Abstract
Inhibition of dipeptidyl peptidase-4 (DPP-4) activity has been shown to improve glycemic control in patients with type 2 diabetes by prolonging and potentiating the actions of incretin hormones. This study is designed to determine the effects of the DPP-4 inhibitor sitagliptin on improving islet function in a mouse model of insulin resistance and insulin secretion defects. ICR mice were pre-treated with high fat diet and a low dose of streptozotocin to induce insulin resistance and impaired insulin secretion, respectively. Diabetic mice were treated with sitagliptin or the sulfonylurea agent glipizide as admixture to high fat diet for ten weeks. Sustained reduction of blood glucose, HbA(1c), circulating glucagon and improvement in oral glucose tolerance were observed in mice treated with sitagliptin. In contrast, glipizide improved glycemic control only during the early weeks and to a lesser degree compared to sitagliptin, and had no effect on circulating glucagon levels or glucose tolerance. The improvement in glycemic control in sitagliptin-treated mice was associated with a significant increase in glucose-dependent insulin secretion in both perfused pancreas and isolated islets. Importantly, in contrast to the lack of effect by glipizide, sitagliptin significantly restored beta and alpha cell mass as well as alpha/beta cell ratio. These data indicate that DPP-4 inhibition by sitagliptin provided better overall improvement of glycemic control compared to glipizide in the high fat diet/streptozotocin induced diabetic mouse model. The ability of sitagliptin to enhance islet cell function may offer insight into the potential for disease modification.
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Saqib U, Siddiqi MI. 3D-QSAR studies on triazolopiperazine amide inhibitors of dipeptidyl peptidase-IV as anti-diabetic agents. SAR AND QSAR IN ENVIRONMENTAL RESEARCH 2009; 20:519-535. [PMID: 19916112 DOI: 10.1080/10629360903278677] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses were carried out on 45 triazolopiperazine amide derivatives as dipeptidyl peptidase IV (DPP-IV) inhibitors in order to elucidate their antidiabetic activities. The studies include Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). Models with good predictive abilities were generated with the cross-validated r(2) (r(2)(cv)) and conventional r(2) values of 0.589 and 0.868 for CoMFA and 0.586 and 0.868 for CoMSIA, respectively. Both models were validated by a test set of nine compounds and gave satisfactory predictive r(2) (r(2)(pred)) values of 0.816 and 0.863, respectively. CoMFA and CoMSIA contour maps were then used to analyse the structural features of the ligands to account for the activity in terms of positively contributing physicochemical properties: steric, electrostatic, hydrophobic and hydrogen bond acceptor fields. The information obtained from CoMFA and CoMSIA three-dimensional contour maps can be used for further design of triazolopiperazine amide-based analogues as anti-diabetic agents.
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Affiliation(s)
- U Saqib
- Molecular and Structural Biology Division, Central Drug Research Institute, Lucknow, India
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Tsai TY, Hsu T, Chen CT, Cheng JH, Chiou MC, Huang CH, Tseng YJ, Yeh TK, Huang CY, Yeh KC, Huang YW, Wu SH, Wang MH, Chen X, Chao YS, Jiaang WT. Rational design and synthesis of potent and long-lasting glutamic acid-based dipeptidyl peptidase IV inhibitors. Bioorg Med Chem Lett 2009; 19:1908-12. [DOI: 10.1016/j.bmcl.2009.02.061] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2008] [Revised: 02/06/2009] [Accepted: 02/16/2009] [Indexed: 10/21/2022]
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Kos K, Baker AR, Jernas M, Harte AL, Clapham JC, O'Hare JP, Carlsson L, Kumar S, McTernan PG. DPP-IV inhibition enhances the antilipolytic action of NPY in human adipose tissue. Diabetes Obes Metab 2009; 11:285-92. [PMID: 19175376 DOI: 10.1111/j.1463-1326.2008.00909.x] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
CONTEXT Dipeptidyl peptidase IV (DPP-IV) inactivates the incretin hormone glucagon-like peptide. It can also affect the orexigenic hormone neuropeptide Y (NPY(1-36)) which is truncated by DPP-IV to NPY(3-36), as a consequence NPY's affinity changes from receptor Y1, which mediates the antilipolytic function of NPY, to other NPY receptors. Little is known whether DPP-IV inhibitors for the treatment of type 2 diabetic (T2DM) patients could influence these pathways. AIMS To investigate the in vitro effects of NPY with DPP-IV inhibition in isolated abdominal subcutaneous (AbdSc) adipocytes on fat metabolism, and assessment of NPY receptor and DPP-IV expression in adipose tissue (AT). METHODS Ex vivo human AT was taken from women undergoing elective surgery (body mass index: 27.5 (mean +/- s.d.) +/- 5 kg/m2, age: 43.7 +/- 10 years, n = 36). Isolated AbdSc adipocytes were treated with human recombinant (rh)NPY (1-100 nM) with and without DPP-IV inhibitor (1 M); glycerol release and tissue distribution of DPP-IV, Y1 and Y5 messenger RNA (mRNA) were measured and compared between lean and obese subjects. RESULTS AND CONCLUSION rhNPY reduced glycerol release, an effect that was further enhanced by co-incubation with a DPP-IV inhibitor [control: 224 (mean +/- s.e.) +/- 37 micromol/l; NPY, 100 nM: 161 +/- 27 micromol/l**; NPY 100 nM/DPP-IV inhibitor, 1 M: 127 +/- 14 micromol/l**; **p < 0.01, n = 14]. DPP-IV was expressed in AbdSc AT and omental AT with relative DPP-IV mRNA expression lower in AbdSc AT taken from obese [77 +/- 6 signal units (SU)] vs. lean subjects (186 +/- 29 SU*, n = 10). Y1 was predominantly expressed in fat and present in all fat depots but higher in obese subjects, particularly the AbdSc AT-depot (obese: 1944 +/- 111 SU vs. lean: 711 +/- 112 SU**, n = 10). NPY appears to be regulated by AT-derived DPP-IV. DPP-IV inhibitors augment the antilipolytic effect of NPY in AT. Further studies are required to show whether this explains the lack of weight loss in T2DM patients treated with DPP-IV inhibitors.
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Affiliation(s)
- K Kos
- Unit for Diabetes and Metabolism, Clinical Sciences Research Institute (CSRI), Warwick Medical School, Coventry, UK
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Development, characterization, and evaluation of a fusion protein of a novel glucagon-like peptide-1 (GLP-1) analog and human serum albumin in Pichia pastoris. Biosci Biotechnol Biochem 2009; 73:688-94. [PMID: 19270384 DOI: 10.1271/bbb.80742] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Glucagon-like peptide-1 (GLP-1) has considerable potential as a possible therapeutic agent for type-2 diabetes. Unfortunately, this glucoincretin is short lived due to degradation by dipeptidyl-peptidase IV and rapid clearance by renal filtration. In this study, we attempted to extend GLP-1 action through the attachment of a lysine residue at the N-terminal of GLP-1 (named KGLP-1), and to make a fusion protein with human serum albumin (HSA) in Pichia pastoris. The protein, designated KGLP-1/HSA, was purified by an immunomagnetic separation technique. High performance liquid chromatography (HPLC) showed that the purified protein had an overall purity of 92.0%, and matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) confirmed the expected molecular mass of 70,297.8 Da. Additionally, the N-terminal sequence of KGLP-1/HSA was confirmed by N-terminal sequencing. The stability and biological activity of KGLP-1/HSA were then evaluated in vitro and in vivo. The findings indicated that fusion KGLP-1/HSA preserved the action of native GLP-1, and the active duration was greatly prolonged.
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Novel trans-2-aryl-cyclopropylamine analogues as potent and selective dipeptidyl peptidase IV inhibitors. Bioorg Med Chem 2009; 17:2388-99. [DOI: 10.1016/j.bmc.2009.02.020] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2008] [Revised: 02/04/2009] [Accepted: 02/05/2009] [Indexed: 11/21/2022]
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Jost MM, Lamerz J, Tammen H, Menzel C, De Meester I, Lambeir AM, Augustyns K, Scharpé S, Zucht HD, Rose H, Jürgens M, Schulz-Knappe P, Budde P. In vivo profiling of DPP4 inhibitors reveals alterations in collagen metabolism and accumulation of an amyloid peptide in rat plasma. Biochem Pharmacol 2009; 77:228-37. [DOI: 10.1016/j.bcp.2008.09.032] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2008] [Revised: 09/22/2008] [Accepted: 09/22/2008] [Indexed: 01/18/2023]
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MATSUI K, ODA T, NISHIZAWA E, SANO R, YAMAMOTO H, FUKUDA S, SASASE T, MIYAJIMA K, UEDA N, ISHII Y, OHTA T, MATSUSHITA M. Pancreatic Function of Spontaneously Diabetic Torii Rats in Pre-Diabetic Stage. Exp Anim 2009; 58:363-74. [DOI: 10.1538/expanim.58.363] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Affiliation(s)
- Kenichi MATSUI
- Japan Tobacco Inc., Central Pharmaceutical Research Institute
| | - Tomohiro ODA
- Japan Tobacco Inc., Central Pharmaceutical Research Institute
| | - Emiko NISHIZAWA
- Japan Tobacco Inc., Central Pharmaceutical Research Institute
| | - Ryuhei SANO
- Japan Tobacco Inc., Central Pharmaceutical Research Institute
| | - Hiromi YAMAMOTO
- Japan Tobacco Inc., Central Pharmaceutical Research Institute
| | - Sumiaki FUKUDA
- Japan Tobacco Inc., Central Pharmaceutical Research Institute
| | - Tomohiko SASASE
- Japan Tobacco Inc., Central Pharmaceutical Research Institute
| | | | - Nobuhisa UEDA
- Japan Tobacco Inc., Central Pharmaceutical Research Institute
| | - Yukihito ISHII
- Japan Tobacco Inc., Central Pharmaceutical Research Institute
| | - Takeshi OHTA
- Japan Tobacco Inc., Central Pharmaceutical Research Institute
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Chronic inhibition of dipeptidyl peptidase-IV with ASP8497 improved the HbA(1c) level, glucose intolerance, and lipid parameter level in streptozotocin-nicotinamide-induced diabetic mice. Naunyn Schmiedebergs Arch Pharmacol 2008; 379:191-9. [PMID: 18762913 DOI: 10.1007/s00210-008-0348-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2008] [Accepted: 08/15/2008] [Indexed: 10/21/2022]
Abstract
Dipeptidyl peptidase-IV (DPP-IV) is the primary inactivator of glucoregulatory incretin hormones, and DPP-IV inhibitors are expected to become a useful new class of anti-diabetic agent. The aim of the present study is to characterize the chronic in vivo profile of the DPP-IV inhibitor ASP8497. In streptozotocin-nicotinamide-induced diabetic mice, ASP8497 was administered orally for 3 weeks at 1, 3, or 10 mg/kg once daily, which improved the hemoglobin A(1c), non-fasting plasma insulin, fasting blood glucose levels, glucose intolerance, and lipid profiles (plasma triglyceride, non-esterified fatty acid and total cholesterol) with neutral effect on body weight. The pancreatic insulin content and hepatic phosphoenolpyruvate carboxykinase (PEPCK) activity recovered dose-dependently in ASP8497-treated groups. These results revealed that ASP8497 was successful in improving glycemic control and metabolic parameters in streptozotocin-nicotinamide-induced diabetic mice. It is therefore suggested that ASP8497 may be a potential agent for the treatment of type 2 diabetes.
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Augstein P, Berg S, Heinke P, Altmann S, Salzsieder E, Demuth HU, Freyse EJ. Efficacy of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide (P32/98) in fatty Zucker rats with incipient and manifest impaired glucose tolerance. Diabetes Obes Metab 2008; 10:850-61. [PMID: 17970756 DOI: 10.1111/j.1463-1326.2007.00813.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
AIM Incretin enhancers are a new class of antidiabetic drugs with promising therapeutic potential for type 2 diabetes. Therapeutic intervention in prediabetes is an attractive strategy for preventing or delaying diabetes onset. The aim of the present study was to investigate the therapeutic effects of incretin enhancement on incipient impaired glucose tolerance (iIGT) and manifest IGT (mIGT) using the dipeptidyl peptidase IV (DPP-4) inhibitor P32/98- and fatty Zucker rat (ZR, fa/fa) as a model. METHODS ZRs were classified into groups with iIGT and mIGT (n = 10 per group). P32/98 (21.61 mg/kg body weight) was administered orally to ZR with iIGT and mIGT once daily for 6 and 3 weeks respectively. Assessments included body weight, morning blood glucose and insulin, oral glucose tolerance test (oGTT; 2 g glucose/kg), plasma parameters and blood glucose day-night profile (DNP). In addition, glucose responsiveness of isolated islets and islet morphology were analysed. RESULTS P32/98 decreased non-fasting morning blood glucose more effectively in ZR with iIGT than in ZR with mIGT. Compared with study entry, P32/98 improved DNP of blood glucose in ZR with mIGT and nearly normalized DNP in ZR with iIGT. An acute bolus of inhibitor reduced glucose load during oGTT in rats chronically treated with placebo or P32/98. In contrast to placebo-treated rats, rats receiving long-term treatment with P32/98 required less insulin during oGTT. This effect was larger in rats with iIGT vs. rats with mIGT. In isolated pancreatic islets of ZR with mIGT, treatment with P32/98 decreased pancreatic insulin content and increased glucose responsiveness, while the beta-cell volume density was unaffected. P32/98 significantly reduced triglycerides and non-esterified fatty acids. Intestinal growth was comparable between inhibitor- and placebo-treated fatty rats. CONCLUSIONS Enhancement of incretin with the DPP-4 inhibitor P32/98 has therapeutic effects in hyperinsulinaemia, hyperglycaemia and IGT in ZR with iIGT and mIGT. Apparently, administration of P32/98 in ZR with iIGT results in more efficient beta-cell function, which is associated with less need for insulin to cope with deterioration of glucose tolerance. Importantly, P32/98 has a strong effect on dyslipidaemia in mIGT. P32/98 has no side effect on intestinal growth. Daily intake of P32/98 is a promising strategy for treatment of glucose intolerance and has the potential to prevent type 2 diabetes.
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Affiliation(s)
- P Augstein
- Institute of Diabetes 'Gerhardt Katsch', Karlsburg, Germany.
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Krishna R, Herman G, Wagner JA. Accelerating drug development using biomarkers: a case study with sitagliptin, a novel DPP4 inhibitor for type 2 diabetes. AAPS JOURNAL 2008; 10:401-9. [PMID: 18686043 DOI: 10.1208/s12248-008-9041-8] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2007] [Accepted: 04/28/2008] [Indexed: 12/28/2022]
Abstract
The leveraged use of biomarkers presents an opportunity in understanding target engagement and disease impact while accelerating drug development. For effective integration in drug development, it is essential for biomarkers to aid in the elucidation of mechanisms of action and disease progression. The recent years have witnessed significant progress in biomarker selection, validation, and qualification, while enabling surrogate and clinical endpoint qualification and application. Biomarkers play a central role in target validation for novel mechanisms. They also play a central role in the learning/confirming paradigm, particularly when utilized in concert with pharmacokinetic/pharmacodynamic modeling. Clearly, these attributes make biomarker integration attractive for scientific and regulatory applications to new drug development. In this review, applications of proximal, or target engagement, and distal, or disease-related, biomarkers are highlighted using the example of the recent development of sitagliptin for type 2 diabetes, wherein elucidation of target engagement and disease-related biomarkers significantly accelerated sitagliptin drug development. Importantly, use of biomarkers as tools facilitated design of clinical efficacy trials while streamlining dose focus and optimization, the net impact of which reduced overall cycle time to filing as compared to the industry average.
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Affiliation(s)
- Rajesh Krishna
- Department of Clinical Pharmacology, Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey, USA
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Chronic administration of alogliptin, a novel, potent, and highly selective dipeptidyl peptidase-4 inhibitor, improves glycemic control and beta-cell function in obese diabetic ob/ob mice. Eur J Pharmacol 2008; 588:325-32. [DOI: 10.1016/j.ejphar.2008.04.018] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2007] [Revised: 03/25/2008] [Accepted: 04/03/2008] [Indexed: 02/05/2023]
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