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Coadministration of sitagliptin or metformin has no major impact on the adverse metabolic outcomes induced by dexamethasone treatment in rats. Life Sci 2021; 286:120026. [PMID: 34627773 DOI: 10.1016/j.lfs.2021.120026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/20/2021] [Accepted: 10/01/2021] [Indexed: 11/23/2022]
Abstract
AIMS Glucocorticoids (GC) in excess cause glucose intolerance and dyslipidemia due to their diabetogenic actions. Conceptually, antidiabetic drugs should attenuate these side effects. Thus, we evaluated whether the coadministration of metformin or sitagliptin (or both) with dexamethasone could attenuate GC-induced adverse effects on metabolism. MATERIALS AND METHODS Adult male rats were treated for 5 consecutive days with dexamethasone (1 mg/kg, body mass (bm), intraperitoneally). Additional groups were coadministered with metformin (300 mg/kg, bm, by oral gavage (og)) or sitagliptin (20 mg/kg, bm, og) or with both compounds in combination. The day after the last treatments, rats were submitted to glucose tolerance tests, pyruvate tolerance test, and euthanized for biometric, biochemical, morphologic, and molecular analyses. KEY FINDINGS Dexamethasone treatment resulted in reduced body mass and food intake, increased blood glucose and plasma insulin, dyslipidemia, glucose intolerance, pyruvate intolerance, and increased hepatic content of glycogen and fat. Sitagliptin coadministration improved glucose tolerance compared with the control group, an effect paralleled with higher levels of active GLP-1 during an oral GTT. Overall, sitagliptin or metformin coadministration did not prevent any of the dexamethasone-induced metabolic disturbances. SIGNIFICANCE Coadministration of sitagliptin or metformin result in no major improvement of glucose and lipid metabolism altered by dexamethasone treatment in male adult rats.
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Abdalla MA, Deshmukh H, Atkin S, Sathyapalan T. The potential role of incretin-based therapies for polycystic ovary syndrome: a narrative review of the current evidence. Ther Adv Endocrinol Metab 2021; 12:2042018821989238. [PMID: 33552465 PMCID: PMC7844452 DOI: 10.1177/2042018821989238] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 01/03/2021] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age. Metabolic consequences associated with PCOS include, but are not limited to, insulin resistance (IR), type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). This narrative review aims to provide a comprehensive overview of the potential therapeutic roles of the incretin-based therapies in the management of PCOS. METHODS We performed a systematic search of databases including PubMed, MEDLINE and EMBASE up to 1 October 2020. We developed a search string of medical subject headings (MeSH) including the terms PCOS, incretin mimetics, glucagon-like peptide-1 (GLP-1), glucagon-like peptide-1 receptor antagonists (GLP-1 RAs), liraglutide, exenatide, semaglutide, dipeptidyl peptidase-4 (DPP-4) inhibitors, combined with IR, testosterone and sex hormone-binding globulin (SHBG). RESULTS We identified 854 relevant articles and, after the initial screening, eight interventional animal studies, one observational animal study, 14 interventional human studies, two case-control studies and one systematic review were included. These studies showed the potential significant roles of GLP-1 RAs and DPP-4 inhibitors in the management of PCOS, with significant improvements in the metabolic parameters, including substantial weight reduction and improved insulin sensitivity. These agents also improved the hormonal parameters through decreased free androgen and increased SHBG. Moreover, they improved menstrual regularity, increased fertility with enhanced ovulation and pregnancy in obese women with PCOS. CONCLUSION GLP-1 RAs and DPP-4 inhibitors have a promising therapeutic role in PCOS; however, larger clinical trials are needed to establish the role of incretin-based therapies in the management of PCOS.
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Affiliation(s)
- Mohammed Altigani Abdalla
- Department of Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull, UK
| | - Harshal Deshmukh
- Department of Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull, UK
| | - Stephen Atkin
- School of Postgraduate Studies and Research, RCSI Medical University of Bahrain, Kingdom of Bahrain
| | - Thozhukat Sathyapalan
- Department of Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull, UK
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Rameshrad M, Razavi BM, Ferns GAA, Hosseinzadeh H. Pharmacology of dipeptidyl peptidase-4 inhibitors and its use in the management of metabolic syndrome: a comprehensive review on drug repositioning. ACTA ACUST UNITED AC 2019; 27:341-360. [PMID: 30674032 DOI: 10.1007/s40199-019-00238-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Accepted: 01/02/2019] [Indexed: 12/14/2022]
Abstract
OBJECTIVES Despite advances in our understanding of metabolic syndrome (MetS) and the treatment of each of its components separately, currently there is no single therapy approved to manage it as a single condition. Since multi-drug treatment increases drug interactions, decreases patient compliance and increases health costs, it is important to introduce single therapies that improve all of the MetS components. EVIDENCE ACQUISITION We conducted a PubMed, Scopus, Google Scholar, Web of Science, US FDA, utdo.ir and clinicaltrial.gov search, gathered the most relevant preclinical and clinical studies that have been published since 2010, and discussed the beneficial effects of dipeptidyl peptidase (DPP)-4 inhibitors to prevent and treat different constituent of the MetS as a single therapy. Furthermore, the pharmacology of DPP-4 inhibitors, focusing on pharmacodynamics, pharmacokinetics, drug interactions and their side effects are also reviewed. RESULTS DPP-4 inhibitors or gliptins are a new class of oral anti-diabetic drugs that seem safe drugs with no severe side effects, commonly GI disturbance, infection and inflammatory bowel disease. They increase mass and function of pancreatic β-cells, and insulin sensitivity in liver, muscle and adipose tissue. It has been noted that gliptin therapy decreases dyslipidemia. DPP-4 inhibitors increase fatty oxidation, and cholesterol efflux, and decrease hepatic triglyceride synthase and de novo lipogenesis. They delay gastric emptying time and lead to satiety. Besides, gliptin therapy has anti-inflammatory and anti-atherogenic impacts, and improves endothelial function and reduces vascular stiffness. CONCLUSION The gathered data prove the efficacy of DPP-4 inhibitors in managing MetS in some levels beyond anti-diabetic effects. This review could be a lead for designing new DPP-4 inhibitors with greatest effects on MetS in future. Introducing drugs with polypharmacologic effects could increase the patient's compliance and decrease the health cost that there is not in multi-drug therapy. Graphical abstract ᅟ.
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Affiliation(s)
- Maryam Rameshrad
- Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Bibi Marjan Razavi
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A A Ferns
- Brighton & Sussex Medical School, Department of Medical Education, Mayfield House, Falmer, Brighton, West Sussex, BN1 9PH, UK
| | - Hossein Hosseinzadeh
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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Lipidized prolactin-releasing peptide improved glucose tolerance in metabolic syndrome: Koletsky and spontaneously hypertensive rat study. Nutr Diabetes 2018; 8:5. [PMID: 29339795 PMCID: PMC5851428 DOI: 10.1038/s41387-017-0015-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 11/01/2017] [Indexed: 12/21/2022] Open
Abstract
Background/Objectives Prolactin-releasing peptide (PrRP) has a potential to decrease food intake and ameliorate obesity, but is ineffective after peripheral administration. We have previously shown that our novel lipidized analogs PrRP enhances its stability in the circulation and enables its central effect after peripheral application. The purpose of this study was to explore if sub-chronic administration of novel PrRP analog palmitoylated in position 11 (palm11-PrRP31) to Koletsky-spontaneously hypertensive obese rats (SHROB) could lower body weight and glucose intolerance as well as other metabolic parameters. Subjects/Methods The SHROB rats (n = 16) were used for this study and age-matched hypertensive lean SHR littermates (n = 16) served as controls. Palm11-PrRP31 was administered intraperitoneally to SHR and SHROB (n = 8) at a dose of 5 mg/kg once-daily for 3 weeks. During the dosing period food intake and body weight were monitored. At the end of the experiment the oral glucose tolerance test was performed; plasma and tissue samples were collected. Thereafter, arterial blood pressure was measured. Results At the end of the experiment, vehicle-treated SHROB rats showed typical metabolic syndrome parameters, including obesity, glucose intolerance, dyslipidemia, and hypertension. Peripheral treatment with palm11-PrRP31 progressively decreased the body weight of SHR rats but not SHROB rats, though glucose tolerance was markedly improved in both strains. Moreover, in SHROB palm11-PrRP31 ameliorated the HOMA index, insulin/glucagon ratio, and increased insulin receptor substrate 1 and 2 expression in fat and insulin signaling in the hypothalamus, while it had no effect on blood pressure. Conclusions We demonstrated that our new lipidized PrRP analog is capable of improving glucose tolerance in obese SHROB rats after peripheral application, suggesting that its effect on glucose metabolism is independent of leptin signaling and body weight lowering. These data suggest that this analog has the potential to be a compound with both anti-obesity and glucose-lowering properties.
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Farr OM, Mantzoros CS. Treatment options to prevent diabetes in subjects with prediabetes: Efficacy, cost effectiveness and future outlook. Metabolism 2017; 70:192-195. [PMID: 28095990 PMCID: PMC5871912 DOI: 10.1016/j.metabol.2016.12.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Accepted: 12/31/2016] [Indexed: 01/18/2023]
Affiliation(s)
- Olivia M Farr
- Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA 02215.
| | - Christos S Mantzoros
- Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA 02215
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Mietlicki-Baase EG, McGrath LE, Koch-Laskowski K, Krawczyk J, Pham T, Lhamo R, Reiner DJ, Hayes MR. Hindbrain DPP-IV inhibition improves glycemic control and promotes negative energy balance. Physiol Behav 2017; 173:9-14. [PMID: 28119159 DOI: 10.1016/j.physbeh.2017.01.038] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 01/20/2017] [Accepted: 01/20/2017] [Indexed: 02/06/2023]
Abstract
The beneficial glycemic and food intake-suppressive effects of glucagon-like peptide-1 (GLP-1) have made this neuroendocrine system a leading target for pharmacological approaches to the treatment of diabetes and obesity. One strategy to increase the activity of endogenous GLP-1 is to prevent the rapid degradation of the hormone by the enzyme dipeptidyl peptidase-IV (DPP-IV). However, despite the expression of both DPP-IV and GLP-1 in the brain, and the clear importance of central GLP-1 receptor (GLP-1R) signaling for glycemic and energy balance control, the metabolic effects of central inhibition of DPP-IV activity are unclear. To test whether hindbrain DPP-IV inhibition suppresses blood glucose, feeding, and body weight gain, the effects of 4th intracerebroventricular (ICV) administration of the FDA-approved DPP-IV inhibitor sitagliptin were evaluated. Results indicate that hindbrain delivery of sitagliptin improves glycemic control in a GLP-1R-dependent manner, suggesting that this effect is due at least in part to increased endogenous brainstem GLP-1 activity after sitagliptin administration. Furthermore, 4th ICV injection of sitagliptin reduced 24h body weight gain and energy intake, with a selective suppression of high-fat diet, but not chow, intake. These data reveal a novel role for hindbrain GLP-1R activation in glycemic control and also demonstrate that DPP-IV inhibition in the caudal brainstem promotes negative energy balance.
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Affiliation(s)
- Elizabeth G Mietlicki-Baase
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Lauren E McGrath
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Kieran Koch-Laskowski
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Joanna Krawczyk
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Tram Pham
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Rinzin Lhamo
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - David J Reiner
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Matthew R Hayes
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
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Magdy YM, El-Kharashi OA, Nabih ES, Shaker SM, Abd-Elaziz LF, Aboul-Fotouh S. Potential involvement of JNK1 repression in the hepatic effect of sitagliptin and metformin in rats subjected to high fat diet and chronic mild distress. Biomed Pharmacother 2017; 85:225-238. [DOI: 10.1016/j.biopha.2016.10.098] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 10/30/2016] [Accepted: 10/31/2016] [Indexed: 12/16/2022] Open
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Hou YC, Yang SH, Wu YT, Lai CH. Alterations of neocortico-limbic association fibers and correlation with diet in prediabetes diagnosed by impaired fasting glucose. J Magn Reson Imaging 2016; 43:1500-6. [PMID: 26756544 DOI: 10.1002/jmri.25127] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 12/01/2015] [Indexed: 12/13/2022] Open
Abstract
PURPOSE To assess the existence of alterations in the micro-integrity of the fasciculus in prediabetic subjects. The issue of micro-integrity in white matter tracts has not been adequately addressed in prediabetes. MATERIALS AND METHODS Sixty-four prediabetic subjects and 54 controls were enrolled. All participants completed 24-hour diet records and 3-day diet records and received diffusion tensor imaging at 3T. The data for white matter micro-integrity were analyzed and compared between prediabetic subjects and controls with age and gender as covariates. In addition, voxel-wise regression between white matter micro-integrity, diet, and preprandial glucose levels were used to explore the relationship between white matter micro-integrity and diet or serum glucose levels. RESULTS We found that prediabetic subjects had significant reductions in the micro-integrity of bilateral anterior thalamic radiation, left inferior longitudinal fasciculus, and left superior longitudinal fasciculus (corrected P < 0.05). In addition, total carbohydrate intake amount and preprandial serum glucose levels were negatively correlated with the micro-integrity in the left inferior longitudinal fasciculus and left anterior thalamic radiation (r: -0.47, corrected P < 0.05). CONCLUSION Restrictive alterations in the white matter micro-integrity of the anterior thalamic radiation and inferior and superior longitudinal fasciculi might represent the initial "hot spots" for white matter tract alterations, which might play a role in the development of prediabetes. J. Magn. Reson. Imaging 2016;43:1500-1506.
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Affiliation(s)
- Yi-Cheng Hou
- Department of Nutrition, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan, ROC
| | - Shwu-Huey Yang
- School of Nutrition and Health Sciences, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan, ROC
| | - Yu-Te Wu
- Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan, ROC.,Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan, ROC.,Brain Research Center, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Chien-Han Lai
- Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan, ROC.,Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan, ROC.,Department of Psychiatry, Cheng Hsin General Hospital, Taipei City, Taiwan, ROC
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Murad HAS, Saleh HA, Abdulaziz GS, Abdulsattar MA, Ali SS. Effect of metformin and pioglitazone on β-catenin and biochemical markers in sitagliptin-induced pancreatitis in diabetic rats. Int J Diabetes Dev Ctries 2015. [DOI: 10.1007/s13410-014-0278-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Ishikawa M, Takai M, Maeda H, Kanamori A, Kubota A, Amemiya H, Iizuka T, Iemitsu K, Iwasaki T, Uehara G, Umezawa S, Obana M, Kaneshige H, Kaneshiro M, Kawata T, Sasai N, Saito T, Takuma T, Takeda H, Tanaka K, Tsurui N, Nakajima S, Hoshino K, Honda S, Machimura H, Matoba K, Minagawa F, Minami N, Miyairi Y, Mokubo A, Motomiya T, Waseda M, Miyakawa M, Naka Y, Terauchi Y, Tanaka Y, Matsuba I. Factors Predicting Therapeutic Efficacy of Combination Treatment With Sitagliptin and Insulin in Type 2 Diabetic Patients: The ASSIST-K Study. J Clin Med Res 2015; 7:607-12. [PMID: 26124906 PMCID: PMC4471747 DOI: 10.14740/jocmr2149w] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/19/2015] [Indexed: 12/17/2022] Open
Abstract
Background It is unclear whether dipeptidyl peptidase-4 inhibitors decrease hemoglobin A1c (HbA1c) in a glucose-dependent manner in patients on insulin therapy who have impaired insulin secretion. This study investigated factors influencing the efficacy of sitagliptin when used concomitantly with insulin to treat type 2 diabetes mellitus (T2DM) in the real-world setting. Methods A retrospective study was conducted of 1,004 T2DM patients at 36 Japanese clinics associated with the Diabetes Task Force of the Kanagawa Physicians Association. Eligible patients had been on insulin for at least 6 months, with a baseline HbA1c of 7.0% (53 mmol/mol) or higher. Baseline characteristics and laboratory data from 495 patients were subjected to multiple regression analysis to identify factors influencing the change of HbA1c. Results Most patients (n = 809) received sitagliptin at a dose of 50 mg. In the 1,004 patients, HbA1c decreased by 0.74% (6 mmol/mol) and body weight increased by 0.1 kg after 6 months of combination therapy. Multiple regression analysis showed that a higher baseline HbA1c, older age, and lower body mass index influenced the change of HbA1c after 6 months. Hypoglycemic symptoms occurred in 7.4%, but none were severe. Conclusions These results emphasize the importance of a higher HbA1c at the commencement of sitagliptin therapy in patients on insulin. Glucose-dependent suppression of glucagon secretion by sitagliptin may be useful in patients with impaired insulin secretion. Sitagliptin can be used concomitantly with insulin irrespective of the insulin regimen, duration of insulin treatment, and concomitant medications.
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Affiliation(s)
- Masashi Ishikawa
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Masahiko Takai
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Hajime Maeda
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Akira Kanamori
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Akira Kubota
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Hikaru Amemiya
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Takashi Iizuka
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Kotaro Iemitsu
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Tomoyuki Iwasaki
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Goro Uehara
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Shinichi Umezawa
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Mitsuo Obana
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Hideaki Kaneshige
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Mizuki Kaneshiro
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Takehiro Kawata
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Nobuo Sasai
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Tatsuya Saito
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Tetsuo Takuma
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Hiroshi Takeda
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Keiji Tanaka
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Nobuaki Tsurui
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Shigeru Nakajima
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Kazuhiko Hoshino
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Shin Honda
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Hideo Machimura
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Kiyokazu Matoba
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Fuyuki Minagawa
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Nobuaki Minami
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Yukiko Miyairi
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Atsuko Mokubo
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Tetsuya Motomiya
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Manabu Waseda
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Masaaki Miyakawa
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Yoshikazu Naka
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Yasushi Tanaka
- Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa 216-8511, Japan
| | - Ikuro Matsuba
- The Study Group of the Diabetes Committee, Kanagawa Physicians Association, 3-1 Fujimi-cho, Naka-ku, Yokoyama City, Kanagawa 231-0037, Japan
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Mamza J, Mehta R, Donnelly R, Idris I. Comparative Efficacy of Adding Sitagliptin to Metformin, Sulfonylurea or Dual Therapy: A Propensity Score-Weighted Cohort Study. Diabetes Ther 2015; 6:213-26. [PMID: 26014844 PMCID: PMC4478174 DOI: 10.1007/s13300-015-0110-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Indexed: 12/20/2022] Open
Abstract
INTRODUCTION The aim of this study was to assess the efficacy of co-administering sitagliptin to patients with inadequate glycemic control following treatment with metformin (MET), sulfonylurea (SU), or MET + SU. METHODS A cohort of 25,386 patients with type 2 diabetes mellitus (hemoglobin A1c [HbA1C] >53 mmol/mol or 7%), newly treated with sitagliptin between 2007 and 2013, was sourced from UK general practices via The Health Improvement Network database. Among these, eligible patients were segregated into three groups: MET (n = 3364), SU (n = 509), or MET + SU therapy (n = 5929). The relative efficacy of sitagliptin added to SU or MET + SU compared with sitagliptin added to MET monotherapy was assessed with regards to HbA1c and body weight changes from baseline up to 52 weeks. The glycemic efficacy was a measure of average treatment effects obtained from multivariable linear regression models and propensity score-matching analysis. RESULTS A total of 9802 patients were included in the study. Overall, addition of sitagliptin 100 mg once daily resulted in 5.5 mmol/mol (0.5%) HbA1c reduction (P < 0.001) and 0.8 kg weight reduction at 1 year (P < 0.001). Efficacy was similar across the treatment groups, but in patients with baseline HbA1c ≥9% adding sitagliptin to MET + SU produced a significantly smaller reduction in HbA1c when compared to the reference group MET (MET + SU vs. MET only: -0.5% vs. -0.7%, P < 0.001). The mean HbA1c reduction from baseline within this subgroup of patients was not significantly different between SU and MET monotherapies (-0.8% vs. -0.7%, respectively, P = 0.4). Across treatment groups, HbA1c reductions with add-on sitagliptin occurred after 24 weeks of treatment with a peak reduction occurring between 36 and 48 weeks, and receded after week 48. CONCLUSION In a real-world general practice setting, sitagliptin was effective in patients with suboptimal glycemic control with MET, SU or dual therapy, maximum between 36 and 48 weeks, but in patients with HbA1c of >9% receiving MET + SU therapy, adding sitagliptin, as a third agent, conferred minimal benefit.
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Affiliation(s)
- Jil Mamza
- Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Royal Derby Hospital, Nottingham, UK
| | - Rajnikant Mehta
- Research Design Services, East Midlands (RDS EM), School of Medicine, University of Nottingham, Queens Medical Centre, Nottingham, UK
| | - Richard Donnelly
- Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Royal Derby Hospital, Nottingham, UK
| | - Iskandar Idris
- Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Royal Derby Hospital, Nottingham, UK
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Apaijai N, Pintana H, Chattipakorn SC, Chattipakorn N. Effects of vildagliptin versus sitagliptin, on cardiac function, heart rate variability and mitochondrial function in obese insulin-resistant rats. Br J Pharmacol 2015; 169:1048-57. [PMID: 23488656 DOI: 10.1111/bph.12176] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2012] [Revised: 02/26/2013] [Accepted: 03/09/2013] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND AND PURPOSE Long-term high-fat diet (HFD) consumption has been shown to cause insulin resistance, which is characterized by hyperinsulinaemia with metabolic inflexibility. Insulin resistance is associated with cardiac sympathovagal imbalance, cardiac dysfunction and cardiac mitochondrial dysfunction. Dipeptidyl peptidase-4 (DPP-4) inhibitors, vildagliptin and sitagliptin, are oral anti-diabetic drugs often prescribed in patients with cardiovascular disease. Therefore, in this study, we sought to determine the effects of vildagliptin and sitagliptin in a murine model of insulin resistance. EXPERIMENTAL APPROACH Male Wistar rats weighing 180-200 g, were fed either a normal diet (20% energy from fat) or a HFD (59% energy from fat) for 12 weeks. These rats were then divided into three subgroups to receive vildagliptin (3 mg·kg(-1)·day(-1)), sitagliptin (30 mg·kg(-1)·day(-1)) or vehicle for another 21 days. Metabolic parameters, oxidative stress, heart rate variability (HRV), cardiac function and cardiac mitochondrial function were determined. KEY RESULTS Rats that received HFD developed insulin resistance characterized by increased body weight, plasma insulin, total cholesterol and oxidative stress levels along with a decreased high-density lipoprotein (HDL) level. Moreover, cardiac dysfunction, depressed HRV, cardiac mitochondrial dysfunction and cardiac mitochondrial morphology changes were observed in HFD rats. Both vildagliptin and sitagliptin decreased plasma insulin, total cholesterol and oxidative stress as well as increased HDL level. Furthermore, vildagliptin and sitagliptin attenuated cardiac dysfunction, prevented cardiac mitochondrial dysfunction and completely restored HRV. CONCLUSIONS AND IMPLICATIONS Both vildagliptin and sitagliptin share similar efficacy in cardioprotection in obese insulin-resistant rats.
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Affiliation(s)
- Nattayaporn Apaijai
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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Canneva F, Golub Y, Distler J, Dobner J, Meyer S, von Hörsten S. DPP4-deficient congenic rats display blunted stress, improved fear extinction and increased central NPY. Psychoneuroendocrinology 2015; 53:195-206. [PMID: 25635612 DOI: 10.1016/j.psyneuen.2015.01.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 01/09/2015] [Accepted: 01/09/2015] [Indexed: 12/31/2022]
Abstract
BACKGROUND Inhibitors of dipeptidyl peptidase 4 (DPP4, CD26) are used for the treatment of type 2 diabetic patients and better glucose tolerance has been confirmed in functionally DPP4-deficient congenic rats (DPP4mut), along with immunological alterations and, interestingly, a stress-resilient phenotype. All these findings are in agreement with the "moonlighting" properties of DPP4, whose proteolytic action is responsible for the inactivation of a number of regulatory peptides including, but not limited to, neuropeptide Y (NPY). Among all candidate substrates, DPP4 displays highest affinity for NPY, an endogenous anxiolytic neurotransmitter that is suggested as a candidate biomarker in post-traumatic stress disorder (PTSD) and depression. METHODS AND RESULTS Central and peripheral NPY levels were measured by ELISA in DPP4mut and DAwt rats revealing a significantly higher concentration of the peptide in the CSF of DPP4mut animals. This finding positively correlated with the blunted stress phenotype measured on an analgesia-meter. Additionally, when a classical fear-conditioning paradigm was investigated, short-term fear extinction was significantly potentiated in DPP4mut rats as compared to wt controls. CONCLUSIONS Our findings indicate a positive correlation between reduced stress-responsiveness and increased central NPY, in DPP4mut rats. Most interestingly, the behavioral phenotype extends to facilitation of fear extinction. These observations raise further interest in DPP4-modulating drugs for the potential effect on NPY metabolism, as a therapeutic tool for psychiatric conditions such as anxiety disorders and PTSD.
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Affiliation(s)
- Fabio Canneva
- Department of Experimental Therapy, Präklinisches Experimentelles Tierzentrum, Univerisitätsklinikum Erlangen, 91054 Erlangen, Germany.
| | - Yulia Golub
- Department of Child and Adolescent Mental Health, University Clinic of Erlangen, 91054 Erlangen, Germany
| | - Joerg Distler
- Department of Experimental Therapy, Präklinisches Experimentelles Tierzentrum, Univerisitätsklinikum Erlangen, 91054 Erlangen, Germany
| | - Julia Dobner
- Department of Experimental Therapy, Präklinisches Experimentelles Tierzentrum, Univerisitätsklinikum Erlangen, 91054 Erlangen, Germany
| | - Sandra Meyer
- Department of Experimental Therapy, Präklinisches Experimentelles Tierzentrum, Univerisitätsklinikum Erlangen, 91054 Erlangen, Germany
| | - Stephan von Hörsten
- Department of Experimental Therapy, Präklinisches Experimentelles Tierzentrum, Univerisitätsklinikum Erlangen, 91054 Erlangen, Germany
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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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Lee TM, Chen WT, Yang CC, Lin SZ, Chang NC. Sitagliptin attenuates sympathetic innervation via modulating reactive oxygen species and interstitial adenosine in infarcted rat hearts. J Cell Mol Med 2014; 19:418-29. [PMID: 25388908 PMCID: PMC4407589 DOI: 10.1111/jcmm.12465] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Accepted: 09/15/2014] [Indexed: 12/24/2022] Open
Abstract
We investigated whether sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, attenuates arrhythmias through inhibiting nerve growth factor (NGF) expression in post-infarcted normoglycemic rats, focusing on adenosine and reactive oxygen species production. DPP-4 bound adenosine deaminase has been shown to catalyse extracellular adenosine to inosine. DPP-4 inhibitors increased adenosine levels by inhibiting the complex formation. Normoglycemic male Wistar rats were subjected to coronary ligation and then randomized to either saline or sitagliptin in in vivo and ex vivo studies. Post-infarction was associated with increased oxidative stress, as measured by myocardial superoxide, nitrotyrosine and dihydroethidium fluorescent staining. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated infarcted rats compared with sham. Compared with vehicle, infarcted rats treated with sitagliptin significantly increased interstitial adenosine levels and attenuated oxidative stress. Sympathetic hyperinnervation was blunted after administering sitagliptin, as assessed by immunofluorescent analysis and western blotting and real-time quantitative RT-PCR of NGF. Arrhythmic scores in the sitagliptin-treated infarcted rats were significantly lower than those in vehicle. Ex vivo studies showed a similar effect of erythro-9-(2-hydroxy-3-nonyl) adenine (an adenosine deaminase inhibitor) to sitagliptin on attenuated levels of superoxide and NGF. Furthermore, the beneficial effects of sitagliptin on superoxide anion production and NGF levels can be reversed by 8-cyclopentyl-1,3-dipropulxanthine (adenosine A1 receptor antagonist) and exogenous hypoxanthine. Sitagliptin protects ventricular arrhythmias by attenuating sympathetic innervation via adenosine A1 receptor and xanthine oxidase-dependent pathways, which converge through the attenuated formation of superoxide in the non-diabetic infarcted rats.
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Affiliation(s)
- Tsung-Ming Lee
- Department of Medicine, Cardiology Section, China Medical University-An Nan Hospital, Tainan, Taiwan; Department of Medicine, China Medical University, Taichung, Taiwan; Department of Internal Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan
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Reimer RA, Grover GJ, Koetzner L, Gahler RJ, Lyon MR, Wood S. Combining sitagliptin/metformin with a functional fiber delays diabetes progression in Zucker rats. J Endocrinol 2014; 220:361-73. [PMID: 24389593 DOI: 10.1530/joe-13-0484] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Our primary objective was to determine whether administering the viscous and fermentable polysaccharide PolyGlycopleX (PGX) with metformin (MET) or sitagliptin/metformin (S/MET) reduces hyperglycemia in Zucker diabetic fatty (ZDF) rats more so than monotherapy of each. Glucose tolerance, adiposity, satiety hormones and mechanisms related to dipeptidyl peptidase 4 activity, gut microbiota and, hepatic and pancreatic histology were examined. Male ZDF rats (9-10 weeks of age) were randomized to: i) cellulose/vehicle (control, C); ii) PGX (5% wt/wt)/vehicle (PGX); iii) cellulose/metformin (200 mg/kg) (MET); iv) cellulose/S/MET (10 mg/kg+200 mg/kg) (S/MET); v) PGX (5%)+MET (200 mg/kg) (PGX+MET); vi) cellulose/sitagliptin/MET (5%)+(10 mg/kg+200 mg/kg) (PGX+S/MET) for 6 weeks. PGX+MET and PGX+S/MET reduced glycemia compared with C and singular treatments (P=0.001). Weekly fasted and fed blood glucose levels were lower in PGX+MET and PGX+S/MET compared with all other groups at weeks 4, 5, and 6 (P=0.001). HbA1c was lower in PGX+S/MET than C, MET, S/MET, and PGX at week 6 (P=0.001). Fat mass was lower and GLP1 was higher in PGX+S/MET compared with all other groups (P=0.001). β-cell mass was highest and islet degeneration lowest in PGX+S/MET. Hepatic lipidosis was significantly lower in PGX+S/MET compared with PGX or S/MET alone. When combined with PGX, both MET and S/MET markedly reduce glycemia; however, PGX+S/MET appears advantageous over PGX+MET in terms of increased β-cell mass and reduced adiposity. Both combination treatments attenuated diabetes in the obese Zucker rat.
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Affiliation(s)
- Raylene A Reimer
- Faculty of Kinesiology Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, 2500 University Drive Northwest, Calgary, Alberta, Canada T2N 1N4 Product Safety Labs, Department of Pharmacology, Dayton, New Jersey, USA Department of Physiology and Biophysics, Robert Wood Johnson Medical School, Piscataway, New Jersey, USA Factors Group of Nutritional Companies, Inc. R&D, 3655 Bonneville Place, Burnaby, British Columbia, Canada Canadian Centre for Functional Medicine, 1552 United Boulevard, Coquitlam, British Columbia, Canada University of British Columbia, Food, Nutrition and Health Program, Vancouver, British Columbia, Canada
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Hemmeryckx B, Swinnen M, Gallacher DJ, Rong Lu H, Roger Lijnen H. Effect of sitagliptin treatment on metabolism and cardiac function in genetic diabetic mice. Eur J Pharmacol 2014; 723:175-80. [DOI: 10.1016/j.ejphar.2013.12.036] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 12/08/2013] [Accepted: 12/14/2013] [Indexed: 01/23/2023]
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Abstract
Although obesity is a well-known risk factor for hypertension, the mechanisms by which hypertension develops in obese patients are not entirely clear. Animal models of obesity and their different susceptibilities to develop hypertension have revealed some of the mechanisms linking obesity and hypertension. Adipose tissue is an endocrine organ secreting hormones that impact blood pressure, such as elements of the renin-angiotensin system whose role in hypertension have been established. In addition, the appetite-suppressing adipokine leptin activates the sympathetic nervous system via the melanocortin system, and this activation, especially in the kidney, increases blood pressure. Leptin secretion from adipocytes is increased in most models of obesity due to leptin resistance, although the resistance is often selective to the anorexigenic effect, while the susceptibility to the hypertensive effect remains intact. Understanding the pathways by which obesity contributes to increased blood pressure will hopefully pave the way to and better define the appropriate treatment for obesity-induced hypertension.
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19
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Renoprotective effect of sitagliptin against hypertensive nephropathy induced by chronic administration of L-NAME in rats: Role of GLP-1 and GLP-1 receptor. Eur J Pharmacol 2013; 720:158-65. [DOI: 10.1016/j.ejphar.2013.10.033] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Revised: 10/11/2013] [Accepted: 10/17/2013] [Indexed: 01/21/2023]
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Fellmann L, Regnault V, Greney H, Gasparik V, Muscat A, Max JP, Gigou L, Oréa V, Chetrite G, Pizard A, Niederhoffer N, Julien C, Lacolley P, Fève B, Bousquet P. A new pyrroline compound selective for I1-imidazoline receptors improves metabolic syndrome in rats. J Pharmacol Exp Ther 2013; 346:370-80. [PMID: 23818682 DOI: 10.1124/jpet.113.205328] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2025] Open
Abstract
Symptoms of the metabolic syndrome (MetS), such as insulin resistance, obesity, and hypertension, have been associated with sympathetic hyperactivity. In addition, the adiponectin pathway has interesting therapeutic potentials in MetS. Our purpose was to investigate how targeting both the sympathetic nervous system and the adipose tissue (adiponectin secretion) with a drug selective for nonadrenergic I1-imidazoline receptors (I1Rs) may represent a new concept in MetS pharmacotherapy. LNP599 [3-chloro-2-methyl-phenyl)-(4-methyl-4,5-dihydro-3H-pyrrol-2-yl)-amine hydrochloride], a new pyrroline derivative, displaced the specific [(125)I]para-iodoclonidine binding to I1R with nanomolar affinity and had no significant affinity for a large set of receptors, transporters, and enzymes. In addition, it can cross the blood-brain barrier and has good intestinal absorption, permitting oral as well as intravenous delivery. The presence of I1Rs was demonstrated in 3T3-L1 adipocytes; LNP599 had a specific stimulatory action on adiponectin secretion in adipocytes. Short-term administration of LNP599 (10 mg/kg i.v.) in anesthetized Sprague-Dawley rats markedly decreased sympathetic activity, causing hypotension and bradycardia. Long-term treatment of spontaneously hypertensive heart failure rats with LNP599 (20 mg/kg PO) had favorable effects on blood pressure, body weight, insulin resistance, glucose tolerance, and lipid profile, and it increased plasma adiponectin. The pyrroline derivative, which inhibits sympathetic activity and stimulates adiponectin secretion, has beneficial effects on all the MetS abnormalities. The use of one single drug with both actions may constitute an innovative strategy for the management of MetS.
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Affiliation(s)
- Lyne Fellmann
- Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université de Strasbourg, France
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Pintana H, Apaijai N, Chattipakorn N, Chattipakorn SC. DPP-4 inhibitors improve cognition and brain mitochondrial function of insulin-resistant rats. J Endocrinol 2013; 218:1-11. [PMID: 23591914 DOI: 10.1530/joe-12-0521] [Citation(s) in RCA: 147] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Recent evidence has demonstrated that insulin resistance is related to the development of type 2 diabetes mellitus. Our previous study found that high-fat diet (HFD) consumption caused not only peripheral and brain insulin resistance but also brain mitochondrial dysfunction and cognitive impairment. Vildagliptin and sitagliptin, dipeptidyl-peptidase-4 inhibitors, are recently developed anti-diabetic drugs. However, the effects of both drugs on cognitive behaviors and brain mitochondrial function in HFD-induced insulin-resistant rats have not yet been investigated. Sixty male Wistar rats were divided into two groups to receive either normal diet or HFD for 12 weeks. Rats in each group were then further divided into three treatment groups to receive either vehicle, vildagliptin (3 mg/kg per day), or sitagliptin (30 mg/kg per day) for 21 days. The cognitive behaviors of the rats were tested using the Morris Water Maze test. Blood samples were collected to determine metabolic parameters and plasma oxidative stress levels. Upon completion of the study, the animals were killed and the brains were removed to investigate brain and hippocampal mitochondrial function as well as to determine oxidative stress levels. We demonstrated that both drugs significantly improved the metabolic parameters and decreased circulating and brain oxidative stress levels in HFD-induced insulin-resistant rats. In addition, both drugs completely prevented brain and hippocampal mitochondrial dysfunction and equally improved the learning behaviors impaired by the HFD. Our findings suggest that the inhibition of dipeptidyl-peptidase-4 enzymes with vildagliptin or sitagliptin in insulin-resistant rats not only increases peripheral insulin sensitivity but also decreases brain dysfunction.
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Affiliation(s)
- Hiranya Pintana
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
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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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Comparative Clinical Pharmacokinetics of Dipeptidyl Peptidase-4 Inhibitors. Clin Pharmacokinet 2012; 51:501-14. [DOI: 10.1007/bf03261927] [Citation(s) in RCA: 98] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Fellmann L, Nascimento AR, Tibiriça E, Bousquet P. Murine models for pharmacological studies of the metabolic syndrome. Pharmacol Ther 2012. [PMID: 23178510 DOI: 10.1016/j.pharmthera.2012.11.004] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Metabolic syndrome has been described as the association of insulin resistance, hypertension, hyperlipidemia and obesity. Its prevalence increased dramatically, mainly in developed countries. Animal models are essential to understand the pathophysiology of this syndrome. This review presents the murine models of metabolic syndrome the most often used in pharmacological studies. The most common metabolic syndrome models exhibit a non-functional leptin pathway, or metabolic disorders induced by high fat diets. In a first part, and after a short introduction on leptin, its receptor and mechanism of action, we provide a detailed description of each model: SHROB, SHHF, JCR:LA-cp, Zucker, ZDF, Wistar Ottawa Karlsburg W, and Otsuka Long-Evans Tokushima Fatty rats, ob/ob, db/db, agouti yellow and Mc4R KO mice. The second part of this review is dedicated to metabolic syndrome models obtained by high fat feeding.
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Affiliation(s)
- Lyne Fellmann
- Laboratory of Neurobiology and Cardiovascular Pharmacology, EA4438, Faculty of Medicine, University of Strasbourg, France
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Golightly LK, Drayna CC, McDermott MT. Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors. Clin Pharmacokinet 2012. [PMID: 22686547 DOI: 10.2165/11632930-000000000-00000] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors collectively comprise a presently unique form of disease management for persons with type 2 diabetes mellitus. The aim of this review is to compare the clinical pharmacokinetics of available DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin) for the purpose of identifying potential selection preferences according to individual patient variables and co-morbidities. DPP-4 inhibitors are readily absorbed orally. Following oral ingestion, absorption occurs mainly in the small intestine, with median times to maximum (peak) plasma concentration ranging from 1 to 3 hours. The fraction of each dose absorbed ranges from approximately 30% with linagliptin to 75-87% for all others. Numerical differences in maximum (peak) plasma drug concentrations and areas under the plasma concentration-time curve among the DPP-4 inhibitors vary by an order of magnitude. However, functional capacity measured in terms of glucose-lowering ability remains comparable among all available DPP-4 inhibitors. Distribution of DPP-4 inhibitors is strongly influenced by both lipophilicity and protein binding. Apparent volumes of distribution (V(d)) for most agents range from 70 to 300 L. Linagliptin exhibits a V(d) of more than 1000 L, indicating widespread distribution into tissues. Binding to target proteins in plasma and peripheral tissues exerts a major influence upon broadening linagliptin distribution. DPP-4 inhibitor metabolism is widely variable, with reported terminal half-lives ranging from approximately 3 to more than 200 hours. Complex relationships between rates of receptor binding and dissociation appear to strongly influence the durations of action of those DPP-4 inhibitors with comparatively shorter half-lives. Durations of activity often are not reflective of clearance and, with the exception of vildagliptin which may be administered either once daily in the evening or twice daily, these medications are effective when used with a once-daily dosing schedule. Saxagliptin and, to a lesser extent, sitagliptin are largely metabolized by hepatic cytochrome P450 (CYP) 3A4 and 3A5 isoforms. With the exception of the primary hydroxylated metabolite of saxagliptin, which is 2-fold less potent than its parent molecule, metabolic products of hepatic biotransformation are minimally active and none appreciably contribute to either the therapeutic or the toxic effects of DPP-4 inhibitors. No DPP-4 inhibitor has been shown to inhibit or to induce hepatic CYP-mediated drug metabolism. Accordingly, the number of clinically significant drug-drug interactions associated with these agents is minimal, with only saxagliptin necessitating dose adjustment if administered concurrently with medications that strongly inhibit CYP3A4. Linagliptin undergoes enterohepatic cycling with a large majority (85%) of the absorbed dose eliminated in faeces via biliary excretion. Other DPP-4 inhibitors predominantly undergo renal excretion, with 60-85% of each dose eliminated as unchanged parent compound in the urine. Systematic reviews of clinical trials suggest that the overall efficacy of DPP-4 inhibitors in patients with type 2 diabetes generally is similar. Apart from these generalizations, pharmacokinetic distinctions that potentially influence product selection are tentative. When considered in total, data reviewed in this report suggest that the best overall balance between potency and the clinical pharmacokinetic characteristics of distribution, metabolism and elimination may be observed with linagliptin followed closely by vildagliptin, saxagliptin, sitagliptin and alogliptin.
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Reimer RA, Grover GJ, Koetzner L, Gahler RJ, Juneja P, Lyon MR, Wood S. Sitagliptin reduces hyperglycemia and increases satiety hormone secretion more effectively when used with a novel polysaccharide in obese Zucker rats. J Nutr 2012; 142:1812-20. [PMID: 22915295 PMCID: PMC3718709 DOI: 10.3945/jn.112.163204] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
The novel polysaccharide (NPS) PolyGlycopleX (PGX) has been shown to reduce glycemia. Pharmacological treatment with sitagliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, also reduces glycemia by increasing glucagon-like peptide-1 (GLP-1). Our objective was to determine if using NPS in combination with sitagliptin reduces hyperglycemia in Zucker diabetic fatty (ZDF) rats more so than either treatment alone. Male ZDF rats were randomized to: 1) cellulose/vehicle [control (C)]; 2) NPS (5% wt:wt)/vehicle (NPS); 3) cellulose/sitagliptin [10 mg/(kg · d) (S)]; or 4) NPS (5%) + S [10 mg/(kg · d) (NPS+S)]. Glucose tolerance, adiposity, satiety hormones, and mechanisms related to DPP4 activity and hepatic and pancreatic histology were examined. A clinically relevant reduction in hyperglycemia occurred in the rats treated with NPS+S (P = 0.001) compared with NPS and S alone. Blood glucose, measured weekly in fed and feed-deprived rats and during an oral glucose tolerance test, was lower in the NPS+S group compared with all other groups (all P = 0.001). At wk 6, glycated hemoglobin was lower in the NPS+S group than in the C and S (P = 0.001) and NPS (P = 0.06) groups. PGX (P = 0.001) and S (P = 0.014) contributed to increased lean mass. Active GLP-1 was increased by S (P = 0.001) and GIP was increased by NPS (P = 0.001). Plasma DPP4 activity was lower in the NPS+S and S groups than in the NPS and C groups (P = 0.007). Insulin secretion and β-cell mass was increased with NPS (P < 0.05). NPS alone reduced LDL cholesterol and hepatic steatosis (P < 0.01). Independently, NPS and S improve several metabolic outcomes in ZDF rats, but combined, their ability to markedly reduce glycemia suggests they may be a promising dietary/pharmacological co-therapy for type 2 diabetes management.
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Affiliation(s)
- Raylene A Reimer
- Faculty of Kinesiology, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, Calgary, AB, Canada.
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Affiliation(s)
- Ananda Basu
- Endocrine Research Unit, Division of Endocrinology and Metabolism, Mayo College of Medicine, Rochester, Minnesota, USA.
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