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Müller TD, Adriaenssens A, Ahrén B, Blüher M, Birkenfeld AL, Campbell JE, Coghlan MP, D'Alessio D, Deacon CF, DelPrato S, Douros JD, Drucker DJ, Figueredo Burgos NS, Flatt PR, Finan B, Gimeno RE, Gribble FM, Hayes MR, Hölscher C, Holst JJ, Knerr PJ, Knop FK, Kusminski CM, Liskiewicz A, Mabilleau G, Mowery SA, Nauck MA, Novikoff A, Reimann F, Roberts AG, Rosenkilde MM, Samms RJ, Scherer PE, Seeley RJ, Sloop KW, Wolfrum C, Wootten D, DiMarchi RD, Tschöp MH. Glucose-dependent insulinotropic polypeptide (GIP). Mol Metab 2025; 95:102118. [PMID: 40024571 PMCID: PMC11931254 DOI: 10.1016/j.molmet.2025.102118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 02/06/2025] [Accepted: 02/24/2025] [Indexed: 03/04/2025] Open
Abstract
BACKGROUND Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in the maintenance of glucose tolerance in healthy humans. Until recently GIP had not been developed as a therapeutic and thus has been overshadowed by the other incretin, glucagon-like peptide 1 (GLP-1), which is the basis for several successful drugs to treat diabetes and obesity. However, there has been a rekindling of interest in GIP biology in recent years, in great part due to pharmacology demonstrating that both GIPR agonism and antagonism may be beneficial in treating obesity and diabetes. This apparent paradox has reinvigorated the field, led to new lines of investigation, and deeper understanding of GIP. SCOPE OF REVIEW In this review, we provide a detailed overview on the multifaceted nature of GIP biology and discuss the therapeutic implications of GIPR signal modification on various diseases. MAJOR CONCLUSIONS Following its classification as an incretin hormone, GIP has emerged as a pleiotropic hormone with a variety of metabolic effects outside the endocrine pancreas. The numerous beneficial effects of GIPR signal modification render the peptide an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, drug-induced nausea and both bone and neurodegenerative disorders.
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Affiliation(s)
- Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany; Walther-Straub Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University Munich (LMU), Germany.
| | - Alice Adriaenssens
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Bo Ahrén
- Department of Clinical Sciences, Lund, Lund University, Lund, Sweden
| | - Matthias Blüher
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Andreas L Birkenfeld
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen 72076, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Jonathan E Campbell
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA; Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
| | - Matthew P Coghlan
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - David D'Alessio
- Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
| | - Carolyn F Deacon
- School of Biomedical Sciences, Ulster University, Coleraine, UK; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Stefano DelPrato
- Interdisciplinary Research Center "Health Science", Sant'Anna School of Advanced Studies, Pisa, Italy
| | | | - Daniel J Drucker
- The Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Natalie S Figueredo Burgos
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Peter R Flatt
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK
| | - Brian Finan
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Ruth E Gimeno
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Fiona M Gribble
- Institute of Metabolic Science-Metabolic Research Laboratories & MRC-Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Matthew R Hayes
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Christian Hölscher
- Neurodegeneration Research Group, Henan Academy of Innovations in Medical Science, Xinzheng, China
| | - Jens J Holst
- Department of Biomedical Sciences and the Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Patrick J Knerr
- Indianapolis Biosciences Research Institute, Indianapolis, IN, USA
| | - Filip K Knop
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christine M Kusminski
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Arkadiusz Liskiewicz
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany; Department of Physiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Guillaume Mabilleau
- Univ Angers, Nantes Université, ONIRIS, Inserm, RMeS UMR 1229, Angers, France; CHU Angers, Departement de Pathologie Cellulaire et Tissulaire, Angers, France
| | | | - Michael A Nauck
- Diabetes, Endocrinology and Metabolism Section, Department of Internal Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Aaron Novikoff
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany
| | - Frank Reimann
- Institute of Metabolic Science-Metabolic Research Laboratories & MRC-Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Anna G Roberts
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen, Copenhagen, Denmark
| | - Ricardo J Samms
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Philip E Scherer
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Randy J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Kyle W Sloop
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Christian Wolfrum
- Institute of Food, Nutrition and Health, ETH Zurich, 8092, Schwerzenbach, Switzerland
| | - Denise Wootten
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | | | - Matthias H Tschöp
- Helmholtz Munich, Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technical University of Munich, Munich, Germany
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Kerry RG, Mahapatra SR, Nayak S, Naik H, Kisku K, Panigrahi B, Misra N, Majhi S. In silico analysis of Rutin and Morin against diabetes-associated molecular targets. In Silico Pharmacol 2025; 13:68. [PMID: 40291446 PMCID: PMC12018676 DOI: 10.1007/s40203-025-00353-1] [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: 12/02/2024] [Accepted: 04/03/2025] [Indexed: 04/30/2025] Open
Abstract
Diabetes is one of the oldest diseases known to occur in humans and is regulated by a complex interplay of metabolic, genetic, and environmental factors. Several therapeutic options exist, including medications, exercise, improved health measures, psychological and mental well-being, and amelioration of disparity and depression. Current therapeutic options although are effective, they tends to display side effects that includes significant complications like gastrointestinal discomfort, decreased effectiveness and weight gain. Plant-derived bioactive substances with antidiabetic and/or hypoglycaemic properties have been found to be effective, however, the mechanism of action of the majority of herbs are still being characterized and standardized. However, in the present in-silico prediction for phytocompounds, Rutin (RU) and Morin (MO) revealed them to be more effective than or equal to conventional inhibitors in blocking the enzymes and receptors that contribute to diabetes development. Results of the in-silico investigations have clearly demonstrated the importance of RU and MO in binding diabetic-susceptible enzymes (alpha-amylase, DPP-4, and maltase-glucoamylase) and receptors (GLP-1R, SGLT1 and SGLT2). Additionally, in vitro antidiabetic enzymatic assays demonstrated the possible inhibitory activity of RU and MO against two diabetes-related molecular targets.
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Affiliation(s)
- Rout George Kerry
- Department of Biotechnology, Utkal University, Vani Vihar, Bhubaneswar, Odisha 751004 India
- Centre for Biotechnology, Siksha ‘O’ Anusandhan (Deemed to be University), Kalinga Nagar, Bhubaneswar, Odisha 751003 India
| | - Soumya Ranjan Mahapatra
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Bhubaneswar, 751024 India
| | - Sanghamitra Nayak
- Centre for Biotechnology, Siksha ‘O’ Anusandhan (Deemed to be University), Kalinga Nagar, Bhubaneswar, Odisha 751003 India
| | - Hemangini Naik
- Department of Biotechnology and Bioinformatics, Sambalpur University, Jyoti Vihar, Burla, 768019 India
| | - Kanika Kisku
- Department of Botany, Ravenshaw University, Cuttack, 753003 India
| | - Bijayananda Panigrahi
- Transcription Regulation Group, International Centre for Genetic Engineering and Biotechnology, Delhi, New Delhi 110067 India
| | - Namrata Misra
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Bhubaneswar, 751024 India
- KIIT-Technology Business Incubator (KIIT-TBI), Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Bhubaneswar, 751024 India
| | - Sanatan Majhi
- Department of Biotechnology, Utkal University, Vani Vihar, Bhubaneswar, Odisha 751004 India
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Waterman HL, Smith MS, Farmer B, Yankey K, Howard T, Kraft G, Edgerton DS, Cherrington AD. Hepatic Metabolic Memory Triggered by AM Exposure to Glucagon Alters Afternoon Glucose Metabolism. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.25.639957. [PMID: 40060516 PMCID: PMC11888283 DOI: 10.1101/2025.02.25.639957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/14/2025]
Abstract
The second meal effect describes an improved glycemic response observed after consuming a second identical meal. We previously showed that morning (AM) exposure to hyperinsulinemia primes the liver for enhanced hepatic glucose uptake and glycogen storage in the afternoon (PM), with no significant effect on PM non-hepatic glucose uptake. Given that meals often trigger both insulin and glucagon secretion, we aimed to determine if AM hyperglucagonemia alters the priming effect of AM hyperinsulinemia on PM hepatic glucose metabolism. To test this, dogs were exposed to a 4h AM hyperinsulinemic-euglycemic clamp, with insulin delivered in a pattern mimicking the insulin profile observed earlier during a 4h AM duodenal glucose infusion. This period of hyperinsulinemia was paired with either basal (Prime, n=8) or elevated (Prime + ↑GGN, n=8) glucagon, maintaining a consistent insulin-to-glucagon molar ratio throughout the AM clamp. After a 1.5h rest period, the dogs underwent a 2.5h PM hyperinsulinemic-hyperglycemic clamp, during which glucose, insulin, and glucagon levels, along with the artery-to-portal vein glucose gradient, were carefully controlled to replicate postprandial conditions. During the PM clamp, the mean net hepatic glucose uptake (NHGU) in the Prime + ↑GGN group was only 59% of that in the Prime group (3.6±0.4 vs. 6.1±0.6 mg/kg/min, P<0.0027, respectively). Additionally, PM direct glycogen synthesis was two-fold greater in the Prime group compared to the Prime + ↑GGN group (3.2±0.7 vs. 1.5±0.2 mg/kg/min, P<0.0014, respectively). The observed difference in PM NHGU between the groups was not due to enhanced PM hepatic glucose uptake (HGU), which was similar in both groups (5.7±0.5 mg/kg/min in the Prime group vs. 5.2±0.3 mg/kg/min in the Prime + ↑GGN group), but rather a prolonged effect of AM hyperglucagonemia on PM hepatic glucose production (HGP) (-0.3±0.3 mg/kg/min in the Prime group vs. 1.7±0.4 mg/kg/min in the Prime + ↑GGN group, P<0.0072). This increase in PM HGP in the Prime + ↑GGN group was not driven by differences in PM gluconeogenic flux but by futile glucose cycling between glucose and glucose-6-phosphate, as well as hepatic glycogen storage and breakdown. In summary, these findings suggest that morning exposure to elevated glucagon shifts the insulin-driven priming effect on afternoon hepatic glucose metabolism by promoting sustained glucose cycling at the expense of glycogen synthesis and glycolysis, leading to persistent HGP despite identical PM insulin, glucose, and glucagon levels.
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Affiliation(s)
- Hannah L Waterman
- Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine
| | - Marta S Smith
- Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine
| | - Ben Farmer
- Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine
| | - Kalisha Yankey
- Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine
| | - Tristan Howard
- Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine
| | - Guillaume Kraft
- Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine
| | - Dale S Edgerton
- Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine
| | - Alan D Cherrington
- Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine
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Lukka PB, Tang W, Hammarstedt A, Conrad T, Heijer M, Karlsson C, Boulton DW. Racial Comparison of the Pharmacokinetics and Safety of Fixed-dose Combination of Dapagliflozin/Sitagliptin in Western and Korean Healthy Adults. Clin Ther 2024; 46:717-725. [PMID: 39179458 DOI: 10.1016/j.clinthera.2024.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 07/15/2024] [Accepted: 07/17/2024] [Indexed: 08/26/2024]
Abstract
PURPOSE We evaluated the pharmacokinetics, safety, and tolerability of a fixed-dose combination (FDC) of dapagliflozin/sitagliptin versus individual component (IC) tablets in healthy Western and Korean participants. The combination of these antihyperglycemic drugs provides efficient glucose control, and the use of FDC has generally been shown to improve medication adherence in individuals with type 2 diabetes mellitus (T2DM). METHODS Two randomized, open-label, two-period, two-treatment, single-dose, single-center, crossover bioequivalence studies conducted on healthy fasted German participants (aged 18-55 years; Western study) and South Korean participants (aged 19-55 years; Korean study) were included. In both studies, pharmacokinetic parameters (maximum [peak] plasma concentration [Cmax], area under the plasma concentration-time curve from zero to the last quantifiable concentration [AUClast], and area under the plasma concentration-time curve from zero to infinity [AUCinf]) were used to assess the bioequivalence of 10 mg dapagliflozin/100 mg sitagliptin FDC (Treatment A) with their ICs (Treatment B) under fasted conditions. Safety and tolerability were assessed throughout the study. FINDINGS Forty-six healthy participants (male, 60.9%; mean age, 39.5 years; mean body mass index [BMI], 23.9 kg/m2) were randomized in the Western study, and 51 healthy participants (male, 100.0%; mean age, 24.6 years; mean BMI, 23.9 kg/m2) were randomized in the Korean study. In both studies, the participants were randomized 1:1 into treatment sequence AB and treatment sequence BA. Dapagliflozin/sitagliptin FDC was bioequivalent to IC tablets in both Western and Korean studies, as the 90% confidence interval of the FDC to IC ratios of the geometric least-squares means of the pharmacokinetic parameters for both dapagliflozin and sitagliptin was within the 0.8000-1.2500 bioequivalence criterion limit. The observed differences in pharmacokinetic parameters, such as Cmax, AUClast, and AUCinf, between the Western and Korean studies were not clinically meaningful. Dapagliflozin/sitagliptin FDC and their ICs were well tolerated, with no serious adverse events reported in any of the study populations. IMPLICATIONS The 10 mg dapagliflozin/100 mg sitagliptin FDC and IC formulations were bioequivalent in fasted healthy Western and Korean participants, with no new safety concerns identified, thus offering a useful alternative for patients currently receiving individual medications as part of their treatment regimen. CLINICAL TRIAL REGISTRATION Western study (clinicaltrials.gov: NCT05266404) and Korean study (clinicaltrials.gov: NCT05453786).
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Affiliation(s)
- Pradeep B Lukka
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland.
| | - Weifeng Tang
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland
| | - Ann Hammarstedt
- Late-stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Tom Conrad
- Biometrics, Late-stage Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland
| | - Maria Heijer
- Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Cecilia Karlsson
- Late-stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - David W Boulton
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland
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Cordiner RLM, Bedair K, Mari A, Pearson E. Low-Dose Sulfonylurea Plus DPP4 Inhibitor Lower Blood Glucose and Enhance Beta-Cell Function Without Hypoglycemia. J Clin Endocrinol Metab 2024; 109:2106-2115. [PMID: 38267622 PMCID: PMC11244179 DOI: 10.1210/clinem/dgae033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 12/14/2023] [Accepted: 01/23/2024] [Indexed: 01/26/2024]
Abstract
CONTEXT Low-dose sulfonylureas (SUs) have been found to augment the classical incretin effect, increase glucose sensitivity and late phase incretin potentiation. OBJECTIVE To evaluate potential synergy between low-dose SU plus a dipeptidyl peptidase 4 (DPP4) inhibitor. METHODS Unblinded randomized crossover study at the Clinical Research Centre, University of Dundee. Thirty participants with T2DM (HbA1c < 64 mmol/mol) were treated with diet or metformin. Participants completed 4, 14-day blocks in a random order: control, gliclazide 20 mg (SU), sitagliptin 100 mg (DPP4 inhibitor [DPP4i]), or combination (SUDPP4i). A mixed meal test was conducted after each intervention. The primary outcome was the effect of treatment on beta-cell glucose sensitivity. Secondary outcomes included frequency of glucose <3 mmol/L on continuous glucose monitoring, subanalyses by genotype (KNCJ11 E23K), gender, and body mass index. RESULTS SU combination with DPP4i showed additive effect on glucose lowering: mean glucose area under the curve (mean 95% CI) (mmol/L) was control 11.5 (10.7-12.3), DPP4i 10.2 (9.4-11.1), SU 9.7 (8.9-10.5), SUDPP4i 8.7 (7.9-9.5) (P < .001). Glucose sensitivity mirrored the additive effect (pmol min-1 m-2 mM-1): control 71.5 (51.1-91.9), DPP4i 75.9 (55.7-96.0), SU 86.3 (66.1-106.4), SUDPP4i 94.1 (73.9-114.3) (P = .04). The additive effect was seen in men but not women. Glucose time in range <3 mmol/L on continuous glucose monitoring (%) was unaffected: control 1 (2-4), DPP4i 2 (3-6), SU 1 (0-4), SUDPP4i 3 (2-7) (P = .65). CONCLUSION Low-dose sulfonylurea plus DPP4i has a potent glucose-lowering effect through augmentation of beta-cell function. A double-blind randomized controlled trial would formalize efficacy and safety of this combination, which may avoid negative aspects of SU.
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Affiliation(s)
- Ruth L M Cordiner
- Division of Population, Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK
| | - Khaled Bedair
- Division of Population, Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK
| | - Andrea Mari
- National Research Council, Institute of Neuroscience, University of Padua, 35127 Padua, Italy
| | - Ewan Pearson
- Division of Population, Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK
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Beitelshees AL, Streeten EA, Shahidzadeh Yazdi Z, Whitlatch HB, Mitchell BD, Shuldiner AR, Montasser ME, Taylor SI. Acute pharmacodynamic responses to sitagliptin: Drug-induced increase in early insulin secretion in oral glucose tolerance test. Clin Transl Sci 2024; 17:e13809. [PMID: 38700326 PMCID: PMC11067710 DOI: 10.1111/cts.13809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 03/11/2024] [Accepted: 04/09/2024] [Indexed: 05/05/2024] Open
Abstract
DPP4 inhibitors are widely prescribed as treatments for type 2 diabetes. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. Sitagliptin (100 mg) was administered to 47 healthy volunteers. Several endpoints were measured to assess clinically relevant responses - including the effect of sitagliptin on glucose and insulin levels during an oral glucose tolerance test (OGTT). This pilot study confirmed that sitagliptin (100 mg) decreased the area under the curve for glucose during an OGTT (p = 0.0003). Furthermore, sitagliptin promoted insulin secretion during the early portion of the OGTT as reflected by an increase in the ratio of plasma insulin at 30 min divided by plasma insulin at 60 min (T30:T60) from mean ± SEM 0.87 ± 0.05 to 1.62 ± 0.36 mU/L (p = 0.04). The magnitude of sitagliptin's effect on insulin secretion (as judged by the increase in the T30:T60 ratio for insulin) was correlated with the magnitude of sitagliptin-induced increase in the area under the curve for intact plasma GLP1 levels during the first hour of the OGTT. This study confirmed previously reported sex differences in glucose and insulin levels during an OGTT. Specifically, females exhibited higher levels of glucose and insulin at the 90-180 min time points. However, we did not detect significant sex-associated differences in the magnitude of sitagliptin-induced changes in T30:T60 ratios for either glucose or insulin. In conclusion, T30:T60 ratios for insulin and glucose during an OGTT provide useful indices to assess pharmacodynamic responses to DPP4 inhibitors.
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Affiliation(s)
- Amber L. Beitelshees
- Division of Endocrinology, Diabetes, and Nutrition, Department of MedicineUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | - Elizabeth A. Streeten
- Division of Endocrinology, Diabetes, and Nutrition, Department of MedicineUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | - Zhinous Shahidzadeh Yazdi
- Division of Endocrinology, Diabetes, and Nutrition, Department of MedicineUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | - Hilary B. Whitlatch
- Division of Endocrinology, Diabetes, and Nutrition, Department of MedicineUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | - Braxton D. Mitchell
- Division of Endocrinology, Diabetes, and Nutrition, Department of MedicineUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | - Alan R. Shuldiner
- Division of Endocrinology, Diabetes, and Nutrition, Department of MedicineUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | - May E. Montasser
- Division of Endocrinology, Diabetes, and Nutrition, Department of MedicineUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | - Simeon I. Taylor
- Division of Endocrinology, Diabetes, and Nutrition, Department of MedicineUniversity of Maryland School of MedicineBaltimoreMarylandUSA
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Patil M, Casari I, Warne LN, Falasca M. G protein-coupled receptors driven intestinal glucagon-like peptide-1 reprogramming for obesity: Hope or hype? Biomed Pharmacother 2024; 172:116245. [PMID: 38340396 DOI: 10.1016/j.biopha.2024.116245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 01/23/2024] [Accepted: 02/01/2024] [Indexed: 02/12/2024] Open
Abstract
'Globesity' is a foremost challenge to the healthcare system. The limited efficacy and adverse effects of available oral pharmacotherapies pose a significant obstacle in the fight against obesity. The biology of the leading incretin hormone glucagon-like-peptide-1 (GLP-1) has been highly captivated during the last decade owing to its multisystemic pleiotropic clinical outcomes beyond inherent glucoregulatory action. That fostered a pharmaceutical interest in synthetic GLP-1 analogues to tackle type-2 diabetes (T2D), obesity and related complications. Besides, mechanistic insights on metabolic surgeries allude to an incretin-based hormonal combination strategy for weight loss that emerged as a forerunner for the discovery of injectable 'unimolecular poly-incretin-agonist' therapies. Physiologically, intestinal enteroendocrine L-cells (EECs) are the prominent endogenous source of GLP-1 peptide. Despite comprehending the potential of various G protein-coupled receptors (GPCRs) to stimulate endogenous GLP-1 secretion, decades of translational GPCR research have failed to yield regulatory-approved endogenous GLP-1 secretagogue oral therapy. Lately, a dual/poly-GPCR agonism strategy has emerged as an alternative approach to the traditional mono-GPCR concept. This review aims to gain a comprehensive understanding by revisiting the pharmacology of a few potential GPCR-based complementary avenues that have drawn attention to the design of orally active poly-GPCR agonist therapy. The merits, challenges and recent developments that may aid future poly-GPCR drug discovery are critically discussed. Subsequently, we project the mechanism-based therapeutic potential and limitations of oral poly-GPCR agonism strategy to augment intestinal GLP-1 for weight loss. We further extend our discussion to compare the poly-GPCR agonism approach over invasive surgical and injectable GLP-1-based regimens currently in clinical practice for obesity.
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Affiliation(s)
- Mohan Patil
- Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia
| | - Ilaria Casari
- Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia
| | - Leon N Warne
- Little Green Pharma, West Perth, Western Australia 6872, Australia
| | - Marco Falasca
- University of Parma, Department of Medicine and Surgery, Via Volturno 39, 43125 Parma, Italy.
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Huang Q, Zou X, Chen Y, Gao L, Cai X, Zhou L, Gao F, Zhou J, Jia W, Ji L. Personalized glucose-lowering effect of chiglitazar in type 2 diabetes. iScience 2023; 26:108195. [PMID: 37942014 PMCID: PMC10628820 DOI: 10.1016/j.isci.2023.108195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 09/13/2023] [Accepted: 10/10/2023] [Indexed: 11/10/2023] Open
Abstract
Chiglitazar (carfloglitazar) is a peroxisome proliferator-activated receptor pan-agonist presenting non-inferior glucose-lowering efficacy with sitagliptin in patients with type 2 diabetes. To delineate the subgroup of patients with greater benefit from chiglitazar, we conducted a machine learning-based post-hoc analysis in two randomized controlled trials. We established a character phenomap based on 13 variables and estimated HbA1c decline to the effects of chiglitazar in reference to sitagliptin. Out of 1,069 patients, 63.3% were found to have greater reduction in HbA1c levels with chiglitazar, while 36.7% showed greater reduction with sitagliptin. This distinction in treatment response was statistically significant between groups (pinteraction<0.001). To identify patients who would gain the most glycemic control benefit from chiglitazar, we developed a machine learning model, ML-PANPPAR, which demonstrated robust performance using sex, BMI, HbA1c, HDL, and fasting insulin. The phenomapping-derived tool successfully identified chiglitazar responders and enabled personalized drug allocation in patients with drug-naïve diabetes.
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Affiliation(s)
- Qi Huang
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing 100044, China
| | - Xiantong Zou
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing 100044, China
| | - Yingli Chen
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing 100044, China
| | - Leili Gao
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing 100044, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing 100044, China
| | - Lingli Zhou
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing 100044, China
| | - Fei Gao
- Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai 200233, China
| | - Jian Zhou
- Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai 200233, China
| | - Weiping Jia
- Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai 200233, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing 100044, China
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9
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Salehi M, Peterson R, Tripathy D, Pezzica S, DeFronzo R, Gastaldelli A. Differential effect of gastric bypass versus sleeve gastrectomy on insulinotropic action of endogenous incretins. Obesity (Silver Spring) 2023; 31:2774-2785. [PMID: 37853989 PMCID: PMC10593483 DOI: 10.1002/oby.23872] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 06/09/2023] [Accepted: 06/26/2023] [Indexed: 10/20/2023]
Abstract
OBJECTIVE Prandial hyperinsulinemia after Roux-en-Y gastric bypass surgery (GB), and to lesser degree after sleeve gastrectomy (SG), has been attributed to rapid glucose flux from the gut and increased insulinotropic gut hormones. However, β-cell sensitivity to exogenous incretin is reduced after GB. This study examines the effect of GB versus SG on prandial glycemia and β-cell response to increasing concentrations of endogenous incretins. METHODS Glucose kinetics, insulin secretion rate (ISR), and incretin responses to 50-g oral glucose ingestion were compared between ten nondiabetic participants with GB versus nine matched individuals with SG and seven nonoperated normal glucose tolerant control individuals (CN) with and without administration of 200 mg of sitagliptin. RESULTS Fasting glucose and hormonal levels were similar among three groups. Increasing plasma concentrations of endogenous incretins by two- to three-fold diminished prandial glycemia and increased β-cell secretion in all three groups (p < 0.05), but insulin secretion per insulin sensitivity (i.e., disposition index) was increased only in GB (p < 0.05 for interaction). However, plot of the slope of ISR (from premeal to peak values) versus plasma glucagon-like peptide-1 concentration was smaller after GB compared with SG and CN. CONCLUSIONS After GB, increasing incretin activity augments prandial β-cell response whereas the β-cell sensitivity to increasing plasma concentrations of endogenous incretin is diminished.
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Affiliation(s)
- Marzieh Salehi
- Division of Diabetes, University of Texas at San Antonio, San Antonio, TX, United States
- STVHCS, Audie Murphy Hospital, San Antonio, TX, United States
| | - Richard Peterson
- Department of Surgery, University of Texas at San Antonio, San Antonio, TX, United States
| | - Devjit Tripathy
- Division of Diabetes, University of Texas at San Antonio, San Antonio, TX, United States
| | - Samantha Pezzica
- Cardiometabolic Risk Unit, CNR Institute of Clinical Physiology, Pisa, Italy
| | - Ralph DeFronzo
- Division of Diabetes, University of Texas at San Antonio, San Antonio, TX, United States
| | - Amalia Gastaldelli
- Division of Diabetes, University of Texas at San Antonio, San Antonio, TX, United States
- Cardiometabolic Risk Unit, CNR Institute of Clinical Physiology, Pisa, Italy
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10
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Beitelshees AL, Streeten EA, Yazdi ZS, Whitlatch HB, Mitchell BD, Shuldiner AR, Montasser ME, Taylor SI. Acute pharmacodynamic responses to sitagliptin: Drug-induced increase in early insulin secretion in oral glucose tolerance test. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.09.24.23296026. [PMID: 37808823 PMCID: PMC10557823 DOI: 10.1101/2023.09.24.23296026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Aim DPP4 inhibitors are widely prescribed as treatments for type 2 diabetes. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. Methods Sitagliptin (100 mg) was administered to 47 healthy volunteers. Several endpoints were measured to assess clinically relevant responses - including the effect of sitagliptin on glucose and insulin levels during an oral glucose tolerance test (OGTT). Results This pilot study confirmed that sitagliptin (100 mg) decreased the area under the curve for glucose during an OGTT (p=0.0003). Furthermore, sitagliptin promoted insulin secretion during the early portion of the OGTT as reflected by an increase in the ratio of plasma insulin at 30 min divided by plasma insulin at 60 min (T30:T60) from 0.87+/-0.05 to 1.62+/-0.36 mU/L (p=0.04). The magnitude of sitagliptin's effect on insulin secretion (as judged by the increase in the T30:T60 ratio for insulin) was correlated with the magnitude of sitagliptin-induced increase in the area under the curve for intact plasma GLP1 levels during the first hour of the OGTT. This study confirmed previously reported sex differences in glucose and insulin levels during an OGTT. Specifically, females exhibited higher levels of glucose and insulin at the 90-180 min time points. However, we did not detect significant sex-associated differences in the magnitude of sitagliptin-induced changes in T30:T60 ratios for either glucose or insulin. Conclusions T30:T60 ratios for insulin and glucose during an OGTT provide useful indices to assess pharmacodynamic responses to DPP4 inhibitors.
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Affiliation(s)
- Amber L. Beitelshees
- Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Elizabeth A. Streeten
- Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Zhinous Shahidzadeh Yazdi
- Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Hilary B. Whitlatch
- Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Braxton D. Mitchell
- Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Alan R. Shuldiner
- Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - May E. Montasser
- Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Simeon I. Taylor
- Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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11
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Li Q, Deng X, Xu YJ, Dong L. Development of Long-Acting Dipeptidyl Peptidase-4 Inhibitors: Structural Evolution and Long-Acting Determinants. J Med Chem 2023; 66:11593-11631. [PMID: 37647598 DOI: 10.1021/acs.jmedchem.3c00412] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
Considerable effort has been made to achieve less frequent dosing in the development of DPP-4 inhibitors. Enthusiasm for long-acting DPP-4 inhibitors is based on the promise that such agents with less frequent dosing regimens are associated with improved patient adherence, but the rational design of long-acting DPP-4 inhibitors remains a major challenge. In this Perspective, the development of long-acting DPP-4 inhibitors is comprehensively summarized to highlight the evolution of initial lead compounds on the path toward developing long-acting DPP-4 inhibitors over nearly three decades. The determinants for long duration of action are then examined, including the nature of the target, potency, binding kinetics, crystal structures, selectivity, and preclinical and clinical pharmacokinetic and pharmacodynamic profiles. More importantly, several possible approaches for the rational design of long-acting drugs are discussed. We hope that this information will facilitate the design and development of safer and more effective long-acting DPP-4 inhibitors and other oral drugs.
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Affiliation(s)
- Qing Li
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China
| | - Xiaoyan Deng
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China
| | - Yan-Jun Xu
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China
| | - Lin Dong
- West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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12
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Zhang L, Hu A, Wang Y, Yang Y, Liu Y, Xu L, Wang L, Cheng Z. Medication adjustment of afatinib and combination therapy with sitagliptin for alleviating afatinib-induced diarrhea in rats. Neoplasia 2023; 43:100922. [PMID: 37567055 PMCID: PMC10423691 DOI: 10.1016/j.neo.2023.100922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 07/31/2023] [Accepted: 08/02/2023] [Indexed: 08/13/2023]
Abstract
Afatinib, as the first-line treatment for non-small cell lung cancer (NSCLC), causes severe gastrointestinal adverse reactions that greatly affect patients' quality of life and even potentially result in treatment discontinuation. Multiple dose adjustments and concomitant use of anti-diarrheal medications are commonly employed to manage diarrhea, also allowing for a recovery period between each adjustment. However, these approaches are based on empirical guidance and still have limitations. This study aims to explore reliable approaches to alleviate diarrhea by focusing on two strategies: adjusting the dosing regimen of afatinib itself and implementing combination therapy. In this study, we firstly revealed a dose-dependent relationship between afatinib-induced diarrhea and gastrointestinal epithelial damage, resulting in atrophy, reduced expression of tight junction proteins, and increased permeability. We further found that even after discontinuation of the medication, although the severity of diarrhea had improved to baseline, the tight junction proteins and permeability of the intestinal epithelium did not fully recover, and the pharmacokinetics studies showed that drug absorption significantly increased than normal. This indicated the recovery period was longer than expected and may accelerate the occurrence of subsequent episodes of diarrhea. Hence, it would be prudent to consider adjustments to the starting dose or the recovery interval. Furthermore, we initially investigated the relationship between DPP enzyme and afatinib-induced diarrhea and found a significant decrease in plasma DPP enzyme activity following afatinib-induced diarrhea. Subsequently, we conducted continuous treatment with sitagliptin and observed significant improvement in afatinib-induced diarrhea. We observed that sitagliptin can promote the production of anti-inflammatory factors, increase the expression of intestinal epithelial tight junction proteins, and improve intestinal microbiota, further validating the mechanism through the use of GLP-23-33 as GLP-2 receptor inhibitor. In conclusion, sitagliptin exhibits promising potential as a therapeutic option for managing afatinib-induced diarrhea. Taken together, our study provides valuable insights into alleviating afatinib-induced diarrhea through both afatinib medication adjustment and sitagliptin combination therapy.
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Affiliation(s)
- Li Zhang
- Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
| | - Anna Hu
- Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
| | - Yan Wang
- Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
| | - Yuxin Yang
- Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
| | - Yalan Liu
- Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
| | - Lian Xu
- Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
| | - Lei Wang
- Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China; Department of Rheumatology and Immunology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, China; Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou 510632, China.
| | - Zeneng Cheng
- Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China.
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13
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Ahmed M, Saeed A, Khan MZ, Javaid SZ, Aslam F, Dar SI. A Comparison of the Effects of Empagliflozin and Sitagliptin, When Combined With Metformin, on Lipid Levels in Patients with Type 2 Diabetes: A Clinical Investigation. Cureus 2023; 15:e44709. [PMID: 37809225 PMCID: PMC10552574 DOI: 10.7759/cureus.44709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/05/2023] [Indexed: 10/10/2023] Open
Abstract
Introduction Type 2 diabetes (T2D) is emerging as a major global health concern. An associated condition, dyslipidemia, which acts as a significant modifiable risk factor for T2D, exhibits variations across different ethnicities and socioeconomic backgrounds. While many patients rely on metformin as their primary treatment, it does not always effectively control hyperglycemia. As a result, there is a growing need for adjunctive treatments, including sodium-glucose cotransporter-2 (SGLT2) and dipeptidyl peptidase-4 (DPP-4) inhibitors. This study evaluated the comparative effects of empagliflozin (an SGLT2 inhibitor) and sitagliptin (a DPP-4 inhibitor), both combined with metformin, on the lipid profiles of individuals with T2D. Methods Over six months at the Federal Government Polyclinic Hospital in Islamabad, we enrolled 126 participants diagnosed with T2D. Using a nonprobability consecutive sampling technique, we divided them into two groups. Group A received metformin and empagliflozin, while Group B was administered metformin and sitagliptin. We assessed their fasting lipid profiles three months into the treatment. Results Both groups consisted of 63 patients each. We observed that those in Group B, treated with sitagliptin and metformin, demonstrated a more significant reduction in total cholesterol and low-density lipoprotein-C levels than those in Group A, treated with empagliflozin and metformin. This difference proved to be statistically meaningful. Conclusion The combination of sitagliptin and metformin showed enhanced benefits in lipid profile management compared to the combination of empagliflozin and metformin in patients with T2D. This discovery underscores the need for holistic treatment modalities that factor in blood glucose levels and cardiovascular health.
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Affiliation(s)
- Mazhar Ahmed
- Internal Medicine, Federal Government Polyclinic Hospital, Islamabad, PAK
| | - Asjad Saeed
- Internal Medicine, Federal Government Polyclinic Hospital, Islamabad, PAK
| | | | - Sana Z Javaid
- Internal Medicine, Shifa College of Medicine, Shifa International Hospital, Islamabad, PAK
| | - Farhan Aslam
- Internal Medicine, Federal Government Polyclinic Hospital, Islamabad, PAK
| | - Savida Ilyas Dar
- Internal Medicine, Federal Government Polyclinic Hospital, Islamabad, PAK
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14
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Chai S, Zhang R, Carr RD, Deacon CF, Zheng Y, Rajpathak S, Chen J, Yu M. Impact of dipeptidyl peptidase-4 inhibitors on glucose-dependent insulinotropic polypeptide in type 2 diabetes mellitus: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2023; 14:1203187. [PMID: 37635974 PMCID: PMC10450336 DOI: 10.3389/fendo.2023.1203187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 07/24/2023] [Indexed: 08/29/2023] Open
Abstract
Aims Glucose-dependent insulinotropic polypeptide (GIP) confers a variety of metabolic benefits in type 2 diabetes mellitus (T2DM). This meta-analysis was conducted to investigate the impact of dipeptidyl peptidase 4 (DPP4) inhibitors on GIP levels in T2DM patients. Methods Medline (PubMed), CENTER (Cochrane Library), and Embase (Ovid) were searched and randomized controlled trials (RCTs) evaluating the impact of DPP4 inhibitors on fasting and postprandial GIP levels were obtained. For postprandial GIP, only studies with the data of GIP changes reported as the total area under the curve (AUCGIP) using a meal or oral glucose tolerance test were included. A random-effects model was used for data pooling after incorporating heterogeneity. Results Overall, 14 RCTs with 541 T2DM patients were included. Compared to placebo/no treatment, the use of DPP4 inhibitors significantly increased the fasting GIP level (standard mean difference [SMD]: 0.77, 95% confidence interval [CI]: 0.48-1.05, P<0.001; I2 = 52%) and postprandial AUCGIP (SMD: 1.33, 95% CI: 1.02-1.64, P<0.001; I2 = 65%). Influence analysis by excluding one dataset at a time showed consistent results. Sensitivity analyses only including studies with radioimmunoassay showed also consistent results (fasting GIP: SMD: 0.75, 95% CI: 0.51-1.00, P<0.001; I2 = 0%; and postprandial AUCGIP: SMD: 1.48, 95% CI: 1.18-1.78, P<0.001; I2 = 54%). Further subgroup analyses demonstrated that the influence of DPP4 inhibitors on fasting and postprandial GIP levels in T2DM patients was not significantly changed by study characteristics such as study design, patient mean age, baseline glycated hemoglobin (HbA1c) concentration, body mass index (BMI), background treatment, treatment duration, or method for postprandial GIP measurement (all P for subgroup effects <0.05). Conclusion The use of DPP4 inhibitors effectively increases the fasting and postprandial GIP concentrations in T2DM patients. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42022356716.
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Affiliation(s)
- Shangyu Chai
- Merck Research Laboratories (MRL) Global Medical Affairs, Merck Sharp & Dohme (MSD) China, Shanghai, China
| | - Ruya Zhang
- Merck Research Laboratories (MRL) Global Medical Affairs, Merck Sharp & Dohme (MSD) China, Shanghai, China
| | - Richard David Carr
- Hatter Cardiovascular Institute, University College London, London, United Kingdom
- School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom
| | - Carolyn F. Deacon
- School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Yiman Zheng
- Merck Research Laboratories (MRL) Global Medical Affairs, Merck Sharp & Dohme (MSD) China, Shanghai, China
| | - Swapnil Rajpathak
- Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ, United States
| | - Jingya Chen
- Merck Research Laboratories (MRL) Global Medical Affairs, Merck Sharp & Dohme (MSD) China, Shanghai, China
| | - Miao Yu
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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15
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Kim D, Choi M, Jin BH, Hong T, Kim CO, Yoo BW, Park MS. Pharmacokinetic and pharmacodynamic drug-drug interactions between evogliptin and empagliflozin or dapagliflozin in healthy male volunteers. Clin Transl Sci 2023; 16:1469-1478. [PMID: 37282359 PMCID: PMC10432875 DOI: 10.1111/cts.13566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 05/19/2023] [Accepted: 05/27/2023] [Indexed: 06/08/2023] Open
Abstract
Evogliptin (EV) is a novel dipeptidyl peptidase-4 inhibitor (DPP4i) for glycemic control in patients with type 2 diabetes mellitus (T2DM). This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between EV and sodium glucose cotransporter-2 inhibitors (SGLT2i) in healthy volunteers since combination therapy of DPP4i and SGLT2i has been considered as an effective option for T2DM treatment. A randomized, open-label, multiple-dose, two-arm, three-period, three treatments, two-sequence crossover study was conducted in healthy Korean volunteers. In arm 1, subjects were administered 5 mg of EV once daily for 7 days, 25 mg of empagliflozin (EP) once daily for 5 days, and the combination once daily for 5 days (EV + EP). In arm 2, subjects were administered 5 mg of EV once daily for 7 days, 10 mg of dapagliflozin (DP) once daily for 5 days, and the combination once daily for 5 days (EV + DP). Serial blood samples were collected for PK analysis, and oral glucose tolerance tests were conducted for PD analysis. In each arm, a total of 18 subjects completed the study. All adverse events (AEs) were mild with no serious AEs. The geometric mean ratio and confidence interval of the main PK parameters (maximum concentration of the drug in plasma at steady state and area under the plasma drug concentration-time curve within a dosing interval at a steady state) between EV and either EP or DP alone were not significantly altered by co-administration. Administration of EV + EP or EV + DP did not result in significant PD changes, as determined by the glucose-lowering effect. Administration of EV + EP or EV + DP had no significant effects on the PK profiles of each drug. All treatments were well-tolerated.
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Affiliation(s)
- Dasohm Kim
- Department of Clinical Pharmacology, Severance HospitalYonsei University College of MedicineSeoulSouth Korea
- Department of Pharmaceutical Medicine and Regulatory SciencesColleges of Medicine and Pharmacy, Yonsei UniversityIncheonSouth Korea
| | - Minkyu Choi
- Department of Clinical Pharmacology, Severance HospitalYonsei University College of MedicineSeoulSouth Korea
- Department of Pharmaceutical Medicine and Regulatory SciencesColleges of Medicine and Pharmacy, Yonsei UniversityIncheonSouth Korea
| | - Byung Hak Jin
- Department of Clinical Pharmacology, Severance HospitalYonsei University College of MedicineSeoulSouth Korea
- Department of Pharmaceutical Medicine and Regulatory SciencesColleges of Medicine and Pharmacy, Yonsei UniversityIncheonSouth Korea
| | - Taegon Hong
- Department of Clinical Pharmacology, Severance HospitalYonsei University College of MedicineSeoulSouth Korea
| | - Choon Ok Kim
- Department of Clinical Pharmacology, Severance HospitalYonsei University College of MedicineSeoulSouth Korea
| | - Byung Won Yoo
- Department of Clinical Pharmacology, Severance HospitalYonsei University College of MedicineSeoulSouth Korea
| | - Min Soo Park
- Department of Clinical Pharmacology, Severance HospitalYonsei University College of MedicineSeoulSouth Korea
- Department of Pharmaceutical Medicine and Regulatory SciencesColleges of Medicine and Pharmacy, Yonsei UniversityIncheonSouth Korea
- Department of PediatricsYonsei University College of MedicineSeoulSouth Korea
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16
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Saini K, Sharma S, Khan Y. DPP-4 inhibitors for treating T2DM - hype or hope? an analysis based on the current literature. Front Mol Biosci 2023; 10:1130625. [PMID: 37287751 PMCID: PMC10242023 DOI: 10.3389/fmolb.2023.1130625] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 05/08/2023] [Indexed: 06/09/2023] Open
Abstract
DPP-4 inhibition is an interesting line of therapy for treating Type 2 Diabetes Mellitus (T2DM) and is based on promoting the incretin effect. Here, the authors have presented a brief appraisal of DPP-4 inhibitors, their modes of action, and the clinical efficiency of currently available drugs based on DPP-4 inhibitors. The safety profiles as well as future directions including their potential application in improving COVID-19 patient outcomes have also been discussed in detail. This review also highlights the existing queries and evidence gaps in DPP-4 inhibitor research. Authors have concluded that the excitement surrounding DPP-4 inhibitors is justified because in addition to controlling blood glucose level, they are good at managing risk factors associated with diabetes.
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17
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Lin WR, Liu KH, Ling TC, Wang MC, Lin WH. Role of antidiabetic agents in type 2 diabetes patients with chronic kidney disease. World J Diabetes 2023; 14:352-363. [PMID: 37122432 PMCID: PMC10130897 DOI: 10.4239/wjd.v14.i4.352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 01/10/2023] [Accepted: 04/04/2023] [Indexed: 04/12/2023] Open
Abstract
Insulin resistance is a condition in which the target tissues have a decreased response to insulin signaling, resulting in glucose uptake defect, and an increased blood sugar level. Pancreatic beta cells thus enhance insulin production to compensate. This situation may cause further beta cell dysfunction and failure, which can lead diabetes mellitus (DM). Insulin resistance is thus an important cause of the development of type 2 DM. Insulin resistance has also been found to have a strong relationship with cardiovascular disease and is common in chronic kidney disease (CKD) patients. The mechanisms of insulin resistance in CKD are complex and multifactorial. They include physical inactivity, inflammation and oxidative stress, metabolic acidosis, vitamin D deficiency, adipose tissue dysfunction, uremic toxins, and renin-angiotensin-aldosterone system activation. Currently, available anti-diabetic agents, such as biguanides, sulfonylureas, thiazolidinediones, alfa-glucosidase inhibitors, glucagon-like peptide-1-based agents, and sodium-glucose co-transporter-2 inhibitors, have different effects on insulin resistance. In this short review, we describe the potential mechanisms of insulin resistance in CKD patients. We also review the interaction of currently available anti-diabetic medications with insulin resistance.
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Affiliation(s)
- Wei-Ren Lin
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Kuan-Hung Liu
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Tsai-Chieh Ling
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Ming-Cheng Wang
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Wei-Hung Lin
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
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18
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Salehi M, Peterson R, Tripathy D, Pezzica S, DeFronzo R, Gastaldelli A. Insulinotropic effect of endogenous incretins is greater after gastric bypass than sleeve gastrectomy despite diminished beta-cell sensitivity to plasma incretins. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.03.28.23287755. [PMID: 37034666 PMCID: PMC10081422 DOI: 10.1101/2023.03.28.23287755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
BACKGROUND/AIMS Prandial hyperinsulinemia after Roux-en Y gastric bypass surgery (GB), and to lesser degree after sleeve gastrectomy (SG), has been attributed to rapid glucose flux from the gut and increased insulinotropic gut hormones. However, β-cell sensitivity to exogenous incretin is markedly reduced after GB. This study examines the effect of GB versus SG on prandial glycemia and β-cell response to increasing concentrations of endogenous incretins. METHODS Glucose kinetics, insulin secretion rate (ISR), and incretin responses to 50-gram oral glucose ingestion were compared between 10 non-diabetic subjects with GB versus 9 matched individuals with SG and 7 non-operated normal glucose tolerant controls (CN) on two days with and without administration of 200 mg sitagliptin. RESULTS Fasting glucose and hormonal levels were similar among 3 groups. Increasing plasma concentrations of endogenous incretins by 2-3-fold diminished post-OGTT glycemia and increased β-cell secretion in all 3 groups (p<0.05), but insulin secretion per insulin sensitivity (i.e., disposition index) was increased only in GB (p<0.05 for interaction). As a result, sitagliptin administration led to hypoglycemia in 3 of 10 GB. Yet, plot of the slope of ISR versus the increase in endogenous incretin concentration was smaller after GB compared to both SG and CN. CONCLUSION Augmented glycemic-induced β-cell response caused by enhanced incretin activity is unique to GB and not shared with SG. However, the β-cell sensitivity to increasing concentrations of endogenous incretin is smaller after bariatric surgery, particularly after GB, compared to non-operated controls, indicating a long-term adaptation of gut-pancreas axis after these procedures. HIGHLIGHTS What is known?: Glycemic effects of gastric bypass (GB) and sleeve gastrectomy (SG) is attributed to rapid nutrient flux and enhanced insulinotropic effects of gut hormones but β-cell sensitivity to exogenous GLP-1 or GIP is diminished after GB. What the present findings add?: Post-OGTT β-cell sensitivity to enhanced endogenous incretins by DPP4i is markedly reduced in bariatric subjects versus non-operated controls, and yet insulin secretory response (disposition index) is increased leading to hypoglycemia in GB and not SG. Significance?: Blunted sensitivity to GLP-1 may represent β-cell adaptation to massive elevation in GLP-1 secretion following bariatric surgery to protect against hypoglycemia.The differential effect of enhanced concentrations of incretins on post-OGTT insulin response (disposition index) among GB versus SG highlights a distinct adaptive process among the two procedures.Augmented insulinotropic effects of gut hormones on postprandial insulin secretory response after GB despite a reduced beta-cell sensitivity to plasma concentrations of GLP-1 makes a case for non-hormonal mechanisms of GLP-1 action after GB.Better understanding of long-term effects of bariatric surgery on gut-pancreas axis activity is critical in development of GLP-1-based strategies to address glucose abnormalities (both hyperglycemia and hypoglycemia) in these settings.
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Chawla M, Chawla P, Jethwani P, Shah K, Reddy S. Metformin Sustained-Release and Vildagliptin Fixed-Dose Combination for Optimizing Glycemic Control: A Review with Real-World Case Reports. Clin Pract 2023. [DOI: 10.3390/clinpract13020045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2023] Open
Abstract
(1) Background: There is a high burden of poor glycemic control in the Indian population with type 2 diabetes mellitus (T2DM). Currently, the use of metformin sustained-release (SR)–vildagliptin fixed-dose combination (FDC) is very low as compared to metformin immediate-release (IR)–vildagliptin FDC which is associated with higher adverse events (AEs). Here, we present real-world effectiveness of metformin SR–vildagliptin FDC treatment in patients with T2DM; (2) Methods: This retrospective analysis was carried out from the medical records of adult T2DM patients visiting a single study center in India (December 2020–February 2021). A total of 10 patients (aged ≥20 years) were treated with vildagliptin 50 mg and metformin SR 500 mg FDC for 15 days. The treatment response was assessed by the percentage of time spent in the target glucose range (TIR at baseline and 15 days after treatment); (3) Results: The glycated hemoglobin (HbA1c) levels at baseline varied between 6.5% to 12%. The glycemic control improved in 70% of patients (mean increase in TIR: 18.9%). Treatment adherence was 100%. No gastrointestinal symptoms or AEs were reported; (4) Conclusions: Early intervention with metformin SR–vildagliptin FDC in patients with T2DM can ensure therapy compliance in terms of superior efficacy along with safety and tolerability. Key summary points: Early initiation of combination therapy helps in early achievement of glycemic goals; Early initiation of metformin and vildagliptin FDC results in significant glycemic control with good tolerability and compliance; Metformin SR–vildagliptin FDC has lower adverse events, compared to metformin IR–vildagliptin FDC; A case series of ten patients with T2DM treated with metformin SR–vildagliptin FDC is presented to assess the real-world effectiveness of this combination.
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Chen L, Zhang J, Sun Y, Zhao Y, Liu X, Fang Z, Feng L, He B, Zou Q, Tracey GJ. A phase I open-label clinical trial to study drug-drug interactions of Dorzagliatin and Sitagliptin in patients with type 2 diabetes and obesity. Nat Commun 2023; 14:1405. [PMID: 36918550 PMCID: PMC10014962 DOI: 10.1038/s41467-023-36946-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 02/22/2023] [Indexed: 03/16/2023] Open
Abstract
This is a phase 1, open-label, single-sequence, multiple-dose, single-center trial conducted in the US (NCT03790839), to evaluate the clinical pharmacokinetics, safety and pharmacodynamics of dorzagliatin co-administered with sitagliptin in patients with T2D and obesity. The trial has completed. 15 patients with T2D and obesity were recruited and treated with sitagliptin 100 mg QD on Day 1-5, followed by a combination of sitagliptin 100 mg QD with dorzagliatin 75 mg BID at second stage on Day 6-10 and the third stage of dorzagliatin 75 mg BID alone on Day 11-15. Primary outcomes include pharmacokinetic geometric mean ratio (GMR), safety and tolerability. Secondary outcomes include the incremental area under the curve for 4 hours post oral glucose tolerance test (iAUC) of pharmacodynamic biomarkers and glucose sensitivity. GMR for AUC0-24h and Cmax were 92.63 (90% CI, 85.61, 100.22) and 98.14 (90% CI, 83.73, 115.03) in combination/sitagliptin, and 100.34 (90% CI, 96.08, 104.79) and 102.34 (90% CI, 86.92, 120.50) in combination/dorzagliatin, respectively. Combination treatment did not increase the adverse events and well-tolerated in T2D patients. Lack of clinically meaningful pharmacokinetic interactions between dorzagliatin and sitagliptin, and an improvement of glycemic control under combination potentially support their co-administration for diabetes management.
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Affiliation(s)
- Li Chen
- Hua Medicine (Shanghai) Limited, Shanghai, China.
| | - Jiayi Zhang
- Hua Medicine (Shanghai) Limited, Shanghai, China
| | - Yu Sun
- Hua Medicine (Shanghai) Limited, Shanghai, China
| | - Yu Zhao
- Hua Medicine (Shanghai) Limited, Shanghai, China
| | - Xiang Liu
- Hua Medicine (Shanghai) Limited, Shanghai, China
| | - Zhiyin Fang
- Hua Medicine (Shanghai) Limited, Shanghai, China
| | - Lingge Feng
- Hua Medicine (Shanghai) Limited, Shanghai, China
| | - Bin He
- Hua Medicine (Shanghai) Limited, Shanghai, China
| | - Quanfei Zou
- Hua Medicine (Shanghai) Limited, Shanghai, China
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Patel R, Parmar N, Palit SP, Rathwa N, Begum R. A novel combination of sitagliptin and melatonin ameliorates T2D manifestations: studies on experimental diabetic models. J Endocrinol Invest 2023:10.1007/s40618-023-02014-6. [PMID: 36692817 DOI: 10.1007/s40618-023-02014-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 01/16/2023] [Indexed: 01/25/2023]
Abstract
INTRODUCTION Type 2 diabetes (T2D) is an endocrine disorder characterized by hyperglycemia, insulin resistance, dysregulated glucose and lipid metabolism, reduced pancreatic β-cell function and mass, and a reduced incretin effect. Circadian rhythm disruption is associated with increased T2D risk. We have investigated the therapeutic potential of a combination of melatonin (M) and sitagliptin (S), a dipeptidyl peptidase IV (DPP-IV) inhibitor, in the amelioration of T2D manifestations in high-fat diet (HFD) induced T2D mouse model and also on β-cell proliferation under gluco-lipotoxicity stress in vitro. METHODS For in vivo study, mice were fed with HFD for 25 weeks to induce T2D and were treated with monotherapies and S + M for four weeks. For the in vitro study, primary mouse islets were exposed to normal glucose and high glucose + palmitate to induce gluco-lipotoxic stress. RESULTS Our results suggest that monotherapies and S + M improve metabolic parameters and glyco-lipid metabolism in the liver and adipose tissue, respectively, and improve mitochondrial function in the skeletal muscle. Moreover, it increases peripheral insulin sensitivity. Our in vitro and in vivo studies suggest that β-cell mass was preserved in all the drug-treated groups. CONCLUSION The combination treatment is superior to monotherapies in the management of T2D.
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Affiliation(s)
- R Patel
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India
| | - N Parmar
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India
| | - S P Palit
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India
| | - N Rathwa
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India
| | - R Begum
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India.
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Guan HP, Xiong Y. Learn from failures and stay hopeful to GPR40, a GPCR target with robust efficacy, for therapy of metabolic disorders. Front Pharmacol 2022; 13:1043828. [PMID: 36386134 PMCID: PMC9640913 DOI: 10.3389/fphar.2022.1043828] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 10/13/2022] [Indexed: 09/10/2023] Open
Abstract
GPR40 is a class A G-protein coupled receptor (GPCR) mainly expressed in pancreas, intestine, and brain. Its endogenous ligand is long-chain fatty acids, which activate GPR40 after meal ingestion to induce secretion of incretins in the gut, including GLP-1, GIP, and PYY, the latter control appetite and glucose metabolism. For its involvement in satiety regulation and metabolic homeostasis, partial and AgoPAM (Positive Allosteric Modulation agonist) GPR40 agonists had been developed for type 2 diabetes (T2D) by many pharmaceutical companies. The proof-of-concept of GPR40 for control of hyperglycemia was achieved by clinical trials of partial GPR40 agonist, TAK-875, demonstrating a robust decrease in HbA1c (-1.12%) after chronic treatment in T2D. The development of TAK-875, however, was terminated due to liver toxicity in 2.7% patients with more than 3-fold increase of ALT in phase II and III clinical trials. Different mechanisms had since been proposed to explain the drug-induced liver injury, including acyl glucuronidation, inhibition of mitochondrial respiration and hepatobiliary transporters, ROS generation, etc. In addition, activation of GPR40 by AgoPAM agonists in pancreas was also linked to β-cell damage in rats. Notwithstanding the multiple safety concerns on the development of small-molecule GPR40 agonists for T2D, some partial and AgoPAM GPR40 agonists are still under clinical development. Here we review the most recent progress of GPR40 agonists development and the possible mechanisms of the side effects in different organs, and discuss the possibility of developing novel strategies that retain the robust efficacy of GPR40 agonists for metabolic disorders while avoid toxicities caused by off-target and on-target mechanisms.
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Sitagliptin Versus Placebo to Reduce the Incidence and Severity of Posttransplant Diabetes Mellitus After Kidney Transplantation-A Single-center, Randomized, Double-blind Controlled Trial. Transplantation 2022; 107:1180-1187. [PMID: 36279020 PMCID: PMC10125117 DOI: 10.1097/tp.0000000000004373] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND Postkidney transplant diabetes mellitus (PTDM) affects cardiovascular, allograft, and recipient health. We tested whether early intervention with sitagliptin for hyperglycemia (blood glucose >200 mg/dL) within the first week of transplant and discontinued at 3 mo could prevent development of PTDM in patients without preexisting diabetes. METHODS The primary efficacy objective was to improve 2-h oral glucose tolerance test (OGTT) by > 20 mg/dL at 3 mo posttransplant. The secondary efficacy objective was to prevent new onset PTDM, defined as a normal OGTT at 3 mo. RESULTS Sixty-one patients consented, and 50 patients were analyzed. The 3-mo 2-h OGTT (end of treatment) was 141.00 ± 62.44 mg/dL in the sitagliptin arm and 165.22 ± 72.03 mg/dL ( P = 0.218) in the placebo arm. The 6-mo 2-h OGTT (end of follow-up) was 174.38 ± 77.93 mg/dL in the sitagliptin arm and 171.86 ± 83.69 ng/dL ( P = 0.918) in the placebo arm. Mean intrapatient difference between 3- and 6-mo 2-h OGTT in the 3-mo period off study drug was 27.56 + 52.74 mg/dL in the sitagliptin arm and -0.14 + 45.80 mg/dL in the placebo arm ( P = 0.0692). At 3 mo, 61.54% of sitagliptin and 43.48% of placebo patients had a normal 2-h OGTT ( P = 0.2062), with the absolute risk reduction 18.06%. There were no differences in HbA1c at 3 or 6 mo between sitagliptin and placebo groups. Participants tolerated sitagliptin well. CONCLUSION Although this study did not show a significant difference between groups, it can inform future studies in the use of sitagliptin in the very early posttransplant period.
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Role of Dipeptidyl Peptidase-4 (DPP4) on COVID-19 Physiopathology. Biomedicines 2022; 10:biomedicines10082026. [PMID: 36009573 PMCID: PMC9406088 DOI: 10.3390/biomedicines10082026] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 11/17/2022] Open
Abstract
DPP4/CD26 is a single-pass transmembrane protein with multiple functions on glycemic control, cell migration and proliferation, and the immune system, among others. It has recently acquired an especial relevance due to the possibility to act as a receptor or co-receptor for SARS-CoV-2, as it has been already demonstrated for other coronaviruses. In this review, we analyze the evidence for the role of DPP4 on COVID-19 risk and clinical outcome, and its contribution to COVID-19 physiopathology. Due to the pathogenetic links between COVID-19 and diabetes mellitus and the hyperinflammatory response, with the hallmark cytokine storm developed very often during the disease, we dive deep into the functions of DPP4 on carbohydrate metabolism and immune system regulation. We show that the broad spectrum of functions regulated by DPP4 is performed both as a protease enzyme, as well as an interacting partner of other molecules on the cell surface. In addition, we provide an update of the DPP4 inhibitors approved by the EMA and/or the FDA, together with the newfangled approval of generic drugs (in 2021 and 2022). This review will also cover the effects of DPP4 inhibitors (i.e., gliptins) on the progression of SARS-CoV-2 infection, showing the role of DPP4 in this disturbing disease.
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Okura T, Fujioka Y, Nakamura R, Ito Y, Kitao S, Anno M, Matsumoto K, Shoji K, Okura H, Matsuzawa K, Izawa S, Ueta E, Kato M, Imamura T, Taniguchi SI, Yamamoto K. Dipeptidyl peptidase 4 inhibitor improves insulin resistance in Japanese patients with type 2 diabetes: a single-arm study, a brief report. Diabetol Metab Syndr 2022; 14:78. [PMID: 35672759 PMCID: PMC9171964 DOI: 10.1186/s13098-022-00850-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 05/29/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Dipeptidyl peptidase 4 inhibitor (DPP4i) is an effective medicine for type 2 diabetes mellitus (T2DM). Some articles reported DPP4i improves insulin secretion and insulin resistance. However, these effects are not well established by glucose clamp test and test meal in Japanese. We investigated the effect of DPP4i on insulin resistance and insulin secretion by using the glucose clamp test and meal tolerance test (MTT). METHODS We performed a MTT, and the hyperinsulinemic-euglycemic clamp in 8 Japanese patients with T2DM. This study was a single-arm study. We measured fasting and postprandial glucose, insulin, incretins, and glucagon levels. We also measured serum adiponectin levels. RESULTS HbA1c was significantly decreased after 3 months. The fasting and postprandial glucose levels were significantly decreased. Fasting and postprandial insulin levels were not changed. The insulin resistance derived from the glucose clamp test was significantly improved. HOMA-IR was not significantly changed. GLP-1 and GIP were significantly increased but glucagon did not change. Adiponectin was not significantly changed. CONCLUSIONS Although the number of patients was very small, these results suggested that DPP4i treatment might improve insulin resistance without changing insulin secretion.
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Affiliation(s)
- Tsuyoshi Okura
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan.
| | - Yohei Fujioka
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan
| | - Risa Nakamura
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan
| | - Yuichi Ito
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan
| | - Sonoko Kitao
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan
| | - Mari Anno
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan
| | - Kazuhisa Matsumoto
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan
| | - Kyoko Shoji
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan
| | - Hiroko Okura
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan
| | - Kazuhiko Matsuzawa
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan
| | - Shoichiro Izawa
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan
| | - Etsuko Ueta
- School of Health Science, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Masahiko Kato
- School of Health Science, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Takeshi Imamura
- Division of Molecular Pharmacology, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Shin-Ichi Taniguchi
- Department of Regional Medicine, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Kazuhiro Yamamoto
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan
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Cheng Y, Liu P, Xiang Q, Liang J, Chen H, Zhang H, Yang L. Glucagon-like peptide-1 attenuates diabetes-associated osteoporosis in ZDF rat, possibly through the RAGE pathway. BMC Musculoskelet Disord 2022; 23:465. [PMID: 35581617 PMCID: PMC9112483 DOI: 10.1186/s12891-022-05396-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 04/18/2022] [Indexed: 11/23/2022] Open
Abstract
Background Diabetes-associated osteoporosis are partly caused by accumulation of advanced glycation endproducts (AGEs). Glucagon-like peptide-1 (GLP-1) has been shown to regulate bone turnover. Here we explore whether GLP-1 receptor agonist (GLP1RA) can have a beneficial effect on bone in diabetes by ameliorating AGEs. Methods In the present study, we evaluated the effects of the GLP-1 receptor agonist liraglutide, insulin and dipeptidyl peptidase-4 inhibitor saxagliptin on Zucker diabetic fatty rats. Meanwhile, we observed the effect of GLP-1 on AGEs-mediated osteoblast proliferation and differentiation and the signal pathway. Results Liraglutide prevented the deterioration of trabecular microarchitecture and enhanced bone strength. Moreover, it increased serum Alpl, Ocn and P1NP levels and decreased serum CTX. In vitro we confirmed that GLP-1 could attenuate AGEs-mediated damage in osteogenic proliferation and differentiation. Besides, GLP-1 down-regulated the ROS that caused by AGEs and the mRNA and protein expression of Rage . Conclusions Altogether, our findings suggest that GLP-1 receptor agonist promotes osteoblastogenesis and suppresses bone resorption on obese type 2 diabetic rats to a certain degree. The mechanism of these effects may be partly mediated by AGEs-RAGE-ROS pathway via the interaction with GLP-1 receptor. Supplementary Information The online version contains supplementary material available at 10.1186/s12891-022-05396-5.
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Affiliation(s)
- Yanzhen Cheng
- Department of Endocrinology and Metabolism, Zhujiang Hospital, the Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510000, Guangdong, People's Republic of China
| | - Peng Liu
- Department of Cardiology, Zhujiang Hospital, the Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510000, Guangdong, People's Republic of China
| | - Qianru Xiang
- Department of Endocrinology and Metabolism, Zhujiang Hospital, the Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510000, Guangdong, People's Republic of China
| | - Jiamin Liang
- Department of Endocrinology and Metabolism, Zhujiang Hospital, the Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510000, Guangdong, People's Republic of China
| | - Huafeng Chen
- Department of Endocrinology and Metabolism, Zhujiang Hospital, the Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510000, Guangdong, People's Republic of China
| | - Hua Zhang
- Department of Endocrinology and Metabolism, Zhujiang Hospital, the Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510000, Guangdong, People's Republic of China.
| | - Li Yang
- Department of Nutrition, Zhujiang Hospital, the Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510000, Guangdong, People's Republic of China.
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Meier JJ, Quast DR, Nauck MA, Schenker N, Deacon CF, Holst JJ, Plum-Mörschel L, Kapitza C. Acute effects of linagliptin on intact and total glucagon-like peptide-1 and gastric inhibitory polypeptide levels in insulin-dependent type 2 diabetes patients with and without moderate renal impairment. Diabetes Obes Metab 2022; 24:806-815. [PMID: 34984794 DOI: 10.1111/dom.14636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 12/12/2021] [Accepted: 01/01/2022] [Indexed: 11/26/2022]
Abstract
AIMS To investigate the effect of renal impairment on incretin metabolism in patients with type 2 diabetes mellitus (T2DM) before and after treatment with the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin. MATERIALS AND METHODS Long-standing T2DM patients with normal (estimated glomerular filtration rate [eGFR] >90 mL/min/1.73m2 ) and impaired (eGFR <60 mL/min/1.73m2 ) renal function on stable treatment with insulin were included. Before and after 8 days of treatment with 5 mg linagliptin once daily, patients underwent a 75-g oral glucose tolerance test (OGTT) and total and intact glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), glucose, insulin, C-peptide and glucagon concentrations were measured. The primary outcome was the difference between the study groups in change of intact GLP-1 concentrations. RESULTS Of 115 patients screened, 29 were analysed (15 [51.7%] with and 14 [48.3%] without renal impairment). Renal function differed significantly between the groups (101 ± 11 vs. 47 ± 13 mL/min/1.73m2 ; P < 0.0001), while glycaemic control was similar (glycated haemoglobin 68 ± 5 vs. 66 ± 5 mmol/mol; P = 0.45). Baseline GLP-1 and GIP levels were comparable. Glucose concentrations during the OGTT were significantly lowered by linagliptin treatment in patients with renal impairment (P = 0.017), but not in those with normal renal function (P = 0.17). Treatment with linagliptin resulted in a significant increase in intact GLP-1 and GIP levels in patients with normal (P = 0.048 and P = 0.0001, respectively) and impaired (P = 0.040 and P = 0.0011, respectively) renal function during the OGTT. However, the primary outcome (difference between the groups in change of intact GLP-1 concentrations) was not significant (P = 0.22). Overall, linagliptin was well tolerated. CONCLUSIONS Treatment with linagliptin increases intact incretin levels in patients with T2DM. Impaired renal function does not compromise the effects of linagliptin on active or total incretin levels as well as on glucagon secretion. Thus, treatment with linagliptin is suitable for patients with T2DM, independently of renal function.
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Affiliation(s)
- Juris J Meier
- Diabetes Division, St Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
- Department of Internal Medicine, Gastroenterology and Diabetes, Augusta Clinic Bochum, Bochum, Germany
| | - Daniel R Quast
- Diabetes Division, St Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Michael A Nauck
- Diabetes Division, St Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Nina Schenker
- Diabetes Division, St Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Carolyn F Deacon
- Department of Biomedical Sciences and NovoNordisk Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Panum Institute, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences and NovoNordisk Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Panum Institute, Copenhagen, Denmark
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Development, validation and application of a liquid chromatography-tandem mass spectrometry method for the activity and inhibition of DPP-4. Bioanalysis 2022; 14:369-378. [PMID: 35249375 DOI: 10.4155/bio-2022-0004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background: Inhibition of the enzyme dipeptidyl peptidase 4 (DPP-4) is a pharmaceutical treatment for type 2 diabetes. To demonstrate bioequivalence of enzyme inhibition of a new dosage form of the inhibitor vildagliptin, a method for enzyme activity was developed, validated and applied using liquid chromatography and tandem mass spectrometry (LC-MS/MS). Results: The method was validated fit for purpose, including accuracy, precision as well as the stability of the activity and the inhibition of DPP-4 in human plasma. Conclusion: A method for the determination of the activity and inhibition of DPP-4 was developed using LC-MS/MS readout; the characteristics and performance of the method met predefined acceptance criteria and were fit for the purpose of a bioequivalence clinical trial.
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Florentin M, Kostapanos MS, Papazafiropoulou AK. Role of dipeptidyl peptidase 4 inhibitors in the new era of antidiabetic treatment. World J Diabetes 2022; 13:85-96. [PMID: 35211246 PMCID: PMC8855136 DOI: 10.4239/wjd.v13.i2.85] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/29/2021] [Accepted: 01/26/2022] [Indexed: 02/06/2023] Open
Abstract
The last few years important changes have occurred in the field of diabetes treatment. The priority in the therapy of patients with diabetes is not glycemic control per se rather an overall management of risk factors, while individualization of glycemic target is suggested. Furthermore, regulatory authorities now require evidence of cardiovascular (CV) safety in order to approve new antidiabetic agents. The most novel drug classes, i.e., sodium-glucose transporter 2 inhibitors (SGLT2-i) and some glucagon-like peptide-1 receptor agonists (GLP-1 RA), have been demonstrated to reduce major adverse CV events and, thus, have a prominent position in the therapeutic algorithm of hyperglycemia. In this context, the role of previously used hypoglycemic agents, including dipeptidyl peptidase 4 (DPP-4) inhibitors, has been modified. DPP-4 inhibitors have a favorable safety profile, do not cause hypoglycemia or weight gain and do not require dose uptitration. Furthermore, they can be administered in patients with chronic kidney disease after dose modification and elderly patients with diabetes. Still, though, they have been undermined to a third line therapeutic choice as they have not been shown to reduce CV events as is the case with SGLT2-i and GLP-1 RA. Overall, DPP-4 inhibitors appear to have a place in the management of patients with diabetes as a safe class of oral glucose lowering agents with great experience in their use.
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Affiliation(s)
- Matilda Florentin
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina 45221, Greece
| | - Michael S Kostapanos
- Lipid Clinic, Department of General Medicine, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom
| | - Athanasia K Papazafiropoulou
- 1st Department of Internal Medicine and Diabetes Center, Tzaneio General Hospital of Piraeus, Athens 18536, Greece
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Andersen DB, Holst JJ. Peptides in the regulation of glucagon secretion. Peptides 2022; 148:170683. [PMID: 34748791 DOI: 10.1016/j.peptides.2021.170683] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/21/2021] [Accepted: 11/02/2021] [Indexed: 02/06/2023]
Abstract
Glucose homeostasis is maintained by the glucoregulatory hormones, glucagon, insulin and somatostatin, secreted from the islets of Langerhans. Glucagon is the body's most important anti-hypoglycemic hormone, mobilizing glucose from glycogen stores in the liver in response to fasting, thus maintaining plasma glucose levels within healthy limits. Glucagon secretion is regulated by both circulating nutrients, hormones and neuronal inputs. Hormones that may regulate glucagon secretion include locally produced insulin and somatostatin, but also urocortin-3, amylin and pancreatic polypeptide, and from outside the pancreas glucagon-like peptide-1 and 2, peptide tyrosine tyrosine and oxyntomodulin, glucose-dependent insulinotropic polypeptide, neurotensin and ghrelin, as well as the hypothalamic hormones arginine-vasopressin and oxytocin, and calcitonin from the thyroid. Each of these hormones have distinct effects, ranging from regulating blood glucose, to regulating appetite, stomach emptying rate and intestinal motility, which makes them interesting targets for treating metabolic diseases. Awareness regarding the potential effects of the hormones on glucagon secretion is important since secretory abnormalities could manifest as hyperglycemia or even lethal hypoglycemia. Here, we review the effects of each individual hormone on glucagon secretion, their interplay, and how treatments aimed at modulating the plasma levels of these hormones may also influence glucagon secretion and glycemic control.
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Affiliation(s)
- Daniel B Andersen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Panum Institute, Blegdamsvej 3B, 2200, Copenhagen N, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Panum Institute, Blegdamsvej 3B, 2200, Copenhagen N, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
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Lin L, Wang L. Knockdown of DPP4 promotes the proliferation and the activation of the CREB/aromatase pathway in ovarian granulosa cells. Mol Med Rep 2022; 25:73. [PMID: 35014677 PMCID: PMC8767454 DOI: 10.3892/mmr.2022.12589] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 09/21/2021] [Indexed: 11/23/2022] Open
Abstract
Dipeptidyl peptidase 4 (DPP4) has been revealed to be upregulated in women suffering from polycystic ovary syndrome (PCOS), which is a common reproductive disorder. The present study was designed to investigate the effects of inhibition of DPP4 expression on the proliferation of ovarian granulosa cells as well as on the activation of the cAMP response element‑binding protein (CREB)/aromatase pathway. The expression levels of DPP4 in rat serum samples with or without PCOS and ovarian granulosa cells (KGN cells) were detected using reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analyses. Cell viability and cell cycle progression were detected using the Cell Counting Kit‑8 assay and flow cytometric analysis, respectively. The 5‑ethynyl‑2'‑deoxyuridine assay was employed to detect the proliferation of glycolaldehyde‑bovine serum albumin (GOA‑BSA)‑treated KGN cells. In addition, RT‑qPCR and western blot analyses were applied to detect the expression levels of CREB, specific cell cycle‑associated proteins and cytochrome P450 (CYP) 19A1 and CYP11A1 enzymes in KGN cells. The expression levels of DPP4 were upregulated in rats with PCOS. Inhibition of DPP4 expression promoted the proliferation and cell cycle arrest of KGN cells. It was also revealed that the expression levels of cell cycle‑associated proteins were upregulated in DPP4‑silenced KGN cells. In addition, their proliferation was decreased following treatment with GOA‑BSA, while the addition of sitagliptin partially reversed these effects. Additionally, sitagliptin reversed the inhibitory effects caused by GOA‑BSA treatment on the cell cycle progression and on the activation of the CREB/aromatase pathway in KGN cells, as determined by the increased expression levels of the cell cycle‑associated proteins as well as those of the CREB protein and the CYP19A1 and CYP11A1 enzymes. In conclusion, inhibition of DPP4 expression promoted the proliferation of KGN cells and the activation of the CREB/aromatase pathway.
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Affiliation(s)
- Lina Lin
- Center for Reproductive Medicine, Shantou Central Hospital, Shantou, Guangdong 515041, P.R. China
| | - Liman Wang
- Center for Reproductive Medicine, Shantou Central Hospital, Shantou, Guangdong 515041, P.R. China
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Sharma A, Virmani T, Sharma A, Chhabra V, Kumar G, Pathak K, Alhalmi A. Potential Effect of DPP-4 Inhibitors Towards Hepatic Diseases and Associated Glucose Intolerance. Diabetes Metab Syndr Obes 2022; 15:1845-1864. [PMID: 35733643 PMCID: PMC9208633 DOI: 10.2147/dmso.s369712] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 06/10/2022] [Indexed: 11/23/2022] Open
Abstract
Dipeptidyl-peptidase-4 (DPP-4) is an enzyme having various properties and physiological roles in lipid accumulation, resistance to anticancer agents, and immune stimulation. DPP-4 includes membrane-bound peptidases and is a kind of enzyme that cleaves alanine or proline-containing peptides such as incretins, chemokines, and appetite-suppressing hormones (neuropeptide) at their N-terminal dipeptides. DPP-4 plays a role in the final breakdown of peptides produced by other endo and exo-peptidases from nutritious proteins and their absorption in these tissues. DPP-4 enzyme activity has different modes of action on glucose metabolism, hunger regulation, gastrointestinal motility, immune system function, inflammation, and pain regulation. According to the literature survey, as DPP-4 levels increase in individuals with liver conditions, up-regulation of hepatic DPP-4 expression is likely to be the cause of glucose intolerance or insulin resistance. This review majorly focuses on the cleavage of alanine or proline-containing peptides such as incretins by the DPP-4 and its resulting conditions like glucose intolerance and cause of DPP-4 level elevation due to some liver conditions. Thus, we have discussed the various effects of DPP-4 on the liver diseases like hepatitis C, non-alcoholic fatty liver, hepatic regeneration and stem cell, hepatocellular carcinoma, and the impact of elevated DPP-4 levels in association with liver diseases as a cause of glucose intolerance and their treatment drug of choices. In addition, the effect of DPP-4 inhibitors on obesity and their negative aspects are also discussed in brief.
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Affiliation(s)
- Ashwani Sharma
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Tarun Virmani
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Anjali Sharma
- Freelancer, Pharmacovigilance Expert, Uttar Pradesh, India
| | - Vaishnavi Chhabra
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Girish Kumar
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Kamla Pathak
- Faculty of Pharmacy, Uttar Pradesh University of Medical Sciences, Uttar Pradesh, 206130, India
| | - Abdulsalam Alhalmi
- Department of Pharmaceutical Science, College of Pharmacy, Aden University, Aden, Yemen
- Correspondence: Abdulsalam Alhalmi, Department of Pharmaceutical Science, College of Pharmacy, Aden University, Aden, Yemen, Email
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Yuan W, Yong W, Zhu J, Shi D. DPP4 Regulates DHCR24-Mediated Cholesterol Biosynthesis to Promote Methotrexate Resistance in Gestational Trophoblastic Neoplastic Cells. Front Oncol 2021; 11:704024. [PMID: 34926239 PMCID: PMC8675944 DOI: 10.3389/fonc.2021.704024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 11/17/2021] [Indexed: 11/17/2022] Open
Abstract
Metabolic reprogramming could promote cellular adaptation in response to chemotherapeutic drugs in cancer cells. Herein, we aimed to characterize the metabolomic profiles regulated by Dipeptidyl Peptidase 4 (DPP4) in methotrexate (MTX)-resistant gestational trophoblastic neoplastic (GTN) cells. A total of eighty metabolites were found to be commonly altered in DPP4-depleted JAR/MTX and JEG3/MTX cells. Cholesterol biosynthesis-related metabolites were markedly impacted by DPP4 knockdown in MTX-resistant sublines. Manipulation of DPP4 expression remarkably affected the level of cellular cholesterol in GTN cells. Our analysis also identified 24-Dehydrocholesterol Reductase (DHCR24) as a potential downstream effector of DPP4. Manipulation of DHCR24 expression affected cellular cholesterol level, reactive oxygen species (ROS) accumulation, and chemosensitivity to MTX in GTN cell models. In addition, over-expression of DHCR24 could markedly restore cellular cholesterol level and rescue cell survival in DPP4-depleted MTX-resistant GTN cells. Highly correlated expression of DPP4 and DHCR24 was observed in clinical GTN specimens. Further, DPP4 inhibitor sitagliptin effectively inhibited cholesterol biosynthesis, reduced DHCR24 expression and enhanced MTX-induced cytotoxicity in vitro and in vivo. In conclusion, our findings suggested that DPP4 might regulate DHCR24-mediated cholesterol biosynthesis to promote methotrexate resistance in GTN cells. Targeting DPP4/DHCR24 signaling might help to sensitize MTX-resistant GTN to MTX treatment.
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Affiliation(s)
- Weijie Yuan
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, China.,The Hunan Provincial Key Laboratory of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Changsha, China
| | - Wenjing Yong
- Department of Obstetrics, Xiangya Hospital, Central South University, Changsha, China
| | - Jing Zhu
- Department of Gynecology, Xiangya Hospital, Central South University, Changsha, China
| | - Dazun Shi
- Department of Gynecology, Xiangya Hospital, Central South University, Changsha, China
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Lim J, Ferruzzi MG, Hamaker BR. Dietary starch is weight reducing when distally digested in the small intestine. Carbohydr Polym 2021; 273:118599. [PMID: 34560999 DOI: 10.1016/j.carbpol.2021.118599] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 08/09/2021] [Accepted: 08/19/2021] [Indexed: 12/25/2022]
Abstract
Nowadays, carbohydrate-based foods have a negative consumer connotation and low carb diets have become a popular way to lose weight. Here, we show how digestible starch and flavonoids can be used as a dietary approach to manage food intake and weight gain through elevation of glucagon-like peptide-1 (GLP-1) secretion for gut-brain axis communication. This was achieved by extending the digestion of cooked starch to the distal small intestine using luteolin or quercetin as α-amylase-specific inhibitors with competitive inhibition mechanism. In a mouse model, extended and complete digestion produced a signature blunted glycemic profile that induced elevation of GLP-1 and positive regulation of hypothalamic neuropeptides with significantly reduced food intake and weight gain (p < 0.05). These findings represent a shift in paradigm of dietary carbohydrates from weight increasing to reducing, and have implications for industry and public health related to the design of carbohydrate-based foods/ingredients for managing obesity and diabetes.
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Affiliation(s)
- Jongbin Lim
- Whistler Center for Carbohydrate Research and Department of Food Science, Purdue University, West Lafayette, IN 47907, USA
| | - Mario G Ferruzzi
- Plants for Human Health Institute, North Carolina State University, Kannapolis, NC 28081, USA; Department of Food, Bioprocessing and Nutrition Sciences, North Carolina State University, Raleigh, NC 27606, USA
| | - Bruce R Hamaker
- Whistler Center for Carbohydrate Research and Department of Food Science, Purdue University, West Lafayette, IN 47907, USA.
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Iijima T, Hosonuma S, Kurai H, Kajitani H, Sakurai S, Tomaru T, Jojima T, Usui I, Aso Y. Acute effect of add-on therapy with tofogliflozin, a sodium glucose co-transporter 2 inhibitor, on 24-hours glucose profile and glycaemic variability evaluated by continuous glucose monitoring in patients with type 2 diabetes receiving dipeptidyl peptidase-4 inhibitors. Int J Clin Pract 2021; 75:e14732. [PMID: 34388297 DOI: 10.1111/ijcp.14732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 08/03/2021] [Indexed: 12/01/2022] Open
Abstract
AIM To investigate acute effects of add-on therapy with the sodium glucose co-transporter 2 inhibitor tofogliflozin to dipeptidyl peptidase (DPP)-4 inhibitors on 24-hours glucose profile and glycaemic variability evaluated by continuous glucose monitoring (CGM) in patients with type 2 diabetes. PATIENTS AND METHODS We studied 17 patients with type 2 diabetes who were hospitalised for glycaemic control. CGM was performed for 7 consecutive days in the last week of hospitalization. Tofogliflozin 20 mg/d was started on day 4 after initiating CGM and was administered to 10 patients receiving DPP-4 inhibitors and 7 patients not receiving DPP-4 inhibitors. We compared several CGM parameters between day 2-3 (ie, before treatment with tofogliflozin) and day 5-6 (ie, after starting treatment with tofogliflozin). RESULTS After starting treatment with tofogliflozin, mean 24-hours glucose and postprandial glucose after each meal were significantly decreased in both groups of patients. Time in range (ie, at a glucose level of 70-180 mg/dL) was significantly increased in both groups. The standard deviation of 24-hours glucose and mean amplitude of glycaemic excursions (MAGE), 2 indexes of glycaemic variability, were significantly decreased in patients receiving DPP-4 inhibitors but were unchanged in those not receiving these drugs. CONCLUSIONS Add-on therapy with tofogliflozin to DPP-4 inhibitors acutely reduces 24-hours glucose levels and improves glycaemic variability in patients with type 2 diabetes.
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Affiliation(s)
- Toshie Iijima
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Soichiro Hosonuma
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Hidetaka Kurai
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Hayato Kajitani
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Shintaro Sakurai
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Takuya Tomaru
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Teruo Jojima
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Isao Usui
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Yoshimasa Aso
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
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Charoo NA, Abdallah DB, Bakheit AA, Haque KU, Hassan HA, Abrahamsson B, Cristofoletti R, Langguth P, Mehta M, Parr A, Polli JE, Shah VP, Tajiri T, Dressman J. Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Sitagliptin Phosphate Monohydrate. J Pharm Sci 2021; 111:2-13. [PMID: 34597625 DOI: 10.1016/j.xphs.2021.09.031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/15/2021] [Accepted: 09/15/2021] [Indexed: 01/21/2023]
Abstract
Sitagliptin is an antihyperglycemic drug used in adults for the treatment of diabetes Type 2. Literature data and in-house experiments were applied in this monograph to assess whether methods based on the Biopharmaceutics Classification System (BCS) could be used to assess the bioequivalence of solid immediate-release (IR) oral dosage forms containing sitagliptin phosphate monohydrate, as an alternative to a pharmacokinetic study in human volunteers. The solubility and permeability characteristics of sitagliptin were reviewed according to the BCS, along with dissolution, therapeutic index, therapeutic applications, pharmacokinetics, pharmacodynamic characteristics, reports of bioequivalence (BE) / bioavailability problems, data on interactions between the drug and excipients and other data germane to the subject. All data reviewed in this monograph unambiguously support classification of sitagliptin as a BCS Class 1 drug. In light of its broad therapeutic index and lack of severe adverse effects, the clinical risks associated with moderately supraoptimal doses were deemed inconsequential, as were the risks associated with moderately suboptimal doses. Taking all evidence into consideration, it was concluded that the BCS-based biowaiver can be implemented for solid IR oral drug products containing sitagliptin phosphate monohydrate, provided (a) the test product is formulated solely with excipients commonly present in solid IR oral drug products approved in ICH or associated countries and used in amounts commonly applied in this type of product, (b) data in support of the BCS-based biowaiver are obtained using the methods recommended by the WHO, FDA, EMA or ICH and (c) the test product and the comparator product (which is the innovator product in this case) meet all in vitro dissolution specifications provided in the WHO, FDA, EMA or ICH guidance.
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Affiliation(s)
- Naseem A Charoo
- Succor Pharma Solutions, Dubai Science Park, Dubai, United Arab Emirates
| | - Daud B Abdallah
- Department of Pharmaceutics, Faculty of Pharmacy, The National Ribat University, Khartoum, Sudan
| | - Ahmed Abdalla Bakheit
- Department of Pharmaceutics, Faculty of Pharmacy, The National Ribat University, Khartoum, Sudan
| | - Kashif Ul Haque
- Succor Pharma Solutions, Dubai Science Park, Dubai, United Arab Emirates
| | - Hassan Ali Hassan
- Department of Pharmaceutics, Faculty of Pharmacy, University of Khartoum, Sudan
| | - Bertil Abrahamsson
- Oral Product Development, Pharmaceutical Technology & Development, Operations AstraZeneca, Gothenburg, Sweden
| | - Rodrigo Cristofoletti
- Brazilian Health Surveillance Agency (ANVISA), Division of Bioequivalence, Brasilia, Brazil
| | - Peter Langguth
- Department of Pharmaceutical Technology and Biopharmaceutics, Johannes Gutenberg University, Mainz, Germany
| | - Mehul Mehta
- United States Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD, USA
| | - Alan Parr
- Bioceutics LCC, Raleigh-Durham, North Carolina, USA
| | - James E Polli
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA
| | - Vinod P Shah
- International Pharmaceutical Federation (FIP), The Hague, the Netherlands
| | - Tomokazu Tajiri
- Astellas Pharma Inc, Analytical Research Laboratories, Yaizu, Japan
| | - Jennifer Dressman
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany.
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Kelly A, Sheikh S, Stefanovski D, Peleckis AJ, Nyirjesy SC, Eiel JN, Sidhaye A, Localio R, Gallop R, De Leon DD, Hadjiliadis D, Rubenstein RC, Rickels MR. Effect of Sitagliptin on Islet Function in Pancreatic Insufficient Cystic Fibrosis With Abnormal Glucose Tolerance. J Clin Endocrinol Metab 2021; 106:2617-2634. [PMID: 34406395 PMCID: PMC8660013 DOI: 10.1210/clinem/dgab365] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Indexed: 01/21/2023]
Abstract
PURPOSE Impaired incretin secretion may contribute to the defective insulin secretion and abnormal glucose tolerance (AGT) that associate with worse clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). The study objective was to test the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitor-induced increases in intact incretin hormone [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] concentrations augment insulin secretion and glucagon suppression and lower postprandial glycemia in PI-CF with AGT. METHODS 26 adults from Children's Hospital of Philadelphia and University of Pennsylvania CF Center with PI-CF and AGT [defined by oral glucose tolerance test glucose (mg/dL): early glucose intolerance (1-h ≥ 155 and 2-h < 140), impaired glucose tolerance (2-h ≥ 140 and < 200 mg/dL), or diabetes (2-h ≥ 200)] were randomized to a 6-month double-blind trial of DPP-4 inhibitor sitagliptin 100 mg daily or matched placebo; 24 completed the trial (n = 12 sitagliptin; n = 12 placebo). Main outcome measures were mixed-meal tolerance test (MMTT) responses for intact GLP-1 and GIP, insulin secretory rates (ISRs), glucagon suppression, and glycemia and glucose-potentiated arginine (GPA) test-derived measures of β- and α-cell function. RESULTS Following 6-months of sitagliptin vs placebo, MMTT intact GLP-1 and GIP responses increased (P < 0.001), ISR dynamics improved (P < 0.05), and glucagon suppression was modestly enhanced (P < 0.05) while GPA test responses for glucagon were lower. No improvements in glucose tolerance or β-cell sensitivity to glucose, including for second-phase insulin response, were found. CONCLUSIONS In glucose intolerant PI-CF, sitagliptin intervention augmented meal-related incretin responses with improved early insulin secretion and glucagon suppression without affecting postprandial glycemia.
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Affiliation(s)
- Andrea Kelly
- Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Correspondence: Andrea Kelly, MD, MSCE, Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.
| | - Saba Sheikh
- Division of Pulmonary Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphias, PA, USA
| | - Darko Stefanovski
- Department of Biostatistics, University of Pennsylvania School of Veterinary Medicine, Kennett Square, PA, USA
| | - Amy J Peleckis
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Sarah C Nyirjesy
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Jack N Eiel
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Aniket Sidhaye
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Russell Localio
- Department of Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
| | - Robert Gallop
- Department of Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
- Department of Mathematics, West Chester University of Pennsylvania, West Chester, PA, USA
| | - Diva D De Leon
- Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Denis Hadjiliadis
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Ronald C Rubenstein
- Division of Pulmonary Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphias, PA, USA
- Division of Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, USA
| | - Michael R Rickels
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
- Michael R. Rickels, MD, MS, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA.
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Kumar S. Comparison of Safety and Efficacy of Glimepiride-Metformin and Vildagliptin- Metformin Treatment in Newly Diagnosed Type 2 Diabetic Patients. Indian J Endocrinol Metab 2021; 25:326-331. [PMID: 35136740 PMCID: PMC8793962 DOI: 10.4103/ijem.ijem_276_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 08/24/2021] [Indexed: 11/28/2022] Open
Abstract
OBJECTIVE To compare the safety and efficacy of glimepiride and vildagliptin as add-on therapy to metformin in newly diagnosed patients with type 2 diabetes mellitus (T2DM). METHODS This 24-week, prospective, comparative, observational study was conducted among newly diagnosed patients with T2DM. The primary endpoint was a change in fasting plasma glucose (FPG), postpradinal glucose (PPG), and HbA1c from the baseline to week 24. The key secondary endpoints were monitoring treatment-emergent adverse events such as hypoglycemia, overall gastrointestinal symptoms and weight gain, and electrocardiogram (ECG) findings. RESULTS A total of 100 eligible patients were divided into two groups: group A (n = 50) received vildagliptin plus metformin and group B (n = 50) received glimepiride plus metformin. The mean age of the patients was 49.98 years and 52.12 years in group A and group B, respectively. Electrocardiographic findings were within normal limits in all the patients from group A, whereas 47 patients from group B showed normal ECG findings. A significant decrease in HbA1c, fasting and post-prandial plasma glucose was observed with group A and group B from the baseline to week-24. However, at week-24, reduction in HbA1c and blood glucose parameters were comparable between the groups. Safety outcomes did not show any events of hypoglycemia with vildagliptin. Mild hypoglycemia was reported with glimepiride in five patients. CONCLUSION Vildagliptin-metformin appeared to be equally effective to glimepiride-metformin in reducing HbA1c level and blood glucose parameters, however, resulted in better adverse event profiles with lower risks of hypoglycemia.
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Affiliation(s)
- Surendra Kumar
- Department of Endocrinology, Patna Medical College, Patna, Bihar, India
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Brierley DI, de Lartigue G. Reappraising the role of the vagus nerve in GLP-1-mediated regulation of eating. Br J Pharmacol 2021; 179:584-599. [PMID: 34185884 PMCID: PMC8714868 DOI: 10.1111/bph.15603] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 06/03/2021] [Accepted: 06/16/2021] [Indexed: 12/19/2022] Open
Abstract
Here, we provide a focused review of the evidence for the roles of the vagus nerve in mediating the regulatory effects of peripherally and centrally produced GLP-1 on eating behaviour and energy balance. We particularly focus on recent studies which have used selective genetic, viral, and transcriptomic approaches to provide important insights into the anatomical and functional organisation of GLP-1-mediated gut-brain signalling pathways. A number of these studies have challenged canonical ideas of how GLP-1 acts in the periphery and the brain to regulate eating behaviour, with important implications for the development of pharmacological treatments for obesity.
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Affiliation(s)
- Daniel I Brierley
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK
| | - Guillaume de Lartigue
- Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, Florida, USA
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40
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Ahrén B. Glucose-lowering action through targeting islet dysfunction in type 2 diabetes: Focus on dipeptidyl peptidase-4 inhibition. J Diabetes Investig 2021; 12:1128-1135. [PMID: 33949781 PMCID: PMC8264410 DOI: 10.1111/jdi.13564] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/13/2021] [Accepted: 04/18/2021] [Indexed: 12/28/2022] Open
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibition is a glucose-lowering medication for type 2 diabetes. It works through stimulation of insulin secretion and inhibition of glucagon secretion in a glucose-dependent manner, resulting in lowered fasting and postprandial glycemia with low risk of hypoglycemia. As impaired insulin secretion and augmented glucagon secretion are key factors underlying hyperglycemia in type 2 diabetes, DPP-4 inhibition represents a therapy that targets the underlying mechanisms of the disease. If insufficient in monotherapy, it can preferably be used in combination with metformin, which targets insulin resistance, and also in combination with sodium-glucose cotransporter 2 inhibition, thiazolidinediones and insulin, which target other mechanisms. In individuals of East Asian origin, islet dysfunction is of particular importance for the development of type 2 diabetes. Consequently, it has been shown in several studies that DPP-4 is efficient in these populations. This mini-review highlights the islet mechanisms of DPP-4 inhibition, islet dysfunction as a key factor for hyperglycemia in type 2 diabetes and that, consequently, DPP-4 is of particular value in populations where islet dysfunction is central, such as in individuals of East Asian origin.
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Affiliation(s)
- Bo Ahrén
- Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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Yang Y, Cai Z, Zhang J. DPP-4 inhibitors may improve the mortality of coronavirus disease 2019: A meta-analysis. PLoS One 2021; 16:e0251916. [PMID: 34015003 PMCID: PMC8136680 DOI: 10.1371/journal.pone.0251916] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 05/05/2021] [Indexed: 12/13/2022] Open
Abstract
Aims DPP-4 inhibitors are predicted to exert a protective effect on the progression of coronavirus disease 2019 (COVID-19). We conducted this meta-analysis to investigate this hypothesis. Methods Four databases, namely, PubMed, Web of Science, EMBASE and the Cochrane Library, were used to identify studies on DPP-4 and COVID-19. The outcome indicators were the mortality of COVID-19. Funnel plots, Begg’s tests and Egger’s tests were used to assess publication bias. Results Four articles were included with a total of 1933 patients with COVID-19 and type 2 diabetes. The use of DPP-4 inhibitors was negatively associated with the risk of mortality (odds ratio (OR) = 0.58 95% confidence interval (CI), 0.34–0.99). Conclusions DPP-4 inhibitors may improve the mortality of patients with COVID-19 and type 2 diabetes. As few relevant studies are available, more large-scale studies need to be performed.
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Affiliation(s)
- Yan Yang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zixin Cai
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Jingjing Zhang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- * E-mail:
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Naimi RM, Hvistendahl MK, Thomassen LM, Johnsen H, Christiansen CB, Holst JJ, Hartmann B, Jeppesen PB. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, in patients with short bowel syndrome and colon in continuity: an open-label pilot study. BMJ Open Gastroenterol 2021; 8:e000604. [PMID: 33975891 PMCID: PMC8117993 DOI: 10.1136/bmjgast-2021-000604] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/29/2021] [Accepted: 04/08/2021] [Indexed: 01/19/2023] Open
Abstract
OBJECTIVE Patients with short bowel syndrome (SBS) and colon in continuity have better adaptation potential compared with patients with jejunostomy. Adaptation may involve enhanced postprandial secretion of the enteroendocrine hormones glucagon-like peptide (GLP)-1 and GLP-2 which are normally degraded by dipeptidyl peptidase (DPP)-4. Nevertheless, some patients with SBS with colon in continuity suffer from high-volume faecal excretions and have been shown to benefit from treatment with GLP-2. Therefore, we aimed to evaluate efficacy of sitagliptin, a DPP-4 inhibitor, on reducing faecal excretions in this patient group. DESIGN In an open-label, case series, proof-of-concept pilot study, 100 mg oral sitagliptin was given two times per day for 8 weeks to patients with SBS with ≥50% colon in continuity with or without the need for parenteral support (PS). To assess intestinal function, metabolic balance studies were done at baseline and following 8 weeks of treatment. RESULTS Of the 10 patients planned for enrolment, 8 patients were included; 7 patients completed the study. Although postprandial endogenous GLP-2 concentrations increased by 49 hours×pmol/L (39, 105; p=0.018) (median (min, max)), sitagliptin did not significantly reduce median faecal wet weight (-174 g/day (-1510, 675; p=0.176)) or increase intestinal wet weight absorption. However, heterogeneity in the treatment effect was observed: intestinal wet weight absorption increased in all four patients with intestinal failure. One patient achieved a reduction in PS by 500 mL per administration day. CONCLUSION Following this negative, small pilot study, larger, placebo-controlled, studies are needed to establish the therapeutic potential of DPP-4 inhibition in patients with SBS.
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Affiliation(s)
- Rahim Mohammad Naimi
- Department of Medical Gastroenterology and Hepatology, Rigshospitalet, Copenhagen, Denmark
| | - Mark Krogh Hvistendahl
- Department of Medical Gastroenterology and Hepatology, Rigshospitalet, Copenhagen, Denmark
| | | | - Hanna Johnsen
- Department of Medical Gastroenterology and Hepatology, Rigshospitalet, Copenhagen, Denmark
| | - Charlotte Bayer Christiansen
- NNF Centre for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens Juul Holst
- NNF Centre for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- NNF Centre for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Palle Bekker Jeppesen
- Department of Medical Gastroenterology and Hepatology, Rigshospitalet, Copenhagen, Denmark
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Lu VB, Gribble FM, Reimann F. Nutrient-Induced Cellular Mechanisms of Gut Hormone Secretion. Nutrients 2021; 13:nu13030883. [PMID: 33803183 PMCID: PMC8000029 DOI: 10.3390/nu13030883] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/27/2021] [Accepted: 03/05/2021] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal tract can assess the nutrient composition of ingested food. The nutrient-sensing mechanisms in specialised epithelial cells lining the gastrointestinal tract, the enteroendocrine cells, trigger the release of gut hormones that provide important local and central feedback signals to regulate nutrient utilisation and feeding behaviour. The evidence for nutrient-stimulated secretion of two of the most studied gut hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), along with the known cellular mechanisms in enteroendocrine cells recruited by nutrients, will be the focus of this review. The mechanisms involved range from electrogenic transporters, ion channel modulation and nutrient-activated G-protein coupled receptors that converge on the release machinery controlling hormone secretion. Elucidation of these mechanisms will provide much needed insight into postprandial physiology and identify tractable dietary approaches to potentially manage nutrition and satiety by altering the secreted gut hormone profile.
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Jepsen SL, Albrechtsen NJW, Windeløv JA, Galsgaard KD, Hunt JE, Farb TB, Kissow H, Pedersen J, Deacon CF, Martin RE, Holst JJ. Antagonizing somatostatin receptor subtype 2 and 5 reduces blood glucose in a gut- and GLP-1R-dependent manner. JCI Insight 2021; 6:143228. [PMID: 33434183 PMCID: PMC7934931 DOI: 10.1172/jci.insight.143228] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 01/06/2021] [Indexed: 12/11/2022] Open
Abstract
Somatostatin (SS) inhibits glucagon-like peptide-1 (GLP-1) secretion in a paracrine manner. We hypothesized that blocking somatostatin subtype receptor 2 (SSTR2) and 5 (SSTR5) would improve glycemia by enhancing GLP-1 secretion. In the perfused mouse small intestine, the selective SSTR5 antagonist (SSTR5a) stimulated glucose-induced GLP-1 secretion to a larger degree than the SSTR2 antagonist (SSTR2a). In parallel, mice lacking the SSTR5R showed increased glucose-induced GLP-1 secretion. Both antagonists improved glycemia in vivo in a GLP-1 receptor-dependent (GLP-1R-dependent) manner, as the glycemic improvements were absent in mice with impaired GLP-1R signaling and in mice treated with a GLP-1R-specific antagonist. SSTR5a had no direct effect on insulin secretion in the perfused pancreas, whereas SSTR2a increased insulin secretion in a GLP-1R-independent manner. Adding a dipeptidyl peptidase 4 inhibitor (DPP-4i) in vivo resulted in additive effects on glycemia. However, when glucose was administered intraperitoneally, the antagonist was incapable of lowering blood glucose. Oral administration of SSTR5a, but not SSTR2a, lowered blood glucose in diet-induced obese mice. In summary, we demonstrate that selective SSTR antagonists can improve glucose control primarily through the intestinal GLP-1 system in mice.
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Affiliation(s)
- Sara L Jepsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nicolai J Wewer Albrechtsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Johanne A Windeløv
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Katrine D Galsgaard
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jenna E Hunt
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Thomas B Farb
- Lilly Research Laboratories, Lilly, Indianapolis, Indiana, USA
| | - Hannelouise Kissow
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens Pedersen
- Department of Endocrinology and Nephrology, Hillerød University Hospital, Hillerød, Denmark
| | - Carolyn F Deacon
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Rainer E Martin
- Medicinal Chemistry, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Fang X, Du Z, Duan C, Zhan S, Wang T, Zhu M, Shi J, Meng J, Zhang X, Yang M, Zuo Y. Beinaglutide shows significantly beneficial effects in diabetes/obesity-induced nonalcoholic steatohepatitis in ob/ob mouse model. Life Sci 2021; 270:118966. [PMID: 33482185 DOI: 10.1016/j.lfs.2020.118966] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/21/2020] [Accepted: 12/22/2020] [Indexed: 12/12/2022]
Abstract
AIMS Beinaglutide has been approved for glucose lowering in type 2 diabetes mellitus (T2DM) in China. In addition to glycemic control, significant weight loss is observed from real world data. This study is designed to investigate the pharmacological and pharmacokinetic profiles of beinaglutide in different models. METHODS The pharmacological efficacy of beinaglutide was evaluated in C57BL/6 and ob/ob mice after single administration. Pharmacokinetic profiles in mice were investigated after single or multiple administration. Sub-chronic pharmacological efficacy was investigated in ob/ob mice for two weeks treatment and diet-induced ob/ob mice model of nonalcoholic steatohepatitis (NASH) for four weeks treatment. KEY FINDINGS Beinaglutide could dose-dependently reduce the glucose levels and improve insulin secretion in glucose tolerance tests, inhibit food intake and gastric emptying after single administration. At higher doses, beinaglutide could inhibit food intake over 4 h, which results in weight loss in ob/ob mice after about two weeks treatment. No tachyphylaxis is observed for beinaglutide in food intake with repeated administration. In NASH model, beinaglutide could reduce liver weight and hepatic steatosis and improve insulin sensitivity. Signiant changes of gene levels were observed in fatty acid β-oxidation (Ppara, Acadl, Acox1), mitochondrial function (Mfn1, Mfn2), antioxidation (Sod2), Sirt1, and et al. SIGNIFICANCE: Our results characterize the pharmacological and pharmacokinetic profiles of beinaglutide in mice and supported that chronic use of beinaglutde could lead to weight loss and reduce hepatic steatosis, which suggest beinaglutide may be effective therapy for the treatment of obesity and NASH.
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Affiliation(s)
- Xiankang Fang
- Innovation Center, Shanghai Benemae Pharmaceutical Corporation, 916 Ziping Road, Zhoupu, PuDong, Shanghai, China.
| | - Zhiqiang Du
- Innovation Center, Shanghai Benemae Pharmaceutical Corporation, 916 Ziping Road, Zhoupu, PuDong, Shanghai, China
| | - Chunling Duan
- Innovation Center, Shanghai Benemae Pharmaceutical Corporation, 916 Ziping Road, Zhoupu, PuDong, Shanghai, China
| | - Shanshan Zhan
- Innovation Center, Shanghai Benemae Pharmaceutical Corporation, 916 Ziping Road, Zhoupu, PuDong, Shanghai, China
| | - Tian Wang
- Innovation Center, Shanghai Benemae Pharmaceutical Corporation, 916 Ziping Road, Zhoupu, PuDong, Shanghai, China
| | - Mengyu Zhu
- Innovation Center, Shanghai Benemae Pharmaceutical Corporation, 916 Ziping Road, Zhoupu, PuDong, Shanghai, China
| | - Jiajie Shi
- Innovation Center, Shanghai Benemae Pharmaceutical Corporation, 916 Ziping Road, Zhoupu, PuDong, Shanghai, China
| | - Juan Meng
- Innovation Center, Shanghai Benemae Pharmaceutical Corporation, 916 Ziping Road, Zhoupu, PuDong, Shanghai, China
| | - Xianhua Zhang
- Innovation Center, Shanghai Benemae Pharmaceutical Corporation, 916 Ziping Road, Zhoupu, PuDong, Shanghai, China
| | - Maiyun Yang
- Innovation Center, Shanghai Benemae Pharmaceutical Corporation, 916 Ziping Road, Zhoupu, PuDong, Shanghai, China
| | - Yajun Zuo
- Innovation Center, Shanghai Benemae Pharmaceutical Corporation, 916 Ziping Road, Zhoupu, PuDong, Shanghai, China
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Solerte SB, D'Addio F, Trevisan R, Lovati E, Rossi A, Pastore I, Dell'Acqua M, Ippolito E, Scaranna C, Bellante R, Galliani S, Dodesini AR, Lepore G, Geni F, Fiorina RM, Catena E, Corsico A, Colombo R, Mirani M, De Riva C, Oleandri SE, Abdi R, Bonventre JV, Rusconi S, Folli F, Di Sabatino A, Zuccotti G, Galli M, Fiorina P. Sitagliptin Treatment at the Time of Hospitalization Was Associated With Reduced Mortality in Patients With Type 2 Diabetes and COVID-19: A Multicenter, Case-Control, Retrospective, Observational Study. Diabetes Care 2020; 43:2999-3006. [PMID: 32994187 PMCID: PMC7770266 DOI: 10.2337/dc20-1521] [Citation(s) in RCA: 186] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 09/01/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Poor outcomes have been reported in patients with type 2 diabetes and coronavirus disease 2019 (COVID-19); thus, it is mandatory to explore novel therapeutic approaches for this population. RESEARCH DESIGN AND METHODS In a multicenter, case-control, retrospective, observational study, sitagliptin, an oral and highly selective dipeptidyl peptidase 4 inhibitor, was added to standard of care (e.g., insulin administration) at the time of hospitalization in patients with type 2 diabetes who were hospitalized with COVID-19. Every center also recruited at a 1:1 ratio untreated control subjects matched for age and sex. All patients had pneumonia and exhibited oxygen saturation <95% when breathing ambient air or when receiving oxygen support. The primary end points were discharge from the hospital/death and improvement of clinical outcomes, defined as an increase in at least two points on a seven-category modified ordinal scale. Data were collected retrospectively from patients receiving sitagliptin from 1 March through 30 April 2020. RESULTS Of the 338 consecutive patients with type 2 diabetes and COVID-19 admitted in Northern Italy hospitals included in this study, 169 were on sitagliptin, while 169 were on standard of care. Treatment with sitagliptin at the time of hospitalization was associated with reduced mortality (18% vs. 37% of deceased patients; hazard ratio 0.44 [95% CI 0.29-0.66]; P = 0.0001), with an improvement in clinical outcomes (60% vs. 38% of improved patients; P = 0.0001) and with a greater number of hospital discharges (120 vs. 89 of discharged patients; P = 0.0008) compared with patients receiving standard of care, respectively. CONCLUSIONS In this multicenter, case-control, retrospective, observational study of patients with type 2 diabetes admitted to the hospital for COVID-19, sitagliptin treatment at the time of hospitalization was associated with reduced mortality and improved clinical outcomes as compared with standard-of-care treatment. The effects of sitagliptin in patients with type 2 diabetes and COVID-19 should be confirmed in an ongoing randomized, placebo-controlled trial.
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Affiliation(s)
- Sebastiano Bruno Solerte
- Department of Internal Medicine, Geriatric and Diabetology Unit, University of Pavia, Italy
- School of Geriatrics, University of Pavia Azienda di Servizi alla Persona-Pavia, Pavia, Italy
| | - Francesca D'Addio
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche L. Sacco, Università di Milano, Milan, Italy
| | - Roberto Trevisan
- Unità Operativa Complessa Malattie Endocrine 1-Diabetologia, Ospedale Papa Giovanni XXIII Azienda Socio Sanitaria Territoriale-PG XXIII, Bergamo, Italy
| | - Elisabetta Lovati
- Internal Medicine Unit, University of Pavia and IRCCS Policlinico San Matteo, Pavia, Italy
| | - Antonio Rossi
- Division of Endocrinology, Azienda Socio Sanitaria Territoriale Fatebenefratelli Sacco, Milan, Italy
| | - Ida Pastore
- Division of Endocrinology, Azienda Socio Sanitaria Territoriale Fatebenefratelli Sacco, Milan, Italy
| | - Marco Dell'Acqua
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche L. Sacco, Università di Milano, Milan, Italy
- Division of Endocrinology, Azienda Socio Sanitaria Territoriale Fatebenefratelli Sacco, Milan, Italy
| | - Elio Ippolito
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche L. Sacco, Università di Milano, Milan, Italy
| | - Cristiana Scaranna
- Unità Operativa Complessa Malattie Endocrine 1-Diabetologia, Ospedale Papa Giovanni XXIII Azienda Socio Sanitaria Territoriale-PG XXIII, Bergamo, Italy
| | - Rosalia Bellante
- Unità Operativa Complessa Malattie Endocrine 1-Diabetologia, Ospedale Papa Giovanni XXIII Azienda Socio Sanitaria Territoriale-PG XXIII, Bergamo, Italy
| | - Silvia Galliani
- Unità Operativa Complessa Malattie Endocrine 1-Diabetologia, Ospedale Papa Giovanni XXIII Azienda Socio Sanitaria Territoriale-PG XXIII, Bergamo, Italy
| | - Alessandro Roberto Dodesini
- Unità Operativa Complessa Malattie Endocrine 1-Diabetologia, Ospedale Papa Giovanni XXIII Azienda Socio Sanitaria Territoriale-PG XXIII, Bergamo, Italy
| | - Giuseppe Lepore
- Unità Operativa Complessa Malattie Endocrine 1-Diabetologia, Ospedale Papa Giovanni XXIII Azienda Socio Sanitaria Territoriale-PG XXIII, Bergamo, Italy
| | - Francesca Geni
- Department of Internal Medicine, Geriatric and Diabetology Unit, University of Pavia, Italy
- School of Geriatrics, University of Pavia Azienda di Servizi alla Persona-Pavia, Pavia, Italy
| | - Roberta Maria Fiorina
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche L. Sacco, Università di Milano, Milan, Italy
| | - Emanuele Catena
- Department of Anesthesia and Intensive Care Unit, Azienda Socio Sanitaria Territoriale Fatebenefratelli Sacco, Luigi Sacco Hospital, Università di Milano, Milan, Italy
| | - Angelo Corsico
- Pneumology Unit, Fondazione IRCCS Policlinico San Matteo and Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Riccardo Colombo
- Department of Anesthesia and Intensive Care Unit, Azienda Socio Sanitaria Territoriale Fatebenefratelli Sacco, Luigi Sacco Hospital, Università di Milano, Milan, Italy
| | - Marco Mirani
- Endocrinology and Diabetology Unit, Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Carlo De Riva
- Unità Operativa di Malattie Endocrine ULSS3-Ospedale dell'Angelo Mestre, Mestre, Italy
| | | | - Reza Abdi
- Renal Division, Brigham and Women's Hospital, Boston, MA
| | | | - Stefano Rusconi
- Department of Biomedical and Clinical Sciences "Luigi Sacco," Univeristà di Milano, Milan, Italy
- III Division of Infectious Diseases, Azienda Socio Sanitaria Territoriale Fatebenefratelli Sacco, Luigi Sacco Hospital, Milan, Italy
| | - Franco Folli
- Endocrinology and Metabolism, Department of Health Science, Università di Milano, Azienda Socio Sanitaria Territoriale Santi Paolo e Carlo, Milan, Italy
| | - Antonio Di Sabatino
- Internal Medicine Unit, University of Pavia and IRCCS Policlinico San Matteo, Pavia, Italy
| | - Gianvincenzo Zuccotti
- Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche, Università di Milano, Milan, Italy
- Department of Pediatrics, "V. Buzzi" Children's Hospital, Milan, Italy
| | - Massimo Galli
- Department of Biomedical and Clinical Sciences "Luigi Sacco," Univeristà di Milano, Milan, Italy
- III Division of Infectious Diseases, Azienda Socio Sanitaria Territoriale Fatebenefratelli Sacco, Luigi Sacco Hospital, Milan, Italy
| | - Paolo Fiorina
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche L. Sacco, Università di Milano, Milan, Italy
- Division of Endocrinology, Azienda Socio Sanitaria Territoriale Fatebenefratelli Sacco, Milan, Italy
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA
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Deacon CF. Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2020; 16:642-653. [PMID: 32929230 DOI: 10.1038/s41574-020-0399-8] [Citation(s) in RCA: 207] [Impact Index Per Article: 41.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/22/2020] [Indexed: 12/17/2022]
Abstract
Dipeptidyl peptidase 4 inhibitors (DPP4i) have been available for treating type 2 diabetes mellitus since 2006. Although they are a diverse group, DPP4i are all small, orally available molecules that interact with the catalytic site of DPP4 without disturbing any of its other known functions, including its effects on the immune system. DPP4i have no intrinsic glucose-lowering activity, so their efficacy as anti-diabetic agents is related directly to their ability to inhibit DPP4 activity and is mediated through the effects of the substrates they protect. Of these, the incretin hormone, glucagon-like peptide 1, is probably the most important. As the effects of glucagon-like peptide 1 are glucose-dependent, the risk of hypoglycaemia with DPP4i is low. Class effects, which are directly related to the mechanism of action, are common to all DPP4i; these include their overall good safety profile and tolerability, as well as their efficacy in improving glycaemic control, but also, potentially, a small increased risk of acute pancreatitis. Compound-specific effects are those related to their differing chemistries and/or pharmacokinetic profiles. These compound-specific effects could affect the way in which individual DPP4i are used therapeutically and potentially explain off-target adverse effects, such as hospitalization for heart failure, which is seen only with one DPP4i. Overall, DPP4i have a favourable therapeutic profile and are safe and effective in the majority of patients with type 2 diabetes mellitus.
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Affiliation(s)
- Carolyn F Deacon
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Mori-Anai K, Tashima Y, Nakada T, Nakamaru Y, Takahata T, Saito R. Mechanistic evaluation of the effect of sodium-dependent glucose transporter 2 inhibitors on delayed glucose absorption in patients with type 2 diabetes mellitus using a quantitative systems pharmacology model of human systemic glucose dynamics. Biopharm Drug Dispos 2020; 41:352-366. [PMID: 33085977 DOI: 10.1002/bdd.2253] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 10/13/2020] [Accepted: 10/18/2020] [Indexed: 01/24/2023]
Abstract
Sodium-dependent glucose transporter (SGLT) 2 is specifically expressed in the kidney, while SGLT1 is present in the kidneys and small intestine. SGLT2 inhibitors are a class of oral antidiabetic drugs that lower elevated plasma glucose levels by promoting the urinary excretion of excess glucose through the inhibition of renal glucose reuptake. The inhibition selectivity for SGLT2 over SGLT1 (SGLT2/1 selectivity) of marketed SGLT2 inhibitors is diverse, while SGLT2/1 selectivity of canagliflozin is relatively low. Although canagliflozin suppresses postprandial glucose levels, the degree of contribution for SGLT1 inhibition to this effect remains unproven. To analyze the effect of SGLT2 inhibitors on postprandial glucose level, we constructed a novel quantitative systems pharmacology (QSP) model, called human systemic glucose dynamics (HSGD) model, integrating intestinal absorption, metabolism, and renal reabsorption of glucose. This HSGD model reproduced the postprandial plasma glucose concentration-time profiles during a meal tolerance test under different clinical trial conditions. Simulations after canagliflozin administration showed a dose-dependent delay of time (Tmax,glc ) to reach maximum concentration of glucose (Cmax,glc ), and the delay of Tmax,glc disappeared when inhibition of SGLT1 was negated. In addition, contribution ratio of intestinal SGLT1 inhibition to the decrease in Cmax,glc was estimated to be 23%-28%, when 100 and 300 mg of canagliflozin are administered. This HSGD model enabled us to provide the partial contribution of intestinal SGLT1 inhibition to the improvement of postprandial hyperglycemia as well as to quantitatively describe the plasma glucose dynamics following SGLT2 inhibitors.
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Affiliation(s)
| | | | - Tomohisa Nakada
- Mitsubishi Tanabe Pharma Corporation, Yokohama, Kanagawa, Japan
| | | | | | - Ryuta Saito
- Mitsubishi Tanabe Pharma Corporation, Yokohama, Kanagawa, Japan
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Pan Z, Yang Y, Zhang J. Efficacy and safety of DPP-IV inhibitors combined with basal insulin in the treatment of type 2 diabetes. J Diabetes 2020; 13:375-389. [PMID: 33016503 DOI: 10.1111/1753-0407.13119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 08/29/2020] [Accepted: 09/26/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND To evaluate the efficacy and safety of dipeptidyl peptidase IV (DPP-IV) inhibitors when added to insulin therapy in patients with type 2 diabetes mellitus (T2DM). METHODS PubMed, EMBASE, the Web of Science, and the Cochrane Library were systematically searched for randomized controlled trials (RCTs) exploring the efficacy or safety of DPP-IV inhibitors in T2DM patients. The quality of the included RCTs was assessed with the Cochrane risk-of-bias tool. For outcomes, odds ratios or weighted mean differences (WMDs) with 95% CIs were calculated using both random- and fixed-effects models. RESULTS A total of 16 studies were included in the meta-analysis with 5418 participants. Glycosylated hemoglobin (HbA1c) was significantly decreased in the DPP-IV inhibitors with insulin (DPP-IVi/INS) group compared with the insulin-alone (with or without placebo) group (WMD = -0.62%; 95% CI: -0.74, -0.49; P < .05). Consistent with this finding, the fasting blood glucose (FBG)-lowering effect (WMD = -0.61 mmol/L; 95% CI: -0.77, -0.45; P < .05) and 2-hour postprandial glucose (2hPPG)-lowering efficacy (WMD = -2.39 mmol/L; 95% CI: -2.81, -1.97; P < .05) in the DPP-IVi/INS group were also significantly better than in the insulin-alone group. Regarding safety indicators, compared with the insulin-alone group, DPP-IVi/INS treatments had no association with the risk of adverse effects, including hypoglycemia, adverse events (AEs), and serious adverse events (SAEs). CONCLUSIONS Compared with insulin treatment alone, treatment with DPP-IVi/INS improved HbA1c, FBG, and 2hPPG without increasing the risk of hypoglycemia, AEs, or SAEs.
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Affiliation(s)
| | - Yan Yang
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jingjing Zhang
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
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Aoki K, Kamiyama H, Takihata M, Taguri M, Shibata E, Shinoda K, Yoshii T, Nakajima S, Terauchi Y. Effect of liraglutide on lipids in patients with type 2 diabetes: a pilot study. Endocr J 2020; 67:957-962. [PMID: 32554954 DOI: 10.1507/endocrj.ej19-0464] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The mechanism for the cholesterol-lowering effect of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) remains unknown in patients with type 2 diabetes. We evaluated the effect of liraglutide on serum lipid profiles, including cholesterol synthesis and absorption markers, during daily clinical practice in Japanese patients with type 2 diabetes. We enrolled 38 patients with type 2 diabetes mellitus who were not treated with a GLP-1 RA (≥20 years of age, HbA1c ≥6.5%). Liraglutide, a GLP-1 RA, was administered subcutaneously once a day for three months to these patients. Blood samples and body weights were collected at 0, 1, and 3 months. Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) at 1 month, and non-high-density lipoprotein cholesterol (non-HDL-C) and calculated TC at 1 and 3 months, were decreased, while the cholesterol synthesis and cholesterol absorption markers were unchanged by this treatment. In patients with LDL-C levels over 100 mg/dL, LDL-C, non-HDL-C, TC, and calculated TC levels were decreased significantly by the treatment at 1 and 3 months, and the cholesterol absorption marker, campesterol, was decreased at 3 months. The administration of liraglutide for 3 months decreased non-HDL-C and calculated TC significantly, while the cholesterol synthesis and absorption markers were not changed by this treatment.
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Affiliation(s)
- Kazutaka Aoki
- Internal Medicine, Kanagawa Dental University, Yokosuka, Japan
- Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | | | | | - Masataka Taguri
- Department of Data Science, Yokohama City University School of Data Science, Yokohama, Japan
| | - Eriko Shibata
- Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | | | | | | | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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