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Caturano A, Erul E, Nilo R, Nilo D, Russo V, Rinaldi L, Acierno C, Gemelli M, Ricotta R, Sasso FC, Giordano A, Conte C, Ürün Y. Insulin resistance and cancer: molecular links and clinical perspectives. Mol Cell Biochem 2025:10.1007/s11010-025-05245-8. [PMID: 40089612 DOI: 10.1007/s11010-025-05245-8] [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: 12/18/2024] [Accepted: 02/23/2025] [Indexed: 03/17/2025]
Abstract
The association between insulin resistance (IR), type 2 diabetes mellitus (T2DM), and cancer is increasingly recognized and poses an escalating global health challenge, as the incidence of these conditions continues to rise. Studies indicate that individuals with T2DM have a 10-20% increased risk of developing various solid tumors, including colorectal, breast, pancreatic, and liver cancers. The relative risk (RR) varies depending on cancer type, with pancreatic and liver cancers showing a particularly strong association (RR 2.0-2.5), while colorectal and breast cancers demonstrate a moderate increase (RR 1.2-1.5). Understanding these epidemiological trends is crucial for developing integrated management strategies. Given the global rise in T2DM and cancer cases, exploring the complex relationship between these conditions is critical. IR contributes to hyperglycemia, chronic inflammation, and altered lipid metabolism. Together, these factors create a pro-tumorigenic environment conducive to cancer development and progression. In individuals with IR, hyperinsulinemia triggers the insulin-insulin-like growth factor (IGF1R) signaling pathway, activating cancer-associated pathways such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PIK3CA), which promote cell proliferation and survival, thereby supporting tumor growth. Both IR and T2DM are linked to increased morbidity and mortality in patients with cancer. By providing an in-depth analysis of the molecular links between insulin resistance and cancer, this review offers valuable insights into the role of metabolic dysfunction in tumor progression. Addressing insulin resistance as a co-morbidity may open new avenues for risk assessment, early intervention, and the development of integrated treatment strategies to improve patient outcomes.
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Affiliation(s)
- Alfredo Caturano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138, Naples, Italy
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166, Rome, Italy
| | - Enes Erul
- Department of Medical Oncology, Faculty of Medicine, Ankara University, Ankara, 06620, Turkey
| | - Roberto Nilo
- Data Collection G-STeP Research Core Facility, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168, Rome, Italy
| | - Davide Nilo
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138, Naples, Italy
| | - Vincenzo Russo
- Department of Biology, College of Science and Technology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, 19122, USA
- Division of Cardiology, Department of Medical Translational Sciences, University of Campania Luigi Vanvitelli, 80138, Naples, Italy
| | - Luca Rinaldi
- Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, 86100, Campobasso, Italy
| | - Carlo Acierno
- Azienda Ospedaliera Regionale San Carlo, 85100, Potenza, Italy
| | - Maria Gemelli
- Medical Oncology Unit, IRCCS MultiMedica, Milan, Italy
| | | | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138, Naples, Italy
| | - Antonio Giordano
- Department of Biology, College of Science and Technology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, 19122, USA
| | - Caterina Conte
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166, Rome, Italy
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, 20099, Milan, Italy
| | - Yüksel Ürün
- Department of Medical Oncology, Faculty of Medicine, Ankara University, Ankara, 06620, Turkey.
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Grajales-Reyes JG. Advances in energy balance & metabolism circuitry. ADVANCES IN GENETICS 2025; 113:1-28. [PMID: 40409794 DOI: 10.1016/bs.adgen.2025.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2025]
Abstract
Advancements in informatics, genetics, and neuroscience have greatly expanded our understanding of how the central nervous system (CNS) regulates energy balance and metabolism. This chapter explores the key neural circuits within the hypothalamus and brainstem that integrate behavioral and physiological processes to maintain metabolic homeostasis. It also examines the dynamic interplay between the CNS and peripheral organs, mediated through hormonal and neuronal signals, which fine-tune appetite, energy expenditure, and body weight. Furthermore, we highlight groundbreaking research that unveils molecular and cellular pathways governing energy regulation, representing a new frontier in addressing obesity and metabolic disorders. Innovative approaches, such as neurogenetic and neuromodulation techniques, are explored as promising strategies for improving weight management and metabolic health. By providing a comprehensive perspective on the mechanisms underlying energy balance, this chapter underscores the transformative potential of emerging therapeutic innovations.
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Affiliation(s)
- Jose G Grajales-Reyes
- Department of Anesthesiology, Yale University, New Haven, CT, United States; Laboratory of Neurovascular Control of Homeostasis, Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, United States.
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Swiderski M, Vinogradova Y, Knaggs RD, Harman K, Harwood RH, Prasad V, Persson MSM, Figueredo G, Layfield C, Gran S. Association between drugs and vaccines commonly prescribed to older people and bullous pemphigoid: a case-control study. Br J Dermatol 2025; 192:440-449. [PMID: 39467333 DOI: 10.1093/bjd/ljae416] [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: 04/30/2024] [Revised: 10/22/2024] [Accepted: 10/23/2024] [Indexed: 10/30/2024]
Abstract
BACKGROUND Bullous pemphigoid (BP) is an autoimmune skin disease that mainly affects older people. Based on case series and small hospital-based studies, a number of drugs have been associated with BP. More reliable and precise estimates of associations between a broad selection of drugs/vaccines and BP will enable greater awareness of any potential increased risk of BP following the administration of certain medicines and help identify clinical, histological and genomic characteristics of drug-induced BP for different culprit drugs. Greater awareness could lead to earlier recognition or suspicion of BP and referral to a dermatologist for diagnosis. Earlier diagnosis may lead to less aggressive treatment and improved wellbeing. OBJECTIVES To determine the association between drugs/vaccines commonly prescribed to older people and the risk of developing BP. METHODS We conducted a population-based nested case-control study between 1998 and 2021 using electronic primary care records from the Clinical Practice Research Datalink. We matched patients with BP with up to five controls. Exposures were drugs/vaccines commonly prescribed to older people. We used multivariable conditional logistic regression adjusting for multiple drug use. For antibiotics, in a sensitivity analysis, we considered that drugs may be prescribed for undiagnosed symptoms of BP that resemble skin infection (protopathic bias). RESULTS Antibiotics were associated with the highest risk of BP [odds ratio (OR) 4.60, 95% confidence interval (CI) 4.40-4.80]. However, after adjusting for protopathic bias, the OR decreased to 2.08 (95% CI 1.99-2.17). Also, after adjusting for protopathic bias, of all the antibiotic classes and subclasses, penicillins [OR 3.44, 95% CI 3.29-3.60 (sensitivity analysis OR 1.74, 95% CI 1.66-1.84)] and penicillinase-resistant penicillins [OR 7.56, 95% CI 7.15-8.00 (sensitivity analysis OR 2.64, 95% CI 2.45-2.85)] had the strongest associations with BP risk. Other drugs strongly associated with increased risk were gliptins (OR 2.77, 95% CI 2.37-3.23) and second-generation antipsychotics (OR 2.58, 95% CI 2.20-3.03). CONCLUSIONS Healthcare professionals need to be aware of BP risk in older people, particularly when prescribing penicillinase-resistant penicillins, gliptins and second-generation antipsychotic drugs, to recognize and manage BP early. Owing to the low disease prevalence, we do not suggest avoiding certain drugs/vaccines to prevent BP. Further research should consider recency, dosage and duration of antibiotic treatments.
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Affiliation(s)
| | | | - Roger D Knaggs
- School of Pharmacy, University of Nottingham, Nottingham, UK
| | - Karen Harman
- Department of Dermatology, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Rowan H Harwood
- School of Health Sciences, University of Nottingham, Nottingham, UK
| | - Vibhore Prasad
- School of Medicine, University of Nottingham, Nottingham, UK
- King's College London, London, UK
- NHS Nottinghamshire, Nottingham, UK
| | | | | | - Carron Layfield
- School of Medicine, University of Nottingham, Nottingham, UK
| | - Sonia Gran
- School of Medicine, University of Nottingham, Nottingham, UK
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Biagetti B, Araujo-Castro M, Marazuela M, Puig-Domingo M. Treatment of acromegaly-induced diabetes: an updated proposal. Pituitary 2024; 28:15. [PMID: 39738706 DOI: 10.1007/s11102-024-01477-x] [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] [Accepted: 11/26/2024] [Indexed: 01/02/2025]
Abstract
Acromegaly-induced diabetes presents unique features due to the direct effects of excess growth hormone (GH) and insulin-like growth factor 1 (IGF-) on glucose metabolism, especially insulin resistance in association to low body fat content and water retention. Increased cardiovascular risk is much higher when acromegaly is complicated with diabetes, thus requiring a holistic management that addresses also these specific characteristics which differ from those of classical type 2 diabetes.The optimal management of diabetes in acromegaly requires not only an effective control of carbohydrate disturbances per se, but also the concurrent control of GH hypersecretion as it will directly impact on glucose control. If surgical treatment is not effective to normalize GH and IGF-1 levels, pharmacologic therapy for acromegaly must consider the metabolic effects that the different drugs may induce, as some of them may worsen carbohydrate metabolism. When treating acromegaly-induced diabetes, a comprehensive approach is essential, incorporating medications that may also protect against acromegaly associated comorbidities. Metformin remains the first-line therapy due to its ability to reduce hepatic glucose production enhance insulin sensitivity and its cost effectiveness. The newer drug classes, such as glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors, offer benefits similar to those seen in type 2 diabetes, but the unique metabolic profile of acromegaly-including an enhanced ketogenic state and the effects of incretins on GH secretion-have to be considered as it may influence outcomes. Understanding the distinct pathophysiology of acromegaly-induced diabetes and the benefits of these newer drug classes for the patient with acromegaly is crucial for optimizing treatment outcomes and improving the quality of life.
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Affiliation(s)
- Betina Biagetti
- Endocrinology & Nutrition Department, Hospital Universitario Vall de Hebrón. CIBERER U747 (ISCIII), ENDO-ERN, Barcelona, Spain.
| | - Marta Araujo-Castro
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain
- Instituto de Investigación Biomédica Ramón y Cajal (IRYCIS), Madrid, Spain
| | - Mónica Marazuela
- Endocrinology & Nutrition Department, Hospital Universitario La Princesa Madrid, Madrid, Spain
| | - Manel Puig-Domingo
- Endocrinology & Nutrition Department, Hospital Universitario Germans Trias i Pujol. CIBERER U747 (ISCIII), Universitat Autònoma de Barcelona, Badalona, Spain.
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Hung WT, Sutopo CCY, Mahatmanto T, Wu ML, Hsu JL. Exploring the Antidiabetic and Antihypertensive Potential of Peptides Derived from Bitter Melon Seed Hydrolysate. Biomedicines 2024; 12:2452. [PMID: 39595018 PMCID: PMC11591893 DOI: 10.3390/biomedicines12112452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/19/2024] [Accepted: 10/23/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND/OBJECTIVES Type 2 diabetes (T2D) has become a critical global health issue, with an increasing prevalence that contributes to significant morbidity and mortality. Inhibiting dipeptidyl peptidase-IV (DPP4) is a promising strategy for managing T2D. This study aimed to explore the DPP4 inhibitory peptide derived from bitter melon seed protein (BMSP) hydrolysate. METHODS Reversed-phase high-performance liquid chromatography (RP-HPLC) was utilized to fractionate the hydrolysate. Peptide in the highest activity fraction was analyzed using liquid chromatography-mass spectrometry (LC-MS/MS). Peptide synthetic was used for further characterizations, such as bioactivity exploration, inhibition mechanism, molecular docking, and peptide stability against in vitro simulated gastrointestinal (SGI) digestion. RESULTS The BMSP hydrolysate was digested with gastrointestinal proteases (GP) and assessed for DPP4 inhibitory activity, yielding an IC50 of 1448 ± 105 μg/mL. Following RP-HPLC fractionation, MPHW (MW4) and VPSGAPF (VF7) were identified from fraction F8 with DPP4 IC50 values of 128.0 ± 1.3 µM and 150.6 ± 3.4 µM, respectively. Additionally, MW4 exhibited potential antihypertensive effects through ACE inhibition with an IC50 of 172.2 ± 10.6 µM. The inhibitory kinetics and molecular docking simulations indicated that both MW4 and VF7 were competitive inhibitors of DPP4, while MW4 was also a competitive inhibitor of ACE. Importantly, both peptides remained stable during simulated gastrointestinal digestion, suggesting their resistance to human digestive processes and their capacity to maintain biological activity. CONCLUSIONS The findings suggest that BMSP-GP hydrolysate may have potential in terms of the development of health foods or therapeutic agents. However, in vivo studies are also essential for further confirmation of efficacy.
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Affiliation(s)
- Wei-Ting Hung
- Department of Food Science, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan;
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
| | | | - Tunjung Mahatmanto
- Department of Food Science and Biotechnology, Faculty of Agricultural Technology, Universitas Brawijaya, Malang 65145, Indonesia;
| | - Mei-Li Wu
- Department of Food Science, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan;
| | - Jue-Liang Hsu
- Department of Food Science and Biotechnology, Faculty of Agricultural Technology, Universitas Brawijaya, Malang 65145, Indonesia;
- Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
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Guerboub AA, Louday L, Issouani J, Errahali Y. Adverse Effects of Gliptins in Type 2 Diabetics in Morocco. Ann Afr Med 2024; 23:606-610. [PMID: 39138963 PMCID: PMC11556469 DOI: 10.4103/aam.aam_35_24] [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: 02/26/2024] [Revised: 03/08/2024] [Accepted: 04/08/2024] [Indexed: 08/15/2024] Open
Abstract
INTRODUCTION Gliptins are a relatively recent class of oral antidiabetic agents used in the treatment of type 2 diabetes. The aim of this study is to identify the adverse effects of gliptins in patients with type 2 diabetes, compare the tolerability of these drugs with data from the literature, and determine patients' behavior in the face of these adverse effects with a view to optimizing their management. METHODS Our study is cross-sectional, descriptive, and analytical, involving 100 patients aged over 20 years, followed at the Endocrinology Department of the Military Hospital Mohammed V. RESULTS The average age of the patients was 63 years, with a sex ratio F/H of 1.13. The median age of diabetes in the patients was 13 years, with an average blood glucose level of 1.64 and an average hemoglobin A1c of 8.26. The comorbidities were 30% cardiovascular disease, 25% hypertension, and 14% dyslipidemia, and 30% of patients had no comorbidities. Forth-six percent of patients reported adverse events and 54% did not report any adverse event. Twenty-eight percent of the adverse events were gastrointestinal, 18% skin disorders, 14% urinary tract infections, 12% hypoglycemia, 12% nervous system disorders, 8% airway infections, and 8% general disorders. CONCLUSION This study shows that gliptins remain a safe option as the side effects seem fairly well tolerated by patients. Adverse events may impact patient compliance and pose a problem of adherence to treatment. Thus, it would be advantageous to develop therapeutic education for diabetic patients to detect and manage adverse effects.
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Affiliation(s)
- Ahmed Anas Guerboub
- Endocrinology Department, Faculty of Medicine and Pharmacy, Mohammed V Military Academic Hospital, Mohammed V-Souissi University, Rabat, Morocco
| | - Loubna Louday
- Endocrinology Department, Faculty of Medicine and Pharmacy, Mohammed V Military Academic Hospital, Mohammed V-Souissi University, Rabat, Morocco
| | - Jade Issouani
- Endocrinology Department, Faculty of Medicine and Pharmacy, Mohammed V Military Academic Hospital, Mohammed V-Souissi University, Rabat, Morocco
| | - Yassine Errahali
- Endocrinology Department, Faculty of Medicine and Pharmacy, Mohammed V Military Academic Hospital, Mohammed V-Souissi University, Rabat, Morocco
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Kurimoto M, Yuda N, Tanaka M, Tanaka M, Okochi M. Peptide array screening with anti-GLP-1 monoclonal antibody: Discovery of cysteine-containing DPP-IV inhibitory peptides. J Biosci Bioeng 2024; 138:351-359. [PMID: 39085020 DOI: 10.1016/j.jbiosc.2024.07.001] [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: 04/10/2024] [Revised: 06/24/2024] [Accepted: 07/01/2024] [Indexed: 08/02/2024]
Abstract
Inhibition of dipeptidyl peptidase IV (DPP-IV) is an effective pharmacotherapy for the management of type 2 diabetes. Recent findings have suggested that various dietary proteins can serve as precursors to peptides that inhibit DPP-IV. Although several DPP-IV inhibitory peptides derived from food materials have been reported, more effective inhibitory peptides remain to be discovered. This study aimed to identify potent DPP-IV inhibitory peptides that earlier approaches had overlooked by employing a screening method that combined peptide arrays and neutralizing antibodies. Octa-peptides covering the complete amino acid sequences of four casein proteins and two whey proteins were synthesized on arrays via a solid-phase method. These peptides were then reacted with a monoclonal antibody specifically engineered to recognize glucagon-like peptide 1 (GLP-1), a substrate of DPP-IV. The variable region of the anti-GLP-1 monoclonal antibody is utilized to mimic the substrate-binding region of DPP-IV, enabling the antibody to bind to peptides that interact with DPP-IV. Based on this feature, 26 peptides were selected as DPP-IV inhibitory peptide candidates, 11 of which showed strong DPP-IV inhibitory activity. Five of these peptides consistently contained cysteines positioned two to four residues from the N-terminus. Treatment with disulfide formation decreased the DPP-IV inhibitory activity of these cysteine-containing peptides, while the inhibitory activity of α-lactalbumin hydrolysates increased with reducing treatment. These results revealed that the thiol group is important for DPP-IV inhibitory activity. This study provides a useful screen for DPP-IV inhibitory peptides and indicates the importance of reductive cysteine residues within DPP-IV inhibitory peptides.
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Affiliation(s)
- Masaki Kurimoto
- Innovative Research Institute, Morinaga Milk Industry Co., Ltd., 5-1-83 Higashihara, Zama, Kanagawa 252-8583, Japan; Department of Chemical Science and Engineering, Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8552, Japan
| | - Naoki Yuda
- Innovative Research Institute, Morinaga Milk Industry Co., Ltd., 5-1-83 Higashihara, Zama, Kanagawa 252-8583, Japan
| | - Masayoshi Tanaka
- Department of Chemical Science and Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan
| | - Miyuki Tanaka
- Innovative Research Institute, Morinaga Milk Industry Co., Ltd., 5-1-83 Higashihara, Zama, Kanagawa 252-8583, Japan
| | - Mina Okochi
- Department of Chemical Science and Engineering, Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8552, Japan.
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Takada H, Matsumura T, Shimamura H, Matsui M, Kon S, Fukumoto A, Kubota T, Yoshida K, Iwahashi H, Takahashi MP. Investigation of Glucose Metabolism by Continuous Glucose Monitoring and Validation of Dipeptidyl Peptidase 4 Inhibitor Use in Patients with Myotonic Dystrophy Type 1. J Clin Med 2024; 13:5252. [PMID: 39274465 PMCID: PMC11396113 DOI: 10.3390/jcm13175252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/29/2024] [Accepted: 09/03/2024] [Indexed: 09/16/2024] Open
Abstract
Objectives: We characterized blood glucose fluctuations in patients with myotonic dystrophy type 1 (DM1). After confirming the incretin secretion capacity of patients with DM1, we intended to clarify whether dipeptidyl peptidase 4 (DPP-4) inhibitor administration was appropriate in cases of DM1 with diabetes mellitus. Methods: A 48 h continuous glucose monitoring (CGM) was performed in 29 Japanese patients with DM1. An oral glucose tolerance test (OGTT) was performed in patients with DM1 and five disease controls, and levels of blood glucose, insulin, and incretin (glucagon-like peptide-1 and gastric inhibitory polypeptide) were measured. DPP-4 inhibitors were administered to patients with diabetes mellitus complicated by DM1, and the CGM results were compared. Results: The CGM showed distinct patterns of blood glucose variability among patients classified by an OGTT pattern with significant differences in glucose parameters such as time above 140 mg/dL and mean amplitude of glycemic excursions between the groups. High sensor glucose values were observed in a certain number of patients who were classified as having normal or impaired glucose tolerance by the OGTT. The CGM confirmed the presence of low glucose levels in several patients. Incretin secretion, the target of DPP-4 inhibitors, was preserved in patients with DM1. DPP-4 inhibitor treatment resulted in lower glucose levels and improved insulin secretion in some patients. Conclusions: This is the first CGM study for DM1 patients. The CGM identified potential early abnormalities in glucose metabolism in DM1. In the future, it will be crucial to explore effective methods for harnessing CGM and assessing it quantitatively in DM1.
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Affiliation(s)
- Hiroto Takada
- Department of Neurology, NHO Aomori National Hospital, Aomori 038-1331, Aomori, Japan
| | - Tsuyoshi Matsumura
- Department of Neurology, NHO Osaka Toneyama Medical Center, Toyonaka 560-8552, Osaka, Japan
| | - Haruna Shimamura
- Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Suita 565-0871, Osaka, Japan
| | - Misa Matsui
- Department of Neurology, NHO Osaka Toneyama Medical Center, Toyonaka 560-8552, Osaka, Japan
| | - Seiko Kon
- Department of Neurology, NHO Aomori National Hospital, Aomori 038-1331, Aomori, Japan
| | - Aono Fukumoto
- Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Suita 565-0871, Osaka, Japan
| | - Tomoya Kubota
- Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Suita 565-0871, Osaka, Japan
| | - Kosuke Yoshida
- Department of Neurology, NHO Asahikawa Medical Center, Asahikawa 070-8644, Hokkaido, Japan
| | - Hiromi Iwahashi
- Department of Internal Medicine, Toyonaka Municipal Hospital, Toyonaka 560-8565, Osaka, Japan
| | - Masanori P Takahashi
- Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Suita 565-0871, Osaka, Japan
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Ahmed N, Razzaq F, Arfan M, Gatasheh MK, Nasir H, Ali JS, Hafeez H. A Convenient Synthesis of Short α-/β-Mixed Peptides as Potential α-Amylase Inhibitors. Molecules 2024; 29:4028. [PMID: 39274877 PMCID: PMC11396456 DOI: 10.3390/molecules29174028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 08/15/2024] [Accepted: 08/20/2024] [Indexed: 09/16/2024] Open
Abstract
Over the last decades, the increased incidence of metabolic disorders, such as type two diabetes and obesity, has motivated researchers to investigate new enzyme inhibitors. Inhibition of the α-amylase enzyme is one therapeutic approach in lowering glucose levels in the blood to manage diabetes mellitus. The objective of this study was to synthesize short α-/β-mixed peptides in the solution phase. The Boc-protected α-L-leucine was converted to β-analogue by using Arndt-Eistert synthesis with the advantage of no racemization and retention of configuration. Three novel short peptides were successfully synthesized: N(Boc)-Gly-β-Leu-OCH3(14), N(Boc)-O(Bz)α-Ser-β-Leu-OCH3(16), and N(Boc)-O(Bz)-α-Tyr-α-Gly-β-Leu-OCH3(17), characterized by FTIR and 1H NMR analysis. The synthesized peptide 16 showed highest inhibitory activity (45.22%) followed by peptide 14 (18.51%) and peptide 17 (17.05%), respectively. Intriguingly, peptide 16 showed higher inhibition on α-amylase compared with other α-/β-mixed peptides.
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Affiliation(s)
- Naeem Ahmed
- Department of Chemistry, School of Natural Sciences, National University of Sciences and Technology, Islamabad 44000, Pakistan
| | - Fakhira Razzaq
- Department of Chemistry, School of Natural Sciences, National University of Sciences and Technology, Islamabad 44000, Pakistan
- Department of Chemistry, Michigan Technological University, 1400 Townsend Dr., Houghton, MI 49931, USA
| | - Muhammad Arfan
- Department of Chemistry, School of Natural Sciences, National University of Sciences and Technology, Islamabad 44000, Pakistan
| | - Mansour K Gatasheh
- Department of Biochemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
| | - Hammad Nasir
- Department of Chemistry, School of Natural Sciences, National University of Sciences and Technology, Islamabad 44000, Pakistan
| | - Joham Sarfraz Ali
- The Department of Biological Sciences (DBS), National University of Medical Sciences (NUMS), Rawalpindi 46000, Pakistan
| | - Hamna Hafeez
- Department of Chemistry, School of Natural Sciences, National University of Sciences and Technology, Islamabad 44000, Pakistan
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Gonzalez-Gutierrez L, Motiño O, Barriuso D, de la Puente-Aldea J, Alvarez-Frutos L, Kroemer G, Palacios-Ramirez R, Senovilla L. Obesity-Associated Colorectal Cancer. Int J Mol Sci 2024; 25:8836. [PMID: 39201522 PMCID: PMC11354800 DOI: 10.3390/ijms25168836] [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: 07/12/2024] [Revised: 08/02/2024] [Accepted: 08/07/2024] [Indexed: 09/02/2024] Open
Abstract
Colorectal cancer (CRC) affects approximately 2 million people worldwide. Obesity is the major risk factor for CRC. In addition, obesity contributes to a chronic inflammatory stage that enhances tumor progression through the secretion of proinflammatory cytokines. In addition to an increased inflammatory response, obesity-associated cancer presents accrued molecular factors related to cancer characteristics, such as genome instability, sustained cell proliferation, telomere dysfunctions, angiogenesis, and microbial alteration, among others. Despite the evidence accumulated over the last few years, the treatments for obesity-associated CRC do not differ from the CRC treatments in normal-weight individuals. In this review, we summarize the current knowledge on obesity-associated cancer, including its epidemiology, risk factors, molecular factors, and current treatments. Finally, we enumerate possible new therapeutic targets that may improve the conditions of obese CRC patients. Obesity is key for the development of CRC, and treatments resulting in the reversal of obesity should be considered as a strategy for improving antineoplastic CRC therapies.
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Affiliation(s)
- Lucia Gonzalez-Gutierrez
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
| | - Omar Motiño
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
| | - Daniel Barriuso
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
| | - Juan de la Puente-Aldea
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
| | - Lucia Alvarez-Frutos
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, 75006 Paris, France;
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
- Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France
| | - Roberto Palacios-Ramirez
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
| | - Laura Senovilla
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
- Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, 75006 Paris, France;
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
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11
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Mudgil P, Gan CY, Yap PG, Redha AA, Alsaadi RHS, Mohteshamuddin K, Aguilar-Toalá JE, Vidal-Limon AM, Liceaga AM, Maqsood S. Exploring the dipeptidyl peptidase IV inhibitory potential of probiotic-fermented milk: An in vitro and in silico comprehensive investigation into peptides from milk of different farm animals. J Dairy Sci 2024:S0022-0302(24)01060-9. [PMID: 39122154 DOI: 10.3168/jds.2024-25108] [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: 04/30/2024] [Accepted: 07/15/2024] [Indexed: 08/12/2024]
Abstract
Bioactive peptides produced via enzymatic hydrolysis have been widely investigated for their dipeptidyl peptidase-IV (DPP-IV) inhibitory properties. However, deficit of studies on fermentation as a mean to produce DPP-IV inhibitory peptides prompted us to draw a comparative study on DPP-IV inhibitory peptides generated from cow, camel, goat, and sheep milk using probiotic fermentation. Further, peptide identification, in silico molecular interactions with DPP-IV, and ensemble docking were performed. Results obtained suggested that goat milk consistently exhibited higher hydrolysis than other milk types. Further, Pediococcus pentosaceus (PP-957) emerged as a potent probiotic, with significantly lower DPP-IV-IC50 values 0.17, 0.12, and 0.25 µg/mL protein equivalent in fermented cow, camel, and goat milk, respectively. Overall, peptides (RPPPPVAM, CHNLDELKDTR, and VLSLSQPK) exhibited strong binding affinity with binding energies of -9.31, -9.18 and -8.9 Kcal·mol-1, respectively, suggesting their potential role as DPP-IV inhibitors. Overall, this study, offers valuable information toward antidiabetic benefits of fermented milk products via inhibition of DPP-IV.
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Affiliation(s)
- Priti Mudgil
- Food Science Department, College of Agriculture and Veterinary Medicine, United Arab Emirates University, Al-Ain, 15551, United Arab Emirates..
| | - Chee-Yuen Gan
- Analytical Biochemistry Research Centre (ABrC), Universiti Sains Malaysia, 11800, USM, Penang, Malaysia
| | - Pei-Gee Yap
- Analytical Biochemistry Research Centre (ABrC), Universiti Sains Malaysia, 11800, USM, Penang, Malaysia
| | - Ali Ali Redha
- The Department of Public Health and Sport Sciences, University of Exeter Medical School, Faculty of Health and Life Sciences, University of Exeter, Exeter EX1 2 LU, United Kingdom; Centre for Nutrition and Food Sciences, Queensland Alliance for Agriculture and Food Innovation (QDPP-IVFI), The University of Queensland, Brisbane, QLD 4072, Australia
| | - Reem H Sultan Alsaadi
- Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, United Arab Emirates University, Al-Ain, 15551, United Arab Emirates
| | - Khaja Mohteshamuddin
- Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, United Arab Emirates University, Al-Ain, 15551, United Arab Emirates
| | - José E Aguilar-Toalá
- Departamento de Ciencias de la Alimentación. División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana Unidad Lerma. Av. de las Garzas 10. Col. El Panteón, Lerma de Villada 52005, Estado de México, Mexico
| | - Abraham M Vidal-Limon
- Red de Estudios Moleculares Avanzados, Clúster Científico y Tecnológico BioMimic®, Instituto de Ecología A.C. (INECOL), Carretera Antigua a Coatepec 351, El Haya, Xalapa 91073, Veracruz, Mexico
| | - Andrea M Liceaga
- Protein Chemistry and Bioactive Peptides Laboratory. Department of Food Science, Purdue University, 745 Agriculture Mall Dr., West Lafayette, IN 47907, USA
| | - Sajid Maqsood
- Food Science Department, College of Agriculture and Veterinary Medicine, United Arab Emirates University, Al-Ain, 15551, United Arab Emirates.; Zayed Centre of Health Science, United Arab Emirates University, Al-Ain 15551, United Arab Emirates.
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12
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Carpio LE, Olivares M, Benítez-Paez A, Serrano-Candelas E, Barigye SJ, Sanz Y, Gozalbes R. Comparative Binding Study of Gliptins to Bacterial DPP4-like Enzymes for the Treatment of Type 2 Diabetes Mellitus (T2DM). Int J Mol Sci 2024; 25:5744. [PMID: 38891933 PMCID: PMC11171585 DOI: 10.3390/ijms25115744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/21/2024] [Accepted: 05/23/2024] [Indexed: 06/21/2024] Open
Abstract
The role of the gut microbiota and its interplay with host metabolic health, particularly in the context of type 2 diabetes mellitus (T2DM) management, is garnering increasing attention. Dipeptidyl peptidase 4 (DPP4) inhibitors, commonly known as gliptins, constitute a class of drugs extensively used in T2DM treatment. However, their potential interactions with gut microbiota remain poorly understood. In this study, we employed computational methodologies to investigate the binding affinities of various gliptins to DPP4-like homologs produced by intestinal bacteria. The 3D structures of DPP4 homologs from gut microbiota species, including Segatella copri, Phocaeicola vulgatus, Bacteroides uniformis, Parabacteroides merdae, and Alistipes sp., were predicted using computational modeling techniques. Subsequently, molecular dynamics simulations were conducted for 200 ns to ensure the stability of the predicted structures. Stable structures were then utilized to predict the binding interactions with known gliptins through molecular docking algorithms. Our results revealed binding similarities of gliptins toward bacterial DPP4 homologs compared to human DPP4. Specifically, certain gliptins exhibited similar binding scores to bacterial DPP4 homologs as they did with human DPP4, suggesting a potential interaction of these drugs with gut microbiota. These findings could help in understanding the interplay between gliptins and gut microbiota DPP4 homologs, considering the intricate relationship between the host metabolism and microbial communities in the gut.
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Affiliation(s)
- Laureano E. Carpio
- ProtoQSAR SL, CEEI (Centro Europeo de Empresas Innovadoras), Parque Tecnológico de Valencia, 46980 Valencia, Spain; (L.E.C.); (E.S.-C.)
- MolDrug AI Systems SL, 46018 Valencia, Spain
| | - Marta Olivares
- Microbial Ecology, Nutrition and Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), 46980 Valencia, Spain; (M.O.); (A.B.-P.); (Y.S.)
| | - Alfonso Benítez-Paez
- Microbial Ecology, Nutrition and Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), 46980 Valencia, Spain; (M.O.); (A.B.-P.); (Y.S.)
| | - Eva Serrano-Candelas
- ProtoQSAR SL, CEEI (Centro Europeo de Empresas Innovadoras), Parque Tecnológico de Valencia, 46980 Valencia, Spain; (L.E.C.); (E.S.-C.)
| | | | - Yolanda Sanz
- Microbial Ecology, Nutrition and Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), 46980 Valencia, Spain; (M.O.); (A.B.-P.); (Y.S.)
| | - Rafael Gozalbes
- ProtoQSAR SL, CEEI (Centro Europeo de Empresas Innovadoras), Parque Tecnológico de Valencia, 46980 Valencia, Spain; (L.E.C.); (E.S.-C.)
- MolDrug AI Systems SL, 46018 Valencia, Spain
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13
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Arai S, Kurimoto M, Nakada H, Tanaka M, Ochi H, Tanaka M, Okochi M. Screening of novel DPP-IV inhibitory peptides derived from bovine milk proteins using a peptide array platform. J Biosci Bioeng 2024; 137:94-100. [PMID: 38092600 DOI: 10.1016/j.jbiosc.2023.11.007] [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: 09/07/2023] [Revised: 11/06/2023] [Accepted: 11/15/2023] [Indexed: 02/10/2024]
Abstract
Dipeptidyl peptidase IV (DPP-IV) has become an important target in the prevention and treatment of diabetes. Although many DPP-IV inhibitory peptides have been identified by a general approach involving the repeated fractionation of food protein hydrolysates, the obtained results have been dependent on the content of each peptide and fractionation conditions. In the present study, a peptide array that provides comprehensive assays of peptide sequences was used to identify novel DPP-IV inhibitory peptides derived from bovine milk proteins; these peptides were then compared with those identified using the general approach. While the general approach identified only known peptides that were abundant in the hydrolysate, the peptide array-based approach identified 10 novel DPP-IV inhibitory peptides, all of which had proline at the second residue from the N-terminus. The proper or combined use of these two approaches, which have different advantages, will enable the efficient development of novel bioactive foods and drugs.
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Affiliation(s)
- Sayuri Arai
- Innovative Research Institute, Morinaga Milk Industry Co., Ltd., 5-1-83 Higashihara, Zama, Kanagawa 252-8583, Japan
| | - Masaki Kurimoto
- Innovative Research Institute, Morinaga Milk Industry Co., Ltd., 5-1-83 Higashihara, Zama, Kanagawa 252-8583, Japan
| | - Hajime Nakada
- Food Ingredients & Technology Institute, Morinaga Milk Industry Co., Ltd., 5-1-83 Higashihara, Zama, Kanagawa 252-8583, Japan
| | - Masayoshi Tanaka
- Department of Chemical Science and Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan
| | - Hiroshi Ochi
- Food Ingredients & Technology Institute, Morinaga Milk Industry Co., Ltd., 5-1-83 Higashihara, Zama, Kanagawa 252-8583, Japan
| | - Miyuki Tanaka
- Innovative Research Institute, Morinaga Milk Industry Co., Ltd., 5-1-83 Higashihara, Zama, Kanagawa 252-8583, Japan
| | - Mina Okochi
- Department of Chemical Science and Engineering, Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8552, Japan.
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Bai N, Wang J, Liang W, Gao L, Cui W, Wu Q, Li F, Ji L, Cai Y. A Multicenter, Randomized, Double-Blind, Placebo-Controlled, and Dose-Increasing Study on the Safety, Tolerability and PK/PD of Multiple Doses of HSK7653 by Oral Administration in Patients with Type 2 Diabetes Mellitus in China. Diabetes Ther 2024; 15:183-199. [PMID: 37930584 PMCID: PMC10786778 DOI: 10.1007/s13300-023-01496-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 10/11/2023] [Indexed: 11/07/2023] Open
Abstract
INTRODUCTION This study assessed the safety, tolerability, and PK/PD of HSK7653 tablets in Chinese patients with type 2 diabetes mellitus (T2DM). METHODS This was a Phase IIa, multicenter, randomized, double-blind, placebo-controlled, and dose-increasing study with 48 Chinese diabetes patients. Subjects were randomly assigned to placebo and 10/25/50 mg dose groups, and they received oral administration once every two weeks for a total of six times. Safety and tolerability were assessed throughout this study, and PK/PD parameters were analyzed using non-compartment model with WinNonlin. RESULTS The three doses of HSK7653 were well tolerated, and the incidence of TEAE and ADR was not significantly increased compared with the placebo group. Cmax increased linearly with the increasing dose, and the mean t1/2 was 64.0-87.0 h. The first dose and last dose PK parameters were similar. After oral administration of 10-50 mg HSK7653 every two weeks, the average Rac_Cmax and Rac_AUC were 0.9-1.0 and 1.0-1.1 respectively; therefore, HSK7653 was not accumulated in vivo. All three doses significantly inhibited DPP-4 activity and increased plasma GLP-1 level and serum insulin levels. When the plasma concentration of HSK7653 was ≥ 20.0 ng/mL, the DPP-4 inhibition rate in all subjects was maintained at > 80.0%. In 10 and 25 mg dose groups, the HbA1c levels maintained a downward trend compared with the placebo group. DISCUSSION HSK7653 showed desirable pharmacokinetic and pharmacodynamic properties with good safety and tolerability in Chinese T2DM patients. DPP-4 inhibition rate and plasma GLP-1 levels were higher in each dose group than in placebo group. TRIAL REGISTRATION NUMBER CTR20182505 (Drug Clinical Trial Registration and Information Disclosure Platform, www.chinadrugtrials.org.cn ).
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Affiliation(s)
- Nan Bai
- Center of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Jin Wang
- Center of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Wenxin Liang
- Center of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Leili Gao
- Department of Endocrinology, Peking University People's Hospital, Beijing, 100044, China
| | - Wei Cui
- Phase I Clinical Research Department, Tianjin Union Medical Center, Tianjin, 300121, China
| | - Qinghe Wu
- Clinical Research Department, Haisco Pharmaceutical Group, Chengdu, 611130, China
| | - Fangqiong Li
- Clinical Research Department, Haisco Pharmaceutical Group, Chengdu, 611130, China
| | - Linong Ji
- Department of Endocrinology, Peking University People's Hospital, Beijing, 100044, China.
| | - Yun Cai
- Center of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Center of Chinese PLA General Hospital, Beijing, 100853, China.
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15
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Yamada Y, Sato T, Oda H, Harada N, Yoshizawa A, Nishikawa S, Kayawake H, Tanaka S, Yutaka Y, Hamaji M, Nakajima D, Ohsumi A, Date H. Favorable effect of CD26/DPP-4 inhibitors on postoperative outcomes after lung transplantation: A propensity-weighted analysis. J Heart Lung Transplant 2024; 43:66-76. [PMID: 37634575 DOI: 10.1016/j.healun.2023.08.014] [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: 04/06/2023] [Revised: 07/24/2023] [Accepted: 08/18/2023] [Indexed: 08/29/2023] Open
Abstract
BACKGROUND We have shown the efficacy of CD26/dipeptidyl peptidase 4 (CD26/DPP-4) inhibitors, antidiabetic agents, in allograft protection after experimental lung transplantation (LTx). We aimed to elucidate whether CD26/DPP-4 inhibitors effectively improve postoperative outcomes after clinical LTx. METHODS We retrospectively reviewed the records of patients undergoing LTx at our institution between 2010 and 2021 and extracted records of patients with diabetes mellitus (DM) at 6 months post-LTx. The patient characteristics and postoperative outcomes were analyzed. We established 6 months post-LTx as the landmark point for predicting overall survival (OS) and chronic lung allograft dysfunction (CLAD)-free survival. Hazard ratios were estimated by Cox regression after propensity score weighting, using CD26/DPP-4 inhibitor treatment up to 6 months post-LTx as the exposure variable. We evaluated CLAD samples pathologically, including for CD26/DPP-4 immunohistochemistry. RESULTS Of 102 LTx patients with DM, 29 and 73 were treated with and without CD26/DPP-4 inhibitors, respectively. Based on propensity score adjustment using standardized mortality ratio weighting, the 5-year OS rates were 77.0% and 44.3%, and the 5-year CLAD-free survival rates 77.8% and 49.1%, in patients treated with and without CD26/DPP-4 inhibitors, respectively. The hazard ratio for CD26/DPP-4 inhibitor use was 0.34 (95% confidence interval (CI) 0.14-0.82, p = 0.017) for OS and 0.47 (95% CI 0.22-1.01, p = 0.054) for CLAD-free survival. We detected CD26/DPP-4 expression in the CLAD grafts of patients without CD26/DPP-4 inhibitors. CONCLUSIONS Analysis using propensity score weighting showed that CD26/DPP-4 inhibitors positively affected the postoperative prognosis of LTx patients with DM.
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Affiliation(s)
- Yoshito Yamada
- Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan; Department of Thoracic Surgery, Kyoto Katsura Hospital, Kyoto, Japan.
| | - Tosiya Sato
- Department of Biostatistics, Kyoto University School of Public Health, Kyoto, Japan
| | - Hiromi Oda
- Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan
| | - Norio Harada
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Akihiko Yoshizawa
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Shigeto Nishikawa
- Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan
| | - Hidenao Kayawake
- Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan
| | - Satona Tanaka
- Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan
| | - Yojiro Yutaka
- Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan
| | - Masatsugu Hamaji
- Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan
| | - Daisuke Nakajima
- Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan
| | - Akihiro Ohsumi
- Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan
| | - Hiroshi Date
- Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan
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16
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Batra H, Mouabbi JA, Ding Q, Sahin AA, Raso MG. Lobular Carcinoma of the Breast: A Comprehensive Review with Translational Insights. Cancers (Basel) 2023; 15:5491. [PMID: 38001750 PMCID: PMC10670219 DOI: 10.3390/cancers15225491] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/09/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023] Open
Abstract
The second most common breast carcinoma, invasive lobular carcinoma, accounts for approximately 15% of tumors of breast origin. Its incidence has increased in recent times due in part to hormone replacement therapy and improvement in diagnostic modalities. Although believed to arise from the same cell type as their ductal counterpart, invasive lobular carcinomas (ILCs) are a distinct entity with different regulating genetic pathways, characteristic histologies, and different biology. The features most unique to lobular carcinomas include loss of E-Cadherin leading to discohesion and formation of a characteristic single file pattern on histology. Because most of these tumors exhibit estrogen receptor positivity and Her2 neu negativity, endocrine therapy has predominated to treat these tumors. However novel treatments like CDK4/6 inhibitors have shown importance and antibody drug conjugates may be instrumental considering newer categories of Her 2 Low breast tumors. In this narrative review, we explore multiple pathological aspects and translational features of this unique entity. In addition, due to advancement in technologies like spatial transcriptomics and other hi-plex technologies, we have tried to enlist upon the characteristics of the tumor microenvironment and the latest associated findings to better understand the new prospective therapeutic options in the current era of personalized treatment.
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Affiliation(s)
- Harsh Batra
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Jason Aboudi Mouabbi
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Qingqing Ding
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (Q.D.); (A.A.S.)
| | - Aysegul A. Sahin
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (Q.D.); (A.A.S.)
| | - Maria Gabriela Raso
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
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17
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Koufakis T, Zografou I, Doumas M, Kotsa K. The Current Place of DPP4 Inhibitors in the Evolving Landscape of Type 2 Diabetes Management: Is It Time to Bid Adieu? Am J Cardiovasc Drugs 2023; 23:601-608. [PMID: 37682449 DOI: 10.1007/s40256-023-00610-8] [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] [Accepted: 08/24/2023] [Indexed: 09/09/2023]
Abstract
During the last decade, the landscape of type 2 diabetes (T2D) management has been completely transformed, moving from a glucose-centric perspective to a holistic approach that also takes into account weight control and organ protection. Dipeptidyl peptidase-4 inhibitors (DPP4i) are oral agents that have been used for the treatment of T2D for almost 20 years. Although they present an excellent safety profile, including the risk of hypoglycemia, they lack the spectacular cardiorenal benefits and weight-loss effects of the newer antidiabetic agents. This poses the question of whether they still deserve a place in the arsenal of drugs against T2D. In this article, we use a hypothetical case scenario to illustrate possible patient profiles where DPP4i could prove useful in the clinical setting. We discuss the advantages and disadvantages of the category, focusing on glycemic control, weight management, and cardiorenal protection, which are the pillars of modern T2D management, also considering its safety profile and cost-effectiveness. We conclude that in most cases, DPP4i present a more favorable risk-benefit ratio compared to sulfonylureas, which are still widely prescribed throughout the world. We also suggest that future research should clarify the reasons behind the contradictory findings between human and animal studies on cardiorenal effects of the class and identify subgroups of patients who would derive most benefit with DPP4i treatment.
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Affiliation(s)
- Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 1 St. Kiriakidi Street, 54636, Thessaloniki, Greece
| | - Ioanna Zografou
- Second Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Michael Doumas
- Second Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 1 St. Kiriakidi Street, 54636, Thessaloniki, Greece.
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18
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Reghunath SR, Rashid M, Chandran VP, Thunga G, Shivashankar KN, Acharya LD. Factors contributing to the adverse drug reactions associated with the dipeptidyl peptidase-4 (DPP-4) inhibitors: A scoping review. Diabetes Metab Syndr 2023; 17:102790. [PMID: 37329838 DOI: 10.1016/j.dsx.2023.102790] [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: 09/09/2022] [Revised: 01/30/2023] [Accepted: 05/24/2023] [Indexed: 06/19/2023]
Abstract
BACKGROUND AND AIM Adverse drug reactions are one of the contributors to increased hospital admission and length of hospital stay. Among the various antidiabetic agents prescribed, dipeptidyl peptidase-4 (DPP-4) inhibitors have gained wide recognition and shown more persistence than other novel hypoglycemic agents. We performed a scoping review to identify the risk factors contributing to the adverse drug reactions with DPP-4 inhibitors. METHODOLOGY We followed Preferred Reporting Items for Scoping Review (PRISMA-ScR) Guidelines for reporting the findings. Data sources such as PubMed/MEDLINE, Scopus, Embase, and Cochrane were assessed. We included studies that reported the risk factors contributing to the DPP-4 inhibitor-associated adverse drug reactions. The Joanna Briggs Institute (JBI) critical appraisal checklist was used to assess the methodological quality of the studies. RESULTS Of the 6406 studies retrieved, 11 studies met our inclusion criteria. Of these 11 studies, seven were post-marketing surveillance studies, one nested case-control study, one comparator cohort study, one food and drug administration (FDA) adverse event reporting system (FAERS)-based observational study, and one questionnaire-based cross-sectional survey study. A total of eight factors were identified that contributed to the DPP-4 inhibitor-associated adverse drug reactions. CONCLUSION The included studies suggested age >65 years, females, grade 4 and 5 renal impairment, concomitant drugs, disease and drug therapy duration, liver disease, non-smokers, and non-hypertension as risk factors. Further studies should be conducted to provide insight into these risk factors so that the appropriate use of DPP-4 inhibitors in the diabetic population can be encouraged to improve the health-related quality of life. PROSPERO REGISTRATION CRD42022308764.
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Affiliation(s)
- Swetha R Reghunath
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Udupi District, Karnataka, 576 104, India.
| | - Muhammed Rashid
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Udupi District, Karnataka, 576 104, India.
| | - Viji Pulikkel Chandran
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Udupi District, Karnataka, 576 104, India.
| | - Girish Thunga
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Udupi District, Karnataka, 576 104, India.
| | - K N Shivashankar
- Department of General Medicine, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Udupi District, Karnataka, 576 104, India.
| | - Leelavathi D Acharya
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Udupi District, Karnataka, 576 104, India.
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19
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Shah M, Jan MS, Sadiq A, Khan S, Rashid U. SAR and lead optimization of (Z)-5-(4-hydroxy-3-methoxybenzylidene)-3-(2-morpholinoacetyl)thiazolidine-2,4-dione as a potential multi-target antidiabetic agent. Eur J Med Chem 2023; 258:115591. [PMID: 37393789 DOI: 10.1016/j.ejmech.2023.115591] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 06/06/2023] [Accepted: 06/22/2023] [Indexed: 07/04/2023]
Abstract
In case of metabolic disorder like Diabetes mellitus (DM), a number of key enzymes are abnormally expressed and hence they might be excellent targets for antidiabetic drug design. Multi-target design strategy has recently attracted great attention to treat challenging diseases. We have previously reported a vanillin-thiazolidine-2,4-dione hybrid 3 as multitarget inhibitor of α-glucosidase, α-amylase, PTP-1B and DPP-4. The reported compound predominantly exhibited good in-vitro DPP-4 inhibition only. Current research describes the goal to optimize an early lead compound. The efforts were focused on enhancing the capability of manipulating multiple pathways at the same time for the treatment of diabetes. The central 5-benzylidinethiazolidine-2,4-dione for Lead compound (Z)-5-(4-hydroxy-3-methoxybenzylidene)-3-(2-morpholinoacetyl)thiazolidine-2,4-dione (Z-HMMTD) was left unchanged. While East and West moieties were altered by the introduction of different building blocks conceived by using a number of rounds of predictive docking studies performed on X-ray crystal structures of four target enzymes. This systematic SAR led to the syntheses of new potent multi-target antidiabetic compounds 47-49 and 55-57 with many fold increase in the in-vitro potency compared to Z-HMMTD. The potent compounds showed good in-vitro and in-vivo safety profile. Compound 56 emerged excellent as glucose-uptake promotor via hemi diaphragm of the rat. Moreover, the compounds demonstrated antidiabetic activity in STZ-induced diabetic animal model.
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Affiliation(s)
- Muhammad Shah
- Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, 22060, Abbottabad, Pakistan
| | - Muhammad Saeed Jan
- Department of Pharmacy, Bacha Khan University, 24420, Charsadda, KPK, Pakistan
| | - Abdul Sadiq
- Department of Pharmacy, University of Malakand, 18000, Chakdara, KP, Pakistan
| | - Sara Khan
- Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, 22060, Abbottabad, Pakistan
| | - Umer Rashid
- Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, 22060, Abbottabad, Pakistan.
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20
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Bouzas C, Pastor R, Garcia S, Monserrat-Mesquida M, Martínez-González MÁ, Salas-Salvadó J, Corella D, Goday A, Martínez JA, Alonso-Gómez ÁM, Fernández-Barceló O, Vioque J, Romaguera D, Lopez-Miranda J, Estruch R, Tinahones FJ, Lapetra J, Serra-Majem L, Riquelme-Gallego B, Martín-Sánchez V, Pintó X, Delgado-Rodriguez M, Matía P, Vidal J, Cardenas-Salas JJ, Daimiel L, Ros E, Toledo E, Manzanares JM, Gonzalez-Monge I, Muñoz MÁ, Martinez-Urbistondo D, Tojal-Sierra L, Muñoz-Bravo C, Miralles-Gisbert S, Martin M, García-Ríos A, Castro-Barquero S, Fernández-García JC, Santos-Lozano JM, Basterra-Gortari FJ, Gutiérrez-Carrasquilla L, Guillem-Saiz P, Satorres A, Abete I, Sorto-Sanchez C, Díez-Espino J, Babio N, Fitó M, Tur JA. Comparative effects of glucagon-like peptide-1 receptors agonists, 4-dipeptidyl peptidase inhibitors, and metformin on metabolic syndrome. Biomed Pharmacother 2023; 161:114561. [PMID: 36934556 DOI: 10.1016/j.biopha.2023.114561] [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: 02/08/2023] [Revised: 03/15/2023] [Accepted: 03/15/2023] [Indexed: 03/19/2023] Open
Abstract
AIMS To assess the comparative effects of glucagon-like peptide-1 receptor agonists (GLP-1RA), 4-dipeptidyl peptidase inhibitors (DPP-4I), and metformin treatment during one year on metabolic syndrome (MetS) components and severity in MetS patients. METHODS Prospective study (n = 6165 adults) within the frame of PREDIMED-Plus trial. The major end-point was changes on MetS components and severity after one- year treatment of GLP-1RA, DPP-4I, and metformin. Anthropometric measurements (weight, height and waist circumference), body mass index (BM), and blood pressure were registered. Blood samples were collected after overnight fasting. Plasma glucose, glycosylated hemoglobin (HbA1c), plasma triglycerides and cholesterol were measured. Dietary intakes as well as physical activity were assessed through validated questionnaires. RESULTS MetS parameters improved through time. The treated groups improved glycaemia compared with untreated (glycaemia ∆ untreated: -1.7 mg/dL(± 13.5); ∆ metformin: - 2.5(± 23.9) mg/dL; ∆ DPP-4I: - 4.5(± 42.6); mg/dL ∆ GLP-1RA: - 4.3(± 50.9) mg/dL; and HbA1c: ∆ untreated: 0.0(± 0.3) %; ∆ metformin: - 0.1(± 0.7) %; ∆ DPP-4I: - 0.1(± 1.0) %; ∆ GLP-1RA: - 0.2(± 1.2) %. Participants decreased BMI and waist circumference. GLP-1RA and DPP-4I participants registered the lowest decrease in BMI (∆ untreated: -0.8(± 1.6) kg/m2; ∆ metformin: - 0.8(± 1.5) kg/m2; ∆ DPP-4I: - 0.6(± 1.3) kg/m2; ∆ GLP-1RA: - 0.5(± 1.2) kg/m2. and their waist circumference (∆ untreated: -2.8(± 5.2) cm; ∆ metformin: - 2.6(± 15.2) cm; ∆ DPP-4I: - 2.1(± 4.8) cm; ∆ GLP-1RA: - 2.4(± 4.1) cm. CONCLUSION In patients with MetS and healthy lifestyle intervention, those treated with GLP-1RA and DPP-4I obtained better glycemic profile. Anthropometric improvements were modest.
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Affiliation(s)
- Cristina Bouzas
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Research Group on Community Nutrition & Oxidative Stress, University of Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
| | - Rosario Pastor
- Research Group on Community Nutrition & Oxidative Stress, University of Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; Faculty of Health Sciences,Catholic University of Avila, 05005 Avila, Spain
| | - Silvia Garcia
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Research Group on Community Nutrition & Oxidative Stress, University of Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
| | - Margalida Monserrat-Mesquida
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Research Group on Community Nutrition & Oxidative Stress, University of Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
| | - Miguel Ángel Martínez-González
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; University of Navarra, Department of Preventive Medicine and Public Health, IDISNA, 31008 Pamplona, Spain; Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, USA
| | - Jordi Salas-Salvadó
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Universitat Rovira i Virgili, Biochemistry and Biotechnology Department, Human Nutrition Unit, IISPV, Hospital Universitari de Sant Joan, 43201 Reus, Spain; Unidad de Nutrición, Lípidos y Endocrinologia, Hospital Universitari de Sant Joan de Reus, Institut d'Insvestigacions Sanitàries Pere Virgili (IISPV), 43201 Reus, Spain
| | - Dolores Corella
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Department of Preventive Medicine, University of Valencia, 46100 Valencia, Spain
| | - Albert Goday
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Unit of Cardiovascular Risk and Nutrition, Institut Hospital del Mar de Investigaciones Médicas Municipal d'Investigació Mèdica (IMIM), 08003 Barcelona, Spain
| | - J Alfredo Martínez
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Cardiometabolics Precision Nutrition Program, IMDEA Food, CEI UAM + CSIC, 28049 Madrid, Spain; Department of Nutrition, Food Sciences, and Physiology, Center for Nutrition Research, University of Navarra, 31008 Pamplona, Spain
| | - Ángel M Alonso-Gómez
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Bioaraba Health Research Institute, Osakidetza Basque Health Service, Araba University Hospital, University of the Basque Country UPV/EHU, 48013 Vitoria, Gasteiz, Spain
| | - Olga Fernández-Barceló
- Department of Nursing, School of Health Sciences, University of Malaga, Institute of Biomedical Research in Málaga (IBIMA-University of Malaga), 29071 Málaga, Spain
| | - Jesús Vioque
- Instituto de Investigación Sanitaria y Biomédica de Alicante, ISABIAL-UMH, 03550 Alicante, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Dora Romaguera
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
| | - José Lopez-Miranda
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Lipids and Atherosclerosis Unit, Department of Internal Medicine, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, 14004 Córdoba, Spain
| | - Ramón Estruch
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Department of Internal Medicine, IDIBAPS, Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain
| | - Francisco J Tinahones
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Virgen de la Victoria Hospital, Department of Endocrinology, University of Málaga, 29010 Málaga, Spain
| | - José Lapetra
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Department of Family Medicine, Research Unit, Distrito Sanitario Atención Primaria Sevilla, 41013 Sevilla, Spain
| | - Lluís Serra-Majem
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Institute for Biomedical Research, University of Las Palmas de Gran Canaria, 35016 Las Palmas, Spain
| | - Blanca Riquelme-Gallego
- CIBER Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Department of Preventive Medicine, University of Granada, 18071 Granada, Spain
| | - Vicente Martín-Sánchez
- CIBER Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Institute of Biomedicine (IBIOMED), University of León, 24071 Leon, Spain
| | - Xavier Pintó
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Lipids and Vascular Risk Unit, Internal Medicine, Hospital Universitario de Bellvitge, Hospital Universitario de Bellvitge, 08907 Barcelona, Spain
| | - Miguel Delgado-Rodriguez
- CIBER Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Department of Health Sciences, Center for Advanced Studies in Olive Grove and Olive Oils, University of Jaen, 23071 Jaen, Spain
| | - Pilar Matía
- Department of Endocrinology and Nutrition, Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain
| | - Josep Vidal
- Department of Endocrinology, IDIBAPS, Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain
| | | | - Lidia Daimiel
- Nutritional Control of the Epigenome Group, Precision Nutrition and Obesity Program, IMDEA Food, CEI UAM + CSIC, 28049 Madrid, Spain
| | - Emilio Ros
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Lipid Clinic, Department of Endocrinology and Nutrition, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Hospital Clínic, 08036 Barcelona, Spain
| | - Estefanía Toledo
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; University of Navarra, Department of Preventive Medicine and Public Health, IDISNA, 31008 Pamplona, Spain
| | - Josep M Manzanares
- Universitat Rovira i Virgili, Biochemistry and Biotechnology Department, Human Nutrition Unit, IISPV, Hospital Universitari de Sant Joan, 43201 Reus, Spain; Unidad de Nutrición, Lípidos y Endocrinologia, Hospital Universitari de Sant Joan de Reus, Institut d'Insvestigacions Sanitàries Pere Virgili (IISPV), 43201 Reus, Spain
| | | | - Miguel-Ángel Muñoz
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Unit of Cardiovascular Risk and Nutrition, Institut Hospital del Mar de Investigaciones Médicas Municipal d'Investigació Mèdica (IMIM), 08003 Barcelona, Spain
| | - Diego Martinez-Urbistondo
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Cardiometabolics Precision Nutrition Program, IMDEA Food, CEI UAM + CSIC, 28049 Madrid, Spain; Internal Medicine Department, HM Sanchinarro, 28050 Madrid, Spain
| | - Lucas Tojal-Sierra
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Bioaraba Health Research Institute, Osakidetza Basque Health Service, Araba University Hospital, University of the Basque Country UPV/EHU, 48013 Vitoria, Gasteiz, Spain
| | - Carlos Muñoz-Bravo
- Division of Preventive Medicine and Public Health, University of Malaga, Institute of Biomedical Research in Málaga (IBIMA-University of Malaga), Málaga, Spain
| | | | - Marian Martin
- Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
| | - Antonio García-Ríos
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Lipids and Atherosclerosis Unit, Department of Internal Medicine, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, 14004 Córdoba, Spain
| | - Sara Castro-Barquero
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Department of Internal Medicine, IDIBAPS, Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain
| | - José Carlos Fernández-García
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Virgen de la Victoria Hospital, Department of Endocrinology, University of Málaga, 29010 Málaga, Spain
| | - José Manuel Santos-Lozano
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Department of Family Medicine, Research Unit, Distrito Sanitario Atención Primaria Sevilla, 41013 Sevilla, Spain
| | - F Javier Basterra-Gortari
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; University of Navarra, Department of Preventive Medicine and Public Health, IDISNA, 31008 Pamplona, Spain
| | - Liliana Gutiérrez-Carrasquilla
- Universitat Rovira i Virgili, Biochemistry and Biotechnology Department, Human Nutrition Unit, IISPV, Hospital Universitari de Sant Joan, 43201 Reus, Spain; Unidad de Nutrición, Lípidos y Endocrinologia, Hospital Universitari de Sant Joan de Reus, Institut d'Insvestigacions Sanitàries Pere Virgili (IISPV), 43201 Reus, Spain
| | - Patricia Guillem-Saiz
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Department of Preventive Medicine, University of Valencia, 46100 Valencia, Spain
| | - Alba Satorres
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Unit of Cardiovascular Risk and Nutrition, Institut Hospital del Mar de Investigaciones Médicas Municipal d'Investigació Mèdica (IMIM), 08003 Barcelona, Spain
| | - Itziar Abete
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Department of Nutrition, Food Sciences, and Physiology, Center for Nutrition Research, University of Navarra, 31008 Pamplona, Spain
| | - Carolina Sorto-Sanchez
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Bioaraba Health Research Institute, Osakidetza Basque Health Service, Araba University Hospital, University of the Basque Country UPV/EHU, 48013 Vitoria, Gasteiz, Spain
| | - Javier Díez-Espino
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; University of Navarra, Department of Preventive Medicine and Public Health, IDISNA, 31008 Pamplona, Spain
| | - Nancy Babio
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Universitat Rovira i Virgili, Biochemistry and Biotechnology Department, Human Nutrition Unit, IISPV, Hospital Universitari de Sant Joan, 43201 Reus, Spain
| | - Montse Fitó
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Unit of Cardiovascular Risk and Nutrition, Institut Hospital del Mar de Investigaciones Médicas Municipal d'Investigació Mèdica (IMIM), 08003 Barcelona, Spain
| | - Josep A Tur
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Research Group on Community Nutrition & Oxidative Stress, University of Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain.
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21
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Novel hit of DPP-4Is as promising antihyperglycemic agents with dual antioxidant/anti-inflammatory effects for type 2 diabetes with/without COVID-19. Bioorg Chem 2022; 128:106092. [PMID: 35985159 PMCID: PMC9364673 DOI: 10.1016/j.bioorg.2022.106092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 08/07/2022] [Indexed: 12/15/2022]
Abstract
DPP-4Is are well recognized therapy for type 2 diabetes. In spite of sharing a common mode of action, the chemical diversity among members of DPP-4Is raised the question whether structural differences may result in distinguished activities. DPP-4Is were recently explored as drug repurposing means for treatment of SARS-CoV-2 due to the urgent need for small molecule drugs for controlling infections. The use of DPP-4Is was not correlated with adverse COVID-19-related consequences among patients with type 2 diabetes. Inspired by these reasons and the importance of pyrimidinone ring as DPP-4I with both antioxidant and anti-inflammatory activities, we succeeded to prepare some novel pyrimidinone and thio-pyrimidinone derivatives, which were then screened for their antidiabetic activity and DPP-4 inhibition. In addition, their anti-inflammatory effect on LPS-stimulated RAW 264.7 cells were evaluated. Furthermore, their antioxidant activities were also tested.
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22
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Humos B, Mahfoud Z, Dargham S, Al Suwaidi J, Jneid H, Abi Khalil C. Hypoglycemia is associated with a higher risk of mortality and arrhythmias in ST-elevation myocardial infarction, irrespective of diabetes. Front Cardiovasc Med 2022; 9:940035. [PMID: 36299875 PMCID: PMC9588908 DOI: 10.3389/fcvm.2022.940035] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 08/31/2022] [Indexed: 11/16/2022] Open
Abstract
Aims We aimed to assess the impact of hypoglycemia in ST-elevation myocardial infarction (STEMI). Background Hypoglycemia increases the risk of mortality in patients with diabetes and high cardiovascular risk. Methods We used the National Inpatient Sample (2005–2017) database to identify adult patients with STEMI as the primary diagnosis. The secondary diagnosis was hypoglycemia. We compared cardiovascular and socio-economic outcomes between STEMI patients with and without hypoglycemia and assessed temporal trends. Results Hypoglycemia tends to complicate 0.17% of all cases hospitalized for STEMI. The mean age (±SD) of STEMI patients hospitalized with hypoglycemia decreased from 67 ± 15 in 2005 to 63 ± 12 in 2017 (p = 0.046). Mortality was stable with time, but the prevalence of ventricular tachycardia, ventricular fibrillation, acute renal failure, cardiogenic shock, total charges, and length of stay (LOS) increased with time (p < 0.05 for all). Compared to non-hypoglycemic patients, those who developed hypoglycemia were older and more likely to be black; only 6.7% had diabetes compared to 28.5% of STEMI patients (p = 0.001). Cardiovascular events were more likely to occur in hypoglycemia: mortality risk increased by almost 2.5-fold (adjusted OR = 2.625 [2.095–3.289]). There was a higher incidence of cardiogenic shock (adjusted OR = 1.718 [1.387–2.127]), atrial fibrillation (adjusted OR = 1.284 [1.025–1.607]), ventricular fibrillation (adjusted OR = 1.799 [1.406–2.301]), and acute renal failure (adjusted OR = 2.355 [1.902–2.917]). Patients who developed hypoglycemia were less likely to have PCI (OR = 0.596 [0.491–0.722]) but more likely to have CABG (OR = 1.792 [1.391–2.308]). They also had a longer in-hospital stay and higher charges/stay. Conclusion Hypoglycemia is a rare event in patients hospitalized with STEMI. However, it was found to have higher odds of mortality, arrhythmias, and other comorbidities, irrespective of diabetes.
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Affiliation(s)
- Basel Humos
- Department of Research, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Ziyad Mahfoud
- Department of Research, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Soha Dargham
- Department of Research, Weill Cornell Medicine-Qatar, Doha, Qatar
| | | | - Hani Jneid
- The Michael E. DeBakey VA Medical Centre, Baylor College of Medicine, Houston, TX, United States
| | - Charbel Abi Khalil
- Department of Research, Weill Cornell Medicine-Qatar, Doha, Qatar,Heart Hospital, Hamad Medical Corporation, Doha, Qatar,Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, United States,*Correspondence: Charbel Abi Khalil,
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23
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Martínez-López YE, Esquivel-Hernández DA, Sánchez-Castañeda JP, Neri-Rosario D, Guardado-Mendoza R, Resendis-Antonio O. Type 2 diabetes, gut microbiome, and systems biology: A novel perspective for a new era. Gut Microbes 2022; 14:2111952. [PMID: 36004400 PMCID: PMC9423831 DOI: 10.1080/19490976.2022.2111952] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The association between the physio-pathological variables of type 2 diabetes (T2D) and gut microbiota composition suggests a new avenue to track the disease and improve the outcomes of pharmacological and non-pharmacological treatments. This enterprise requires new strategies to elucidate the metabolic disturbances occurring in the gut microbiome as the disease progresses. To this end, physiological knowledge and systems biology pave the way for characterizing microbiota and identifying strategies in a move toward healthy compositions. Here, we dissect the recent associations between gut microbiota and T2D. In addition, we discuss recent advances in how drugs, diet, and exercise modulate the microbiome to favor healthy stages. Finally, we present computational approaches for disentangling the metabolic activity underlying host-microbiota codependence. Altogether, we envision that the combination of physiology and computational modeling of microbiota metabolism will drive us to optimize the diagnosis and treatment of T2D patients in a personalized way.
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Affiliation(s)
- Yoscelina Estrella Martínez-López
- Human Systems Biology Laboratory. Instituto Nacional de Medicina Genómica (INMEGEN). México City, México,Programa de Doctorado en Ciencias Médicas, Odontológicas y de la Salud, Universidad Nacional Autónoma de México (UNAM). Ciudad de México, México,Metabolic Research Laboratory, Department of Medicine and Nutrition. University of Guanajuato. León, Guanajuato, México
| | | | - Jean Paul Sánchez-Castañeda
- Human Systems Biology Laboratory. Instituto Nacional de Medicina Genómica (INMEGEN). México City, México,Programa de Maestría en Ciencias Bioquímicas, Universidad Nacional Autónoma de México (UNAM). Ciudad de México, México
| | - Daniel Neri-Rosario
- Human Systems Biology Laboratory. Instituto Nacional de Medicina Genómica (INMEGEN). México City, México,Programa de Maestría en Ciencias Bioquímicas, Universidad Nacional Autónoma de México (UNAM). Ciudad de México, México
| | - Rodolfo Guardado-Mendoza
- Metabolic Research Laboratory, Department of Medicine and Nutrition. University of Guanajuato. León, Guanajuato, México,Research Department, Hospital Regional de Alta Especialidad del Bajío. León, Guanajuato, México,Rodolfo Guardado-Mendoza Metabolic Research Laboratory, Department of Medicine and Nutrition. University of Guanajuato. León, Guanajuato, México
| | - Osbaldo Resendis-Antonio
- Human Systems Biology Laboratory. Instituto Nacional de Medicina Genómica (INMEGEN). México City, México,Coordinación de la Investigación Científica – Red de Apoyo a la Investigación, Universidad Nacional Autónoma de México (UNAM). Ciudad de México, México,CONTACT Osbaldo Resendis-Antonio Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de México (UNAM), Periferico Sur 4809, Arenal Tepepan, Tlalpan, 14610 Ciudad de México, CDMX
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Computer-Aided Screening of Phytoconstituents from Ocimum tenuiflorum against Diabetes Mellitus Targeting DPP4 Inhibition: A Combination of Molecular Docking, Molecular Dynamics, and Pharmacokinetics Approaches. Molecules 2022; 27:molecules27165133. [PMID: 36014373 PMCID: PMC9415412 DOI: 10.3390/molecules27165133] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 08/02/2022] [Accepted: 08/03/2022] [Indexed: 01/20/2023] Open
Abstract
Diabetes mellitus is a major global health concern in the current scenario which is chiefly characterized by the rise in blood sugar levels or hyperglycemia. In the context, DPP4 enzyme plays a critical role in glucose homeostasis. DPP4 targets and inactivates incretin hormones such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) as physiological substrates, which are essential to regulate the amount of insulin that is secreted after eating. Since the inactivation of incretins occurs, the hyperglycemic conditions continue to rise, and result in adverse physiological conditions linked with diabetes mellitus. Hence, inhibition of DPP4 has been the center of focus in the present antidiabetic studies. Although few DPP4 inhibitor drugs, such as alogliptin, saxagliptin, linagliptin, and sitagliptin, are available, their adverse effects on human metabolism are undeniable. Therefore, it becomes essential for the phytochemical intervention of the disease using computational methods prior to performing in vitro and in vivo studies. In this regard, we used an in-silico approach involving molecular docking, molecular dynamics simulations, and binding free energy calculations to investigate the inhibitory potential of Ocimum tenuiflorum phytocompounds against DPP4. In this regard, three phytocompounds (1S-α-pinene, β-pinene, and dehydro-p-cymene) from O. tenuiflorum have been discovered as the potential inhibitors of the DPP4 protein. To summarize, from our in-silico experiment outcomes, we propose dehydro-p-cymene as the potential lead inhibitor of DPP4 protein, thereby discovering new a phytocompound for the effective management of hyperglycemia and diabetes mellitus. The reported compound can be taken for in vitro and in vivo analyses in near future.
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Pradhan R, Patorno E, Tesfaye H, Schneeweiss S, Yin H, Franklin J, Pawar A, Santella C, Yu OHY, Renoux C, Azoulay L. Glucagon-Like Peptide 1 Receptor Agonists and Risk of Anaphylactic Reaction Among Patients With Type 2 Diabetes: A Multisite Population-Based Cohort Study. Am J Epidemiol 2022; 191:1352-1367. [PMID: 35136902 PMCID: PMC9989345 DOI: 10.1093/aje/kwac021] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 01/13/2022] [Accepted: 01/26/2022] [Indexed: 01/28/2023] Open
Abstract
Case reports and a pharmacovigilance analysis have linked glucagon-like peptide 1 receptor agonists (GLP-1 RAs) with anaphylactic reactions, but real-world evidence for this possible association is lacking. Using databases from the United Kingdom (Clinical Practice Research Datalink) and the United States (Medicare, Optum (Optum, Inc., Eden Prairie, Minnesota), and IBM MarketScan (IBM, Armonk, New York)), we employed a new-user, active comparator study design wherein initiators of GLP-1 RAs were compared with 2 different active comparator groups (initiators of dipeptidyl peptidase 4 (DPP-4) inhibitors and initiators of sodium-glucose cotransporter 2 (SGLT-2) inhibitors) between 2007 and 2019. Propensity score fine stratification weighted Cox proportional hazards models were fitted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for an anaphylactic reaction. Database-specific HRs were pooled using random-effects models. Compared with the use of DPP-4 inhibitors (n = 1,641,520), use of GLP-1 RAs (n = 324,098) generated a modest increase in the HR for anaphylactic reaction, with a wide 95% CI (36.9 per 100,000 person-years vs. 32.1 per 100,000 person-years, respectively; HR = 1.15, 95% CI: 0.94, 1.42). Compared with SGLT-2 inhibitors (n = 366,067), GLP-1 RAs (n = 259,929) were associated with a 38% increased risk of anaphylactic reaction (40.7 per 100,000 person-years vs. 29.4 per 100,000 person-years, respectively; HR = 1.38, 95% CI: 1.02, 1.87). In this large, multisite population-based cohort study, GLP-1 RAs were associated with a modestly increased risk of anaphylactic reaction when compared with DPP-4 inhibitors and SGLT-2 inhibitors.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Laurent Azoulay
- Correspondence to Dr. Laurent Azoulay, Centre for Clinical Epidemiology, Jewish General Hospital, Lady Davis Institute, 3755 Côte Sainte-Catherine, Suite H425.1, Montreal, QC H3T 1E2, Canada (e-mail: )
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Chang CH, Lu CH, Chung CH, Su SC, Kuo FC, Liu JS, Li PF, Huang CL, Chen KC, Ho LJ, Kuo CC, Chang CY, Lin MS, Liu YC, Chu NF, Lee CH, Hung YJ, Hsieh PS, Lin FH, Hsieh CH, Chien WC. Dipeptidyl peptidase-4 inhibitors attenuates osteoporosis in patients with diabetes: A nationwide, retrospective, matched-cohort study in Taiwan. J Chin Med Assoc 2022; 85:747-753. [PMID: 35648138 DOI: 10.1097/jcma.0000000000000743] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
BACKGROUND Patients with diabetes have a relatively high risk of fracture due to osteoporosis. However, the risk of osteoporosis associated with the use of oral hypoglycemic drugs and dipeptidyl peptidase-4 inhibitor (DPP-4i) by patients with diabetes is unclear. This study aimed to explore the effect of DPP-4i on the risk of osteoporosis in Taiwanese patients with type 2 diabetes mellitus (T2DM). METHODS This study enrolled 6339 patients on DPP-4i (DPP-4i group) and 25 356 patients without DPP-4i (non-DPP-4i group). They were matched by 1:4 propensity score matching, using confounding variables including sex, age, comorbidities, medication, and index year. Cox proportional hazards analysis was used to compare hospitalization and mortality during an average follow-up period of 7 years. RESULTS The mean age of patients in the two groups was 66 years. Men were slightly higher in number (51.79%) than women. At the end of the follow-up period, 113 (0.36%) patients had osteoporosis, of which 15 (0.24%) were in the case group and 98 (0.39%) in the control group. The risk of all-cause osteoporosis was significantly lower in the DPP-4i group than in the non-DPP-4i group (adjusted hazard ratio [HR] 0.616; 95% confidence interval [CI] 0.358-0.961; p = 0.011). Kaplan-Meier analysis showed that the preventive effect on osteoporosis was positively correlated with the cumulative dose of DPP-4i (log-rank, p = 0.039) with the class effect. CONCLUSION Compared with not using DPP-4i, the use of DPP-4i in Taiwanese T2DM patients was associated with a lower risk of osteoporosis due to the class effect, and the preventive effect was dose-dependent. However, larger prospective studies are needed to validate this finding and to explore the possible mechanism of the preventive effect of DPP-4i.
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Affiliation(s)
- Chia-Hao Chang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Armed Forces General Hospital, Taichung, Taiwan, ROC
| | - Chieh Hua Lu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chi-Hsiang Chung
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, ROC
- Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan, ROC
| | - Sheng-Chiang Su
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Feng-Chih Kuo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Jhih-Syuan Liu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Peng-Fei Li
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
- Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei City, Taiwan, ROC
| | - Chia-Luen Huang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Kuan-Chan Chen
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Li-Ju Ho
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chih-Chun Kuo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chun-Yung Chang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Ming-Shiun Lin
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Yi-Chen Liu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Nain-Feng Chu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chien-Hsing Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Yi-Jen Hung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Po-Shiuan Hsieh
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
- Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Fu-Huang Lin
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chang-Hsun Hsieh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Wu-Chien Chien
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, ROC
- Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan, ROC
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Du W, Nair P, Johnston A, Wu PH, Wirtz D. Cell Trafficking at the Intersection of the Tumor-Immune Compartments. Annu Rev Biomed Eng 2022; 24:275-305. [PMID: 35385679 PMCID: PMC9811395 DOI: 10.1146/annurev-bioeng-110320-110749] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Migration is an essential cellular process that regulates human organ development and homeostasis as well as disease initiation and progression. In cancer, immune and tumor cell migration is strongly associated with immune cell infiltration, immune escape, and tumor cell metastasis, which ultimately account for more than 90% of cancer deaths. The biophysics and molecular regulation of the migration of cancer and immune cells have been extensively studied separately. However, accumulating evidence indicates that, in the tumor microenvironment, the motilities of immune and cancer cells are highly interdependent via secreted factors such as cytokines and chemokines. Tumor and immune cells constantly express these soluble factors, which produce a tightly intertwined regulatory network for these cells' respective migration. A mechanistic understanding of the reciprocal regulation of soluble factor-mediated cell migration can provide critical information for the development of new biomarkers of tumor progression and of tumor response to immuno-oncological treatments. We review the biophysical andbiomolecular basis for the migration of immune and tumor cells and their associated reciprocal regulatory network. We also describe ongoing attempts to translate this knowledge into the clinic.
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Affiliation(s)
- Wenxuan Du
- Institute for NanoBiotechnology Department of Chemical and Biomolecular Engineering, and Johns Hopkins Physical Sciences Oncology Center, Johns Hopkins University, Baltimore, Maryland, USA
| | - Praful Nair
- Institute for NanoBiotechnology Department of Chemical and Biomolecular Engineering, and Johns Hopkins Physical Sciences Oncology Center, Johns Hopkins University, Baltimore, Maryland, USA
| | - Adrian Johnston
- Institute for NanoBiotechnology Department of Chemical and Biomolecular Engineering, and Johns Hopkins Physical Sciences Oncology Center, Johns Hopkins University, Baltimore, Maryland, USA
| | - Pei-Hsun Wu
- Institute for NanoBiotechnology Department of Chemical and Biomolecular Engineering, and Johns Hopkins Physical Sciences Oncology Center, Johns Hopkins University, Baltimore, Maryland, USA
| | - Denis Wirtz
- Institute for NanoBiotechnology Department of Chemical and Biomolecular Engineering, and Johns Hopkins Physical Sciences Oncology Center, Johns Hopkins University, Baltimore, Maryland, USA,Department of Oncology, Department of Pathology, and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Khan A, Khan I, Halim SA, Rehman NU, Karim N, Ahmad W, Khan M, Csuk R, Al-Harrasi A. Anti-diabetic potential of β-boswellic acid and 11-keto-β-boswellic acid: Mechanistic insights from computational and biochemical approaches. Pharmacotherapy 2022; 147:112669. [PMID: 35121344 DOI: 10.1016/j.biopha.2022.112669] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 01/20/2022] [Accepted: 01/24/2022] [Indexed: 12/27/2022]
Abstract
β-Boswellic acid (β-BA) and 11-keto-β-boswellic acid (β-KBA) are crucial bioactive compounds, mostly isolated from frankincense. These compounds are known for their potent anticancer and anti-inflammatory activities. Herein, we have explored the complete anti-diabetic potential of β-BA and β-KBA with detailed parameters. This research revealed that treatment with β-BA and β-KBA at a dose of 1, 2, and 10 mg/kg body weight for 21 days significantly improved body weight loss, water consumption, and specifically the concentration of blood glucose level (BGL) in diabetic animals, which indicated that the β-BA and β-KBA possess strong anti-diabetic activities. Serum total superoxide dismutase (SOD) and malondialdehyde (MDA) assays were also performed to evaluate the antioxidant effects. The biochemical analysis revealed that these compounds improve an abnormal level of several biochemical parameters like serum lipid values including total cholesterol (TC), triacylglycerol (TG), low-density lipoprotein cholesterol (LDL-C) to a normal level and the high-density lipoprotein cholesterol level (HDL-C). To understand the mechanism of action of β-BA and β-KBA, their most probable biological targets were searched through the inverse docking approach. Our computational analysis reflects that among other probable targets, the Dipeptidyl peptidase 4 (DPP-4) enzyme could be one of the possible binders of β-BA and β-KBA to produce their anti-diabetic activities. These in-silico results were validated by an in-vitro experiment. It indicates that the anti-diabetic effects of β-BA and β-KBA are produced by the inhibition of DDP-4. Thus, these anti-diabetic, antioxidant, and anti-hyperlipidemic effects of β-BA and β-KBA suggest these compounds as potential therapeutics for diabetic conditions.
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Affiliation(s)
- Ajmal Khan
- Natural and Medical Sciences Research Center, University of Nizwa, P.O Box 33, Postal Code 616, Birkat Al Mauz, Nizwa, Sultanate of Oman
| | - Imran Khan
- Department of Pharmacy, University of Swabi, KPK, Pakistan
| | - Sobia Ahsan Halim
- Natural and Medical Sciences Research Center, University of Nizwa, P.O Box 33, Postal Code 616, Birkat Al Mauz, Nizwa, Sultanate of Oman
| | - Najeeb Ur Rehman
- Natural and Medical Sciences Research Center, University of Nizwa, P.O Box 33, Postal Code 616, Birkat Al Mauz, Nizwa, Sultanate of Oman
| | - Nasiara Karim
- Department of Pharmacy, University of Malakand, Chakdara 18800, KPK, Pakistan
| | - Waqar Ahmad
- Department of Pharmacy, University of Malakand, Chakdara 18800, KPK, Pakistan
| | - Majid Khan
- Natural and Medical Sciences Research Center, University of Nizwa, P.O Box 33, Postal Code 616, Birkat Al Mauz, Nizwa, Sultanate of Oman; H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
| | - Rene Csuk
- Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Center, University of Nizwa, P.O Box 33, Postal Code 616, Birkat Al Mauz, Nizwa, Sultanate of Oman.
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Preoperative optimization of diabetes. Int Anesthesiol Clin 2022; 60:8-15. [PMID: 34897217 DOI: 10.1097/aia.0000000000000351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Daza-Arnedo R, Rico-Fontalvo JE, Pájaro-Galvis N, Leal-Martínez V, Abuabara-Franco E, Raad-Sarabia M, Montejo-Hernández J, Cardona-Blanco M, Cabrales-Juan J, Uparella-Gulfo I, Montiel LS. Dipeptidyl Peptidase-4 Inhibitors and Diabetic Kidney Disease: A Narrative Review. Kidney Med 2021; 3:1065-1073. [PMID: 34939016 PMCID: PMC8664739 DOI: 10.1016/j.xkme.2021.07.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Diabetic kidney disease is one of the most frequent complications in patients with diabetes mellitus and affects morbidity and mortality. The recent therapies include oral hypoglycemic drugs that, in addition to optimizing glycemic control and reducing the risk of hypoglycemia, may affect the development and progression of diabetic kidney disease; these novel therapies include inhibitors of the enzyme dipeptidyl peptidase 4 (DPP-4), a group of oral hypoglycemic therapeutic agents that act at the level of the incretin system. DPP-4 inhibitors show additional pleiotropic effects in in vitro models, reducing inflammation, fibrosis, and oxidative damage, further suggesting potential kidney protective effects. Although existing trials suggest a possible benefit in the progression of diabetic kidney disease, further studies are needed to demonstrate kidney-specific benefits of DPP-4 inhibitors.
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Affiliation(s)
- Rodrigo Daza-Arnedo
- Nuevo Hospital Bocagrande, Comité de Nefrodiabetes, Asociación Colombiana de Nefrología, Cartagena, Colombia
| | | | | | | | | | - María Raad-Sarabia
- Departamento de Medicina Interna, Universidad del Sinú, Cartagena, Colombia
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Wang L, Wang E, Prado Balcazar J, Wu Z, Xiang K, Wang Y, Huang Q, Negrete M, Chen K, Li W, Fu Y, Dohlman A, Mines R, Zhang L, Kobayashi Y, Chen T, Shi G, Shen JP, Kopetz S, Tata PR, Moreno V, Gersbach C, Crawford G, Hsu D, Huang E, Bu P, Shen X. Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2004673. [PMID: 34378358 PMCID: PMC8498885 DOI: 10.1002/advs.202004673] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 06/09/2021] [Indexed: 06/13/2023]
Abstract
Colorectal cancer (CRC) metastasizes mainly to the liver, which accounts for the majority of CRC-related deaths. Here it is shown that metastatic cells undergo specific chromatin remodeling in the liver. Hepatic growth factor (HGF) induces phosphorylation of PU.1, a pioneer factor, which in turn binds and opens chromatin regions of downstream effector genes. PU.1 increases histone acetylation at the DPP4 locus. Precise epigenetic silencing by CRISPR/dCas9KRAB or CRISPR/dCas9HDAC revealed that individual PU.1-remodeled regulatory elements collectively modulate DPP4 expression and liver metastasis growth. Genetic silencing or pharmacological inhibition of each factor along this chromatin remodeling axis strongly suppressed liver metastasis. Therefore, microenvironment-induced epimutation is an important mechanism for metastatic tumor cells to grow in their new niche. This study presents a potential strategy to target chromatin remodeling in metastatic cancer and the promise of repurposing drugs to treat metastasis.
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Affiliation(s)
- Lihua Wang
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Ergang Wang
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | | | - Zhenzhen Wu
- Key Laboratory of RNA BiologyKey Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
- University of Chinese Academy of SciencesBeijing100049China
| | - Kun Xiang
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Yi Wang
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Qiang Huang
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Marcos Negrete
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Kai‐Yuan Chen
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Wei Li
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Yujie Fu
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Anders Dohlman
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Robert Mines
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Liwen Zhang
- Key Laboratory of RNA BiologyKey Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
- University of Chinese Academy of SciencesBeijing100049China
| | - Yoshihiko Kobayashi
- Department of Cell BiologyRegeneration NextDuke University School of MedicineDurhamNC27710USA
| | - Tianyi Chen
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Guizhi Shi
- Laboratory Animal Research CenterInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
| | - John Paul Shen
- Department of Gastrointestinal Medical OncologyMD AndersonDurhamNC77030USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical OncologyMD AndersonDurhamNC77030USA
| | - Purushothama Rao Tata
- Department of Cell BiologyRegeneration NextDuke University School of MedicineDurhamNC27710USA
| | - Victor Moreno
- Department of Clinical SciencesUniversity of BarcelonaBarcelona08193Spain
- Prevention and Control ProgramCatalan Institute of Oncology‐IDIBELLCIBERESPBarcelonaE08907Spain
| | - Charles Gersbach
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Gregory Crawford
- Department of PediatricsDuke University School of MedicineDurhamNC27710USA
| | - David Hsu
- Department of MedicineDuke University School of MedicineDurhamNC27710USA
| | - Emina Huang
- Department of Cancer Biology and Colorectal SurgeryLerner Research Institute, Cleveland ClinicClevelandOH44195USA
| | - Pengcheng Bu
- Key Laboratory of RNA BiologyKey Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
- University of Chinese Academy of SciencesBeijing100049China
- Center for Excellence in BiomacromoleculesChinese Academy of SciencesBeijing100101China
| | - Xiling Shen
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
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Tan X, Yang L, Khunti K, Zhang R, Zhang Y, Rajpathak S, Yu M. Factors associated with switching from sulphonylureas to dipeptidyl peptidase 4 inhibitors among patients with type 2 diabetes in the United States. Diabetes Obes Metab 2021; 23:2251-2260. [PMID: 34132017 DOI: 10.1111/dom.14466] [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: 03/10/2021] [Revised: 05/18/2021] [Accepted: 05/30/2021] [Indexed: 12/01/2022]
Abstract
AIMS Studies examining the prevalence of and factors associated with switching from sulphonylureas (SUs) to dipeptidyl peptidase 4 (DPP-4) inhibitors in real-world settings are lacking. We assessed the factors associated with switching from SUs to DPP-4 inhibitors in the United States. MATERIALS AND METHODS This retrospective cohort study was conducted using the Optum Clinformatics® Data Mart (2009-2018). Adults with type 2 diabetes and newly prescribed at least two SUs were included and were followed for 2 years after the initiation of SU (index date). We compared the characteristics of those who switched from SUs to DPP-4 inhibitors (only; no additional antidiabetic drugs) with those who continued with SUs (without adding other antidiabetic drugs) using multivariate logistic regression. Multinomial regression analyses were also conducted to assess the factors associated with switching to different drug classes versus continuation with SUs. RESULTS In a sample of 119 107 new SU users, 2.2% (2633) switched to DPP-4 inhibitors, 3.8% (4542) switched to antidiabetic drugs other than DPP-4 inhibitors, 68.3% (81 394) discontinued SUs but did not switch to another antidiabetic drug, 12.9% (15 345) continued with SUs and added other antidiabetic drugs, and 12.8% (15 193) continued with SUs only. Multivariate logistic regression showed that those who had significantly higher likelihood of switching were younger, female [vs. males; adjusted odds ratio (AOR) = 0.70], and living in the south; had previous use of DPP-4 inhibitors (AOR = 1.71); were not using antidiabetic drugs at baseline; had more baseline diabetes-related emergency room visits (AOR = 1.13), depression (AOR = 1.34), post-index hypoglycaemia (AOR = 2.20), and an earlier index year; and were glyburide users (vs. glimepiride users; AOR = 1.29). CONCLUSIONS The discontinuation rate for SUs is high. Factors associated with switching from SUs to DPP-4 inhibitors included age, sex, geographic region, baseline antidiabetic drug use, type of SU, baseline diabetes-related emergency room visits, hypoglycaemia and depression.
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Affiliation(s)
- Xi Tan
- Merck & Co., Inc., Kenilworth, New Jersey, USA
| | | | - Kamlesh Khunti
- Diabetes Research Centre, University of Leicester, Leicester, UK
| | - Ruya Zhang
- MSD China Holding Company, Shanghai, China
| | - Ye Zhang
- MSD China Holding Company, 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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Sitagliptin attenuates arterial calcification by downregulating oxidative stress-induced receptor for advanced glycation end products in LDLR knockout mice. Sci Rep 2021; 11:17851. [PMID: 34497344 PMCID: PMC8426400 DOI: 10.1038/s41598-021-97361-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 08/24/2021] [Indexed: 12/25/2022] Open
Abstract
Diabetes is a complex disease characterized by hyperglycemia, dyslipidemia, and insulin resistance. Plasma advanced glycation end products (AGEs) activated the receptor for advanced glycation end products (RAGE) and the activation of RAGE is implicated to be the pathogenesis of type 2 diabetic mellitus (T2DM) patient vascular complications. Sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, is a new oral hypoglycemic agent for the treatment of T2DM. However, the beneficial effects on vascular calcification remain unclear. In this study, we used a high-fat diet (HFD)-fed low-density lipoprotein receptor deficiency (LDLR−/−) mice model to investigate the potential effects of sitagliptin on HFD-induced arterial calcification. Mice were randomly divided into 3 groups: (1) normal diet group, (2) HFD group and (3) HFD + sitagliptin group. After 24 weeks treatment, we collected the blood for chemistry parameters and DPP4 activity measurement, and harvested the aorta to evaluate calcification using immunohistochemistry and calcium content. To determine the effects of sitagliptin, tumor necrosis factor (TNF)-α combined with S100A12 was used to induce oxidative stress, activation of nicotinamide adenine dinucleotide phosphate (NADPH), up-regulation of bone markers and RAGE expression, and cell calcium deposition on human aortic smooth muscle cells (HASMCs). We found that sitagliptin effectively blunted the HFD-induced artery calcification and significantly lowered the levels of fasting serum glucose, triglyceride (TG), nitrotyrosine and TNF-α, decreased the calcium deposits, and reduced arterial calcification. In an in-vitro study, both S100A12 and TNF-α stimulated RAGE expression and cellular calcium deposits in HASMCs. The potency of S100A12 on HASMCs was amplified by the presence of TNF-α. Sitagliptin and Apocynin (APO), an NADPH oxidase inhibitor, inhibited the TNF-α + S100A12-induced NADPH oxidase and nuclear factor (NF)-κB activation, cellular oxidative stress, RAGE expression, osteo transcription factors expression and calcium deposition. In addition, treatment with sitagliptin, knockdown of RAGE or TNF-α receptor blunted the TNF-α + S100A12-induced RAGE expression. Our findings suggest that sitagliptin may suppress the initiation and progression of arterial calcification by inhibiting the activation of NADPH oxidase and NF-κB, followed by decreasing the expression of RAGE.
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Lee SE, Kim KA, Son KJ, Song SO, Park KH, Park SH, Nam JY. Trends and risk factors in severe hypoglycemia among individuals with type 2 diabetes in Korea. Diabetes Res Clin Pract 2021; 178:108946. [PMID: 34252506 DOI: 10.1016/j.diabres.2021.108946] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 07/02/2021] [Accepted: 07/06/2021] [Indexed: 11/24/2022]
Abstract
AIMS Because of the development of new classes of antidiabetic drugs, hypoglycemic events were expected to decrease. We investigated the trends and risk factors for severe hypoglycemia in subjects with type 2 diabetes in Korea. METHODS We conducted repeated cross-sectional analyses using a Korean National Health Insurance Service-National Sample Cohort from 2006 to 2015. Severe hypoglycemia was defined as hospitalization or a visit to an emergency department with diagnosis of hypoglycemia using ICD-10 codes. RESULTS During the study period, the prevalence of type 2 diabetes continuously increased. The percentage of patients prescribed metformin and dipeptidyl peptidase-4 inhibitor increased, while the use of sulfonylurea decreased considerably, especially since 2009. The proportion of patients prescribed ≥3 classes of drugs continually increased. Age-standardized incidence of severe hypoglycemia per 1000 patients with diabetes increased from 6.00 to 8.24 between 2006 and 2010, and then fell to 6.49 in 2015. Predictors of severe hypoglycemia included female, older age, comorbidities, polypharmacy, and sulfonylurea or insulin usage. CONCLUSIONS Trends of severe hypoglycemia were associated with changes in drug classes rather than number of antidiabetic drugs. Relentless efforts to reduce the prescription of drugs with a high risk of hypoglycemia should be implemented, particularly for older women with multiple comorbidities.
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Affiliation(s)
- Seung Eun Lee
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Republic of Korea.
| | - Kyoung-Ah Kim
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Republic of Korea.
| | - Kang Ju Son
- Department of Research and Analysis, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea; Department of Biostatistics and Computing, Yonsei University Graduate School, Seoul, Republic of Korea.
| | - Sun Ok Song
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea.
| | - Kyeong Hye Park
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea.
| | - Se Hee Park
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea.
| | - Joo Young Nam
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea.
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Kitazawa M, Katagiri T, Suzuki H, Matsunaga S, H Yamada M, Ikarashi T, Yamamoto M, Furukawa K, Iwanaga M, Hatta M, Fujihara K, Yamada T, Tanaka S, Sone H. A 52-week randomized controlled trial of ipragliflozin or sitagliptin in type 2 diabetes combined with metformin: The N-ISM study. Diabetes Obes Metab 2021; 23:811-821. [PMID: 33416200 PMCID: PMC7898334 DOI: 10.1111/dom.14288] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 11/27/2020] [Accepted: 12/03/2020] [Indexed: 12/14/2022]
Abstract
AIM To compare the long-term efficacy of sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors as second-line drugs after metformin for patients not at high risk of atherosclerotic cardiovascular disease (ASCVD). MATERIALS AND METHODS In a 52-week randomized open-label trial, we compared ipragliflozin and sitagliptin in Japanese patients diagnosed with type 2 diabetes, without prior ASCVD and treated with metformin. The primary endpoint was a glycated haemoglobin (HbA1c) reduction of ≥0.5% (5.5 mmol/mol) without weight gain at 52 weeks. RESULTS Of a total of 111 patients (mean age 59.2 years, mean body mass index [BMI] 26.6 kg/m2 , 61.3% men), 54 patients received ipragliflozin and 57 received sitagliptin. After 52 weeks, achievement of the primary endpoint was not significantly different (37.0% and 40.3%; P = 0.72). HbA1c reduction rate at 24 weeks was greater for sitagliptin (56.1%) than for ipragliflozin (31.5%; P = 0.01). From 24 to 52 weeks, the HbA1c reduction with sitagliptin was attenuated, with no significant difference in HbA1c reduction after 52 weeks between sitagliptin (54.4%) and ipragliflozin (38.9%; P = 0.10). Improvements in BMI, C-peptide and high-density lipoprotein cholesterol were greater with ipragliflozin than with sitagliptin. Adverse events occurred in 17 patients with ipragliflozin and in 10 patients with sitagliptin (P = 0.11). CONCLUSION The HbA1c-lowering effect at 24 weeks was greater with sitagliptin than with ipragliflozin, but with no difference in efficacy related to HbA1c and body weight at 52 weeks. However, some ASCVD risk factors improved with ipragliflozin.
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Affiliation(s)
- Masaru Kitazawa
- Department of Internal MedicineNiigata University Faculty of MedicineNiigataJapan
| | | | | | | | - Mayuko H Yamada
- Department of Internal MedicineNiigata University Faculty of MedicineNiigataJapan
| | | | - Masahiko Yamamoto
- Department of Internal MedicineNiigata University Faculty of MedicineNiigataJapan
| | | | - Midori Iwanaga
- Department of Internal MedicineNiigata University Faculty of MedicineNiigataJapan
| | - Mariko Hatta
- Department of Internal MedicineNiigata University Faculty of MedicineNiigataJapan
| | - Kazuya Fujihara
- Department of Internal MedicineNiigata University Faculty of MedicineNiigataJapan
| | - Takaho Yamada
- Department of Internal MedicineNiigata University Faculty of MedicineNiigataJapan
| | - Shiro Tanaka
- Department of Clinical Biostatistics/Clinical Biostatistics CourseGraduate School of Medicine Kyoto UniversityKyotoJapan
| | - Hirohito Sone
- Department of Internal MedicineNiigata University Faculty of MedicineNiigataJapan
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Katsuno T, Shiraiwa T, Iwasaki S, Park H, Watanabe N, Kaneko S, Terasaki J, Hanafusa T, Imagawa A, Shimomura I, Ikegami H, Koyama H, Namba M, Miyagawa JI. Benefit of Early Add-on of Linagliptin to Insulin in Japanese Patients With Type 2 Diabetes Mellitus: Randomized-Controlled Open-Label Trial (TRUST2). Adv Ther 2021; 38:1514-1535. [PMID: 33507500 DOI: 10.1007/s12325-021-01631-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 01/15/2021] [Indexed: 12/22/2022]
Abstract
INTRODUCTION This trial was conducted to assess the long-term safety, efficacy, and benefit of early add-on of linagliptin to insulin in patients with type 2 diabetes mellitus (T2DM). METHODS This trial enrolled 246 subjects. The subjects were randomized to the linagliptin group or the control group and were observed for 156 weeks. After week 16, subjects in the control group were also allowed to add linagliptin to evaluate the benefit of early add-on of linagliptin to insulin. The primary end point was a change in HbA1c from baseline to week 16. Secondary end points included fasting plasma glucose, daily insulin dose, and frequency of adverse events. RESULTS HbA1c and fasting plasma glucose levels significantly decreased from baseline to week 16 in the linagliptin group compared with the control group. The significant improvement in HbA1c continued until week 52. The daily insulin dose significantly decreased in the linagliptin group compared with the control group. The frequency of hypoglycemia and adverse events was comparable in both groups. CONCLUSIONS Add-on of linagliptin to insulin was tolerated, improved glycemic control, and reduced the daily insulin dose. This study demonstrates the long-term safety, efficacy and benefit of early add-on of linagliptin to insulin in Japanese T2DM patients.
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Affiliation(s)
- Tomoyuki Katsuno
- Division of Diabetes, Endocrinology and Clinical Immunology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan.
- Department of Occupational Therapy, School of Rehabilitation, Hyogo University of Health Sciences, Hyogo, Japan.
| | | | | | | | | | | | - Jungo Terasaki
- Department of Internal Medicine (I), Osaka Medical College, Takatsuki, Osaka, Japan
| | | | - Akihisa Imagawa
- Department of Internal Medicine (I), Osaka Medical College, Takatsuki, Osaka, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hiroshi Ikegami
- Department of Endocrinology, Metabolism and Diabetes, Kindai University, Osaka, Japan
| | - Hidenori Koyama
- Division of Diabetes, Endocrinology and Clinical Immunology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Mitsuyoshi Namba
- Division of Diabetes, Endocrinology and Clinical Immunology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
- Takarazuka City Hospital, Hyogo, Japan
| | - Jun-Ichiro Miyagawa
- Division of Diabetes, Endocrinology and Clinical Immunology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
- Keiseikai Medical Corporation, Osaka, Japan
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Yang F, Dang S, Lv H, Shi B. Combined treatment with a gastric inhibitory polypeptide receptor antagonist and a peptidyl peptidase-4 inhibitor improves metabolic abnormalities in diabetic mice. J Int Med Res 2021; 49:300060520985664. [PMID: 33512261 PMCID: PMC7871083 DOI: 10.1177/0300060520985664] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Objectives Dipeptidyl peptidase-4 inhibition and gastric inhibitory polypeptide (GIP) receptor antagonism have therapeutic effects in type 2 diabetes mellitus. We assessed the effects of sitagliptin and Pro3(GIP) in a mouse model of diabetes. Methods Diabetes was induced in C57BL/6J mice by a high-fat diet and intraperitoneal injection of streptozocin. Blood glucose was assessed weekly. Six weeks later, serum triglycerides, total cholesterol and glucose tolerance were assessed and pancreatic and adipose tissues were collected. Results Combination therapy with sitagliptin and Pro3(GIP) resulted in significantly greater reductions of blood glucose and triglycerides than either monotherapy. Combination therapy also improved insulin sensitivity and glucose tolerance. β-cell mass and insulin-positive cell percentage in the pancreas was higher in mice receiving combination therapy compared with either monotherapy. Crown-like structures, inflammatory markers in adipose tissue, and serum leptin concentrations were decreased in mice receiving combination therapy compared with either monotherapy. Conclusions Combination therapy with Pro3(GIP) and sitagliptin improved metabolic abnormalities in diabetic mice. Changes in serum leptins and reduced inflammatory cell infiltration in adipose tissue might account for the observed effects.
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Affiliation(s)
- Fei Yang
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Medical University, Xi'an Shaanxi Province, China
| | - Shan Dang
- Department of Gastroenterology, Shaanxi Provincial Peoplès Hospital, Xi'an Shaanxi Province, China
| | - Hongjun Lv
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi Province, China
| | - Bingyin Shi
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi Province, China
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Ishii H, Nakajima H, Kamei N, Niiya T, Hiyoshi T, Hiramori Y, Ohtsu S, Noto T, Shimono D. Quality-of-Life Comparison of Dapagliflozin Versus Dipeptidyl Peptidase 4 Inhibitors in Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Trial (J-BOND Study). Diabetes Ther 2020; 11:2959-2977. [PMID: 33057967 PMCID: PMC7644655 DOI: 10.1007/s13300-020-00941-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 10/03/2020] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION No study has compared the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase 4 inhibitors (DPP4is) on patients' quality-of-life (QOL). METHODS We enrolled 253 drug-naïve Japanese patients with type 2 diabetes mellitus (T2DM), randomly assigned them into a dapagliflozin (SGLT2i) group or DPP4i group in approximately 1:1 ratio, and monitored them for 24 weeks. The primary endpoint was the proportion of subjects indicating improvement in the "overall quality of life" domain of SHIELD-WQ-9 at week 24. Secondary endpoints included other domains of SHIELD-WQ-9, DTR-QOL, EQ-5D-5L, medication preference, medication adherence, diet therapy adherence, body weight, body mass index (BMI), abdominal circumference, HbA1c, and frequency of adverse events. RESULTS The proportion of subjects indicating improvement in the "overall quality of life" domain of SHIELD-WQ-9 at week 24 was higher in the dapagliflozin group (28.4%) than in the DPP4i group (18.6%) (p = 0.08). The proportion of subjects indicating improvement in the "physical health" domain of SHIELD-WQ-9 at week 24 was significantly higher in the dapagliflozin group (42.2%) than in the DPP4i group (23.7%) (p = 0.004). Total scores and domain 1 scores of DTR-QOL showed greater improvement in the dapagliflozin group (14.3 ± 15.6 and 15.5 ± 20.8, respectively) than in the DPP4i group (10.2 ± 15.6 and 10.3 ± 19.5, respectively) (both p = 0.05). EQ-5D-5L scores had significantly improved in the DPP4i group (0.023 ± 0.088) (p = 0.005); the intergroup difference was not significant (p = 0.14). Body weight (p < 0.001), BMI (p < 0.001), and abdominal circumference (p = 0.019) had significantly decreased in the dapagliflozin group compared with the corresponding values in the DPP4i group. CONCLUSION Dapagliflozin showed a comparable or more favorable benefit on Japanese patients' QOL compared with DPP4is. Dapagliflozin was well tolerated. It significantly reduced body weight, which was significantly correlated with improvement in the patients' QOL. This study demonstrates that dapagliflozin can be used as a first-line drug for T2DM in Japan with a beneficial impact on patients' QOL. TRIAL REGISTRATION University Hospital Medical Information Network Clinical Trial Registry (UMIN000030514); Japan Registry of Clinical Trials (jRCTs051180165).
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Affiliation(s)
- Hitoshi Ishii
- Department of Doctor-Patient Relationships, Nara Medical University, Kashihara, Nara, Japan.
| | - Hiroki Nakajima
- Department of Diabetes and Endocrinology, Nara Medical University, Kashihara, Nara, Japan
| | - Nozomu Kamei
- Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima, Hiroshima, Japan
| | | | - Toru Hiyoshi
- Division of Diabetes and Endocrinology, Japanese Red Cross Medical Center, Shibuya-ku, Tokyo, Japan
| | | | | | - Takashi Noto
- Nishiyamato Diabetes Clinic, Kita-Katsuragi-gun, Nara, Japan
| | - Dai Shimono
- Futata Tetsuhiro Clinic, Fukuoka, Fukuoka, Japan
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Nong NTP, Chen YK, Shih WL, Hsu JL. Characterization of Novel Dipeptidyl Peptidase-IV Inhibitory Peptides from Soft-Shelled Turtle Yolk Hydrolysate Using Orthogonal Bioassay-Guided Fractionations Coupled with In Vitro and In Silico Study. Pharmaceuticals (Basel) 2020; 13:ph13100308. [PMID: 33066488 PMCID: PMC7602288 DOI: 10.3390/ph13100308] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 09/30/2020] [Accepted: 10/13/2020] [Indexed: 02/07/2023] Open
Abstract
Five novel peptides (LPLF, WLQL, LPSW, VPGLAL, and LVGLPL) bearing dipeptidyl peptidase IV (DPP-IV) inhibitory activities were identified from the gastrointestinal enzymatic hydrolysate of soft-shelled turtle yolk (SSTY) proteins. Peptides were isolated separately using reversed-phase (RP) chromatography in parallel with off-line strong cation exchange (SCX) chromatography followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to determine sequences. Among these peptides, LPSW showed the highest DPP-IV inhibitory activity with an IC50 value of 269.7 ± 15.91 µM. The results of the pre-incubation experiment and the kinetic study of these peptides indicated that WLQL is a true inhibitor and its inhibition toward DPP-IV is of an uncompetitive model, while LPLF, LPSW, and VPGLAL are real-substrates and competitive inhibitors against DPP-IV. The DPP-IV inhibitory peptides derived from SSTY hydrolysate in study are promising in the management of hyperglycemia in Type 2 diabetes.
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Affiliation(s)
- Nhung Thi Phuong Nong
- Department of Tropical Agriculture and International Cooperation, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan;
- Department of Basic Science, Thainguyen University of Agriculture and Forestry, Quyetthang Ward, Thai Nguyen 250000, Vietnam
| | - Yu-Kuo Chen
- Department of Food Science, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan;
| | - Wen-Ling Shih
- Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan;
| | - Jue-Liang Hsu
- Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan;
- International Master’s Degree Program in Food Science, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Research Center for Animal Biologics, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Correspondence: ; Tel.: +886-8-7703202 (ext. 5197); Fax: +886-8-7740550
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Huang J, Jia Y, Sun S, Meng L. Adverse event profiles of dipeptidyl peptidase-4 inhibitors: data mining of the public version of the FDA adverse event reporting system. BMC Pharmacol Toxicol 2020; 21:68. [PMID: 32938499 PMCID: PMC7493367 DOI: 10.1186/s40360-020-00447-w] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Accepted: 09/07/2020] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND To describe and analyze the patterns of adverse events associated with dipeptidyl peptidase-4 inhibitors (DPP-4is) (sitagliptin, saxagliptin, linagliptin, vildagliptin, and alogliptin) from the FDA Adverse Event Reporting System (FAERS) and to highlight areas of safety concerns. METHODS Adverse events spontaneously submitted to the FAERS between 2004 Q1 to 2019 Q2 were included. The online tool OpenVigil 2.1 was used to query the database. The research relied on definitions of preferred terms (PTs) specified by the Medical Dictionary for Regulatory Activities (MedDRA) and the standardized MedDRA Queries (SMQ). The reporting odds ratio (ROR), with 95% confidence intervals (CIs) was calculated for disproportionality analysis. RESULTS Over 16 years, a total of 9706 adverse event reports were identified. Alogliptin was excluded from further analysis due to insufficient sample size. Compared with the non-insulin antidiabetic drugs, the four DPP-4is were all disproportionately associated with four SMQs: "gastrointestinal nonspecific inflammation and dysfunctional conditions," "hypersensitivity," "severe cutaneous adverse reactions," and "noninfectious diarrhoea". As for PT level analyses, DPP-4is are associated with higher reporting of the gastrointestinal tract, pancreas, malignancies, infection, musculoskeletal disorders, general disorders, hypersensitivity, and skin AEs. CONCLUSIONS Data mining of the FAERS is useful for examining DPP-4 inhibitors-associated adverse events. The findings of the present study are compatible with clinical experience, and it provides valuable information to decision-makers and healthcare providers in clinical practice.
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Affiliation(s)
- Jing Huang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yuntao Jia
- Department of Pharmacy, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Shusen Sun
- Department of Pharmacy Practice, College of Pharmacy and Health Sciences, Western New England University, 1215 Wilbraham Road, Springfield, USA.,Department of Pharmacy, Xiangya Hospital Central South University, Changsha, Hunan, China.,Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Long Meng
- Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Stoian AP, Sachinidis A, Stoica RA, Nikolic D, Patti AM, Rizvi AA. The efficacy and safety of dipeptidyl peptidase-4 inhibitors compared to other oral glucose-lowering medications in the treatment of type 2 diabetes. Metabolism 2020; 109:154295. [PMID: 32553739 DOI: 10.1016/j.metabol.2020.154295] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 06/07/2020] [Accepted: 06/11/2020] [Indexed: 12/16/2022]
Abstract
INTRODUCTION The dipeptidyl peptidase-4 inhibitors (DPP-4is), which belong to the class of incretin-based medications, are recommended as second or third-line therapies in guidelines for the management of type 2 diabetes mellitus. They have a favorable drug tolerability and safety profile compared to other glucose-lowering agents. OBJECTIVE This review discusses data concerning the use of DPP-4is and their cardiovascular profile, and gives an updated comparison with the other oral glucose-lowering medications with regards to safety and efficacy. Currently available original studies, abstracts, reviews articles, systematic reviews and meta-analyses were included in the review. DISCUSSION DPP4is are moderately efficient in decreasing the HbA1c by an average of 0.5% as monotherapy, and 1.0% in combination therapy with other drugs. They have a good tolerability and safety profile compared to other glucose-lowering drugs. However, there are possible risks pertaining to acute pancreatitis and pancreatic cancer. CONCLUSION Cardiovascular outcome trials thus far have proven the cardiovascular safety for ischemic events in patients treated with sitagliptin, saxagliptin, alogliptin, linagliptin and vildagliptin. Data showing increased rate of hospitalisation in the case of saxagliptin did not seem to be a class effect.
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Affiliation(s)
- Anca Pantea Stoian
- Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Alexandros Sachinidis
- PROMISE Department, School of Medicine, University of Palermo, Palermo, Italy; 2nd Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Roxana Adriana Stoica
- Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Dragana Nikolic
- PROMISE Department, School of Medicine, University of Palermo, Palermo, Italy
| | - Angelo Maria Patti
- PROMISE Department, School of Medicine, University of Palermo, Palermo, Italy
| | - Ali A Rizvi
- Division of Endocrinology, Metabolism, and Lipids, Emory University School of Medicine, Atlanta, GA, USA.
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Zhang C, Ye F, Wang J, He P, Lei M, Huang L, Huang A, Tang P, Lin H, Liao Y, Liang Y, Ni J, Yan P. Design, Synthesis, and Evaluation of a Series of Novel Super Long-Acting DPP-4 Inhibitors for the Treatment of Type 2 Diabetes. J Med Chem 2020; 63:7108-7126. [PMID: 32452679 DOI: 10.1021/acs.jmedchem.0c00374] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In the present work, a novel series of trifluoromethyl-substituted tetrahydropyran derivatives were rationally designed and synthesized as potent DPP-4 inhibitors with significantly improved duration time of action over current commercially available DPP-4 inhibitors. The incorporation of the trifluoromethyl group on the 6-position of the tetrahydropyran ring of omarigliptin with the configuration of (2R,3S,5R,6S) not only significantly improves the overall pharmacokinetic profiles in mice but also maintains comparable DPP-4 inhibition activities. Further preclinical development of compound 2 exhibited its extraordinary efficacy in vivo and good safety profile. Clinical studies of compound 2 (Haisco HSK7653) are now ongoing in China, which revealed that inhibitor 2 could serve as an efficient candidate with a once-biweekly therapeutic regimen.
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Affiliation(s)
- Chen Zhang
- Haisco Pharmaceutical Group Company Ltd., 136 Baili Road, Wenjiang district, Chengdu 611130, China
| | - Fei Ye
- Haisco Pharmaceutical Group Company Ltd., 136 Baili Road, Wenjiang district, Chengdu 611130, China
| | - Jianmin Wang
- Haisco Pharmaceutical Group Company Ltd., 136 Baili Road, Wenjiang district, Chengdu 611130, China
| | - Ping He
- Haisco Pharmaceutical Group Company Ltd., 136 Baili Road, Wenjiang district, Chengdu 611130, China
| | - Ming Lei
- Haisco Pharmaceutical Group Company Ltd., 136 Baili Road, Wenjiang district, Chengdu 611130, China
| | - Longbin Huang
- Haisco Pharmaceutical Group Company Ltd., 136 Baili Road, Wenjiang district, Chengdu 611130, China
| | - Anbang Huang
- Haisco Pharmaceutical Group Company Ltd., 136 Baili Road, Wenjiang district, Chengdu 611130, China
| | - Pingming Tang
- Haisco Pharmaceutical Group Company Ltd., 136 Baili Road, Wenjiang district, Chengdu 611130, China
| | - Hongjun Lin
- Haisco Pharmaceutical Group Company Ltd., 136 Baili Road, Wenjiang district, Chengdu 611130, China
| | - Yuting Liao
- Haisco Pharmaceutical Group Company Ltd., 136 Baili Road, Wenjiang district, Chengdu 611130, China
| | - Yong Liang
- Haisco Pharmaceutical Group Company Ltd., 136 Baili Road, Wenjiang district, Chengdu 611130, China
| | - Jia Ni
- Haisco Pharmaceutical Group Company Ltd., 136 Baili Road, Wenjiang district, Chengdu 611130, China
| | - Pangke Yan
- Haisco Pharmaceutical Group Company Ltd., 136 Baili Road, Wenjiang district, Chengdu 611130, China
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Chen KC, Chung CH, Lu CH, Tzeng NS, Lee CH, Su SC, Kuo FC, Liu JS, Hsieh CH, Chien WC. Association between the Use of Dipeptidyl Peptidase 4 Inhibitors and the Risk of Dementia among Patients with Type 2 Diabetes in Taiwan. J Clin Med 2020; 9:E660. [PMID: 32121372 PMCID: PMC7141309 DOI: 10.3390/jcm9030660] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 02/22/2020] [Accepted: 02/27/2020] [Indexed: 02/06/2023] Open
Abstract
STUDY OBJECTIVES Diabetes mellitus per se and its related therapy have been frequently associated with an increased risk of developing dementia. However, studies that explored the risk of dementia from the use of the novel oral antidiabetic medication dipeptidyl peptidase 4 inhibitor (DPP-4i) have been limited, especially in Asian populations. The present study aimed to determine the effect of DPP-4i on the subsequent risk of dementia among patients with type 2 diabetes (T2D) in Taiwan. METHODS This study utilized data from the Longitudinal Health Insurance Database between 2008 and 2015. We enrolled 2903 patients aged ≥50 years, who were on DPP-4i for a diagnosis of T2D and had no dementia. A total of 11,612 subjects were included and compared with a propensity score-matched control group who did not use DPP-4i (non-DPP-4i group). Survival analysis was performed to estimate and compare the risk of dementia-including Alzheimer's disease, vascular dementia, and other dementia types-between the two groups. Results: Both groups had a mean age of 68 years, had a preponderance of women (61.8%), and were followed up for a mean duration of 7 years. The risk of all-cause dementia was significantly lower in the DPP-4i group than in the non-DPP-4i group (hazard ratio (HR) 0.798; 95% confidence interval (CI) 0.681-0.883; p < 0.001), with a class effect. This trend was particularly observed for vascular dementia (HR 0.575; 95% CI 0.404-0.681; p < 0.001), but not in Alzheimer's disease (HR 0.891; 95% CI 0.712-1.265; p = 0.297). The Kaplan-Meier analysis showed that the preventive effect on dementia was positively correlated with the cumulative dose of DPP-4i. Conclusions: DPP-4i decreased the risk of dementia with a class effect, especially vascular dementia, but not in Alzheimer's disease. Our results provide important information on the drug choice when managing patients with T2D in clinical practice.
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Affiliation(s)
- Kuan-Chan Chen
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan; (K.-C.C.); (C.-H.L.); (C.-H.L.); (S.-C.S.); (F.-C.K.); (J.-S.L.)
| | - Chi-Hsiang Chung
- School of Public Health, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Chieh-Hua Lu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan; (K.-C.C.); (C.-H.L.); (C.-H.L.); (S.-C.S.); (F.-C.K.); (J.-S.L.)
| | - Nian-Sheng Tzeng
- Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei 114, Taiwan;
- Student Counseling Center, National Defense Medical Center, Taipei 11490, Taiwan
| | - Chien-Hsing Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan; (K.-C.C.); (C.-H.L.); (C.-H.L.); (S.-C.S.); (F.-C.K.); (J.-S.L.)
| | - Sheng-Chiang Su
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan; (K.-C.C.); (C.-H.L.); (C.-H.L.); (S.-C.S.); (F.-C.K.); (J.-S.L.)
| | - Feng-Chih Kuo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan; (K.-C.C.); (C.-H.L.); (C.-H.L.); (S.-C.S.); (F.-C.K.); (J.-S.L.)
| | - Jhih-Syuan Liu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan; (K.-C.C.); (C.-H.L.); (C.-H.L.); (S.-C.S.); (F.-C.K.); (J.-S.L.)
| | - Chang-Hsun Hsieh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan; (K.-C.C.); (C.-H.L.); (C.-H.L.); (S.-C.S.); (F.-C.K.); (J.-S.L.)
| | - Wu-Chien Chien
- School of Public Health, National Defense Medical Center, Taipei 11490, Taiwan;
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
- Graduate Institute of Life Science, National Defense Medical Center 11490, Taipei, Taiwan
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Libianto R, Davis TM, Ekinci EI. Advances in type 2 diabetes therapy: a focus on cardiovascular and renal outcomes. Med J Aust 2020; 212:133-139. [PMID: 31910303 DOI: 10.5694/mja2.50472] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Treatment options for type 2 diabetes have expanded. While metformin remains the first line treatment in most cases, choices for second line treatment now extend beyond sulfonylureas and include the sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP1) receptor agonists, and dipeptidyl peptidase 4 (DPP4) inhibitors. SGLT2 inhibitors are recommended for people with atherosclerotic cardiovascular disease, heart failure or kidney disease. Diabetic ketoacidosis is an uncommon but important side effect; its occurrence can be minimised with appropriate patient education and management, especially during perioperative periods and times of illness. GLP1 receptor agonists are recommended for people with atherosclerotic cardiovascular disease. Gastrointestinal side effects are common but are less prominent with the longer acting agents and can be minimised with slow titration of the shorter acting agents. DPP4 inhibitors are generally well tolerated, but alogliptin and saxagliptin should be used with caution in people with risk factors for heart failure. To optimise the management of type 2 diabetes, clinicians need to be aware of the pharmacological characteristics of each class of blood glucose-lowering medications and of the effect on cardiovascular health and renal function, balanced by potential adverse effects. Medications that have cardiovascular or renal benefits should be prescribed for patients with these comorbidities, and this is reflected in recent international guidelines.
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Affiliation(s)
| | | | - Elif I Ekinci
- Melbourne University, Melbourne, VIC.,Austin Health, Melbourne, VIC
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45
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Gökçay Canpolat A, Şahin M. Glucose Lowering Treatment Modalities of Type 2 Diabetes Mellitus. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1307:7-27. [PMID: 32200500 DOI: 10.1007/5584_2020_516] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
This chapter gives an overview of present knowledge and clinical aspects of antidiabetic drugs according to the recently available research evidence and clinical expertise.Many agents are acting on eight groups of pathophysiological mechanisms, which is commonly called as "Ominous Octet" by DeFronzo. The muscle, liver and β-cell, the fat cell, gastrointestinal tract, α-cell, kidney, and brain play essential roles in the development of glucose intolerance in type 2 diabetic individuals (Defronzo, Diabetes 58:773-795, 2009).A treatment paradigm shift is seen in the initiation of anti-hyperglycemic agents from old friends (meglitinides or sulphonylürea) to newer agents effecting on GLP-1 RA or SGLT-2 inhibitors. It is mostly about the other protective positive effects of these agents for kidney, heart, etc. Although there are concerns for the long term safety profiles; they are used widely around the World. The delivery of patient-centered care, facilitating medication adherence, the importance of weight loss in obese patients, the importance of co-morbid conditions are the mainstays of selecting the optimal agent.
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Affiliation(s)
- Asena Gökçay Canpolat
- Department of Endocrinology and Metabolism, Ankara University School of Medicine, Ankara, Turkey
| | - Mustafa Şahin
- Department of Endocrinology and Metabolism, Ankara University School of Medicine, Ankara, Turkey.
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46
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Soare A, Györfi HA, Matei AE, Dees C, Rauber S, Wohlfahrt T, Chen C, Ludolph I, Horch RE, Bäuerle T, Hörsten S, Mihai C, Distler O, Ramming A, Schett G, Distler JHW. Dipeptidylpeptidase 4 as a Marker of Activated Fibroblasts and a Potential Target for the Treatment of Fibrosis in Systemic Sclerosis. Arthritis Rheumatol 2019; 72:137-149. [DOI: 10.1002/art.41058] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 07/23/2019] [Indexed: 12/17/2022]
Affiliation(s)
- Alina Soare
- Friedrich‐Alexander University Erlangen‐Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany, and Davila University of Medicine and Pharmacy Bucharest Romania
| | - Hermina A. Györfi
- Friedrich‐Alexander University Erlangen‐Nuremberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Alexandru E. Matei
- Friedrich‐Alexander University Erlangen‐Nuremberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Clara Dees
- Friedrich‐Alexander University Erlangen‐Nuremberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Simon Rauber
- Friedrich‐Alexander University Erlangen‐Nuremberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Thomas Wohlfahrt
- Friedrich‐Alexander University Erlangen‐Nuremberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Chih‐Wei Chen
- Friedrich‐Alexander University Erlangen‐Nuremberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Ingo Ludolph
- Friedrich‐Alexander University Erlangen‐Nuremberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Raymund E. Horch
- Friedrich‐Alexander University Erlangen‐Nuremberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Tobias Bäuerle
- Friedrich‐Alexander University Erlangen‐Nuremberg Erlangen Germany
| | - Stephan Hörsten
- Friedrich‐Alexander University Erlangen‐Nuremberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Carina Mihai
- University Hospital Zurich, Zurich, Switzerland, and Carol Davila University of Medicine and Pharmacy Bucharest Romania
| | | | - Andreas Ramming
- Friedrich‐Alexander University Erlangen‐Nuremberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Georg Schett
- Friedrich‐Alexander University Erlangen‐Nuremberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Jörg H. W. Distler
- Friedrich‐Alexander University Erlangen‐Nuremberg and Universitätsklinikum Erlangen Erlangen Germany
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47
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Iheagwam FN, Ogunlana OO, Chinedu SN. Model Optimization and In Silico Analysis of Potential Dipeptidyl Peptidase IV Antagonists from GC-MS Identified Compounds in Nauclea latifolia Leaf Extracts. Int J Mol Sci 2019; 20:ijms20235913. [PMID: 31775302 PMCID: PMC6929178 DOI: 10.3390/ijms20235913] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 09/30/2019] [Accepted: 10/03/2019] [Indexed: 12/15/2022] Open
Abstract
Dipeptidyl peptidase IV (DPP-IV) is a pharmacotherapeutic target in type 2 diabetes. Inhibitors of this enzyme constitute a new class of drugs used in the treatment and management of type 2 diabetes. In this study, phytocompounds in Nauclea latifolia (NL) leaf extracts, identified using gas chromatography–mass spectroscopy (GC-MS), were tested for potential antagonists of DPP-IV via in silico techniques. Phytocompounds present in N. latifolia aqueous (NLA) and ethanol (NLE) leaf extracts were identified using GC–MS. DPP-IV model optimization and molecular docking of the identified compounds/standard inhibitors in the binding pocket was simulated. Drug-likeness, pharmacokinetic and pharmacodynamic properties of promising docked leads were also predicted. Results showed the presence of 50 phytocompounds in NL extracts of which only 2-O-p-methylphenyl-1-thio-β-d-glucoside, 3-tosylsedoheptulose, 4-benzyloxy-6-hydroxymethyl-tetrahydropyran-2,3,5-triol and vitamin E exhibited comparable or better binding iGEMDOCK and AutoDock Vina scores than the clinically prescribed standards. These four compounds exhibited promising drug-likeness as well as absorption, distribution, metabolism, excretion and toxicity (ADMET) properties suggesting their candidature as novel leads for developing DPP-IV inhibitors.
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Affiliation(s)
- Franklyn Nonso Iheagwam
- Department of Biochemistry, Covenant University, PMB 1023, Ota 112212, Ogun State, Nigeria; (O.O.O.); (S.N.C.)
- Covenant University Public Health and Wellness Research Cluster (CUPHWERC), Covenant University, PMB 1023, Ota 112212, Ogun State, Nigeria
- Correspondence: ; Tel.: +234-8163615298
| | - Olubanke Olujoke Ogunlana
- Department of Biochemistry, Covenant University, PMB 1023, Ota 112212, Ogun State, Nigeria; (O.O.O.); (S.N.C.)
- Covenant University Public Health and Wellness Research Cluster (CUPHWERC), Covenant University, PMB 1023, Ota 112212, Ogun State, Nigeria
| | - Shalom Nwodo Chinedu
- Department of Biochemistry, Covenant University, PMB 1023, Ota 112212, Ogun State, Nigeria; (O.O.O.); (S.N.C.)
- Covenant University Public Health and Wellness Research Cluster (CUPHWERC), Covenant University, PMB 1023, Ota 112212, Ogun State, Nigeria
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48
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Proença C, Freitas M, Ribeiro D, Tomé SM, Araújo AN, Silva AMS, Fernandes PA, Fernandes E. The dipeptidyl peptidase-4 inhibitory effect of flavonoids is hindered in protein rich environments. Food Funct 2019; 10:5718-5731. [PMID: 31441917 DOI: 10.1039/c9fo00722a] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors present a unique approach for the management of type 2 diabetes (T2D). In the present study, the inhibition of DPP-4 was evaluated for a large panel of flavonoids, important components of the human diet, using in vitro and ex vivo models. The activity of the isolated enzyme was assayed in vitro. Subsequently, the most active flavonoids were tested ex vivo in human whole blood and plasma. In this study, contrary to the in vitro fluorometric tests, flavonoids did not show inhibitory activity against DPP-4. Due to the discrepancy in the results between the in vitro and ex vivo approaches, plasma protein binding values were determined, presenting values from 43.9 to 100.0%. This work provides a new insight into the inhibitory activity for DPP-4, based on the flavonoid scaffold. Additionally, the obtained results showed that the inhibitory effect of flavonoids against DPP-4 was hindered in protein rich environments, like that occurring in blood, and indicated the need for experimental refinement in drug discovery for blood targets.
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Affiliation(s)
- Carina Proença
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
| | - Marisa Freitas
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
| | - Daniela Ribeiro
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
| | - Sara M Tomé
- QOPNA and LAQV, REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Alberto N Araújo
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
| | - Artur M S Silva
- QOPNA and LAQV, REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Pedro A Fernandes
- UCIBIO, REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
| | - Eduarda Fernandes
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
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Williams R, Kothny W, Serban C, Lopez‐Leon S, de Vries F, Schlienger R. Association between vildagliptin and risk of angioedema, foot ulcers, skin lesions, hepatic toxicity, and serious infections in patients with type 2 diabetes mellitus: A European multidatabase, noninterventional, postauthorization safety study. Endocrinol Diabetes Metab 2019; 2:e00084. [PMID: 31294090 PMCID: PMC6613220 DOI: 10.1002/edm2.84] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 05/26/2019] [Indexed: 11/07/2022] Open
Abstract
OBJECTIVES This noninterventional, multidatabase, analytical cohort study explored whether vildagliptin is associated with an increased risk of specific safety events of interest, namely angioedema, foot ulcers, or skin lesions, adverse hepatic events, or serious infections compared with other noninsulin antidiabetic drugs (NIADs) using real-world data from five European electronic healthcare databases. DESIGN Patients with type 2 diabetes mellitus aged ≥18 years on NIAD treatment were included between January 2005 and June 2014. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the outcomes of interest were estimated using negative binomial regression. PATIENTS Approximately 2.8% of the included patients (n = 738 054) used vildagliptin at any time during the study, with an average follow-up time of 1.4 years. RESULTS The adjusted IRRs (vildagliptin vs. other NIADs) were in the range of 0.87-3.71 (angioedema), 0.73-1.19 (foot ulcers), 0.37-1.18 (skin lesions), 0.24-1.14 (composite of foot ulcer or skin lesions), 0.29-0.55 (serious hepatic events), and 0.59-1.04 (serious infections), with no lower bound of the 95% CIs > 1. CONCLUSIONS Overall, there was no increased risk of the events of interest in association with vildagliptin use compared with other NIADs.
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Affiliation(s)
| | | | | | | | - Frank de Vries
- Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
- Department of Clinical Pharmacy and ToxicologyMaastricht University Medical CentreMaastrichtThe Netherlands
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Hussain H, Abbas G, Green IR, Ali I. Dipeptidyl peptidase IV inhibitors as a potential target for diabetes: patent review (2015-2018). Expert Opin Ther Pat 2019; 29:535-553. [PMID: 31203700 DOI: 10.1080/13543776.2019.1632290] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Dipeptidyl peptidase 4 (DPP-4) belongs to the family of serine proteases and is involved in the degradation of GLP-1 and GIP hormones, which enhance the production and release of insulin. Targeting DPP-4 inhibitors is increasingly being considered as promising paradigms to treat type 2 diabetes mellitus and therefore DPP-4 inhibitors are being considered as promising antidiabetic drugs. AREAS COVERE This review provides an overview of published patents describing natural and synthetic DPP-4 inhibitors from January 2015 to December 2018. EXPERT OPINION A fair number of new synthetic and natural DPP-4 inhibitors have been reported in the last four years which describe the progress in the development of various heterocyclic scaffolds or heterocyclic hybrid compounds. As a result of this, many marketed DPP-4 inhibitors that have been approved by the appropriate governing bodies during the past decade, have been introduced as inhibitors. Molecular hybridization is an emerging idea in medicinal chemistry and therefore hybrid compounds of DPP-4 inhibitors with other DPP-4 inhibitors or with antidiabetic drugs should be formulated for a comprehensive evaluation. More detailed pharmacovigilance of DPP-4 inhibitors is required because this will address the pancreas-related adverse events as well as their impact on cardiovascular outcomes via long-term studies.
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Affiliation(s)
- Hidayat Hussain
- a Department of Bioorganic Chemistry , Leibniz Institute of Plant Biochemistry , Halle (Saale) , Germany
| | - Ghulam Abbas
- b Department of Biological Sciences and Chemistry , College of Arts and Sciences, University of Nizwa , Nizwa , Sultanate of Oman
| | - Ivan R Green
- c Department of Chemistry and Polymer Science , University of Stellenbosch , Matieland, Stellenbosch , South Africa
| | - Iftikhar Ali
- d Department of Chemistry , Karakoram International University , Gilgit, Gilgit-Baltistan , Pakistan
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