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Sotoudeheian M, Mirahmadi SMS, Salehi Darjani P, Moradi M, Pirhayati M, Dakkali MS, Taghizadeh M, Azarbad R, Pazoki Toroudi H. Sitagliptin, diabetes mellitus, and heart failure: an in-depth review of sitagliptin therapy and heart failure in patients with diabetes mellitus. Diabetol Int 2025; 16:237-256. [PMID: 40166434 PMCID: PMC11954766 DOI: 10.1007/s13340-025-00800-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 01/20/2025] [Indexed: 04/02/2025]
Abstract
Heart failure (HF) is characterized by impairments in cardiac function and heart structural changes. Type-2 diabetes mellitus (T2DM) is a chronic metabolic disorder affecting millions worldwide. It is a risk factor for cardiovascular disease. Patients with T2DM are at an increased risk of developing HF. Multifactorial pathophysiology underlies HF in T2DM patients. Inflammation, oxidative stress, insulin resistance, and endothelial dysfunction are some of the mechanisms involved. Dipeptidyl peptidase-4 (DPP-IV) inhibitors may affect cardiac function by modulating inflammation and oxidative stress, affecting endothelial function, and modifying myocardial fibrosis. An antidiabetic drug class known as DPP-IV inhibitors improves patients' glycemic control in T2DM patients. However, DPP-IV inhibitors have been shown to lower glucose levels and alter HF risk in addition to their glucose-lowering effects. Sitagliptin is an oral medication used to treat T2DM. Sitagliptin is often used in combination with other diabetes medications. A preclinical study showed that sitagliptin improved cardiac function in models of heart failure. The precise mechanisms responsible for this improvement are not yet fully understood, but it could be related to inflammation and oxidative stress. Patients with T2DM are more prone to HF, which highlights the necessity of effective therapies to improve both blood glucose control and cardiovascular health. Sitagliptin offers potential cardioprotective and glucose-lowering benefits for these patients. However, further research is required to fully comprehend the role of sitagliptin in the treatment of HF in individuals with T2DM.
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Affiliation(s)
| | - Seyed-Mohamad-Sadegh Mirahmadi
- Department of General Medicine, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Firoozgar Clinical Research Development Center (FCRDC), FiroozgarH, Tehran, Iran
| | - Pedram Salehi Darjani
- Department of Pharmacology and Toxicology, School of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran
| | - Mohammad Moradi
- Department of General Medicine, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Pirhayati
- Department of General Medicine, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Mehdi Taghizadeh
- Department of Cardiology, Shahid Madani Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Azarbad
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Hamidreza Pazoki Toroudi
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Hemmat Exp, Tehran, Iran
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Feng Y, Shang B, Yang Y, Zhang D, Liu C, Qin Z, Zhou Y, Meng J, Liu X. Impact of DPP-4 Inhibitors on Interleukin Levels in Type 2 Diabetes Mellitus. J Clin Endocrinol Metab 2025; 110:1195-1204. [PMID: 39512193 PMCID: PMC11913085 DOI: 10.1210/clinem/dgae783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 10/17/2024] [Accepted: 11/07/2024] [Indexed: 11/15/2024]
Abstract
BACKGROUND AND OBJECTIVE Accumulating evidence had implicated pathological involvement of interleukins (ILs) in progression and complications in patients with type 2 diabetes mellitus (T2DM). Dipeptidyl peptidase-4 inhibitors (DPP-4i) produced favorable effects on glucose homeostasis in T2DM. This study aimed to evaluate the impact of DPP-4i on IL concentrations in T2DM. DATA SOURCES PubMed, Embase, and the Cochrane library were systematically searched for relevant articles from inception to May 31, 2024. The search included DPP-4i, T2DM, and randomized controlled trials (RCTs) and related terms. STUDY SELECTION AND DATA EXTRACTION Placebo- or active agents-controlled human studies were screened. All the RCTs were identified if they provided detailed information on changes of ILs during DPP-4i treatment. DATA SYNTHESIS A total of 14 RCTs involving 850 participants were identified. Pooled estimates revealed that DPP-4i significantly lowered IL-6 concentrations (-0.54 pg/mL; 95% CI, -0.82 to -0.25; I2 = 10%, P = .0003) compared to placebo. Similar effects were demonstrated for IL-1β (-16.33 pg/mL; 95% CI, -19.56 to -13.11; I2 = 0%, P < .00001), whereas the effect on IL-18 was not statistically significant (-13.55 pg/mL; 95% CI, -76.95 to 49.85; I2 = 0%, P = .68). Subgroup analysis on IL-6 demonstrated that marked effects were found in groups of basal IL-6 concentrations (< 5 pg/mL), body mass index (≥ 28 kg/m2) and type of DPP-4i (linagliptin). CONCLUSION DPP-4i favorably decreased IL-6 levels in patients with T2DM. The impact of DPP-4i on IL-1β and IL-18 needed to be explored with more studies. Further trials should be performed to elucidate this anti-inflammatory effect of DPP-4i during treatment of T2DM.
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Affiliation(s)
- Yiduo Feng
- Department of Nephrology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Beibei Shang
- Department of Pharmacy, Children's Hospital, Capital Institute of Paediatrics, Beijing 100020, China
| | - Yu Yang
- Department of Cardiology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Donglei Zhang
- Department of Hematology, Zhongnan Hospital, Wuhan University, Hubei 430000, China
| | - Changbin Liu
- Department of Rehabilitation Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Zheng Qin
- Department of Cardiology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Yilun Zhou
- Department of Nephrology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Jie Meng
- Department of Pathology, Beijing TongRen Hospital, Capital Medical University, Beijing 100005, China
| | - Xin Liu
- Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
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Nabiyi S, Sajedi F, Zamani A, Behzad M. Effect of sitagliptin therapy on IL-29 and its associated signaling molecules in patients with type 2 diabetes mellitus. Hum Immunol 2024; 85:110833. [PMID: 38897073 DOI: 10.1016/j.humimm.2024.110833] [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: 06/08/2024] [Accepted: 06/14/2024] [Indexed: 06/21/2024]
Abstract
OBJECTIVE The potential immunoregulatory capacity of sitagliptin on interleukin-29 (IL-29) and genes involved in its intracellular pathway were explored in type 2 diabetes mellitus (T2D). MATERIALS AND METHODS T2D patients treated with six months of sitagliptin (Sita+), patients not treated with sitagliptin (Sita-), and healthy controls (HCs) were included. IL-29 levels in the supernatant of stimulated mononuclear immune cells was determined with ELISA. The mRNA expression levels of IL-29, FOS, JUN, NF-AT2, NF-KB1, STAT1-2, IRF1, IRF3, IRF7, and IRF9 was assessed with real-time qPCR. RESULTS Increased protein and gene levels of IL-29 were observed in Sita- group compared to HCs (p < 0.001 and p = 0.026), while those levels were diminished in Sita+ group in comparison with Sita- group (p < 0.001 and p = 0.008). Expression of FOS, NF-AT2 and NF-KB1 in Sita- patients was higher than HCs (p = 0.018, p = 0.021, and p = 0.001). A significant decrease in expression of FOS, NF-AT2, and NF-KB1 was found in Sita+ group versus Sita- parients (p = 0.027, p = 0.003, and p = 0.002). In Sita- patients, IL-29 levels were correlated to glucose metabolism parameters including FPG and HbA1c (p < 0.05 for all). CONCLUSION Sitagliptin administration has a regulatory effect on the aggressive expression of IL-29 and its signaling molecules including FOS, NF-AT2 and NF-KB1 in T2D.
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Affiliation(s)
- Sina Nabiyi
- Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Firozeh Sajedi
- Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Alireza Zamani
- Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mahdi Behzad
- Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
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Wen X, Chang X, He X, Cai Q, Wang G, Liu J. Increased Thyroid DPP4 Expression Is Associated With Inflammatory Process in Patients With Hashimoto Thyroiditis. J Clin Endocrinol Metab 2024; 109:1517-1525. [PMID: 38127960 PMCID: PMC11099486 DOI: 10.1210/clinem/dgad723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 11/10/2023] [Accepted: 12/07/2023] [Indexed: 12/23/2023]
Abstract
CONTEXT Dipeptidyl peptidase-4 (DPP4) is originally described as a surface protein in lymphocytes. Lymphocyte infiltration and subsequent destruction of thyroid tissue have been considered as the central pathological mechanism in Hashimoto thyroiditis (HT). OBJECTIVE The present study aimed to investigate DPP4 expression in peripheral blood and thyroid tissue in HT patients, and explore the role of DPP4 in the pathophysiological process of HT. METHODS This case-control study recruited 40 drug-naive HT patients and 81 control individuals. Peripheral blood and thyroid specimens were collected for assessing the expression and activity of DPP4. Moreover, single-cell RNA sequencing (scRNA-seq) analysis of 6 "para-tumor tissues" samples from scRNA-seq data set GSE184362 and in vitro cell experiments were also conducted. RESULTS The HT patients had similar DPP4 serum concentration and activity as the controls. However, the expression and activity of DPP4 was significantly increased in the thyroid of the HT group than in the control group. The scRNA-seq analysis showed that DPP4 expression was significantly increased in the HT group, and mainly expressed in T cells. Further in vitro studies showed that inhibition of lymphocyte DPP4 activity with sitagliptin downregulated the production of inflammatory factors in co-cultured thyroid cells. CONCLUSION DPP4 expression was significantly increased in the thyroid of the HT group compared with the control group, and was mainly localized in the lymphocytes. Inhibition of lymphocyte DPP4 activity reduced the production of inflammatory factors in co-cultured thyroid cells. Therefore, inhibition of DPP4 may have a beneficial effect by alleviating inflammatory reactions in HT patients.
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Affiliation(s)
- Xiaohui Wen
- Department of Otolaryngology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Xiaona Chang
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Xueqing He
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Qingyun Cai
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Guang Wang
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Jia Liu
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
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Nag S, Mandal S, Mukherjee O, Majumdar T, Mukhopadhyay S, Kundu R. Vildagliptin inhibits high fat and fetuin-A mediated DPP-4 expression, intracellular lipid accumulation and improves insulin secretory defects in pancreatic beta cells. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167047. [PMID: 38296116 DOI: 10.1016/j.bbadis.2024.167047] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/16/2024] [Accepted: 01/26/2024] [Indexed: 02/05/2024]
Abstract
Dipeptidyl peptidase-4 (DPP-4), a ubiquitous proteolytic enzyme, inhibits insulin secretion from pancreatic beta cells by inactivating circulating incretin hormones GLP-1 and GIP. High circulating levels of DPP-4 is presumed to compromise insulin secretion in people with type 2 diabetes (T2D). Our group recently reported lipid induced DPP-4 expression in pancreatic beta cells, mediated by the TLR4-NFkB pathway. In the present study, we looked at the role of Vildagliptin on pancreatic DPP-4 inhibition, preservation of islet mass and restoration of insulin secretion. MIN6 mouse insulinoma cells incubated with palmitate and fetuin-A, a proinflammatory organokine associated with insulin resistance, showed activation of TLR4-NFkB pathway, which was rescued on Vildagliptin treatment. In addition, Vildagliptin, by suppressing palmitate-fetuin-A mediated DPP-4 expression in MIN6, prevented the secretion of IL-1beta and fetuin-A in the culture media. DPP-4 siRNA abrogated TLR4-NFkB pathway mediated islet cell inflammation. Vildagliptin also reduced palmitate-fetuin-A mediated intracellular lipid accumulation in MIN6 and isolated islets from high fat fed (HFD) mice as observed by Oil O Red staining with downregulation of CD36 and PPARgamma. Vildagliptin also preserved islet mass and rescued insulin secretory defect in HFD mice. Our results suggest that inhibition of DPP-4 by Vildagliptin protects pancreatic beta cells from the deleterious effects of lipid and fetuin-A, preserves insulin secretory functions and improves hyperglycemia.
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Affiliation(s)
- Snehasish Nag
- Cell Signaling Laboratory, Department of Zoology, Siksha Bhavana (Institute of Science), Visva-Bharati University, Santiniketan 731235, India
| | - Samanwita Mandal
- Cell Signaling Laboratory, Department of Zoology, Siksha Bhavana (Institute of Science), Visva-Bharati University, Santiniketan 731235, India
| | - Oindrila Mukherjee
- Cell Signaling Laboratory, Department of Zoology, Siksha Bhavana (Institute of Science), Visva-Bharati University, Santiniketan 731235, India
| | - Tanmay Majumdar
- National Institute of Immunology (NII), Aruna Asaf Ali Marg, New Delhi 110067, India
| | - Satinath Mukhopadhyay
- Department of Endocrinology & Metabolism, Institute of Post-Graduate Medical Education & Research-Seth Sukhlal Karnani Memorial Hospital (IPGME&R-SSKM), Kolkata 700020, India
| | - Rakesh Kundu
- Cell Signaling Laboratory, Department of Zoology, Siksha Bhavana (Institute of Science), Visva-Bharati University, Santiniketan 731235, India.
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Hajhashemi V, Sadeghi H, Madab FK. Anti-inflammatory and antinociceptive effects of sitagliptin in animal models and possible mechanisms involved in the antinociceptive activity. Korean J Pain 2024; 37:26-33. [PMID: 38123184 PMCID: PMC10764209 DOI: 10.3344/kjp.23262] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 11/24/2023] [Accepted: 12/03/2023] [Indexed: 12/23/2023] Open
Abstract
Background Sitagliptin is an antidiabetic drug that inhibits dipeptidyl peptidase-4 enzyme. This study aimed to investigate the antinociceptive and anti-inflammatory effects of sitagliptin in formalin and carrageenan tests and determine the possible mechanism(s) of its antinociceptive activity. Methods Male Swiss mice (25-30 g) and male Wistar rats (180-220 g) were used for formalin and carrageenan tests, respectively. In the formalin test, paw licking time and in the carrageenan test, paw thickness were considered as indexes of pain behavior and inflammation respectively. Three doses of sitagliptin (2.5, 5, and 10 mg/kg) were used in these tests. Also, several antagonists and enzyme inhibitors were used to evaluate the role of adrenergic, serotonergic, dopaminergic, and opioid receptors as well as the NO/cGMP/KATP pathway in the antinociceptive effect of sitagliptin (5 mg/kg). Results Sitagliptin showed significant antinociceptive and anti-inflammatory effects in the formalin and carrageenan tests respectively. In the carrageenan test, all three doses of sitagliptin significantly (P < 0.001) reduced paw thickness. Pretreatment with yohimbine, prazosin, propranolol, naloxone, and cyproheptadine could not reverse the antinociceptive effect of sitagliptin (5 mg/Kg), which indicates that adrenergic, opioid, and serotonin receptors (5HT2) are not involved in the antinociceptive effects. L-NAME, methylene blue, glibenclamide, ondansetron, and sulpiride were able to reverse this effect. Conclusions NO/cGMP/KATP, 5HT3 and D2 pathways play an important role in the antinociceptive effect of sitagliptin. Additionally significant anti-inflammatory effects observed in the carrageenan test might contribute in reduction of pain response in the second phase of the formalin test.
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Affiliation(s)
- Valiollah Hajhashemi
- Department of Pharmacology and Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hossein Sadeghi
- Department of Pharmacology, Faculty of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Fatemeh Karimi Madab
- Department of Pharmacology and Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
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Drakul M, Tomić S, Bekić M, Mihajlović D, Vasiljević M, Rakočević S, Đokić J, Popović N, Bokonjić D, Čolić M. Sitagliptin Induces Tolerogenic Human Dendritic Cells. Int J Mol Sci 2023; 24:16829. [PMID: 38069152 PMCID: PMC10706581 DOI: 10.3390/ijms242316829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 11/05/2023] [Accepted: 11/07/2023] [Indexed: 12/18/2023] Open
Abstract
Sitagliptin, an anti-diabetic drug, is a dipeptidyl peptidase (DPP)-4/CD26 inhibitor with additional anti-inflammatory and immunomodulatory properties. In this study, we investigated for the first time the effect of sitagliptin on the differentiation and functions of human dendritic cells generated from monocytes (MoDCs) for 4 days using the standard GM-CSF/IL-4 procedure. LPS/IFN-γ treatment for an additional 24 h was used for maturation induction of MoDCs. Sitagliptin was added at the highest non-cytotoxic concentration (500 µg/mL) either at the beginning (sita 0d protocol) or after MoDC differentiation (sita 4d protocol). Sitagliptin impaired differentiation and maturation of MoDCs as judged with the lower expression of CD40, CD83, CD86, NLRP3, and HLA-DR, retention of CD14 expression, and inhibited production of IL-β, IL-12p70, IL-23, and IL-27. In contrast, the expression of CD26, tolerogenic DC markers (ILT4 and IDO1), and production of immunoregulatory cytokines (IL-10 and TGF-β) were increased. Generally, the sita 0d protocol was more efficient. Sitagliptin-treated MoDCs were poorer allostimulators of T-cells in MoDC/T-cell co-culture and inhibited Th1 and Th17 but augmented Th2 and Treg responses. Tolerogenic properties of sitagliptin-treated MoDCs were additionally confirmed by an increased frequency of CD4+CD25+CD127- FoxP3+ Tregs and Tr1 cells (CD4+IL-10+FoxP3-) in MoDC/T-cell co-culture. The differentiation of IL-10+ and TGF-β+ Tregs depended on the sitagliptin protocol used. A Western blot analysis showed that sitagliptin inhibited p65 expression of NF-kB and p38MAPK during the maturation of MoDCs. In conclusion, sitagliptin induces differentiation of tolerogenic DCs, and the effect is important when considering sitagliptin for treating autoimmune diseases and allotransplant rejection.
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Affiliation(s)
- Marija Drakul
- Medical Faculty Foca, University of East Sarajevo, 73300 Foča, R. Srpska, Bosnia and Herzegovina; (M.D.); (D.M.); (M.V.); (S.R.); (D.B.)
| | - Sergej Tomić
- Institute for the Application of Nuclear Energy, University of Belgrade, 11000 Belgrade, Serbia; (S.T.); (M.B.)
| | - Marina Bekić
- Institute for the Application of Nuclear Energy, University of Belgrade, 11000 Belgrade, Serbia; (S.T.); (M.B.)
| | - Dušan Mihajlović
- Medical Faculty Foca, University of East Sarajevo, 73300 Foča, R. Srpska, Bosnia and Herzegovina; (M.D.); (D.M.); (M.V.); (S.R.); (D.B.)
| | - Miloš Vasiljević
- Medical Faculty Foca, University of East Sarajevo, 73300 Foča, R. Srpska, Bosnia and Herzegovina; (M.D.); (D.M.); (M.V.); (S.R.); (D.B.)
| | - Sara Rakočević
- Medical Faculty Foca, University of East Sarajevo, 73300 Foča, R. Srpska, Bosnia and Herzegovina; (M.D.); (D.M.); (M.V.); (S.R.); (D.B.)
| | - Jelena Đokić
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11000 Belgrade, Serbia; (J.Đ.); (N.P.)
| | - Nikola Popović
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11000 Belgrade, Serbia; (J.Đ.); (N.P.)
| | - Dejan Bokonjić
- Medical Faculty Foca, University of East Sarajevo, 73300 Foča, R. Srpska, Bosnia and Herzegovina; (M.D.); (D.M.); (M.V.); (S.R.); (D.B.)
| | - Miodrag Čolić
- Medical Faculty Foca, University of East Sarajevo, 73300 Foča, R. Srpska, Bosnia and Herzegovina; (M.D.); (D.M.); (M.V.); (S.R.); (D.B.)
- Serbian Academy of Sciences and Arts, 11000 Belgrade, Serbia
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Zhang J, Ma X, Liu F, Zhang D, Ling J, Zhu Z, Chen Y, Yang P, Yang Y, Liu X, Zhang J, Liu J, Yu P. Role of NLRP3 inflammasome in diabetes and COVID-19 role of NLRP3 inflammasome in the pathogenesis and treatment of COVID-19 and diabetes NLRP3 inflammasome in diabetes and COVID-19 intervention. Front Immunol 2023; 14:1203389. [PMID: 37868953 PMCID: PMC10585100 DOI: 10.3389/fimmu.2023.1203389] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 09/18/2023] [Indexed: 10/24/2023] Open
Abstract
2019 Coronavirus Disease (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). A "cytokine storm", i.e., elevated levels of pro-inflammatory cytokines in the bloodstream, has been observed in severe cases of COVID-19. Normally, activation of the nucleotide-binding oligomeric domain-like receptor containing pyrin domain 3 (NLRP3) inflammatory vesicles induces cytokine production as an inflammatory response to viral infection. Recent studies have found an increased severity of necrobiosis infection in diabetic patients, and data from several countries have shown higher morbidity and mortality of necrobiosis in people with chronic metabolic diseases such as diabetes. In addition, COVID-19 may also predispose infected individuals to hyperglycemia. Therefore, in this review, we explore the potential relationship between NLRP3 inflammatory vesicles in diabetes and COVID-19. In contrast, we review the cellular/molecular mechanisms by which SARS-CoV-2 infection activates NLRP3 inflammatory vesicles. Finally, we propose several promising targeted NLRP3 inflammatory vesicle inhibitors with the aim of providing a basis for NLRP3-targeted drugs in diabetes combined with noncoronary pneumonia in the clinical management of patients.
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Affiliation(s)
- Jiayu Zhang
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Huankui Academy, Nanchang University, Jiangxi, Nanchang, China
| | - Xuejing Ma
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Fuwei Liu
- Department of Cardiology, The Affiliated Ganzhou Hospital of Nanchang University, Jiangxi, China
| | - Deju Zhang
- Food and Nutritional Sciences, School of Biological Sciences, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Jitao Ling
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zicheng Zhu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yixuan Chen
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Pingping Yang
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yanlin Yang
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiao Liu
- Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jing Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jianping Liu
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Peng Yu
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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Xie D, Wang Q, Huang W, Zhao L. Dipeptidyl-peptidase-4 inhibitors have anti-inflammatory effects in patients with type 2 diabetes. Eur J Clin Pharmacol 2023; 79:1291-1301. [PMID: 37493797 DOI: 10.1007/s00228-023-03541-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 07/16/2023] [Indexed: 07/27/2023]
Abstract
AIMS Systematic low-grade inflammation is considered to be an important factor leading to the development of T2DM and the progression of its complications. Dipeptidyl-peptidase-4 (DPP-4) inhibitors show potential anti-inflammatory effects in patients with T2DM. This meta-analysis aimed to evaluate the anti-inflammatory effects of DPP-4 inhibitors in patients with T2DM. METHODS A comprehensive search was performed in PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials to identify randomized controlled trials that assess the anti-inflammatory effects of DPP-4 inhibitors. Quantitative data analysis was conducted by a random-effects model. Sensitivity analyses were conducted to determine the robustness of the pooled results. RESULTS Twenty-two studies with 1595 patients with T2DM were included. Pooled results showed that DPP-4 inhibitor therapy was significantly associated with the reduction of C-reactive protein (CRP) (SMD, - 0.56, p < 0.01), TNF-α (SMD, - 1.69, p < 0.01), IL-6 (SMD, - 0.67, p < 0.01), and IL-1β (WMD, - 8.21 pg/ml, p < 0.01). Leave-one-out meta-analysis showed no significant change in the pooled results of CRP and TNF-α. CONCLUSION This meta-analysis demonstrated that DPP-4 inhibitors can significantly attenuate low-grade inflammatory state in patients with T2DM. In addition to improving glycemic control, DDP-4 inhibitors might offer extra therapeutic value by controlling inflammation.
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Affiliation(s)
- Dengpiao Xie
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Qiqi Wang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Wei Huang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China.
| | - Liangbin Zhao
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China.
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Jeong SH, Vorachitti M, Fuentes F. A Case of Euglycemic Diabetic Ketoacidosis (DKA), Influenza, and a Dipeptidyl Peptidase-4 (DPP-4) Inhibitor. Cureus 2023; 15:e39012. [PMID: 37378199 PMCID: PMC10291903 DOI: 10.7759/cureus.39012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/14/2023] [Indexed: 06/29/2023] Open
Abstract
A subclass of diabetic ketoacidosis (DKA) is euglycemic DKA, characterized by the same traits of ketoacidosis and low bicarbonate levels. However, the condition differs from classic DKA because of its normoglycemic levels. Euglycemic DKA was once thought to be incredibly rare, but its incidence has been on the rise with the widespread use of sodium-glucose-cotransporter-2 (SGLT2) inhibitors and other newer anti-diabetic medications. The disorder is not fully understood and is often missed when presenting because of the non-elevated blood sugars. Common triggers for euglycemic DKA include infection, fasting, pregnancy, and medications such as SGLT2 inhibitors. This case report involves a patient with type 2 diabetes mellitus on sitagliptin that presented to the emergency department with shortness of breath, cough, nausea, vomiting, and abdominal pain and tested influenza positive with blood glucose levels of 209 mg/dl. He was started on IV fluids and subcutaneous insulin but developed worsening acidosis. The following day, he was transferred to the ICU for DKA protocol and diagnosed with euglycemic DKA.
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Affiliation(s)
| | - Merica Vorachitti
- Internal Medicine, University of Nevada Reno School of Medicine, Reno, USA
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11
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Foresta A, Ojeda-Fernandez L, Macaluso G, Roncaglioni MC, Tettamanti M, Fortino I, Leoni O, Genovese S, Baviera M. Dipeptidyl Peptidase-4 Inhibitors, Glucagon-like Peptide-1 Receptor Agonists, and Sodium-Glucose Cotransporter-2 Inhibitors and COVID-19 Outcomes. Clin Ther 2023; 45:e115-e126. [PMID: 36933975 PMCID: PMC9974363 DOI: 10.1016/j.clinthera.2023.02.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 02/21/2023] [Accepted: 02/22/2023] [Indexed: 03/05/2023]
Abstract
PURPOSE It has been reported that dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have a role in modulation of inflammation associated with coronavirus disease 2019 (COVID-19). This study assessed the effect of these drug classes on COVID-19-related outcomes. METHODS Using a COVID-19 linkable administrative database, we selected patients aged ≥40 years with at least 2 prescriptions of DPP-4i, GLP-1 RA, or SGLT-2i or any other antihyperglycemic drug and a diagnosis of COVID-19 from February 15, 2020, to March 15, 2021. Adjusted odds ratios (ORs) with 95% CIs were used to calculate the association between treatments and all-cause and in-hospital mortality and COVID-19-related hospitalization. A sensitivity analysis was performed by using inverse probability treatment weighting. FINDINGS Overall, 32,853 subjects were included in the analysis. Multivariable models showed a reduction of the risk for COVID-19 outcomes for users of DPP-4i, GLP-1 RA, and SGLT-2i compared with nonusers, although statistical significance was reached only in DPP-4i users for total mortality (OR, 0.89; 95% CI, 0.82-0.97). The sensitivity analysis confirmed the main results reaching a significant reduction for hospital admission in GLP-1 RA users and in-hospital mortality in SGLT-2i users compared with nonusers. IMPLICATIONS This study found a beneficial effect in the risk reduction of COVID-19 total mortality in DPP-4i users compared with nonusers. A positive trend was also observed in users of GLP-1 RA and SGLT-2i compared with nonusers. Randomized clinical trials are needed to confirm the effect of these drug classes as potential therapy for the treatment of COVID-19.
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Affiliation(s)
- Andreana Foresta
- Laboratory of Cardiovascular Prevention, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
| | - Luisa Ojeda-Fernandez
- Laboratory of Cardiovascular Prevention, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Giulia Macaluso
- Laboratory of Cardiovascular Prevention, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Maria Carla Roncaglioni
- Laboratory of Cardiovascular Prevention, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Mauro Tettamanti
- Laboratory of Geriatric Epidemiology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Ida Fortino
- Unità Organizzativa Osservatorio Epidemiologico Regionale, Lombardy Region, Milan, Italy
| | - Olivia Leoni
- Unità Organizzativa Osservatorio Epidemiologico Regionale, Lombardy Region, Milan, Italy
| | | | - Marta Baviera
- Laboratory of Cardiovascular Prevention, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
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12
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AL-Qabbaa SM, Qaboli SI, Alshammari TK, Alamin MA, Alrajeh HM, Almuthnabi LA, Alotaibi RR, Alonazi AS, Bin Dayel AF, Alrasheed NM, Alrasheed NM. Sitagliptin Mitigates Diabetic Nephropathy in a Rat Model of Streptozotocin-Induced Type 2 Diabetes: Possible Role of PTP1B/JAK-STAT Pathway. Int J Mol Sci 2023; 24:ijms24076532. [PMID: 37047505 PMCID: PMC10095069 DOI: 10.3390/ijms24076532] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 03/27/2023] [Accepted: 03/29/2023] [Indexed: 04/03/2023] Open
Abstract
Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus. This study examined the therapeutic effects of sitagliptin, a dipeptidyl peptidase inhibitor, on DN and explored the underlying mechanism. Male Wistar albino rats (n = 12) were intraperitoneally administered a single dose of streptozotocin (30 mg/kg) to induce diabetes. Streptozotocin-treated and untreated rats (n = 12) were further divided into normal control, normal sitagliptin-treated control, diabetic control, and sitagliptin-treated diabetic groups (n = 6 in each). The normal and diabetic control groups received normal saline, whereas the sitagliptin-treated control and diabetic groups received sitagliptin (100 mg/kg, p.o.). We assessed the serum levels of DN and inflammatory biomarkers. Protein tyrosine phosphatase 1 B (PTP1B), phosphorylated Janus kinase 2 (P-JAK2), and phosphorylated signal transducer activator of transcription (P-STAT3) levels in kidney tissues were assessed using Western blotting, and kidney sections were examined histologically. Sitagliptin reduced DN and inflammatory biomarkers and the expression of PTP1B, p-JAK2, and p-STAT3 (p < 0.001) and improved streptozotocin-induced histological changes in the kidney. These results demonstrate that sitagliptin ameliorates inflammation by inhibiting DPP-4 and consequently modulating the PTP1B-related JAK/STAT axis, leading to the alleviation of DN.
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13
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Nag S, Mandal S, Mukherjee O, Mukherjee S, Kundu R. DPP-4 Inhibitors as a savior for COVID-19 patients with diabetes. Future Virol 2023:10.2217/fvl-2022-0112. [PMID: 37064327 PMCID: PMC10096336 DOI: 10.2217/fvl-2022-0112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 03/01/2023] [Indexed: 04/18/2023]
Abstract
Diabetic patients are at particular risk of severe COVID-19. Human dipeptidyl peptidase-4 (DPP-4) is a membrane-bound aminopeptidase that regulates insulin release by inactivating incretin. DPP-4 inhibitors (DPP-4is) are therefore used as oral anti-diabetic drugs to restore normal insulin levels. These molecules also have anti-inflammatory and anti-hypertension effects. Recent studies on the interactions of SARS-CoV-2 spike glycoprotein and DPP-4 predict a possible entry route for SARS-CoV-2. Therefore, DPP-4is could be effective at reducing the virus-induced 'cytokine storm', thereby ceasing inflammatory injury to vital organs. Moreover, DPP-4is may interfere with viral entry into host cells. Herein, we have reviewed the efficacy of DPP-4is as potential repurposed drugs to reduce the severity of SARS-CoV-2 infection in patients with diabetes.
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Affiliation(s)
- Snehasish Nag
- Department of Zoology, Cell Signaling Laboratory, Visva-Bharati University, Santiniketan, West Bengal, 731 235, India
| | - Samanwita Mandal
- Department of Zoology, Cell Signaling Laboratory, Visva-Bharati University, Santiniketan, West Bengal, 731 235, India
| | - Oindrila Mukherjee
- Department of Zoology, Cell Signaling Laboratory, Visva-Bharati University, Santiniketan, West Bengal, 731 235, India
| | - Suprabhat Mukherjee
- Department of Animal Science, Integrative Biochemistry & Immunology Laboratory, Kazi Nazrul University, Asansol, West Bengal, 713 340, India
- Author for correspondence:
| | - Rakesh Kundu
- Department of Zoology, Cell Signaling Laboratory, Visva-Bharati University, Santiniketan, West Bengal, 731 235, India
- Author for correspondence:
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14
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You S, Bi Y, Miao M, Bao A, Du J, Xu T, Liu CF, Zhang Y, He J, Cao Y, Zhong C. Plasma sDPP4 (Soluble Dipeptidyl Peptidase-4) and Cognitive Impairment After Noncardioembolic Acute Ischemic Stroke. Stroke 2023; 54:113-121. [PMID: 36475470 DOI: 10.1161/strokeaha.122.040798] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND DPP4 (dipeptidyl peptidase-4) inhibitors have been proven to promote neuronal regeneration, reverse the development of cognitive deficits. However, the association of circulating soluble form (sDPP4 [soluble DPP4]) with poststroke cognitive impairment (PSCI) is unclear. We aimed to investigate the association between plasma sDPP4 levels and PSCI in patients with ischemic stroke. METHODS A total of 600 noncardioembolic stroke patients were included based on a preplanned ancillary study from the CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). We used the Montreal Cognitive Assessment to evaluate cognitive function at 3 months follow-up after ischemic stroke. Binary logistic regression analyses were performed to investigate the association of plasma sDPP4 levels with subsequent PSCI. We further calculated integrated discrimination improvement and category-free net reclassification improvement to investigate the incremental prognostic effect of plasma sDPP4 beyond the basic model with conventional risk factors. RESULTS Plasma sDPP4 was inversely associated with PSCI after ischemic stroke, and the adjusted odds ratio (95% CI) for the highest versus lowest quartile of sDPP4 was 0.49 (0.29-0.81; P for trend=0.011). Each 1-SD increase of logarithm-transformed plasma sDPP4 concentration was associated with 17% (odds ratio, 0.83 [95% CI, 0.70-0.99]) lower risk of PSCI. Adding plasma sDPP4 to the basic model notably improved risk reclassification for PSCI, as shown by a category-free net reclassification improvement of 19.10% (95% CI, 2.52%-35.68%; P=0.03) and integrated discrimination improvement of 0.79% (95% CI, 0.13%-1.46%; P=0.02). CONCLUSIONS Higher plasma sDPP4 levels were associated with decreased risk of cognitive impairment after noncardioembolic ischemic stroke.
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Affiliation(s)
- Shoujiang You
- Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, China (S.Y., C.-F.L., Y.C.).,Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China (Y.B., M.M., A.B., J.D., T.X., Y.Z., C.Z.)
| | - Yucong Bi
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China (Y.B., M.M., A.B., J.D., T.X., Y.Z., C.Z.)
| | - Mengyuan Miao
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China (Y.B., M.M., A.B., J.D., T.X., Y.Z., C.Z.)
| | - Anran Bao
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China (Y.B., M.M., A.B., J.D., T.X., Y.Z., C.Z.)
| | - Jigang Du
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China (Y.B., M.M., A.B., J.D., T.X., Y.Z., C.Z.)
| | - Tan Xu
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China (Y.B., M.M., A.B., J.D., T.X., Y.Z., C.Z.)
| | - Chun-Feng Liu
- Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, China (S.Y., C.-F.L., Y.C.).,Institutes of Neuroscience, Soochow University, Suzhou, China (C.-F.L., Y.C.)
| | - Yonghong Zhang
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China (Y.B., M.M., A.B., J.D., T.X., Y.Z., C.Z.)
| | - Jiang He
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (J.H.)
| | - Yongjun Cao
- Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, China (S.Y., C.-F.L., Y.C.).,Institutes of Neuroscience, Soochow University, Suzhou, China (C.-F.L., Y.C.)
| | - Chongke Zhong
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China (Y.B., M.M., A.B., J.D., T.X., Y.Z., C.Z.)
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15
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Theofilis P, Sagris M, Oikonomou E, Antonopoulos AS, Siasos G, Tsioufis K, Tousoulis D. The Anti-Inflammatory Effect of Novel Antidiabetic Agents. Life (Basel) 2022; 12:1829. [PMID: 36362984 PMCID: PMC9696750 DOI: 10.3390/life12111829] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 09/28/2022] [Accepted: 11/05/2022] [Indexed: 08/10/2023] Open
Abstract
The incidence of type 2 diabetes (T2DM) has been increasing worldwide and remains one of the leading causes of atherosclerotic disease. Several antidiabetic agents have been introduced in trying to regulate glucose control levels with different mechanisms of action. These agents, and sodium-glucose cotransporter-2 inhibitors in particular, have been endorsed by contemporary guidelines in patients with or without T2DM. Their widespread usage during the last three decades has raised awareness in the scientific community concerning their pleiotropic mechanisms of action, including their putative anti-inflammatory effect. In this review, we delve into the anti-inflammatory role and mechanism of the existing antidiabetic agents in the cardiovascular system and their potential use in other chronic sterile inflammatory conditions.
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Affiliation(s)
- Panagiotis Theofilis
- 1st Cardiology Department, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece
| | - Marios Sagris
- 3rd Cardiology Department, Thoracic Diseases Hospital “Sotiria”, University of Athens Medical School, 11527 Athens, Greece
| | - Evangelos Oikonomou
- 1st Cardiology Department, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece
- 3rd Cardiology Department, Thoracic Diseases Hospital “Sotiria”, University of Athens Medical School, 11527 Athens, Greece
| | - Alexios S. Antonopoulos
- 1st Cardiology Department, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece
| | - Gerasimos Siasos
- 1st Cardiology Department, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece
- 3rd Cardiology Department, Thoracic Diseases Hospital “Sotiria”, University of Athens Medical School, 11527 Athens, Greece
| | - Kostas Tsioufis
- 1st Cardiology Department, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece
| | - Dimitris Tousoulis
- 1st Cardiology Department, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece
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16
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Ni Y, Zheng L, Nan S, Ke L, Fu Z, Jin J. Enterorenal crosstalks in diabetic nephropathy and novel therapeutics targeting the gut microbiota. Acta Biochim Biophys Sin (Shanghai) 2022; 54:1406-1420. [PMID: 36239349 PMCID: PMC9827797 DOI: 10.3724/abbs.2022140] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 07/03/2022] [Indexed: 12/29/2022] Open
Abstract
The role of gut-kidney crosstalk in the progression of diabetic nephropathy (DN) is receiving increasing concern. On one hand, the decline in renal function increases circulating uremic toxins and affects the composition and function of gut microbiota. On the other hand, intestinal dysbiosis destroys the epithelial barrier, leading to increased exposure to endotoxins, thereby exacerbating kidney damage by inducing systemic inflammation. Dietary inventions, such as higher fiber intake, prebiotics, probiotics, postbiotics, fecal microbial transplantation (FMT), and engineering bacteria and phages, are potential microbiota-based therapies for DN. Furthermore, novel diabetic agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-dependent glucose transporter-2 (SGLT-2) inhibitors, may affect the progression of DN partly through gut microbiota. In the current review, we mainly summarize the evidence concerning the gut-kidney axis in the advancement of DN and discuss therapies targeting the gut microbiota, expecting to provide new insight into the clinical treatment of DN.
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Affiliation(s)
- Yinhua Ni
- College of Biotechnology and BioengineeringZhejiang University of TechnologyHangzhou310032China
| | - Liujie Zheng
- College of Biotechnology and BioengineeringZhejiang University of TechnologyHangzhou310032China
| | - Sujie Nan
- College of Biotechnology and BioengineeringZhejiang University of TechnologyHangzhou310032China
| | - Lehui Ke
- College of Biotechnology and BioengineeringZhejiang University of TechnologyHangzhou310032China
| | - Zhengwei Fu
- College of Biotechnology and BioengineeringZhejiang University of TechnologyHangzhou310032China
| | - Juan Jin
- Urology & Nephrology CenterDepartment of NephrologyZhejiang Provincial People’s Hospital (Affiliated People’s HospitalHangzhou Medical College)Hangzhou310014China
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17
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Effects of DPP4 Inhibitor in Platelet Reactivity and Other Cardiac Risk Markers in Patients with Type 2 Diabetes and Acute Myocardial Infarction. J Clin Med 2022; 11:jcm11195776. [PMID: 36233642 PMCID: PMC9571017 DOI: 10.3390/jcm11195776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/23/2022] [Accepted: 09/25/2022] [Indexed: 12/01/2022] Open
Abstract
Background: The management of acute myocardial infarction (AMI) presents several challenges in patients with diabetes, among them the higher rate of recurrent thrombotic events, hyperglycemia and risk of subsequent heart failure (HF). The objective of our study was to evaluate effects of DPP-4 inhibitors (DPP-4i) on platelet reactivity (main objective) and cardiac risk markers. Methods: We performed a single-center double-blind randomized trial. A total of 70 patients with type 2 diabetes (T2DM) with AMI Killip ≤2 on dual-antiplatelet therapy (aspirin plus clopidogrel) were randomized to receive sitagliptin 100 mg or saxagliptin 5 mg daily or matching placebo. Platelet reactivity was assessed at baseline, 4 days (primary endpoint) and 30 days (secondary endpoint) after randomization, using VerifyNow Aspirin™ assay, expressed as aspirin reaction units (ARUs); B-type natriuretic peptide (BNP) in pg/mL was assessed at baseline and 30 days after (secondary endpoint). Results: Mean age was 62.6 ± 8.8 years, 45 (64.3%) male, and 52 (74.3%) of patients presented with ST-segment elevation MI. For primary endpoint, there were no differences in mean platelet reactivity (p = 0.51) between the DPP-4i (8.00 {−65.00; 63.00}) and placebo (−14.00 {−77.00; 52.00}) groups, as well in mean BNP levels (p = 0.14) between DPP-4i (−36.00 {−110.00; 15.00}) and placebo (−13.00 {−50.00; 27.00}). There was no difference between groups in cardiac adverse events. Conclusions: DPP4 inhibitor did not reduce platelet aggregation among patients with type 2 diabetes hospitalized with AMI. Moreover, the use of DPP-4i did not show an increase in BNP levels or in the incidence of cardiac adverse events. These findings suggests that DPP-4i could be an option for management of T2DM patients with acute MI.
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18
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Mozafari N, Dehshahri A, Ashrafi H, Mohammadi-Samani S, Shahbazi MA, Heidari R, Azarpira N, Azadi A. Vesicles of yeast cell wall-sitagliptin to alleviate neuroinflammation in Alzheimer's disease. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2022; 44:102575. [PMID: 35714923 DOI: 10.1016/j.nano.2022.102575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/26/2022] [Accepted: 06/05/2022] [Indexed: 06/15/2023]
Abstract
A cell-based drug delivery system based on yeast-cell wall loaded with sitagliptin, a drug with an anti-inflammatory effect, was developed to control neuroinflammation associated with Alzheimer's disease. The optimized nanoparticles had a spherical shape with a negative surface charge, and were shown to be less toxic than the carrier and sitagliptin. Moreover, the nanoparticles caused anti-inflammatory effects against tumor necrosis factor-alpha in mice model of neuroinflammation. The pharmacokinetics study showed the brain concentration of drug in the nanoparticles group was much higher than in the control group. To evaluate the effect of P-glycoprotein on brain entry of sitagliptin, the experiment was repeated with verapamil, as a P-glycoprotein inhibitor. Brain concentration of the nanoparticles group remained approximately unchanged, proving the "Trojan Horse" effect of the developed nanocarriers. The results are promising for using yeast-cell wall as a carrier for targeted delivery to immune cells for the management of inflammation.
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Affiliation(s)
- Negin Mozafari
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Dehshahri
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Pharmaceutical Sciences Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hajar Ashrafi
- Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Soliman Mohammadi-Samani
- Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Pharmaceutical Sciences Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad-Ali Shahbazi
- Department of Biomedical Engineering, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands; Zanjan Pharmaceutical Nanotechnology Research Center (ZPNRC), Zanjan University of Medical Sciences, 45139-56184 Zanjan, Iran
| | - Reza Heidari
- Pharmaceutical Sciences Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Azadi
- Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Pharmaceutical Sciences Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran.
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19
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You S, Miao M, Lu Z, Bao A, Du J, Che B, Xu T, Zhong C, Cao Y, Liu CF, Zhang Y, He J. Plasma-Soluble Dipeptidyl Peptidase 4 and Risk of Major Cardiovascular Events After Ischemic Stroke: Secondary Analysis of China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). Neurology 2022; 99:e925-e934. [PMID: 35654589 DOI: 10.1212/wnl.0000000000200784] [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: 11/04/2021] [Accepted: 04/11/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Recent studies have suggested that plasma soluble dipeptidyl peptidase-4 (sDPP4) have important physiological effects, which may influence the prognosis of ischemic stroke. Our study aimed to examine the relationship between plasma sDDP4 levels and long-term clinical outcomes among acute ischemic stroke patients. METHODS Secondary analysis was conducted among 3,564 participants (2,270 men and 1,294 women) from the China Antihypertensive Trial in Acute Ischemic Stroke with baseline measurement of plasma sDPP4 levels. We evaluated the associations between plasma sDPP4 levels and 2-year clinical outcomes using logistic regression and Cox regression models. We further investigated the predictive utility of sDPP4 by calculating net reclassification index (NRI) and integrated discrimination improvement (IDI). RESULTS The highest plasma sDPP4 quartile was associated with lower risk of cardiovascular events (HR 0.62, 95% CI 0.45-0.87), recurrent stroke (HR 0.70, 95% CI 0.49-0.99), all-cause mortality (HR 0.62, 95% CI 0.44-0.87), stroke-specific mortality (HR 0.65, 95% CI 0.44-0.94) and poor functional outcomes (OR 0.66, 95% CI 0.53-0.82) at 2 years compared with the lowest sDPP4 category in multivariable models. The addition of plasma sDPP4 to conventional risk factors model significantly improved risk prediction of all outcomes. DISCUSSION In this study, we found that higher plasma sDPP4 levels in acute ischemic stroke patients were associated with decreased risks of cardiovascular events, recurrent stroke, all-cause mortality, and poor functional outcomes after ischemic stroke. These findings suggest that plasma sDPP4 may be a potential prognostic marker for initial risk stratification in patients with acute ischemic stroke.
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Affiliation(s)
- Shoujiang You
- Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Mengyuan Miao
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou 215123, China
| | - Zian Lu
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou 215123, China
| | - Anran Bao
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou 215123, China
| | - Jigang Du
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou 215123, China
| | - Bizhong Che
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou 215123, China
| | - Tan Xu
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou 215123, China
| | - Chongke Zhong
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou 215123, China
| | - Yongjun Cao
- Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.,Institutes of Neuroscience, Soochow University, Suzhou 215123, China
| | - Chun-Feng Liu
- Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.,Institutes of Neuroscience, Soochow University, Suzhou 215123, China
| | - Yonghong Zhang
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou 215123, China
| | - Jiang He
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA
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Piątkowska-Chmiel I, Gawrońska-Grzywacz M, Popiołek Ł, Herbet M, Dudka J. The novel adamantane derivatives as potential mediators of inflammation and neural plasticity in diabetes mice with cognitive impairment. Sci Rep 2022; 12:6708. [PMID: 35468904 PMCID: PMC9035983 DOI: 10.1038/s41598-022-10187-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 03/14/2022] [Indexed: 12/12/2022] Open
Abstract
Diabetes is a chronic disease leading to memory difficulties and deterioration of learning abilities. The previous studies showed that modulation of inflammatory pathways in the diabetic brain may reduce dysfunction or cell death in brain areas which are important for control of cognitive function. In the present study, we investigated the neuroprotective actions of newly synthesized adamantane derivatives on diabetes-induced cognitive impairment in mice. Our study relied on the fact that both vildagliptin and saxagliptin belong to DPP4 inhibitors and, contain adamantanyl group. Efficacy of tested compounds at reversing diabetes-induced different types of memory impairment was evaluated with the use of selected behavioural tests. The following neuroinflammatory indicators were also analyzed: neuroinflammatory indicators and the expression of genes involved in the inflammatory response of brain (Cav1, Bdnf). Our study demonstrated that new adamantane derivatives, similarly to DPP4 inhibitors, can restrict diabetes-induced cognitive deficits. We demonstrated that the overexpression of GLP-1-glucagon-like peptide as well as Bdnf, Cav1 genes translate into central blockade of pro-inflammatory synthesis of cytokines and significantly improvement on memory performance in diabetes mice. Newly synthesized adamantane derivatives might have important roles in prevention and treatment of cognitive impairment by inflammatory events in patients with diabetes or related diseases.
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Affiliation(s)
- Iwona Piątkowska-Chmiel
- Chair and Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 8b Jaczewskiego Street, 20-090, Lublin, Poland.
| | - Monika Gawrońska-Grzywacz
- Chair and Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 8b Jaczewskiego Street, 20-090, Lublin, Poland
| | - Łukasz Popiołek
- Chair and Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki Street, 20-093, Lublin, Poland
| | - Mariola Herbet
- Chair and Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 8b Jaczewskiego Street, 20-090, Lublin, Poland
| | - Jarosław Dudka
- Chair and Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 8b Jaczewskiego Street, 20-090, Lublin, Poland
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21
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Does DPP-IV Inhibition Offer New Avenues for Therapeutic Intervention in Malignant Disease? Cancers (Basel) 2022; 14:cancers14092072. [PMID: 35565202 PMCID: PMC9103952 DOI: 10.3390/cancers14092072] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/16/2022] [Accepted: 04/18/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary There is growing interest in identifying the effects of antidiabetic agents on cancer risk, progression, and anti-cancer treatment due to the long-term use of these medications and the inherently increased risk of malignancies in diabetic patients. Tumor development and progression are affected by multiple mediators in the tumor microenvironment, several of which may be proteolytically modified by the multifunctional protease dipeptidyl peptidase-IV (DPP-IV, CD26). Currently, low-molecular-weight DPP-IV inhibitors (gliptins) are used in patients with type 2 diabetes based on the observation that DPP-IV inhibition enhances insulin secretion by increasing the bioavailability of incretins. However, the DPP-IV-mediated cleavage of other biopeptides and chemokines is also prevented by gliptins. The potential utility of gliptins in other areas of medicine, including cancer, is therefore being evaluated. Here, we critically review the existing evidence on the role of DPP-IV inhibitors in cancer pathogenesis, their potential to be used in anti-cancer treatment, and the possible perils associated with this approach. Abstract Dipeptidyl peptidase IV (DPP-IV, CD26) is frequently dysregulated in cancer and plays an important role in regulating multiple bioactive peptides with the potential to influence cancer progression and the recruitment of immune cells. Therefore, it represents a potential contributing factor to cancer pathogenesis and an attractive therapeutic target. Specific DPP-IV inhibitors (gliptins) are currently used in patients with type 2 diabetes mellitus to promote insulin secretion by prolonging the activity of the incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Nevertheless, the modulation of the bioavailability and function of other DPP-IV substrates, including chemokines, raises the possibility that the use of these orally administered drugs with favorable side-effect profiles might be extended beyond the treatment of hyperglycemia. In this review, we critically examine the possible utilization of DPP-IV inhibition in cancer prevention and various aspects of cancer treatment and discuss the potential perils associated with the inhibition of DPP-IV in cancer. The current literature is summarized regarding the possible chemopreventive and cytotoxic effects of gliptins and their potential utility in modulating the anti-tumor immune response, enhancing hematopoietic stem cell transplantation, preventing acute graft-versus-host disease, and alleviating the side-effects of conventional anti-tumor treatments.
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22
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Nasr NE, Sadek KM. Role and mechanism(s) of incretin-dependent therapies for treating diabetes mellitus. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:18408-18422. [PMID: 35031999 DOI: 10.1007/s11356-022-18534-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 01/03/2022] [Indexed: 06/14/2023]
Abstract
Diabetes mellitus (DM) is a worldwide ailment which leads to chronic complications like cardiac disorders, renal perturbations, limb amputation and blindness. Type one diabetes (T1DM), Type two diabetes (T2DM), Another types of diabetes, such as genetic errors in function of β-cell and action of insulin, cystic fibrosis, chemical-instigated diabetes or following tissue transplantation), and pregnancy DM (GDM). In response to nutritional ingestion, the gut may release a pancreatic stimulant that affects carbohydrate metabolism. The duodenum produces a 'chemical excitant' that stimulates pancreatic output, and researchers have sought to cure diabetes using gut extract injections, coining the word 'incretin' to describe the phenomena. Incretins include GIP and GLP-1. The 'enteroinsular axis' is the link between pancreas and intestine. Nutrient, neuronal and hormonal impulses from intestine to cells secreting insulin were thought to be part of this axis. In addition, the hormonal component, incretin, must meet two requirements: (1) it secreted by foods, mainly carbohydrates, and (2) it must induce an insulinotropic effect which is glucose-dependent. In this review, we clarify the ability of using incretin-dependent treatments for treating DM.
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Affiliation(s)
- Nasr E Nasr
- Department of Biochemistry, Faculty of Veterinary Medicine, Kafr El-Sheikh University, Kafr El-Sheikh, Egypt
| | - Kadry M Sadek
- Department of Biochemistry, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt.
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23
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Daneshjou D, Mehranjani MS, Zadehmodarres S, Shariatzadeh MA, Mofarahe ZS. Sitagliptin/metformin improves the fertilization rate and embryo quality in polycystic ovary syndrome patients through increasing the expression of GDF9 and BMP15: A new alternative to metformin (a ra ndomized trial). J Reprod Immunol 2022; 150:103499. [DOI: 10.1016/j.jri.2022.103499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 01/25/2022] [Accepted: 02/10/2022] [Indexed: 10/19/2022]
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24
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Ngcobo SR, Nkambule BB, Nyambuya TM, Mokgalaboni K, Ntsethe A, Mxinwa V, Ziqubu K, Ntamo Y, Nyawo TA, Dludla PV. Activated monocytes as a therapeutic target to attenuate vascular inflammation and lower cardiovascular disease-risk in patients with type 2 diabetes: A systematic review of preclinical and clinical studies. Biomed Pharmacother 2022; 146:112579. [PMID: 35062054 DOI: 10.1016/j.biopha.2021.112579] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 12/20/2021] [Accepted: 12/20/2021] [Indexed: 12/20/2022] Open
Abstract
Low grade inflammation is associated with the progression of atherosclerosis. Patients with type 2 diabetes (T2D) have altered cholesterol levels, which are targeted by free radicals to promote lipid peroxidation. Elevated levels of monocyte-associated cytokines such as interleukin (IL)-6, monocyte chemoattractant protein 1 (MCP-1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and tumor necrosis factor-alpha (TNF-α), subsequently drive endothelial tissue injury. In fact, the levels of circulating platelet-monocyte aggregates in patients with T2D is a robust marker for atherosclerosis and a cardiovascular disease (CVD)-risk factor. To identify eligible studies, we searched the major online databases using PubMed and Google Scholar. The cumulative evidence synthesized in the current review suggests that, traditional therapies which include thiazolidinediones, statins and some calcium channel blockers can be useful in the primary prevention of atherosclerosis by inhibiting the formation of monocyte-derived microparticles, and pro-inflammatory cytokines such as IL-6, TNF-α, MCP-1, and NF-κB in patients with T2D. Future studies are needed to ascertain whether the combination of dietary interventions and glucose or lipid lowering agents can provide an enhanced cardioprotection in patients with T2D.
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Affiliation(s)
- Siphamandla R Ngcobo
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban 4000, South Africa
| | - Bongani B Nkambule
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban 4000, South Africa
| | - Tawanda M Nyambuya
- Department of Health Sciences, Namibia University of Science and Technology, Windhoek 9000, Namibia
| | - Kabelo Mokgalaboni
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban 4000, South Africa
| | - Aviwe Ntsethe
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban 4000, South Africa
| | - Vuyolwethu Mxinwa
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban 4000, South Africa
| | - Khanyisani Ziqubu
- Department of Biochemistry, North-West University, Mmabatho 2745, South Africa
| | - Yonela Ntamo
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa
| | - Thembeka A Nyawo
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa; Centre for Cardiometabolic Research in Africa (CARMA), Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa
| | - Phiwayinkosi V Dludla
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa.
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25
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Furuhashi M, Sakuma I, Morimoto T, Higashiura Y, Sakai A, Matsumoto M, Sakuma M, Shimabukuro M, Nomiyama T, Arasaki O, Node K, Ueda S. Differential Effects of DPP-4 Inhibitors, Anagliptin and Sitagliptin, on PCSK9 Levels in Patients with Type 2 Diabetes Mellitus who are Receiving Statin Therapy. J Atheroscler Thromb 2022; 29:24-37. [PMID: 33342939 PMCID: PMC8737073 DOI: 10.5551/jat.58396] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Aim:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades the low-density lipoprotein (LDL) receptor, leading to hypercholesterolemia and cardiovascular risk. Treatment with a statin leads to a compensatory increase in circulating PCSK9 level. Anagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to decrease LDL cholesterol (LDL-C) levels to a greater extent than that by sitagliptin, another DPP-4 inhibitor, in the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. We investigated PCSK9 concentration in type 2 diabetes mellitus (T2DM) and the impact of treatment with anagliptin or sitagliptin on PCSK9 level as a sub-analysis of the REASON trial.
Methods:
PCSK9 concentration was measured at baseline and after 52 weeks of treatment with anagliptin (
n
=122) or sitagliptin (
n
=128) in patients with T2DM who were receiving statin therapy. All of the included patients had been treated with a DPP-4 inhibitor prior to randomization.
Results:
Baseline PCSK9 level was positively, but not significantly, correlated with LDL-C and was independently associated with platelet count and level of triglycerides. Concomitant with reduction of LDL-C, but not hemoglobin A1c (HbA1c), by anagliptin, PCSK9 level was significantly increased by treatment with sitagliptin (218±98 vs. 242±115 ng/mL,
P
=0.01), but not anagliptin (233±97 vs. 250±106 ng/mL,
P
=0.07).
Conclusions:
PCSK9 level is independently associated with platelet count and level of triglycerides, but not LDL-C, in patients with T2DM. Anagliptin reduces LDL-C level independent of HbA1c control in patients with T2DM who are on statin therapy possibly by suppressing excess statin-mediated PCSK9 induction and subsequent degradation of the LDL receptor.
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Affiliation(s)
- Masato Furuhashi
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine
| | | | | | - Yukimura Higashiura
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine
| | - Akiko Sakai
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine
| | - Megumi Matsumoto
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine
| | - Mio Sakuma
- Department of Clinical Epidemiology, Hyogo College of Medicine
| | - Michio Shimabukuro
- Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical University
| | - Takashi Nomiyama
- Department of Diabetes, Metabolism and Endocrinology, International University of Health and Welfare Ichikawa Hospital
| | - Osamu Arasaki
- Department of Cardiology, Tomishiro Central Hospital
| | - Koichi Node
- Department of Cardiovascular Medicine, Saga University
| | - Shinichiro Ueda
- Department of Pharmacology and Therapeutics, University of the Ryukyus
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Shi H, Peng M, Liu Y, Kan Z, Li W, Yang T. Retracted: Effect of dipeptidyl peptidase-4 inhibitors on the progression of atherosclerosis in patients with type 2 diabetes mellitus: A meta-analysis of randomised controlled trials. Int J Clin Pract 2021; 75:e14213. [PMID: 33819377 DOI: 10.1111/ijcp.14213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 03/14/2021] [Indexed: 11/26/2022] Open
Abstract
Yang, T, Li, W, Kan, Z, Liu, Y, Peng, M, Shi, H, Effect of dipeptidyl peptidase-4 inhibitors on the progression of atherosclerosis in patients with type 2 diabetes mellitus: A meta-analysis of randomised controlled trials. Int J Clin Pract. 2021; 00:e14213. https://onlinelibrary.wiley.com/doi/10.1111/ijcp.14213. The above article from the International Journal of Clinical Practice, published online on 5 April 2021 in Wiley Online Library (wileyonlinelibrary.com), has been retracted at the request of the authors, and by agreement of the journal Editor in Chief, Charles Young, and John Wiley and Sons Ltd. The retraction has been agreed following an author review of the research which led to the removal of some studies which did not meet the inclusion criteria. Following the removal of these studies the overall sample size was too small and the studies still included too heterogenuous for the results and conclusions to be reliable.
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Affiliation(s)
- Hongshuo Shi
- College of traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Min Peng
- Department of Traditional Chinese Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yufan Liu
- College of traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zunqi Kan
- College of traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wenwen Li
- College of traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Tiantian Yang
- Department of Traditional Chinese Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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27
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SARS-CoV-2 and diabetes: A potential therapeutic effect of dipeptidyl peptidase 4 inhibitors in diabetic patients diagnosed with COVID-19. Metabol Open 2021; 12:100134. [PMID: 34661092 PMCID: PMC8511553 DOI: 10.1016/j.metop.2021.100134] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 10/10/2021] [Indexed: 01/08/2023] Open
Abstract
COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 and has become an urgent economic and health challenge. Dipeptidyl peptidase 4 (DPP4), also mentioned as a cluster of differentiation 26 (CD26) is a serine exopeptidase found in two arrangements: a soluble form (sDPP-4) and a plasma membrane-bound form. Because other coronaviruses enter the cells by binding to DPP-4, it has been speculated that DPP-4 inhibitors may exert activity against COVID-19. Therefore, this review aimed to summarize the potential therapeutic effect of dipeptidyl peptidase 4 inhibitors in diabetic patients diagnosed with COVID-19. To include different studies, publications related to Dipeptidyl peptidase-4 inhibitor use and clinical outcomes from COVID-19 were searched from the databases such as Web of Science, PubMed, Medline, Elsevier, Google Scholar, and SCOPUS, via English key terms. A direct engrossment of DPP4 in COVID-19 needs to be elucidated, there is also evidence confirming that DPP4 inhibitors exert anti-fibrotic and modulate inflammation activity. Thus, the use of DPP-4 inhibitors could reduce mortality due to COVID-19 or improve the progression of COVID-19; this evidence may support the management of diabetic patients diagnosed with COVID-19; however more well-designed investigation is urgently required.
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28
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Elazab ST, Samir O, Abass ME. Synergistic effects of sitagliptin and losartan against fipronil-induced hepatotoxicity in rats. Vet World 2021; 14:1901-1907. [PMID: 34475715 PMCID: PMC8404120 DOI: 10.14202/vetworld.2021.1901-1907] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 06/10/2021] [Indexed: 01/24/2023] Open
Abstract
Background and Aim Fipronil (FPN) is a potent pesticide that is heavily used around the world in agriculture. However, its irrational use could potentially have deleterious effects on animals and humans. The present study aimed to investigate the ability of sitagliptin (Sit) and losartan (LOS), when used both individually or concurrently, to guard rat liver against the acute hepatotoxicity caused by FPN. Materials and Methods Forty-two adult male Wistar rats were equally divided into seven groups (6/group). Group I (control) received normal saline (0.5 mL/rat, vehicle for all treatments) by gavage once daily for 10 days. Group II received oral Sit (10 mg/kg body weight [BW]) daily for 10 days and Group III received oral LOS (5 mg/kg BW) daily for 10 days. Group IV received oral FPN (19.4 mg/kg BW; 1/5 of the oral LD50) for the past 5 days of the study. Groups V and VI received oral Sit (10 mg/kg BW) and LOS (5 mg/kg BW) daily, respectively, 5 days prior and 5 days during FPN administration (19.4 mg/kg BW). Group VII received oral Sit (10 mg/kg BW) and LOS (5 mg/kg BW) for 10 days with daily FPN during the past 5 days. After the end of the treatment period, the rats were humanely sacrificed and blood and liver tissue samples were collected for biochemical analysis and histopathological and immunohistochemical investigations. Results FPN administration resulted in elevated alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase serum concentrations as well as increased malondialdehyde levels and reduced catalase, superoxide dismutase, glutathione peroxidase, and glutathione activity. The histopathological investigation showed disorganization of the hepatic cords and focal necrosis of the hepatocytes in FPN-intoxicated rats. Furthermore, the immunohistochemical examination showed that hepatic caspase-3 was overexpressed in the FPN-treated rats. The administration of Sit and LOS before and alongside FPN markedly mitigated the alterations caused by FPN and the hepatoprotective effects were more prominent in the combination group. Conclusion Sit and LOS, both individually or in combination, confers considerable hepatoprotection against FPN-induced hepatotoxicity.
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Affiliation(s)
- Sara T Elazab
- Department of Pharmacology, Faculty of Veterinary Medicine, Mansoura University, Mansoura,35516, Egypt
| | - Omar Samir
- Laboratory Animal Resource Center in Transborder Medical Research Center, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.,Department of Pathology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Marwa E Abass
- Department of Surgery, Anesthesiology and Radiology Faculty of Veterinary Medicine, Mansoura University, Mansoura, 35516, Egypt
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29
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In Situ Neutral System Synthesis, Spectroscopic, and Biological Interpretations of Magnesium(II), Calcium(II), Chromium(III), Zinc(II), Copper(II) and Selenium(IV) Sitagliptin Complexes. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18158030. [PMID: 34360322 PMCID: PMC8345415 DOI: 10.3390/ijerph18158030] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/18/2021] [Accepted: 07/21/2021] [Indexed: 12/29/2022]
Abstract
Magnesium(II), calcium(II), chromium(III), zinc(II), copper(II), and selenium(IV) sitagliptin (STG) complexes—with the general formulas [Mg(STG)2(Cl)2]·6H2O, [Ca(STG)2(Cl)2], [Cr(STG)2(Cl)2]Cl.6H2O, [Zn(STG)2(Cl)2], [Cu(STG)2(Cl)2]·2H2O, and [Se(STG)2(Cl)2]Cl2, respectively—were designed and synthesized by the chemical reactions between metal(II, III, and IV) chloride salts with an STG ligand in situ methanol solvent in a 1:2 stoichiometric ratio (metal:ligand). Tentative structures of the complexes were proposed based on elemental analysis, molar conductance, magnetic moments, thermogravimetric analysis, and spectral (infrared, electronic, and 1H NMR) data. The particle size and morphological investigation were checked on the bases of scanning electron microscopy, transmission electron microscopy, and X-ray powder diffraction analyses. All the Mg2+, Ca2+, Cr3+, Zn2+, Cu2+, and Se4+ complexes were found to be six-coordinated, wherein the STG ligands act as bidentate chelating agents. This study demonstrates that pancreatic tissues are affected by the induction of experimental diabetes mellitus and clarifies the potential of the synthesized STG complexes, which was found to more significantly improve insulin secretion and the pancreatic and glycometabolic complications of diabetic rats than STG alone.
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30
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Ramos-Rincón JM, Pérez-Belmonte LM, Carrasco-Sánchez FJ, Jansen-Chaparro S, De-Sousa-Baena M, Bueno-Fonseca J, Pérez-Aguilar M, Arévalo-Cañas C, Bacete Cebrian M, Méndez-Bailón M, Fiteni Mera I, González García A, Navarro Romero F, Tuñón de Almeida C, Muñiz Nicolás G, González Noya A, Hernández Milian A, García García GM, Alcalá Pedrajas JN, Herrero García V, Corral-Gudino L, Comas Casanova P, Meijide Míguez H, Casas-Rojo JM, Gómez-Huelgas R. Cardiometabolic Therapy and Mortality in Very Old Patients With Diabetes Hospitalized due to COVID-19. J Gerontol A Biol Sci Med Sci 2021; 76:e102-e109. [PMID: 33945610 PMCID: PMC8135901 DOI: 10.1093/gerona/glab124] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Indexed: 12/19/2022] Open
Abstract
Background The effects of cardiometabolic drugs on the prognosis of diabetic patients with COVID-19, especially very old patients, are not well-known. This work aims to analyze the association between preadmission cardiometabolic therapy (antidiabetic, antiaggregant, antihypertensive, and lipid-lowering drugs) and in-hospital mortality among patients ≥80 years with type 2 diabetes mellitus hospitalized for COVID-19. Methods We conducted a nationwide, multicenter, observational study in patients ≥80 years with type 2 diabetes mellitus hospitalized for COVID-19 between March 1 and May 29, 2020. The primary outcome measure was in-hospital mortality. A multivariate logistic regression analysis were performed to assess the association between preadmission cardiometabolic therapy and in-hospital mortality. Results Of the 2,763 patients ≥80 years old hospitalized due to COVID-19, 790 (28.6%) had T2DM. Of these patients, 385 (48.7%) died during admission. On the multivariate analysis, the use of dipeptidyl peptidase-4 inhibitors (AOR 0.502, 95%CI 0.309-0.815, p=0.005) and angiotensin receptor blockers (AOR 0.454, 95%CI 0.274-0.759, p=0.003) were independent protectors against in-hospital mortality whereas the use of acetylsalicylic acid was associated with higher in-hospital mortality (AOR 1.761, 95%CI 1.092-2.842, p=0.020). Other antidiabetic drugs, angiotensin-converting enzyme inhibitors and statins showed neutral association with in-hospital mortality. Conclusions We found important differences between cardiometabolic drugs and in-hospital mortality in older patients with type 2 diabetes mellitus hospitalized for COVID-19. Preadmission treatment with dipeptidyl peptidase-4 inhibitors and angiotensin receptor blockers could reduce in-hospital mortality; other antidiabetic drugs, angiotensin-converting enzyme inhibitors and statins seem to have a neutral effect; and acetylsalicylic acid could be associated with excess mortality.
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Affiliation(s)
| | - Luis M Pérez-Belmonte
- Internal Medicine Department, Regional University Hospital of Málaga, Biomedical Research Institute of Málaga (IBIMA), University of Málaga (UMA), Spain
| | | | - Sergio Jansen-Chaparro
- Internal Medicine Department, Regional University Hospital of Málaga, Biomedical Research Institute of Málaga (IBIMA), University of Málaga (UMA), Spain
| | | | - José Bueno-Fonseca
- Internal Medicine Department, Regional University Hospital of Málaga, Biomedical Research Institute of Málaga (IBIMA), University of Málaga (UMA), Spain
| | - Maria Pérez-Aguilar
- Internal Medicine Department, Juan Ramón Jiménez University Hospital, Huelva, Spain
| | - Coral Arévalo-Cañas
- Internal Medicine Department, 12 de Octubre University Hospital, Madrid, Spain
| | - Marta Bacete Cebrian
- Internal Medicine Department, Gregorio Marañon University Hospital, Madrid, Spain
| | - Manuel Méndez-Bailón
- Internal Medicine Department, San Carlos Clinical Hospital, Complutense University, Madrid, Spain
| | | | | | | | | | | | | | | | | | | | | | - Luis Corral-Gudino
- Internal Medicine Department, Río Hortega University Hospital, Regional Health Management of Castilla y Leon (SACYL), Valladolid University, Spain
| | | | | | | | - Ricardo Gómez-Huelgas
- Internal Medicine Department, Regional University Hospital of Málaga, Biomedical Research Institute of Málaga (IBIMA), University of Málaga (UMA), Spain
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Helmstädter J, Keppeler K, Aust F, Küster L, Frenis K, Filippou K, Vujacic-Mirski K, Tsohataridis S, Kalinovic S, Kröller-Schön S, Oelze M, Bosmann M, Münzel T, Daiber A, Steven S. GLP-1 Analog Liraglutide Improves Vascular Function in Polymicrobial Sepsis by Reduction of Oxidative Stress and Inflammation. Antioxidants (Basel) 2021; 10:antiox10081175. [PMID: 34439423 PMCID: PMC8388926 DOI: 10.3390/antiox10081175] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/20/2021] [Accepted: 07/21/2021] [Indexed: 12/12/2022] Open
Abstract
Sepsis causes high mortality in the setting of septic shock. LEADER and other trials revealed cardioprotective and anti-inflammatory properties of glucagon-like peptide-1 (GLP-1) analogs like liraglutide (Lira). We previously demonstrated improved survival in lipopolysaccharide (LPS)-induced endotoxemia by inhibition of GLP-1 degradation. Here we investigate the effects of Lira in the polymicrobial sepsis model of cecal ligation and puncture (CLP). C57BL/6J mice were intraperitoneally injected with Lira (200 µg/kg/d; 3 days) and sepsis induced by CLP after one day of GLP-1 analog treatment. Survival and body temperature were monitored. Aortic vascular function (isometric tension recording), protein expression (immunohistochemistry and dot blot) and gene expression (qRT-PCR) were determined. Endothelium-dependent relaxation in the aorta was impaired by CLP and correlated with markers of inflammation (e.g., interleukin 6 and inducible nitric oxide synthase) and oxidative stress (e.g., 3-nitrotyrosine) was higher in septic mice, all of which was almost completely normalized by Lira therapy. We demonstrate that the GLP-1 analog Lira ameliorates sepsis-induced endothelial dysfunction by the reduction of vascular inflammation and oxidative stress. Accordingly, the findings suggest that the antioxidant and anti-inflammatory effects of GLP-1 analogs may be a valuable tool to protect the cardiovascular system from dysbalanced inflammation in polymicrobial sepsis.
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Affiliation(s)
- Johanna Helmstädter
- Center for Cardiology, Department of Cardiology 1–Molecular Cardiology, University Medical Center, 55131 Mainz, Germany; (J.H.); (K.K.); (F.A.); (L.K.); (K.F.); (K.F.); (K.V.-M.); (S.T.); (S.K.); (S.K.-S.); (M.O.); (T.M.); (A.D.)
| | - Karin Keppeler
- Center for Cardiology, Department of Cardiology 1–Molecular Cardiology, University Medical Center, 55131 Mainz, Germany; (J.H.); (K.K.); (F.A.); (L.K.); (K.F.); (K.F.); (K.V.-M.); (S.T.); (S.K.); (S.K.-S.); (M.O.); (T.M.); (A.D.)
| | - Franziska Aust
- Center for Cardiology, Department of Cardiology 1–Molecular Cardiology, University Medical Center, 55131 Mainz, Germany; (J.H.); (K.K.); (F.A.); (L.K.); (K.F.); (K.F.); (K.V.-M.); (S.T.); (S.K.); (S.K.-S.); (M.O.); (T.M.); (A.D.)
| | - Leonie Küster
- Center for Cardiology, Department of Cardiology 1–Molecular Cardiology, University Medical Center, 55131 Mainz, Germany; (J.H.); (K.K.); (F.A.); (L.K.); (K.F.); (K.F.); (K.V.-M.); (S.T.); (S.K.); (S.K.-S.); (M.O.); (T.M.); (A.D.)
| | - Katie Frenis
- Center for Cardiology, Department of Cardiology 1–Molecular Cardiology, University Medical Center, 55131 Mainz, Germany; (J.H.); (K.K.); (F.A.); (L.K.); (K.F.); (K.F.); (K.V.-M.); (S.T.); (S.K.); (S.K.-S.); (M.O.); (T.M.); (A.D.)
| | - Konstantina Filippou
- Center for Cardiology, Department of Cardiology 1–Molecular Cardiology, University Medical Center, 55131 Mainz, Germany; (J.H.); (K.K.); (F.A.); (L.K.); (K.F.); (K.F.); (K.V.-M.); (S.T.); (S.K.); (S.K.-S.); (M.O.); (T.M.); (A.D.)
| | - Ksenija Vujacic-Mirski
- Center for Cardiology, Department of Cardiology 1–Molecular Cardiology, University Medical Center, 55131 Mainz, Germany; (J.H.); (K.K.); (F.A.); (L.K.); (K.F.); (K.F.); (K.V.-M.); (S.T.); (S.K.); (S.K.-S.); (M.O.); (T.M.); (A.D.)
| | - Simeon Tsohataridis
- Center for Cardiology, Department of Cardiology 1–Molecular Cardiology, University Medical Center, 55131 Mainz, Germany; (J.H.); (K.K.); (F.A.); (L.K.); (K.F.); (K.F.); (K.V.-M.); (S.T.); (S.K.); (S.K.-S.); (M.O.); (T.M.); (A.D.)
| | - Sanela Kalinovic
- Center for Cardiology, Department of Cardiology 1–Molecular Cardiology, University Medical Center, 55131 Mainz, Germany; (J.H.); (K.K.); (F.A.); (L.K.); (K.F.); (K.F.); (K.V.-M.); (S.T.); (S.K.); (S.K.-S.); (M.O.); (T.M.); (A.D.)
| | - Swenja Kröller-Schön
- Center for Cardiology, Department of Cardiology 1–Molecular Cardiology, University Medical Center, 55131 Mainz, Germany; (J.H.); (K.K.); (F.A.); (L.K.); (K.F.); (K.F.); (K.V.-M.); (S.T.); (S.K.); (S.K.-S.); (M.O.); (T.M.); (A.D.)
| | - Matthias Oelze
- Center for Cardiology, Department of Cardiology 1–Molecular Cardiology, University Medical Center, 55131 Mainz, Germany; (J.H.); (K.K.); (F.A.); (L.K.); (K.F.); (K.F.); (K.V.-M.); (S.T.); (S.K.); (S.K.-S.); (M.O.); (T.M.); (A.D.)
| | - Markus Bosmann
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany;
- Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
| | - Thomas Münzel
- Center for Cardiology, Department of Cardiology 1–Molecular Cardiology, University Medical Center, 55131 Mainz, Germany; (J.H.); (K.K.); (F.A.); (L.K.); (K.F.); (K.F.); (K.V.-M.); (S.T.); (S.K.); (S.K.-S.); (M.O.); (T.M.); (A.D.)
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Andreas Daiber
- Center for Cardiology, Department of Cardiology 1–Molecular Cardiology, University Medical Center, 55131 Mainz, Germany; (J.H.); (K.K.); (F.A.); (L.K.); (K.F.); (K.F.); (K.V.-M.); (S.T.); (S.K.); (S.K.-S.); (M.O.); (T.M.); (A.D.)
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Sebastian Steven
- Center for Cardiology, Department of Cardiology 1–Molecular Cardiology, University Medical Center, 55131 Mainz, Germany; (J.H.); (K.K.); (F.A.); (L.K.); (K.F.); (K.F.); (K.V.-M.); (S.T.); (S.K.); (S.K.-S.); (M.O.); (T.M.); (A.D.)
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany;
- Correspondence: ; Tel.: +49-(0)6131-176-948
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Bonora BM, Avogaro A, Fadini GP. Disentangling conflicting evidence on DPP-4 inhibitors and outcomes of COVID-19: narrative review and meta-analysis. J Endocrinol Invest 2021; 44:1379-1386. [PMID: 33512688 PMCID: PMC7845283 DOI: 10.1007/s40618-021-01515-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 01/19/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND The infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread all over the world, becoming pandemic. Several studies have shown that diabetes mellitus (DM) is an independent risk factor that increases mortality and other adverse outcomes of coronavirus disease-19 (COVID-19). Studies have suggested that SARS-CoV-2 may bind dipeptidyl peptidase-4 (DPP4) for entering cells of the respiratory tract. Besides, DPP4 takes part in immune system regulation. Thus, DPP-4 inhibitors (DPP4i) may play a role against COVID-19. METHODS We focused on the impact of DPP4i treatment on COVID-19-related outcomes in people with DM. For this purpose, we conducted a systematic review and meta-analysis to summarize the existing evidence on this topic. RESULTS Retrospective observational studies provide inconsistent results on the association between use of DPP4i and outcomes of COVID-19. While two studies reported significantly lower mortality rates among patients with DM who received DPP4i versus those who did not, a series of other studies showed no effect of DPP4i or even worse outcomes. A meta-analysis of 7 studies yielded a neutral estimate of the risk ratio of COVID-19-related mortality among users of DPP4i (0.81; 95% CI 0.57-1.15). CONCLUSION In the absence of randomized controlled trials, observational research available so far provides inconclusive results and insufficient evidence to recommend use of DPP4i against COVID-19.
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Affiliation(s)
- B M Bonora
- Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padua, Italy
| | - A Avogaro
- Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padua, Italy
| | - G P Fadini
- Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padua, Italy.
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Pinheiro MM, Fabbri A, Infante M. Cytokine storm modulation in COVID-19: a proposed role for vitamin D and DPP-4 inhibitor combination therapy (VIDPP-4i). Immunotherapy 2021; 13:753-765. [PMID: 33906375 PMCID: PMC8080872 DOI: 10.2217/imt-2020-0349] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 04/13/2021] [Indexed: 02/08/2023] Open
Abstract
A dysregulated immune response characterized by the hyperproduction of several pro-inflammatory cytokines (a.k.a. 'cytokine storm') plays a central role in the pathophysiology of severe coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this Perspective article we discuss the evidence for synergistic anti-inflammatory and immunomodulatory properties exerted by vitamin D and dipeptidyl peptidase-4 (DPP-4) inhibitors, the latter being a class of antihyperglycemic agents used for the treatment of Type 2 diabetes, which have also been reported as immunomodulators. Then, we provide the rationale for investigation of vitamin D and DPP-4 inhibitor combination therapy (VIDPP-4i) as an immunomodulation strategy to ratchet down the virulence of SARS-CoV-2, prevent disease progression and modulate the cytokine storm in COVID-19.
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Affiliation(s)
| | - Andrea Fabbri
- Department of Systems Medicine, Division of Endocrinology & Diabetes, Diabetes Research Institute Federation (DRIF), CTO Hospital, University of Rome Tor Vergata, Rome, Italy
| | - Marco Infante
- Department of Systems Medicine, Division of Endocrinology & Diabetes, Diabetes Research Institute Federation (DRIF), CTO Hospital, University of Rome Tor Vergata, Rome, Italy
- UniCamillus, Saint Camillus International University of Health Sciences, Section of Endocrinology, Diabetes and Metabolism, Rome, Italy
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Rome, Italy
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Sitagliptin: a potential drug for the treatment of COVID-19? ACTA PHARMACEUTICA (ZAGREB, CROATIA) 2021; 71:175-184. [PMID: 33151168 DOI: 10.2478/acph-2021-0013] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 04/15/2020] [Indexed: 02/06/2023]
Abstract
Recently, an outbreak of a fatal coronavirus, SARS-CoV-2, has emerged from China and is rapidly spreading worldwide. Possible interaction of SARS-CoV-2 with DPP4 peptidase may partly contribute to the viral pathogenesis. An integrative bioinformatics approach starting with mining the biomedical literature for high confidence DPP4-protein/gene associations followed by functional analysis using network analysis and pathway enrichment was adopted. The results indicate that the identified DPP4 networks are highly enriched in viral processes required for viral entry and infection, and as a result, we propose DPP4 as an important putative target for the treatment of COVID-19. Additionally, our protein-chemical interaction networks identified important interactions between DPP4 and sitagliptin. We conclude that sitagliptin may be beneficial for the treatment of COVID-19 disease, either as monotherapy or in combination with other therapies, especially for diabetic patients and patients with pre-existing cardiovascular conditions who are already at higher risk of COVID-19 mortality.
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Lynch M, Malara A, Timoney I, Vencken S, Ahern T, Awdeh F, Sweeney C, Galligan M, Kelly G, Hughes R, Murad A, Hambly R, O'Shea D, Doran P, Kirby B. Sitagliptin and Narrow-Band Ultraviolet-B for Moderate Psoriasis (DINUP): A Randomised Controlled Clinical Trial. Dermatology 2021; 238:140-147. [PMID: 33866313 DOI: 10.1159/000514494] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 01/17/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor licensed for the treatment of type 2 diabetes mellitus (T2DM), has been reported to improve psoriasis. OBJECTIVE We compared the effects of sitagliptin treatment, a DPP-4 inhibitor, in combination with narrow-band ultraviolet-B (NB-UVB) phototherapy compared to NB-UVB alone on psoriasis severity, quality of life, cardiovascular disease risk factors and immune parameters in people with moderate psoriasis without T2DM. METHODS In this 39-week, single-centre, randomised controlled trial, people were allocated randomly to receive sitagliptin for 24 weeks with NB-UVB or NB-UVB alone. The primary endpoint was the change in Psoriasis Area and Severity Index (PASI) from baseline to 24 weeks. We estimated that 120 participants would be needed to have 80% power to find a significant difference between the groups. RESULTS A total of 118 patients were randomised. The median (IQR) baseline PASI was 8.8 (7.5-11.6). At 24 weeks, the mean difference from baseline in PASI (-1.0 [95% CI -2.0 to 0.0]) was significantly larger in the sitagliptin/NB-UVB arm than in the NB-UVB-alone arm (p = 0.044). There were significant differences in the change in Hospital Anxiety and Depression Scale (-2.5 [95% CI -4.0 to -1.0]; p = 0.002) and EuroQol 5-item questionnaire (0.1 [95% CI 0.0-0.1]; p = 0.036) values from baseline to 24 weeks between the sitagliptin/NB-UVB and the NB-UVB-alone arm. There were no treatment-related serious adverse events. CONCLUSION Sitagliptin therapy combined with NB-UVB phototherapy significantly improved psoriasis severity, albeit modestly, compared to NB-UVB phototherapy alone in patients with moderate psoriasis without T2DM.
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Affiliation(s)
- Maeve Lynch
- Charles Department of Dermatology, St Vincent's University Hospital, Dublin, Ireland.,School of Health Sciences and Charles Institute, University College Dublin, Dublin, Ireland
| | - Anna Malara
- School of Health Sciences and Charles Institute, University College Dublin, Dublin, Ireland
| | - Irene Timoney
- Charles Department of Dermatology, St Vincent's University Hospital, Dublin, Ireland
| | - Sebastian Vencken
- Clinical Research Centre, University College Dublin, Dublin, Ireland
| | - Tomas Ahern
- Department of Endocrinology, St Vincent's University Hospital, Dublin, Ireland
| | - Fatima Awdeh
- Charles Department of Dermatology, St Vincent's University Hospital, Dublin, Ireland
| | - Cheryl Sweeney
- School of Health Sciences and Charles Institute, University College Dublin, Dublin, Ireland
| | - Marie Galligan
- Clinical Research Centre, University College Dublin, Dublin, Ireland
| | - Genevieve Kelly
- Charles Department of Dermatology, St Vincent's University Hospital, Dublin, Ireland
| | - Rosalind Hughes
- Charles Department of Dermatology, St Vincent's University Hospital, Dublin, Ireland
| | - Aizuri Murad
- Charles Department of Dermatology, St Vincent's University Hospital, Dublin, Ireland
| | - Roisin Hambly
- Charles Department of Dermatology, St Vincent's University Hospital, Dublin, Ireland
| | - Donal O'Shea
- School of Health Sciences and Charles Institute, University College Dublin, Dublin, Ireland.,Department of Endocrinology, St Vincent's University Hospital, Dublin, Ireland
| | - Peter Doran
- Clinical Research Centre, University College Dublin, Dublin, Ireland
| | - Brian Kirby
- Charles Department of Dermatology, St Vincent's University Hospital, Dublin, Ireland.,School of Health Sciences and Charles Institute, University College Dublin, Dublin, Ireland
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Liu X, Kang WY, Shang LL, Ge SH. [Sitagliptin inhibits lipopolysaccharide-induced inflammatory response in human gingival fibroblasts by blocking nuclear factor-κB signaling pathway]. HUA XI KOU QIANG YI XUE ZA ZHI = HUAXI KOUQIANG YIXUE ZAZHI = WEST CHINA JOURNAL OF STOMATOLOGY 2021; 39:153-163. [PMID: 33834669 DOI: 10.7518/hxkq.2021.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
OBJECTIVES This study was performed to clarify the effects of sitagliptin on Porphyromonas gingivalis-lipopolysaccharide (LPS)-induced inflammatory response in human gingival fibroblasts (HGFs), explore the molecular mechanism of its roles, and provide a foundation for clinical therapeutics in periodontitis. METHODS Healthy gingival samples were collected from the donors. HGFs were isolated with enzymic digestion method and identified. The effects of LPS and sitagliptin on cell viability were detected by cell-counting kit-8 (CCK8). The mRNA levels of inflammatory cytokines, namely, interleukin (IL)-6, IL-8, C-C motif ligand 2 (CCL2), and superoxide dismutase 2 (SOD2), were evaluated by quantity real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immune sorbent assay (ELISA) was used to measure the secretion protein levels of IL-6, IL-8, and CCL2. Western blot analysis was used to further investigate the activation of nuclear factor (NF)-κB signaling pathway. The effect of NF-κB pathway inhibitor BAY11-7082 on LPS-induced HGF inflammatory cytokines at the gene level was verified by qRT-PCR. RESULTS Low concentrations of sitagliptin (0.1, 0.25, and 0.5 µmol·L-1) did not affect HGF growth in 24 and 48 h, whereas high concentrations of sitagliptin (5-1 000 µmol·L-1) significantly inhibited cell proliferation. Sitagliptin suppressed 5 µg·mL-1 of LPS-induced IL-6, IL-8, CCL2, and SOD2 gene expression levels in HGF in a concentration-dependent manner. Furthermore, sitagliptin significantly decreased the elevated secretion of IL-6, IL-8, and CCL2 protein induced by LPS. Western blot analysis showed that 0.5 µmol·L-1 of sitagliptin significantly inhibited LPS-induced NF-κB signaling pathway activation. Results of qRT-PCR analysis indicated that 0.5 µmol·L-1 of sitagliptin and 5 µmol·L-1 of BAY11-7082 significantly inhibited LPS-induced IL-6, IL-8, CCL2, and SOD2 gene expressions. CONCLUSIONS Sitagliptin could significantly inhibit LPS-induced HGF inflammatory response by blocking the NF-κB signaling pathway activation.
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Affiliation(s)
- Xiang Liu
- Dept. of Periodonto-logy, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan 250012, China
| | - Wen-Yan Kang
- Dept. of Periodonto-logy, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan 250012, China
| | - Ling-Ling Shang
- Dept. of Periodonto-logy, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan 250012, China
| | - Shao-Hua Ge
- Dept. of Periodonto-logy, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan 250012, China
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Zhang Q, Yang M, Xiao Y, Han Y, Yang S, Sun L. Towards Better Drug Repositioning: Targeted Immunoinflammatory Therapy for Diabetic Nephropathy. Curr Med Chem 2021; 28:1003-1024. [PMID: 31701843 DOI: 10.2174/0929867326666191108160643] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/23/2019] [Accepted: 09/26/2019] [Indexed: 11/22/2022]
Abstract
Diabetic nephropathy (DN) is one of the most common and important microvascular complications of diabetes mellitus (DM). The main clinical features of DN are proteinuria and a progressive decline in renal function, which are associated with structural and functional changes in the kidney. The pathogenesis of DN is multifactorial, including genetic, metabolic, and haemodynamic factors, which can trigger a sequence of events. Controlling metabolic risks such as hyperglycaemia, hypertension, and dyslipidaemia is not enough to slow the progression of DN. Recent studies emphasized immunoinflammation as a critical pathogenic factor in the progression of DN. Therefore, targeting inflammation is considered a potential and novel treatment strategy for DN. In this review, we will briefly introduce the inflammatory process of DN and discuss the anti-inflammatory effects of antidiabetic drugs when treating DN.
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Affiliation(s)
- Qin Zhang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ming Yang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ying Xiao
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yachun Han
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shikun Yang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lin Sun
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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Bae JH, Park EG, Kim S, Kim SG, Hahn S, Kim NH. Comparative Renal Effects of Dipeptidyl Peptidase-4 Inhibitors and Sodium-Glucose Cotransporter 2 Inhibitors on Individual Outcomes in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis. Endocrinol Metab (Seoul) 2021; 36:388-400. [PMID: 33789035 PMCID: PMC8090474 DOI: 10.3803/enm.2020.912] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 01/14/2021] [Accepted: 02/15/2021] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND To compare the renal effects of dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors on individual outcomes in patients with type 2 diabetes. METHODS We searched electronic databases (MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials) from inception to June 2019 to identity eligible randomized controlled trials of DPP-4 inhibitors or SGLT2 inhibitors that reported at least one kidney outcome in patients with type 2 diabetes. Outcomes of interest were microalbuminuria, macroalbuminuria, worsening nephropathy, and end-stage kidney disease (ESKD). We performed an arm-based network meta-analysis using Bayesian methods and calculated absolute risks and rank probabilities of each treatment for the outcomes. RESULTS Seventeen studies with 87,263 patients were included. SGLT2 inhibitors significantly lowered the risks of individual kidney outcomes, including microalbuminuria (odds ratio [OR], 0.64; 95% credible interval [CrI], 0.41 to 0.93), macroalbuminuria (OR, 0.48; 95% CrI, 0.24 to 0.72), worsening nephropathy (OR, 0.65; 95% CrI, 0.44 to 0.91), and ESKD (OR, 0.65; 95% CrI, 0.46 to 0.98) as compared with placebo. However, DPP-4 inhibitors did not lower the risks. SGLT2 inhibitors were considerably associated with higher absolute risk reductions in all kidney outcomes than DPP-4 inhibitors, although the benefits were statistically insignificant. The rank probabilities showed that SGLT2 inhibitors were better treatments for lowering the risk of albuminuria and ESKD than placebo or DPP-4 inhibitors. CONCLUSION SGLT2 inhibitors were superior to DPP-4 inhibitors in reducing the risk of albuminuria and ESKD in patients with type 2 diabetes.
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Affiliation(s)
- Jae Hyun Bae
- Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul,
Korea
| | - Eun-Gee Park
- Interdisciplinary Program in Medical Informatics, Seoul National University College of Medicine, Seoul,
Korea
| | - Sunhee Kim
- Interdisciplinary Program in Medical Informatics, Seoul National University College of Medicine, Seoul,
Korea
| | - Sin Gon Kim
- Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul,
Korea
| | - Seokyung Hahn
- Division of Medical Statistics, Medical Research Collaborating Center, Seoul National University Hospital, Seoul,
Korea
- Department of Human Systems Medicine, Seoul National University College of Medicine, Seoul,
Korea
- Institute of Health Policy and Management, Medical Research Center, Seoul National University, Seoul,
Korea
| | - Nam Hoon Kim
- Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul,
Korea
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39
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Yang L, Liang H, Liu X, Wang X, Cheng Y, Zhao Y, Liu L, Huang G, Wang X, Zhou Z. Islet Function and Insulin Sensitivity in Latent Autoimmune Diabetes in Adults Taking Sitagliptin: A Randomized Trial. J Clin Endocrinol Metab 2021; 106:e1529-e1541. [PMID: 33475138 PMCID: PMC7993585 DOI: 10.1210/clinem/dgab026] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Indexed: 12/17/2022]
Abstract
CONTEXT The long-term effects of dipeptidyl peptidase-4 inhibitors on β-cell function and insulin sensitivity in latent autoimmune diabetes in adults (LADA) are unclear. OBJECTIVE To investigate the effects of sitagliptin on β-cell function and insulin sensitivity in LADA patients receiving insulin. DESIGN AND SETTING A randomized controlled trial at the Second Xiangya Hospital. METHODS Fifty-one patients with LADA were randomized to sitagliptin + insulin (SITA) group or insulin alone (CONT) group for 24 months. MAIN OUTCOME MEASURES Fasting C-peptide (FCP), 2-hour postprandial C-peptide (2hCP) during mixed-meal tolerance test, △CP (2hCP - FCP), and updated homeostatic model assessment of β-cell function (HOMA2-B) were determined every 6 months. In 12 subjects, hyperglycemic clamp and hyperinsulinemic euglycemic clamp (HEC) tests were further conducted at 12-month intervals. RESULTS During the 24-month follow-up, there were no significant changes in β-cell function in the SITA group, whereas the levels of 2hCP and △CP in the CONT group were reduced at 24 months. Meanwhile, the changes in HOMA2-B from baseline were larger in the SITA group than in the CONT group. At 24 months, first-phase insulin secretion was improved in the SITA group by hyperglycemia clamp, which was higher than in the CONT group (P < .001), while glucose metabolized (M), insulin sensitivity index, and M over logarithmical insulin ratio in HEC were increased in the SITA group (all P < .01 vs baseline), which were higher than in the CONT group. CONCLUSION Compared with insulin intervention alone, sitagliptin plus insulin treatment appeared to maintain β-cell function and improve insulin sensitivity in LADA to some extent.
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Affiliation(s)
- Lin Yang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Huiying Liang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Affiliated Dongguan People’s Hospital, Southern Medical University (Dongguan People’s Hospital), Dongguan, Guangdong, China
| | - Xinyuan Liu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xia Wang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Ying Cheng
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yunjuan Zhao
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Lingjiao Liu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Gan Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xiangbing Wang
- Division of Endocrinology, Metabolism and Nutrition, Rutgers University-Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Correspondence: Zhiguang Zhou, MD, PhD, Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha 410011, Hunan, China.
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Helmstädter J, Keppeler K, Küster L, Münzel T, Daiber A, Steven S. Glucagon-like peptide-1 (GLP-1) receptor agonists and their cardiovascular benefits-The role of the GLP-1 receptor. Br J Pharmacol 2021; 179:659-676. [PMID: 33764504 PMCID: PMC8820186 DOI: 10.1111/bph.15462] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 03/12/2021] [Accepted: 03/18/2021] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular outcome trials revealed cardiovascular benefits for type 2 diabetes mellitus patients when treated with long‐acting glucagon‐like peptide‐1 (GLP‐1) receptor agonists. In the last decade, major advances were made characterising the physiological effects of GLP‐1 and its action on numerous targets including brain, liver, kidney, heart and blood vessels. However, the effects of GLP‐1 and receptor agonists, and the GLP‐1 receptor on the cardiovascular system have not been fully elucidated. We compare results from cardiovascular outcome trials of GLP‐1 receptor agonists and review pleiotropic clinical and preclinical data concerning cardiovascular protection beyond glycaemic control. We address current knowledge on GLP‐1 and receptor agonist actions on the heart, vasculature, inflammatory cells and platelets, and discuss evidence for GLP‐1 receptor‐dependent versus independent effects secondary of GLP‐1 metabolites. We conclude that the favourable cardiovascular profile of GLP‐1 receptor agonists might expand their therapeutic use for treating cardiovascular disease even in non‐diabetic populations.
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Affiliation(s)
- Johanna Helmstädter
- Department of Cardiology, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
| | - Karin Keppeler
- Department of Cardiology, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
| | - Leonie Küster
- Department of Cardiology, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
| | - Thomas Münzel
- Department of Cardiology, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.,Center of Thrombosis and Hemostasis (CTH), University Medical Center, Mainz, Germany.,Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Mainz, Germany
| | - Andreas Daiber
- Department of Cardiology, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.,Center of Thrombosis and Hemostasis (CTH), University Medical Center, Mainz, Germany.,Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Mainz, Germany
| | - Sebastian Steven
- Department of Cardiology, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.,Center of Thrombosis and Hemostasis (CTH), University Medical Center, Mainz, Germany
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Pinheiro MM, Pinheiro FMM, Diniz SN, Fabbri A, Infante M. Combination of vitamin D and dipeptidyl peptidase-4 inhibitors (VIDPP-4i) as an immunomodulation therapy for autoimmune diabetes. Int Immunopharmacol 2021; 95:107518. [PMID: 33756226 DOI: 10.1016/j.intimp.2021.107518] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/15/2021] [Accepted: 02/16/2021] [Indexed: 12/18/2022]
Abstract
Type 1 diabetes (T1D) and latent autoimmune diabetes in adults (LADA) represent the most common types of autoimmune diabetes and are characterized by different age of onset, degrees of immune-mediated destruction of pancreatic beta cells and rates of disease progression towards insulin dependence. Several immunotherapies aimed to counteract autoimmune responses against beta cells and preserve beta-cell function are currently being investigated, particularly in T1D. Preliminary findings suggest a potential role of combination therapy with vitamin D and dipeptidyl peptidase-4 (DPP-4) inhibitors (VIDPP-4i) in preserving beta-cell function in autoimmune diabetes. This manuscript aims to provide a comprehensive overview of the immunomodulatory properties of vitamin D and DPP-4 inhibitors, as well as the rationale for investigation of their combined use as an immunomodulation therapy for autoimmune diabetes.
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Affiliation(s)
- Marcelo Maia Pinheiro
- UNIVAG, University Center, Dom Orlando Chaves Ave, 2655 - Cristo Rei, Várzea Grande, 78118-000 Mato Grosso, Brazil; Universidade Anhanguera de São Paulo - SP, 3305, Raimundo Pereira de Magalhães Ave., Pirituba, São Paulo, 05145-200 São Paulo, Brazil.
| | - Felipe Moura Maia Pinheiro
- Hospital de Base, Faculdade de Medicina de São José do Rio Preto FAMERP - SP, 5546, Brigadeiro Faria Lima Ave, Vila São Pedro, São José do Rio Preto, 15015-500 São Paulo, Brazil
| | - Susana Nogueira Diniz
- Universidade Anhanguera de São Paulo - SP, 3305, Raimundo Pereira de Magalhães Ave., Pirituba, São Paulo, 05145-200 São Paulo, Brazil
| | - Andrea Fabbri
- Diabetes Research Institute Federation (DRIF), Division of Endocrinology and Diabetes, CTO Andrea Alesini Hospital, ASL Roma 2, Department of Systems Medicine, University of Rome Tor Vergata, Via San Nemesio 21, 00145 Rome, Italy
| | - Marco Infante
- Diabetes Research Institute Federation (DRIF), Division of Endocrinology and Diabetes, CTO Andrea Alesini Hospital, ASL Roma 2, Department of Systems Medicine, University of Rome Tor Vergata, Via San Nemesio 21, 00145 Rome, Italy; UniCamillus, Saint Camillus International University of Health Sciences, Via di Sant'Alessandro, 8, 00131 Rome, Italy; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Via San Nemesio 21, 00145 Rome, Italy.
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Abstract
PURPOSE OF REVIEW To discuss the diagnosis, treatment, and complications of diabetes in people with HIV (PWH) and to review HIV-related factors that may contribute to the development of diabetes or alter decisions in the care and treatment of PWH with diabetes. RECENT FINDINGS For those patients with atherosclerotic cardiovascular disease, heart failure, and/or chronic kidney disease, GLP-1 receptor agonists and SGLT-2 inhibitors should be considered for use. Evidence for this recommendation is, however, based on studies that were not conducted in populations consisting solely of PWH. Diabetes is a significant comorbidity in PWH and adds to their already heightened risk of cardiovascular disease. HIV-specific factors, including interactions of antiretroviral therapy with medications that either treat diabetes and/or prevent cardiovascular disease, should be evaluated.
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Affiliation(s)
- Sudipa Sarkar
- Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Asthma and Allergy Center 3B.74D, Baltimore, MD, 21224, USA.
| | - Todd T Brown
- Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, MD, 21287, USA
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Scheen AJ. DPP-4 inhibition and COVID-19: From initial concerns to recent expectations. DIABETES & METABOLISM 2021; 47:101213. [PMID: 33249199 PMCID: PMC7690941 DOI: 10.1016/j.diabet.2020.11.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 11/15/2020] [Indexed: 12/18/2022]
Abstract
Dipeptidyl peptidase-4 inhibitors (DPP-4is) have gained a key place in the management of type 2 diabetes mellitus (T2DM) essentially because of their good safety profile even in the frail population. DPP-4, originally known as 'T-cell antigen CD26', is expressed in many immune cells and regulates their functions, so the initial concern over the use of DPP-4is was the possible increased susceptibility to infections. Furthermore, because of the high affinity between human DPP-4 and the spike (S) receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it was suspected that this virus, responsible for coronavirus disease 2019 (COVID-19), might be able to use the DPP-4 enzyme as a functional receptor to gain entry into the host. However, DPP-4is also exert anti-inflammatory effects, which could be beneficial in patients exposed to cytokine storms due to COVID-19. Yet, when observational (mostly retrospective) studies compared clinical outcomes in DPP-4i users vs non-users among diabetes patients with COVID-19, the overall results regarding the risk of progression towards more severe forms of the disease and mortality were heterogeneous, thereby precluding any definite conclusions. Nevertheless, new expectations have arisen following recent reports of significant reductions in admissions to intensive care units and mortality in DPP-4i users. However, given the limitations inherent in such observational studies, any available results should be considered, at best, as hypothetical and only suggestive of potentially substantial benefits with DPP-4is in diabetes patients with COVID-19. While the safe use of DPP-4is in COVID-19 patients appears to be an acceptable hypothesis, all such positive findings still need to be confirmed in randomized controlled trials (a few of which are currently ongoing) before any recommendations can be made for clinical practice.
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Affiliation(s)
- André J Scheen
- Division of Diabetes, Nutrition and Metabolic Disorders, CHU Liège, Liège, Belgium; Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), Liège University, Liège, Belgium.
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El-Sahar AE, Shiha NA, El Sayed NS, Ahmed LA. Alogliptin Attenuates Lipopolysaccharide-Induced Neuroinflammation in Mice Through Modulation of TLR4/MYD88/NF-κB and miRNA-155/SOCS-1 Signaling Pathways. Int J Neuropsychopharmacol 2021; 24:158-169. [PMID: 33125461 PMCID: PMC7883892 DOI: 10.1093/ijnp/pyaa078] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 10/03/2020] [Accepted: 10/28/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Endotoxin-induced neuroinflammation plays a crucial role in the pathogenesis and progression of various neurodegenerative diseases. A growing body of evidence supports that incretin-acting drugs possess various neuroprotective effects that can improve learning and memory impairments in Alzheimer's disease models. Thus, the present study aimed to investigate whether alogliptin, a dipeptidyl peptidase-4 inhibitor, has neuroprotective effects against lipopolysaccharide (LPS)-induced neuroinflammation and cognitive impairment in mice as well as the potential mechanisms underlying these effects. METHODS Mice were treated with alogliptin (20 mg/kg/d; p.o.) for 14 days, starting 1 day prior to intracerebroventricular LPS injection (8 μg/μL in 3 μL). RESULTS Alogliptin treatment alleviated LPS-induced cognitive impairment as assessed by Morris water maze and novel object recognition tests. Moreover, alogliptin reversed LPS-induced increases in toll-like receptor 4 and myeloid differentiation primary response 88 protein expression, nuclear factor-κB p65 content, and microRNA-155 gene expression. It also rescued LPS-induced decreases in suppressor of cytokine signaling gene expression, cyclic adenosine monophosphate (cAMP) content, and phosphorylated cAMP response element binding protein expression in the brain. CONCLUSION The present study sheds light on the potential neuroprotective effects of alogliptin against intracerebroventricular LPS-induced neuroinflammation and its associated memory impairment via inhibition of toll-like receptor 4/ myeloid differentiation primary response 88/ nuclear factor-κB signaling, modulation of microRNA-155/suppressor of cytokine signaling-1 expression, and enhancement of cAMP/phosphorylated cAMP response element binding protein signaling.
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Affiliation(s)
- Ayman E El-Sahar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Nesma A Shiha
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Nesrine S El Sayed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Lamiaa A Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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DPP4 Inhibitors and COVID-19-Holy Grail or Another Dead End? Arch Immunol Ther Exp (Warsz) 2021; 69:1. [PMID: 33527308 PMCID: PMC7850901 DOI: 10.1007/s00005-020-00602-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 12/10/2020] [Indexed: 01/08/2023]
Abstract
A novel coronavirus disease, COVID-19, has emerged as a global public health issue. Clinical course of disease significantly correlates with the occurrence of some comorbidities, among them type 2 diabetes. According to recent structural studies the dipeptidyl peptidase 4, a key molecule in the pathophysiology of diabetes, may influence the course of COVID-19. Since DPP4 inhibitors, gliptins, are widely used in diabetes patients, the exact role of DPP4 modulation in SARS-CoV-2 infection, at least in that group, urgently needs to be clarified. In this short review, we discuss this issue with more detail.
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Bakkar MA, Nawaz H, Majeed MI, Naseem A, Ditta A, Rashid N, Ali S, Bajwa J, Bashir S, Ahmad S, Hyat H, Bukhari KS, Bonnier F. Raman spectroscopy for the qualitative and quantitative analysis of solid dosage forms of Sitagliptin. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2021; 245:118900. [PMID: 32920444 DOI: 10.1016/j.saa.2020.118900] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/21/2020] [Accepted: 08/26/2020] [Indexed: 06/11/2023]
Abstract
To demonstrate the potential of Raman spectroscopy for the qualitative and quantitative analysis of solid dosage pharmacological formulations, different concentrations of Sitagliptin, an Active Pharmaceutical Ingredient (API) currently prescribed as an anti-diabetic drug, are characterised. Increase of the API concentrations induces changes in the Raman spectral features specifically associated with the drug and excipients. Principal Component Analysis (PCA) and Partial Least Squares Regression (PLSR), were used for the qualitative and quantitative analysis of the spectral responses. A PLSR model is constructed which enables the prediction of different concentrations of drug in the complex excipient matrices. During the development of the prediction model, the Root Mean Square Error of Cross Validation (RMSECV) was found to be 0.36 mg and the variability explained by the model, according to the (R2) value, was found to be 0.99. Moreover, the concentration of the API in the unknown sample was determined. This concentration was predicted to be 64.28/180 mg (w/w), compared to the 65/180 mg (w/w). These findings demonstrate Raman spectroscopy coupled to PLSR analysis to be a reliable tool to verify Sitagliptin contents in the pharmaceutical samples based on calibration models prepared under laboratory conditions.
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Affiliation(s)
| | - Haq Nawaz
- Department of Chemistry, University of Agriculture, Faisalabad, Pakistan.
| | | | - Ammara Naseem
- Department of Chemistry, University of Agriculture, Faisalabad, Pakistan
| | - Allah Ditta
- Department of Chemistry, University of Agriculture, Faisalabad, Pakistan
| | - Nosheen Rashid
- Department of Chemistry, University of Central Punjab, Faisalabad Campus, Faisalabad, Pakistan
| | - Saqib Ali
- Department of Chemistry, University of Agriculture, Faisalabad, Pakistan
| | - Jawad Bajwa
- Department of Chemistry, Government College University, Faisalabad, Pakistan
| | - Saba Bashir
- Department of Chemistry, University of Agriculture, Faisalabad, Pakistan
| | - Shamsheer Ahmad
- Department of Chemistry, University of Agriculture, Faisalabad, Pakistan
| | - Hamza Hyat
- Department of Chemistry, University of Agriculture, Faisalabad, Pakistan
| | | | - Franck Bonnier
- EA 6295 Nano-médicaments and Nano-sondes, Université de Tours, Tours, France
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Charoenngam N, Rittiphairoj T, Ponvilawan B, Ungprasert P. Use of dipeptidyl peptidase-4 inhibitors is associated with a lower risk of rheumatoid arthritis in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of cohort studies. Diabetes Metab Syndr 2021; 15:249-255. [PMID: 33465685 DOI: 10.1016/j.dsx.2020.12.042] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/25/2020] [Accepted: 12/31/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND AND AIMS Case reports have described occurrence of rheumatoid arthritis (RA) after initiation of Dipeptidyl Peptidase-4 Inhibitors (DPP4i), suggesting a possible adverse effect of the medications. However, the findings from subsequent cohort studies suggest the opposite as they indicate that T2DM patients who used DPP4i tended to have a lower risk of RA. We aimed to investigate the association between use of DPP4i and incident RA in patients with type 2 diabetes mellitus (T2DM) using systematic review and meta-analysis. METHODS Potentially eligible studies were identified from Medline and EMBASE databases from inception to May 2020 using search strategy that comprised of terms for "Dipeptidyl peptidase-4 inhibitor" and "Rheumatoid arthritis". Eligible study must be cohort study consisting of one cohort of patients with T2DM who were DPP4i users and another cohort of comparators with T2DM who did not receive DPP4i. Then, the study must report effect estimates with 95% confidence intervals (95% CIs) comparing incident RA between DPP4i users versus comparators. Point estimates with standard errors retrieved from each study were combined together using the generic inverse variance method. RESULTS A total of 709 articles were identified. After systematic review, four retrospective cohort studies met the eligibility criteria and were included into the meta-analysis. DPP4i users had a significantly lower risk of incident RA compared with comparators with the pooled hazard ratio of 0.72 (95% CI, 0.54-0.96; I2 75%). CONCLUSION This systematic review and meta-analysis found a significant association between DPP4i use and a lower risk of incident RA.
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Affiliation(s)
- Nipith Charoenngam
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Section Endocrinology, Diabetes, Nutrition and Weight Management, Department of Medicine, Boston University School of Medicine, Boston, MA, United States.
| | | | - Ben Ponvilawan
- Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Patompong Ungprasert
- Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, OH, United States
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Li D, Zou H, Yin P, Li W, He J, Wang S, Huang L, Shao S, Chen Y, Yang Y, Yu X. Durability of glycaemic control in type 2 diabetes: A systematic review and meta-analysis for its association with body weight changes. Diabetes Obes Metab 2021; 23:208-217. [PMID: 33016522 DOI: 10.1111/dom.14217] [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: 06/09/2020] [Revised: 08/26/2020] [Accepted: 09/20/2020] [Indexed: 10/23/2022]
Abstract
AIMS To analyse quantitatively the association between the durability of glycaemic control and body weight changes during treatment. MATERIALS AND METHODS This study adhered to an appropriate methodology according to Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Studies with follow-ups >12 months, and final and intermediate assessments of haemoglobin A1c (HbA1c) and body weight were included. Four outcomes assessing therapeutic durability were extracted and synthesized using Stata statistical software, including changes in HbA1c, goal-achievement rate, failure rate and coefficient of failure (CoF). RESULTS After 8.9 months of treatment, HbA1c levels declined from 8.03% [95% confidence interval (CI), 7.91-8.15; I2 = 99.2%] to 7.15% (95% CI, 7.02-7.27; I2 = 99.4%) and then gradually increased up to 7.72% (95% CI, 7.50-7.94; I2 = 99.0%) 5 years later. The goal-achievement rate decreased from 54.8% (after 1 year of treatment) to 19.4% 5 years later. The CoF was 0.123 ± 0.022%/year (P < .001). After stratification, the CoFs were 0.224 ± 0.025%/year (P < .001) for weight gain, 0.137 ± 0.034%/year (P < .001) for neutral weight and -0.024 ± 0.032%/year (P = .450) for weight loss. After stratification by treatment approaches, the CoFs were 0.45%/year for insulin, 0.43%/year for sulphonylurea, 0.34%/year for thiazolidinediones, 0.29%/year for metformin, 0.16% for glucagon-like polypeptide-1 receptor agonists, 0.12% for surgery, -0.03% for sodium-glucose cotransporter-2 inhibitors and -0.21% for dipeptidyl peptidase-IV inhibitors. CONCLUSION Modest weight loss with a goal of 2-3% of body weight should be recommended to improve therapeutic durability and prevent beta-cell deterioration.
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Affiliation(s)
- Danpei Li
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - HuaJie Zou
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ping Yin
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenjun Li
- Computer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junyu He
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuyun Wang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Huang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shiying Shao
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong Chen
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Yang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuefeng Yu
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Singh AK, Singh R, Saboo B, Misra A. Non-insulin anti-diabetic agents in patients with type 2 diabetes and COVID-19: A Critical Appraisal of Literature. Diabetes Metab Syndr 2021; 15:159-167. [PMID: 33352455 PMCID: PMC7832723 DOI: 10.1016/j.dsx.2020.12.026] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 12/13/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND & AIMS Several observational studies have recently reported the outcomes of non-insulin anti-diabetic agents (ADA) in patients with T2DM and coronavirus disease 2019 (COVID-19). We sought to review the literature to appraise the clinicians on these outcomes. METHODS A literature search using the specific keywords was carried out in the database of PubMed, MedRxiv and Google Scholar up till December 11, 2020 applying Boolean method. Full text of all the relevant articles that reported the outcomes of ADA in patients with T2DM and COVID-19 were retrieved. Subsequently, an appraisal of literature report was narratively presented. RESULTS Available studies that reported the outcomes of ADA are either case series or retrospective cohorts or prospective observational studies, in absence of the randomized controlled trials (RCTs). Results from these observational studies suggest that amongst all the non-insulin ADA, metformin users prior to the hospitalization had improved outcomes compared to the non-users. Data for dipeptidyl-peptidase-4 inhibitors (DPP-4i) are encouraging although inconsistent. No documentation of any harm or benefit has been observed for sulfonylureas (SUs), sodium glucose co-transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide receptor agonists (GLP-1RAs). No data is yet available for pioglitazone. CONCLUSION Metformin and DPP-4i should be continued in patients with T2DM until hospitalization or unless contraindicated. No evidence of harm suggests that SUs, SGLT-2i or GLP-1RAs may not be stopped unless very sick, hospitalized or contraindicated. The results from RCTs are needed to claim any meaningful benefit with either metformin or DPP-4i in patients with T2DM and COVID-19.
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Affiliation(s)
| | - Ritu Singh
- G.D Hospital & Diabetes Institute, Kolkata, India
| | | | - Anoop Misra
- Fortis CDOC Hospital for Diabetes and Allied Science, Chirag Enclave, New Delhi, India; National Diabetes, Obesity and Cholesterol Foundation, New Delhi, India; Diabetes Foundation (India), New Delhi, India
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Kjær MB, George J, Kazankov K, Grønbæk H. Current perspectives on the pathophysiology of metabolic associated fatty liver disease: are macrophages a viable target for therapy? Expert Rev Gastroenterol Hepatol 2021; 15:51-64. [PMID: 32878486 DOI: 10.1080/17474124.2020.1817740] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Metabolic associated fatty liver disease (MAFLD) is a new nomenclature for fatty liver replacing nonalcoholic fatty liver disease (NAFLD). MAFLD has emerged as the leading cause of liver-related morbidity and mortality with increasing incidence due to its close association with the global epidemic of obesity and type 2 diabetes mellitus. Macrophages play a key role in MAFLD development and progression of steatohepatitis and fibrosis. Therefore, targeting macrophages may be a new therapeutic approach for MAFLD and MAFLD with steatohepatitis. AREAS COVERED We provide a comprehensive review of the significant role of macrophages in MAFLD. Further, we evaluate the current status of lifestyle interventions and pharmacological treatments with a focus on effects mediated through direct or indirect targeting of macrophages. EXPERT OPINION Targeting macrophages holds promise as a treatment option for the management of MAFLD and steatohepatitis. Improved stratification of patients according to MAFLD phenotype would contribute to more adequate design enhancing the yield of clinical trials ultimately leading to personalized medicine for patients with MAFLD. Furthermore, reflecting the multifactorial pathogenesis of MAFLD, combination therapies based on the various pathophysiological driver events including as pertinent to this review, macrophage recruitment, polarization and action, present an intriguing target for future investigation.
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Affiliation(s)
- Mikkel Breinholt Kjær
- Department of Hepatology and Gastroenterology, Aarhus University Hospital , Aarhus, Denmark
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney , Sydney, Australia
| | - Konstantin Kazankov
- Department of Hepatology and Gastroenterology, Aarhus University Hospital , Aarhus, Denmark
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital , Aarhus, Denmark
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