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Shao DW, Zhao LJ, Sun JF. Synthesis and clinical application of representative small-molecule dipeptidyl Peptidase-4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus (T2DM). Eur J Med Chem 2024; 272:116464. [PMID: 38704940 DOI: 10.1016/j.ejmech.2024.116464] [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: 03/26/2024] [Revised: 04/27/2024] [Accepted: 04/28/2024] [Indexed: 05/07/2024]
Abstract
Diabetes mellitus is a chronic metabolic disorder characterized by high blood glucose levels, which can cause many diseases, including osteoporosis, fractures, arthritis, and foot complications. The inhibitors of dipeptidyl peptidase-4 (DPP-4), an enzyme involved in glucose metabolism regulation, are essential for managing Type 2 Diabetes Mellitus (T2DM). The inhibition of DPP-4 has become a promising treatment approach for T2DM because it can increase levels of active glucagon-like peptide-1 (GLP-1), leading to improved insulin secretion in response to glucose and reduced release of glucagon. The review commences by elucidating the role of DPP-4 in glucose homeostasis and its significance in T2DM pathophysiology. Furthermore, it presents the mechanism of action, preclinical pharmacodynamics, clinical efficacy, and toxicity profiles of small-molecule DPP-4 inhibitors across various clinical stages. This comprehensive review provides valuable insights into the synthesis and clinical application of DPP-4 inhibitors, serving as an invaluable resource for researchers, clinicians, and pharmaceutical professionals interested in diabetes therapeutics and drug development.
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Affiliation(s)
- Dong-Wei Shao
- First People's Hospital of Shangqiu, Henan Province, Shangqiu, 476100, China.
| | - Li-Jie Zhao
- The Rogel Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, United States.
| | - Jin-Feng Sun
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, College of Pharmacy, Yanji, Jilin, 133002, China; Rega Institute for Medical Research, Medicinal Chemistry, KU Leuven, Herestraat 49-Box 1041, 3000, Leuven, Belgium.
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Jung WK, Park SB, Yu HY, Kim J. Improvement effect of gemigliptin on salivary gland dysfunction in exogenous methylglyoxal-injected rats. Heliyon 2024; 10:e29362. [PMID: 38628768 PMCID: PMC11019235 DOI: 10.1016/j.heliyon.2024.e29362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 04/01/2024] [Accepted: 04/07/2024] [Indexed: 04/19/2024] Open
Abstract
The symptom of hyposalivation associated with hypofunction of the salivary glands is a common feature of diabetes. Inadequate saliva production can cause tissue damage in the mouth, making it susceptible to infections and leading to oral health diseases. Previous studies have highlighted the harmful effects of methylglyoxal (MGO) and MGO-derived advanced glycation end products (AGEs) in diabetes. In this study, we investigated the protective effects of gemigliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, against MGO-induced salivary gland dysfunction. MGO treatment of immortalized human salivary gland acinar cells induced apoptosis via reactive oxygen species (ROS)-mediated pathways, but this effect was mitigated by gemigliptin. In vivo experiments involved the simultaneous administration of MGO (17.25 mg/kg) with aminoguanidine (100 mg/kg) and gemigliptin (10 and 100 mg/kg) daily to rats for two weeks. Gemigliptin increased the saliva volume and amylase levels in MGO-injected rats. Gemigliptin reduced the DPP-4 activity in both the salivary glands and serum of MGO-injected rats. Furthermore, gemigliptin exerted anti-glycation effects by reducing the accumulation of AGEs in the saliva, salivary glands, and serum and suppressing the expression of the receptor for AGEs. These actions protected the salivary gland cells from ROS-mediated apoptosis. Overall, gemigliptin protected the salivary gland cells from ROS-mediated cell death, reduced the accumulation of amylase and mucins in the salivary glands, and enhanced the salivary function by upregulating aquaporin 5 expression, and it exerted protective effects against MGO-induced salivary gland dysfunction by enhancing the anti-glycation, antioxidant, and salivary secretion activities. Our findings suggest gemigliptin as a potential therapeutic for patients with salivary gland dysfunction caused by the complications of diabetes.
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Affiliation(s)
- Woo Kwon Jung
- Department of Oral Pathology, School of Dentistry, Jeonbuk National University, Jeonju, 54896, South Korea
| | - Su-Bin Park
- Department of Oral Pathology, School of Dentistry, Jeonbuk National University, Jeonju, 54896, South Korea
| | - Hwa Young Yu
- Department of Oral Pathology, School of Dentistry, Jeonbuk National University, Jeonju, 54896, South Korea
| | - Junghyun Kim
- Department of Oral Pathology, School of Dentistry, Jeonbuk National University, Jeonju, 54896, South Korea
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He J, Zhao D, Peng B, Wang X, Wang S, Zhao X, Xu P, Geng B, Xia Y. A novel mechanism of Vildagliptin in regulating bone metabolism and mitigating osteoporosis. Int Immunopharmacol 2024; 130:111671. [PMID: 38367467 DOI: 10.1016/j.intimp.2024.111671] [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: 11/16/2023] [Revised: 02/05/2024] [Accepted: 02/06/2024] [Indexed: 02/19/2024]
Abstract
Osteoporosis has become a global social problem with the tendency toward the aging population. The challenge in managing osteoporosis is to develop new anti-osteoporosis drugs that target bone anabolism. The purpose of this study was to uncover the novel mechanism of Vildagliptin on bone metabolism. We revealed that Vildagliptin significantly promoted osteogenic differentiation of precursor osteoblasts and bone marrow mesenchymal stem cells (BMSCs). At the same time, it significantly enhanced the polarization of RAW264.7 macrophages to the M2 type and the secretion of osteogenic factors BMP2 and TGF-β1. This was confirmed by the increased osteogenic differentiation observed in the osteoblast-RAW264.7 co-culture system. Moreover, Vildagliptin significantly enhanced the transformation of BMSCs into the osteogenic morphology in the osteoblast-BMSC co-culture system. Finally, Vildagliptin also inhibited osteoclastic differentiation of RAW 264.7 cells. The potential mechanism underlying these effects involved targeting the GAS6/AXL/ERK5 pathway. In the in vivo study, Vildagliptin significantly alleviated postmenopausal osteoporosis in ovariectomized mice. These findings represent the first comprehensive revelation of the regulatory effect of Vildagliptin on bone metabolism. Specifically, Vildagliptin demonstrates the ability to promote bone anabolism and inhibit bone resorption by simultaneously targeting osteoblasts, BMSCs, and osteoclasts. The bone-protective effects of Vildagliptin were further confirmed in a postmenopausal osteoporosis model. The clinical significance of this study lies in laying a theoretical foundation for bone protection therapy in type-2 diabetes patients with compromised bone conditions or postmenopausal osteoporosis.
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Affiliation(s)
- Jinwen He
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an 715004, China
| | - Dacheng Zhao
- Department of Painology, Lanzhou University Second Hospital, Lanzhou 730030, China
| | - Bo Peng
- Department of Orthopaedics, Orthopaedics Clinical Medicine Research Center of Gansu Province, Intelligent Orthopedics Industry Technology Center of Gansu Province, Lanzhou University Second Hospital, Lanzhou 730030, China
| | - Xingwen Wang
- Department of Orthopaedics, Orthopaedics Clinical Medicine Research Center of Gansu Province, Intelligent Orthopedics Industry Technology Center of Gansu Province, Lanzhou University Second Hospital, Lanzhou 730030, China
| | - Shenghong Wang
- Department of Orthopaedics, Orthopaedics Clinical Medicine Research Center of Gansu Province, Intelligent Orthopedics Industry Technology Center of Gansu Province, Lanzhou University Second Hospital, Lanzhou 730030, China
| | - Xiaobing Zhao
- Department of Orthopaedics, Orthopaedics Clinical Medicine Research Center of Gansu Province, Intelligent Orthopedics Industry Technology Center of Gansu Province, Lanzhou University Second Hospital, Lanzhou 730030, China
| | - Peng Xu
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an 715004, China.
| | - Bin Geng
- Department of Orthopaedics, Orthopaedics Clinical Medicine Research Center of Gansu Province, Intelligent Orthopedics Industry Technology Center of Gansu Province, Lanzhou University Second Hospital, Lanzhou 730030, China.
| | - Yayi Xia
- Department of Orthopaedics, Orthopaedics Clinical Medicine Research Center of Gansu Province, Intelligent Orthopedics Industry Technology Center of Gansu Province, Lanzhou University Second Hospital, Lanzhou 730030, China.
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Jung WK, Park SB, Yu HY, Kim J. Gemigliptin Improves Salivary Gland Dysfunction in D-Galactose-Injected Aging Rats. Pharmaceutics 2023; 16:35. [PMID: 38258046 PMCID: PMC10820573 DOI: 10.3390/pharmaceutics16010035] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 12/20/2023] [Accepted: 12/22/2023] [Indexed: 01/24/2024] Open
Abstract
Oral dryness is among the most common conditions experienced by the elderly. As saliva plays a crucial role in maintaining oral health and overall quality of life, the condition is increasingly taking its toll on a rapidly growing aging population. D-galactose (D-gal) stimulates their formation, which in turn cause oxidative stress and accelerate age-related decline in physical function. In this study, we observed a reduction in salivary secretion and amylase levels in aged rats injected with D-gal, confirming salivary gland dysfunction. Treatment with gemigliptin increased DPP-4 inhibition and GLP-1 levels in the salivary glands of aging rats and reduced the expression of AGEs and receptors for advanced glycation end products (RAGE). This effect was caused by the presence of additional reactive oxygen species (ROS) in the salivary glands of the examined rats. Gemigliptin's cytoprotective effect reduced amylase and mucin accumulation and increased AQP5 expression, which are important indicators of salivary gland function. In sum, gemigliptin was shown to improve D-gal-induced decline in the salivary gland function of aged rats through its anti-glycation and antioxidant activities. Gemigliptin shows promise as a treatment strategy for patients experiencing decreased salivary function associated with their advancing age.
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Affiliation(s)
| | | | | | - Junghyun Kim
- Department of Oral Pathology, School of Dentistry, Jeonbuk National University, Jeonju 54896, Republic of Korea; (W.K.J.); (S.-B.P.); (H.Y.Y.)
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Bansal S, Burman A, Tripathi AK. Advanced glycation end products: Key mediator and therapeutic target of cardiovascular complications in diabetes. World J Diabetes 2023; 14:1146-1162. [PMID: 37664478 PMCID: PMC10473940 DOI: 10.4239/wjd.v14.i8.1146] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 03/21/2023] [Accepted: 05/22/2023] [Indexed: 08/11/2023] Open
Abstract
The incidence of type 2 diabetes mellitus is growing in epidemic proportions and has become one of the most critical public health concerns. Cardiovascular complications associated with diabetes are the leading cause of morbidity and mortality. The cardiovascular diseases that accompany diabetes include angina, myocardial infarction, stroke, peripheral artery disease, and congestive heart failure. Among the various risk factors generated secondary to hyperglycemic situations, advanced glycation end products (AGEs) are one of the important targets for future diagnosis and prevention of diabetes. In the last decade, AGEs have drawn a lot of attention due to their involvement in diabetic patho-physiology. AGEs can be derived exogenously and endogenously through various pathways. These are a non-homogeneous, chemically diverse group of compounds formed non-enzymatically by condensation between carbonyl groups of reducing sugars and free amino groups of protein, lipids, and nucleic acid. AGEs mediate their pathological effects at the cellular and extracellular levels by multiple pathways. At the cellular level, they activate signaling cascades via the receptor for AGEs and initiate a complex series of intracellular signaling resulting in reactive oxygen species generation, inflammation, cellular proliferation, and fibrosis that may possibly exacerbate the damaging effects on cardiac functions in diabetics. AGEs also cause covalent modifications and cross-linking of serum and extracellular matrix proteins; altering their structure, stability, and functions. Early diagnosis of diabetes may prevent its progression to complications and decrease its associated comorbidities. In the present review, we recapitulate the role of AGEs as a crucial mediator of hyperglycemia-mediated detrimental effects in diabetes-associated complications. Furthermore, this review presents an overview of future perspectives for new therapeutic interventions to ameliorate cardiovascular complications in diabetes.
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Affiliation(s)
- Savita Bansal
- Department of Biochemistry, Institute of Home Sciences, University of Delhi, New Delhi 110016, India
| | - Archana Burman
- Department of Biochemistry, Institute of Home Economics, University of Delhi, New Delhi 110016, India
| | - Asok Kumar Tripathi
- Department of Biochemistry, University College of Medical Sciences, University of Delhi, New Delhi 110095, India
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Rusinov VL, Sapozhnikova IM, Spasov AA, Chupakhin ON. Fused azoloazines with antidiabetic activity. Russ Chem Bull 2022. [DOI: 10.1007/s11172-022-3687-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
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Lipopeptides in promoting signals at surface/interface of micelles: Their roles in repairing cellular and nuclear damages. FOOD BIOSCI 2022. [DOI: 10.1016/j.fbio.2021.101522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Lee N, Heo YJ, Choi SE, Jeon JY, Han SJ, Kim DJ, Kang Y, Lee KW, Kim HJ. Hepatoprotective effects of gemigliptin and empagliflozin in a murine model of diet-induced non-alcoholic fatty liver disease. Biochem Biophys Res Commun 2022; 588:154-160. [PMID: 34971904 DOI: 10.1016/j.bbrc.2021.12.065] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/14/2021] [Accepted: 12/18/2021] [Indexed: 12/19/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) includes a broad spectrum of liver diseases characterized by steatosis, inflammation, and fibrosis. This study aimed to investigate the potential of dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors in alleviating the progression of NAFLD. The NAFLD model was generated by feeding male C57BL/6J mice a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 7 weeks. After 2 weeks of CDAHFD feeding, the NAFLD model mice were assigned to four groups, namely (ⅰ) VEHICLE, (ⅱ) gemigliptin (GEMI), (ⅲ) empagliflozin (EMPA), and (ⅳ) GEMI + EMPA. For the next 5 weeks, mice received the vehicle or the drug based upon the group to which they belonged. Thereafter, the triglyceride concentration, extent of fibrosis, and the expression of genes encoding inflammatory cytokines, chemokines, and antioxidant enzymes were analyzed in the livers of mice. The NAFLD activity score and hepatic fibrosis grade were assessed via hematoxylin and eosin and Sirius Red staining of the liver tissue samples. All mice belonging to the GEMI, EMPA, and GEMI + EMPA groups showed improvements in the accumulation of liver triglycerides and the expression of inflammatory cytokines and chemokines. Additionally, the oxidative stress was reduced due to inhibition of the c-Jun N-terminal kinase pathway and upregulation of the antioxidant enzymes. Furthermore, in these three groups, the galectin-3 and interleukin 33-induced activity of tumor necrosis factor-α was inhibited, thereby preventing the progression of liver fibrosis. These findings suggest that the GEMI, EMPA, and GEMI + EMPA treatments ameliorate hepatic steatosis, inflammation, oxidative stress, and fibrosis in CDAHFD-induced NAFLD mouse models.
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Affiliation(s)
- Nami Lee
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Yu Jung Heo
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Sung-E Choi
- Department of Physiology, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Ja Young Jeon
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Seung Jin Han
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Dae Jung Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Yup Kang
- Department of Physiology, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Kwan Woo Lee
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea
| | - Hae Jin Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164 Worldcup-ro, Yeoungtong-gu, Suwon, 16499, Republic of Korea.
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Li Y, Li L, Hölscher C. Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases. Rev Neurosci 2018; 27:689-711. [PMID: 27276528 DOI: 10.1515/revneuro-2016-0018] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Accepted: 05/02/2016] [Indexed: 12/13/2022]
Abstract
Incretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Due to their promising action on insulinotropic secretion and improving insulin resistance (IR), incretin-based therapies have become a new class of antidiabetic agents for the treatment of type 2 diabetes mellitus (T2DM). Recently, the links between neurodegenerative diseases and T2DM have been identified in a number of studies, which suggested that shared mechanisms, such as insulin dysregulation or IR, may underlie these conditions. Therefore, the effects of incretins in neurodegenerative diseases have been extensively investigated. Protease-resistant long-lasting GLP-1 mimetics such as lixisenatide, liraglutide, and exenatide not only have demonstrated promising effects for treating neurodegenerative diseases in preclinical studies but also have shown first positive results in Alzheimer's disease (AD) and Parkinson's disease (PD) patients in clinical trials. Furthermore, the effects of other related incretin-based therapies such as GIP agonists, dipeptidyl peptidase-IV (DPP-IV) inhibitors, oxyntomodulin (OXM), dual GLP-1/GIP, and triple GLP-1/GIP/glucagon receptor agonists on neurodegenerative diseases have been tested in preclinical studies. Incretin-based therapies are a promising approach for treating neurodegenerative diseases.
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Matafome P, Rodrigues T, Sena C, Seiça R. Methylglyoxal in Metabolic Disorders: Facts, Myths, and Promises. Med Res Rev 2017; 37:368-403. [PMID: 27636890 DOI: 10.1002/med.21410] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Revised: 08/07/2016] [Accepted: 08/12/2016] [Indexed: 08/26/2024]
Abstract
Glucose and fructose metabolism originates the highly reactive byproduct methylglyoxal (MG), which is a strong precursor of advanced glycation end products (AGE). The MG has been implicated in classical diabetic complications such as retinopathy, nephropathy, and neuropathy, but has also been recently associated with cardiovascular diseases and central nervous system disorders such as cerebrovascular diseases and dementia. Recent studies even suggested its involvement in insulin resistance and beta-cell dysfunction, contributing to the early development of type 2 diabetes and creating a vicious circle between glycation and hyperglycemia. Despite several drugs and natural compounds have been identified in the last years in order to scavenge MG and inhibit AGE formation, we are still far from having an effective strategy to prevent MG-induced mechanisms. This review summarizes the endogenous and exogenous sources of MG, also addressing the current controversy about the importance of exogenous MG sources. The mechanisms by which MG changes cell behavior and its involvement in type 2 diabetes development and complications and the pathophysiological implication are also summarized. Particular emphasis will be given to pathophysiological relevance of studies using higher MG doses, which may have produced biased results. Finally, we also overview the current knowledge about detoxification strategies, including modulation of endogenous enzymatic systems and exogenous compounds able to inhibit MG effects on biological systems.
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Affiliation(s)
- Paulo Matafome
- Laboratory of Physiology, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal
- Department of Complementary Sciences, Coimbra Health School (ESTeSC), Instituto Politécnico de Coimbra, 3045-601, Coimbra, Portugal
| | - Tiago Rodrigues
- Laboratory of Physiology, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal
| | - Cristina Sena
- Laboratory of Physiology, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal
| | - Raquel Seiça
- Laboratory of Physiology, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal
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Kim SH, Yoo JH, Lee WJ, Park CY. Gemigliptin: An Update of Its Clinical Use in the Management of Type 2 Diabetes Mellitus. Diabetes Metab J 2016; 40:339-353. [PMID: 27766241 PMCID: PMC5069390 DOI: 10.4093/dmj.2016.40.5.339] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 07/28/2016] [Indexed: 12/13/2022] Open
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of oral antidiabetic agent for the treatment of type 2 diabetes mellitus. They increase endogenous levels of incretin hormones, which stimulate glucose-dependent insulin secretion, decrease glucagon secretion, and contribute to reducing postprandial hyperglycemia. Although DPP-4 inhibitors have similar benefits, they can be differentiated in terms of their chemical structure, pharmacology, efficacy and safety profiles, and clinical considerations. Gemigliptin (brand name: Zemiglo), developed by LG Life Sciences, is a potent, selective, competitive, and long acting DPP-4 inhibitor. Various studies have shown that gemigliptin is an optimized DPP-4 inhibitor in terms of efficacy, safety, and patient compliance for treatment of type 2 diabetes mellitus. In this review, we summarize the characteristics of gemigliptin and discuss its potential benefits in clinical practice.
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Affiliation(s)
- Sung-Ho Kim
- LG Life Sciences Ltd., R&D Park, Daejeon, Korea
| | | | - Woo Je Lee
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Cheol-Young Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
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Jung E, Kim J, Kim CS, Kim SH, Cho MH. Gemigliptin, a dipeptidyl peptidase-4 inhibitor, inhibits retinal pericyte injury in db/db mice and retinal neovascularization in mice with ischemic retinopathy. Biochim Biophys Acta Mol Basis Dis 2015; 1852:2618-29. [DOI: 10.1016/j.bbadis.2015.09.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Revised: 09/04/2015] [Accepted: 09/16/2015] [Indexed: 12/21/2022]
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Fisman EZ, Tenenbaum A. Antidiabetic treatment with gliptins: focus on cardiovascular effects and outcomes. Cardiovasc Diabetol 2015; 14:129. [PMID: 26415691 PMCID: PMC4587723 DOI: 10.1186/s12933-015-0294-0] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 09/21/2015] [Indexed: 12/11/2022] Open
Abstract
The traditional oral pharmacological therapy for type 2 diabetes mellitus (T2DM) has been based on the prescription of metformin, a biguanide, as first line antihyperglycemic agent world over. It has been demonstrated that after 3 years of treatment, approximately 50 % of diabetic patients could achieve acceptable glucose levels with monotherapy; but by 9 years this had declined to only 25 %. Therefore, the implementation of a combined pharmacological therapy acting via different pathways becomes necessary, and its combination with a compound of the sulfonylurea group was along decades the most frequently employed prescription in routine clinical practice. Meglitinides, glitazones and alpha-glucosidase inhibitors were subsequently developed, but the five mentioned groups of oral antihyperglycemic agents are associated with variable degrees of undesirable or even severe cardiovascular events. The gliptins—also called dipeptidyl peptidase 4 (DPP4) inhibitors—are an additional group of antidiabetic compounds with increasing clinical use. We review the status of the gliptins with emphasis on their capabilities to positively or negatively affect the cardiovascular system, and their potential involvement in major adverse cardiovascular events (MACE). Alogliptin, anagliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin and vildagliptin are the compounds currently in clinical use. Regardless differences in chemical structure and metabolic pathways, gliptins as a group exert favorable changes in experimental models. These changes, as an almost general rule, include improved endothelial function, reduction of inflammatory markers, oxidative stress ischemia/reperfusion injury and atherogenesis. In addition, increased adiponectin levels and modest decreases in lipidemia and blood pressure were reported. In clinical settings, several trials—notably the longer one, employing sitagliptin, with a mean follow-up period of 3 years—did not show an increased risk for ischemic events. Anyway, it should be emphasized that the encouraging results from basic science were not yet translated into clinical evidence, probably due the multiple and pleiotropic enzymatic effects of DPP4 inhibition. Moreover, when employing saxagliptin, while the drug was not associated with an augmented risk for ischemic events, it should be pinpointed that the rate of hospitalization for heart failure was significantly increased. Gliptins as a group constitute a widely accepted therapy for the management of T2DM, usually as a second-line medication. Nonetheless, for the time being, a definite relationship between gliptins treatment and improved cardiovascular outcomes remains uncertain and needs yet to be proven.
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Affiliation(s)
- Enrique Z Fisman
- Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 69978, Tel Aviv, Israel. .,Cardiovascular Diabetology Research Foundation, 58484, Holon, Israel.
| | - Alexander Tenenbaum
- Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 69978, Tel Aviv, Israel. .,Cardiovascular Diabetology Research Foundation, 58484, Holon, Israel. .,Cardiac Rehabilitation Institute, Sheba Medical Center, 52621, Tel Hashomer, Israel.
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Gemigliptin improves renal function and attenuates podocyte injury in mice with diabetic nephropathy. Eur J Pharmacol 2015; 761:116-24. [PMID: 25977232 DOI: 10.1016/j.ejphar.2015.04.055] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 04/21/2015] [Accepted: 04/26/2015] [Indexed: 11/23/2022]
Abstract
Podocytes participate in the formation and regulation of the glomerular filtration barrier. Loss of podocytes occurs during the early stages of diabetic nephropathy and impairs glomerular filtration. Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used as anti-diabetic agents in clinical practice. In this study, we showed that gemigliptin, a novel DPP-4 inhibitor, reduced podocyte apoptosis in type 2 diabetic db/db mice without reducing hyperglycemia. Gemigliptin (100mg/kg/day) was administered orally for 12 weeks in db/db mice. Blood glucose levels and albuminuria were measured. The renal cortex was collected for histological examination, and molecular assays were used to detect 8-hydroxydeoxyguanosine, advanced oxidation protein products (AOPP), the receptor for advanced glycation end products (RAGE), and integrin-linked kinase (ILK). Type 2 diabetic db/db mice exhibited albuminuria, renal histopathological changes, and podocyte loss. Administration of gemigliptin to db/db mice suppressed albuminuria, enzyme activity and expression of DPP-4, and podocyte apoptosis. The effect of gemigliptin on diabetes-induced podocyte loss was associated with the suppression of oxidative damage, AOPP accumulation, RAGE expression, and ILK expression. These results indicate the possible benefits of using gemigliptin in diabetes patients to treat renal impairment without affecting glycemic control.
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