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Patel TA, Zheng H, Patel KP. Sodium-Glucose Cotransporter 2 Inhibitors as Potential Antioxidant Therapeutic Agents in Cardiovascular and Renal Diseases. Antioxidants (Basel) 2025; 14:336. [PMID: 40227417 PMCID: PMC11939188 DOI: 10.3390/antiox14030336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 03/10/2025] [Accepted: 03/12/2025] [Indexed: 04/15/2025] Open
Abstract
Redox (reduction-oxidation) imbalance is a physiological feature regulated by a well-maintained equilibrium between reactive oxygen species (ROS) and oxidative stress (OS), the defense system of the body (antioxidant enzymes). The redox system comprises regulated levels of ROS in the cells, tissues and the overall organ system. The levels of ROS are synchronized by gradients of electrons that are generated due to sequential reduction and oxidation of various biomolecules by various enzymes. Such redox reactions are present in each cell, irrespective of any tissue or organ. Failure in such coordinated regulation of redox reactions leads to the production of excessive ROS and free radicals. Excessively produced free radicals and oxidative stress affect various cellular and molecular processes required for cell survival and growth, leading to pathophysiological conditions and, ultimately, organ failure. Overproduction of free radicals and oxidative stress are the key factors involved in the onset and progression of pathophysiological conditions associated with various cardiovascular and renal diseases. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are glucose-lowering drugs prescribed to diabetic patients. Interestingly, apart from their glucose-lowering effect, these drugs exhibit beneficial effects in non-diabetic patients suffering from various cardiovascular and chronic kidney diseases, perhaps due to their antioxidant properties. Recently, it has been demonstrated that SGLT2is exhibit strong antioxidant properties by reducing ROS and OS. Hence, in this review, we aim to present the novel antioxidant role of SGLT2is and their consequent beneficial effects in various cardiovascular and renal disease states.
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Affiliation(s)
- Tapan A. Patel
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, USA;
| | - Hong Zheng
- Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD 57069, USA
| | - Kaushik P. Patel
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, USA;
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Rättö H, Nurminen M, Aaltonen K. Prescribing patterns before the initiation of novel antidiabetic medicines in public, occupational, and private healthcare: a register study reflecting the guidelines of care in type 2 diabetes. BMC Health Serv Res 2024; 24:1553. [PMID: 39639300 PMCID: PMC11619279 DOI: 10.1186/s12913-024-12010-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 11/27/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND Disparities in access to healthcare has been implied before in Finland, a country with universal healthcare but de facto tiered primary care. Less is however known about the content of care provided in different settings. Previous studies indicate potential disparities in prescribing newer medicines between healthcare sectors. We compared the preceding prescribing patterns of patients who initiated a sodium-glucose co-transporter 2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) analogue in public, occupational, and private healthcare. METHODS We used logistic models and patient-level register data from the city of Oulu, Finland, during 2014-2018. Among patients who initiated SGLT2 inhibitors or GLP-1 analogues, we studied whether it was a first-line treatment or if other antidiabetic medicines preceded the use. In addition, prior use of statins (a lipid-lowering medicine) and insulins were studied. Clinical guidelines for type 2 diabetes recommend in most cases metformin in first-line, and insulin only at later stages or in case of severe hyperglycaemia. Using a lipid-lowering medicine is typically recommended for all. RESULTS The examined novel antidiabetic medicines were seldom initiated in first-line, and no significant differences were observed for preceding statin use across sectors, net of patient characteristics. However, patients in the public sector were more likely to have used insulin previously compared to patients in occupational sector. CONCLUSIONS Before the initiation of the examined novel antidiabetic medicines, no marked differences across sectors in the use of other antidiabetic medicines or statins were observed. The higher likelihood of prior insulin use in the public sector might reflect initiation at a later stage and/or unobserved differences in clinical characteristics across patient populations.
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Affiliation(s)
- Hanna Rättö
- Research Unit, The Social Insurance Institution of Finland, Helsinki, Finland.
- INVEST Research Flagship Centre, University of Turku, Turku, Finland.
| | - Mikko Nurminen
- Research Unit, The Social Insurance Institution of Finland, Helsinki, Finland
| | - Katri Aaltonen
- Research Unit, The Social Insurance Institution of Finland, Helsinki, Finland
- INVEST Research Flagship Centre, University of Turku, Turku, Finland
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Pan R, He Y, Melisandre W, Zhang Y, Su W, Feng J, Jia C, Li S, Liu B. Bibliometric and visual analysis of SGLT2 inhibitors in cardiovascular diseases. Front Pharmacol 2024; 15:1437760. [PMID: 39539627 PMCID: PMC11557488 DOI: 10.3389/fphar.2024.1437760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
Background Cardiovascular diseases (CVD) pose a significant threat to human health due to their high mortality and morbidity rates. Despite advances in treatments, the prevalence and impact of cardiovascular disease continue to increase. Sodium-glucose transporter 2 inhibitors (SGLT2i), initially approved for the treatment of type 2 diabetes, have important research value and promising applications in reducing CVD risk, especially in heart failure (HF) and atherosclerosis patients with cardiovascular disease (ASCVD). This study aims to comprehensively review the latest progress, research trends, cutting-edge hot spots, and future development directions of SGLT2i in the field of CVD through bibliometric analysis. Methods Articles related to MSCs in cardiovascular diseases were sourced from the Web of Science. The bibliometric analysis was conducted using CiteSpace and VOSviewer, and a knowledge map was created based on the data obtained from the retrieved articles. Results In this article, we screened 3,476 relevant studies, including 2,293 articles and 1,183 reviews. The analysis found that the number of papers related to the application of SGLT2i in CVD has generally increased, peaking in 2022. The United States and China contributed the largest number of papers, with the United States accounting for 36.97% of the total and also ranking first in terms of the number of citations. However, China's high-quality papers are slightly lacking and need further improvement. Keyword analysis showed that empagliflozin, dapagliflozin, diabetes, and heart failure were the most common terms, reflecting the main research interests in currently published papers in this field. Conclusion Bibliometric analysis showed a robust and growing interest in the application of SGLT2i for treating CVD. By summarizing the latest progress of SGLT2i in the field of CVD, exploring research hotspots, and looking forward to future research development trends, this article provides valuable insights for thinking about research prospects.
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Affiliation(s)
- Runfang Pan
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuqing He
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wan Melisandre
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yunyi Zhang
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenyuan Su
- Sport Medicine and Rehabilitation Center, Shanghai University of Sport, Shanghai, China
| | - Jiaming Feng
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chengyao Jia
- Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
| | - Shaoling Li
- Department of Pathology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Baonian Liu
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Lho Y, Park Y, Do JY, Kim AY, Park YE, Kang SH. Empagliflozin attenuates epithelial-to-mesenchymal transition through senescence in peritoneal dialysis. Am J Physiol Renal Physiol 2024; 327:F363-F372. [PMID: 38961839 DOI: 10.1152/ajprenal.00028.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 06/25/2024] [Accepted: 06/25/2024] [Indexed: 07/05/2024] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) is considered as one of the senescence processes; reportedly, antisenescence therapies effectively reduce EMT. Some models have shown antisenescence effects with the use of sodium-glucose cotransporter 2 (SGLT2) inhibitor. Therefore, our study investigated the antisenescence effects of empagliflozin as an SGLT2 inhibitor in a peritoneal fibrosis model and their impact on EMT inhibition. For in vitro study, human peritoneal mesothelial cells (HPMCs) were isolated and grown in a 96-well plate. The cell media were exchanged with serum-free M199 medium with d-glucose, with or without empagliflozin. All animal experiments were carried out in male mice. Mice were randomly classified into three treatment groups based on peritoneal dialysis (PD) or empagliflozin. We evaluated changes in senescence and EMT markers in HPMCs and PD model. HPMCs treated with glucose transformed from cobblestone to spindle shape, resulting in EMT. Empagliflozin attenuated these morphological changes. Reactive oxygen species production, DNA damage, senescence, and EMT markers were increased by glucose treatment; however, cotreatment with glucose and empagliflozin attenuated these changes. For the mice with PD, an increase in thickness, collagen deposition, staining for senescence, or EMT markers of the parietal peritoneum was observed, which, however, was attenuated by cotreatment with empagliflozin. p53, p21, and p16 increased in mice with PD compared with those in the control group; however, these changes were decreased by empagliflozin. In conclusion, empagliflozin effectively attenuated glucose-induced EMT in HPMCs through a decrease in senescence. Cotreatment with empagliflozin improved peritoneal thickness and fibrosis in PD.NEW & NOTEWORTHY Epithelial-to-mesenchymal transition (EMT) is considered one of the senescence processes. Antisenescence therapies may effectively reduce EMT in peritoneal dialysis models. Human peritoneal mesothelial cells treated with glucose show an increase in senescence and EMT markers; however, empagliflozin attenuates these changes. Mice undergoing peritoneal dialysis exhibit increased senescence and EMT markers, which are decreased by empagliflozin. These findings suggest that empagliflozin may emerge as a novel strategy for prevention or treatment of peritoneal fibrosis.
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Affiliation(s)
- Yunmee Lho
- Senotherpy-Based Metabolic Disease Control Research Center, College of Medicine, Yeungnam University, Daegu, Republic of Korea
- Division of Nephrology, Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu, Republic of Korea
| | - Yeong Park
- Senotherpy-Based Metabolic Disease Control Research Center, College of Medicine, Yeungnam University, Daegu, Republic of Korea
- Division of Nephrology, Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu, Republic of Korea
| | - Jun Young Do
- Division of Nephrology, Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu, Republic of Korea
| | - A-Young Kim
- Division of Nephrology, Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu, Republic of Korea
| | - Yong-Eun Park
- Department of Surgery, College of Medicine, Yeungnam University, Daegu, Republic of Korea
| | - Seok Hui Kang
- Senotherpy-Based Metabolic Disease Control Research Center, College of Medicine, Yeungnam University, Daegu, Republic of Korea
- Division of Nephrology, Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu, Republic of Korea
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Kim DH, Lee MJ, Kang D, Khang AR, Bae JH, Kim JY, Kim SH, Kang YH, Yi D. Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Transcription Regulation of AgRP and POMC Genes. Curr Issues Mol Biol 2024; 46:7505-7515. [PMID: 39057086 PMCID: PMC11275895 DOI: 10.3390/cimb46070445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 07/10/2024] [Accepted: 07/12/2024] [Indexed: 07/28/2024] Open
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors regulate plasma glucose levels in patients with type 2 diabetes mellitus (T2DM) by inhibiting renal glucose reabsorption. This study investigated the impact of empagliflozin (EMPA), an SGLT2 inhibitor, on hypothalamic energy regulation. To directly investigate the role of SGLT2 inhibitors in the hypothalamus, we administered EMPA through intracerebroventricular (i.c.v.) injections into the murine ventricles. After dental cementing the i.c.v. cannula onto the skull, the mice were given 5 days to recover before receiving vehicle or EMPA (50 nM/2 μL) injections. In a high-fat diet (HFD)-induced obesity model, we determined the gene expression levels of agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) in the hypothalamus. Additionally, we assessed FoxO1 expression, which regulates AgRP and POMC gene transcription in hypothalamic cell lines. We found that EMPA directly influenced the expression of endogenous mRNA of POMC and AgRP, which are critical for energy homeostasis, and modulated their transcription in high-fat diet-induced obese mice. Additionally, EMPA affected the expression of FoxO1, a key transcriptional regulator of glucose homeostasis, thereby regulating the transcriptional activity of POMC and AgRP. These results indicate that EMPA significantly influences hypothalamic energy homeostasis, highlighting its potential as a regulator in obesity and T2DM management.
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Affiliation(s)
- Dong Hee Kim
- Department of BIT Fusion Technology Center, Pusan National University, Busan 46241, Republic of Korea;
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (M.J.L.); (A.R.K.); (J.H.B.); (J.Y.K.); (S.H.K.); (Y.H.K.)
| | - Min Jin Lee
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (M.J.L.); (A.R.K.); (J.H.B.); (J.Y.K.); (S.H.K.); (Y.H.K.)
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Dasol Kang
- Department of Biological Sciences, College of National Sciences, University of Ulsan, Ulsan 44919, Republic of Korea;
| | - Ah Reum Khang
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (M.J.L.); (A.R.K.); (J.H.B.); (J.Y.K.); (S.H.K.); (Y.H.K.)
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Ji Hyun Bae
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (M.J.L.); (A.R.K.); (J.H.B.); (J.Y.K.); (S.H.K.); (Y.H.K.)
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Joo Yeon Kim
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (M.J.L.); (A.R.K.); (J.H.B.); (J.Y.K.); (S.H.K.); (Y.H.K.)
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Su Hyun Kim
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (M.J.L.); (A.R.K.); (J.H.B.); (J.Y.K.); (S.H.K.); (Y.H.K.)
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Yang Ho Kang
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (M.J.L.); (A.R.K.); (J.H.B.); (J.Y.K.); (S.H.K.); (Y.H.K.)
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Dongwon Yi
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (M.J.L.); (A.R.K.); (J.H.B.); (J.Y.K.); (S.H.K.); (Y.H.K.)
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
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Kupai K, Kang HL, Pósa A, Csonka Á, Várkonyi T, Valkusz Z. Bone Loss in Diabetes Mellitus: Diaporosis. Int J Mol Sci 2024; 25:7269. [PMID: 39000376 PMCID: PMC11242219 DOI: 10.3390/ijms25137269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 06/21/2024] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
The objective of this review is to examine the connection between osteoporosis and diabetes, compare the underlying causes of osteoporosis in various forms of diabetes, and suggest optimal methods for diagnosing and assessing fracture risk in diabetic patients. This narrative review discusses the key factors contributing to the heightened risk of fractures in individuals with diabetes, as well as the shared elements impacting the treatment of both diabetes mellitus and osteoporosis. Understanding the close link between diabetes and a heightened risk of fractures is crucial in effectively managing both conditions. There are several review articles of meta-analysis regarding diaporosis. Nevertheless, no review articles showed collected and well-organized medications of antidiabetics and made for inconvenient reading for those who were interested in details of drug mechanisms. In this article, we presented collected and comprehensive charts of every antidiabetic medication which was linked to fracture risk and indicated plausible descriptions according to research articles.
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Affiliation(s)
- Krisztina Kupai
- Department of Internal Medicine, Albert Szent-Györgyi Medical School, University of Szeged, 6703 Szeged, Hungary
- Department of Oral Biology and Experimental Dental Research, Faculty of Dentistry, University of Szeged, 6703 Szeged, Hungary
| | - Hsu Lin Kang
- Department of Oral Biology and Experimental Dental Research, Faculty of Dentistry, University of Szeged, 6703 Szeged, Hungary
| | - Anikó Pósa
- Department of Oral Biology and Experimental Dental Research, Faculty of Dentistry, University of Szeged, 6703 Szeged, Hungary
| | - Ákos Csonka
- Department of Traumatology, University of Szeged, 6725 Szeged, Hungary;
| | - Tamás Várkonyi
- Department of Internal Medicine, Albert Szent-Györgyi Medical School, University of Szeged, 6703 Szeged, Hungary
| | - Zsuzsanna Valkusz
- Department of Internal Medicine, Albert Szent-Györgyi Medical School, University of Szeged, 6703 Szeged, Hungary
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Liao CC, Hsieh CC, Shia WC, Chou MY, Huang CC, Lin JH, Lee SH, Sung HH. Refined protocol for newly onset identification in non-obese diabetic mice: an animal-friendly, cost-effective, and efficient alternative. Lab Anim Res 2024; 40:16. [PMID: 38649958 PMCID: PMC11034171 DOI: 10.1186/s42826-024-00202-w] [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: 01/19/2024] [Revised: 04/01/2024] [Accepted: 04/04/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND Therapeutic interventions for diabetes are most effective when administered in the newly onset phase, yet determining the exact onset moment can be elusive in practice. Spontaneous autoimmune diabetes among NOD mice appears randomly between 12 and 32 weeks of age with an incidence range from 60 to 90%. Furthermore, the disease often progresses rapidly to severe diabetes within days, resulting in a very short window of newly onset phase, that poses significant challenge in early diagnosis. Conventionally, extensive blood glucose (BG) testing is typically required on large cohorts throughout several months to conduct prospective survey. We incorporated ultrasensitive urine glucose (UG) testing into an ordinary BG survey process, initially aiming to elucidate the lag period required for excessive glucose leaking from blood to urine during diabetes progression in the mouse model. RESULTS The observations unexpectedly revealed that small amounts of glucose detected in the urine often coincide with, sometimes even a couple days prior than elevated BG is diagnosed. Accordingly, we conducted the UG-based survey protocol in another cohort that was validated to accurately identified every individual near onset, who could then be confirmed by following few BG tests to fulfill the consecutive BG + criteria. This approach required fewer than 95 BG tests, compared to over 700 tests with traditional BG survey, to diagnose all the 37-38 diabetic mice out of total 60. The average BG level at diagnosis was slightly below 350 mg/dl, lower than the approximately 400 mg/dl observed with conventional BG monitoring. CONCLUSIONS We demonstrated a near perfect correlation between BG + and ultrasensitive UG + results in prospective survey with no lag period detected under twice weekly of testing frequency. This led to the refined protocol based on surveying with noninvasive UG testing, allowing for the early identification of newly onset diabetic mice with only a few BG tests required per mouse. This protocol significantly reduces the need for extensive blood sampling, lancet usage, labor, and animal distress, aligning with the 3Rs principle. It presents a convenient, accurate, and animal-friendly alternative for early diabetes diagnosis, facilitating research on diagnosis, pathogenesis, prevention, and treatment.
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Affiliation(s)
- Chia-Chi Liao
- National Laboratory Animal Center, National Applied Research Laboratories, Taipei, Taiwan
| | - Chia-Chun Hsieh
- National Laboratory Animal Center, National Applied Research Laboratories, Taipei, Taiwan
- Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
| | - Wei-Chung Shia
- Molecular Medicine Laboratory, Department of Research, Changhua Christian Hospital, Changhua, Taiwan
| | - Min-Yuan Chou
- Biomedical Technology and Device Research Lab, Industrial Technology Research Institute, Hsinchu, Taiwan
| | - Chuan-Chuan Huang
- Biomedical Technology and Device Research Lab, Industrial Technology Research Institute, Hsinchu, Taiwan
- Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jhih-Hong Lin
- National Laboratory Animal Center, National Applied Research Laboratories, Tainan, Taiwan
| | - Shu-Hsien Lee
- National Laboratory Animal Center, National Applied Research Laboratories, Tainan, Taiwan
| | - Hsiang-Hsuan Sung
- National Laboratory Animal Center, National Applied Research Laboratories, Taipei, Taiwan.
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van Hulten V, Driessen JHM, Starup-Linde JK, Al-Mashhadi ZK, Viggers R, Klungel OH, Souverein PC, Vestergaard P, Stehouwer CDA, van den Bergh JP. The associations of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors as add-on to metformin with fracture risk in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2023; 25:3235-3247. [PMID: 37503747 DOI: 10.1111/dom.15220] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/28/2023] [Accepted: 07/02/2023] [Indexed: 07/29/2023]
Abstract
AIM To investigate whether sodium-glucose cotransporter-2 (SGLT2) inhibitor use as compared to dipeptidyl peptidase-4 (DPP-4) inhibitor use as add-on to metformin is associated with the risk of any fracture or major osteoporotic fractures (MOFs). METHODS A cohort study using the Clinical Practice Research Datalink (CPRD) Aurum database was conducted. All patients aged 18 years and older with a first-ever prescription for a DPP-4 inhibitor or an SGLT2 inhibitor as add-on to metformin between January 1, 2013 and June 30, 2020 were selected. Patients starting with SGLT2 inhibitors were matched (up to 1:3) on propensity scores to patients starting with DPP-4 inhibitors. Propensity scores were calculated based on sex, age, body mass index, comorbidities, comedication and lifestyle factors. Cox proportional hazard models were used to estimate the risk of fracture with SGLT2 inhibitor use as compared to DPP-4 inhibitor use. RESULTS A total of 13 807 SGLT2 inhibitor users (age 55.4 ± 10.6 years, 36.7% female) were included in this study, matched with 28 524 DPP-4 inhibitor users (age 55.4 ± 8.0 years, 36.4% female). The risk of any fracture with current SGLT2 inhibitor use was similar compared with current DPP-4 inhibitor use (adjusted hazard ratio [aHR] 1.09, 95% confidence interval [CI] 0.91-1.31), as was the risk of MOFs (aHR 0.89, 95% CI 0.64-1.22) and the risk of fractures at any of the individual MOF sites. Additionally, no association was found with duration of SGLT2 inhibitor use (longest duration >811 days) for any of the individual SGLT2 inhibitor agents, or after stratification by sex and age. CONCLUSION Use of SGLT2 inhibitors was not associated with the risk of any fracture, MOFs or fracture at the individual MOF sites when compared to DPP-4 inhibitor use.
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Affiliation(s)
- Veerle van Hulten
- Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre+ (MUMC+), Maastricht, The Netherlands
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
- Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Johanna H M Driessen
- Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre+ (MUMC+), Maastricht, The Netherlands
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
- Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Jakob K Starup-Linde
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Zheer K Al-Mashhadi
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Rikke Viggers
- Steno Diabetes Center North Denmark, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Olaf H Klungel
- Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Patrick C Souverein
- Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Peter Vestergaard
- Steno Diabetes Center North Denmark, Aalborg, Denmark
- Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
| | - Coen D A Stehouwer
- Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre+ (MUMC+), Maastricht, Netherlands
| | - Joop P van den Bergh
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
- Department of Internal Medicine, Division of Rheumatology, Maastricht University Medical Centre+ (MUMC+), Maastricht, The Netherlands
- Department of Internal Medicine, Subdivision of Endocrinology, VieCuri Medical Center, Venlo, The Netherlands
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Duan X, Chen C, Liu X, Wang T, Feng S, Li J, Li G. Interference of periostin attenuates pathological changes, proinflammatory markers and renal fibrosis in diabetic kidney injury. Genes Genomics 2023; 45:1389-1397. [PMID: 37248423 DOI: 10.1007/s13258-023-01400-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Accepted: 05/11/2023] [Indexed: 05/31/2023]
Abstract
BACKGROUND Diabetic nephropathy (DN) is a prevalent complication of diabetes, in which inflammation and fibrosis are the significant pathogenesis. Periostin is a matricellular protein that functions on stabilizing the extracellular matrix by binding to integrins during development. This study aimed to explored the role of periostin in DN. METHODS The animal and cell models of DN were constructed in streptozocin (STZ)-induced mice and high glucose-challenged human mesangial cells (HMCs). The role of periostin in pathological changes, inflammation and fibrosis in DN was investigated through biochemical detection, HE and Masson staining and scores, western blot, enzyme‑linked immunosorbent assay (ELISA) and real-time quantitative PCR (RT-qPCR) assays. RESULTS Knockdown of periostin counteracted the STZ-induced the ratio of kidney weight and body weight, and the concentrations of urine albumin excretion (UAE), serum creatinine (Scr), urine albumin/creatinine ratio (UACR) and blood urea nitrogen (BUN) in mice. Moreover, silencing of periostin alleviated the pathological manifestations and reduced the concentrations of IL-6, TNF-α and IL-1β in mice kidney tissues and sera. Also, downregulation of periostin decreased the relative protein expression of fibronectin, collagen IV and α-SMA in kidney tissues. Meanwhile, interference of periostin attenuated the levels of pro-inflammation factors and the expressions of fibrosis markers in HG-induced HMCs. CONCLUSION Interference of periostin resisted DN via attenuating the pro-inflammatory cytokines release and renal fibrosis in diabetic kidney injury. Our study establishes a basis for its further study and underlying application in clinical practice in diagnosing and treating diabetic kidney injury or other relevant diseases.
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Affiliation(s)
- Xiaoting Duan
- Department of Nephrology, Affiliated Hospital of Hebei Engineering University, No. 81 Congtai Road, Handan City, Hebei Province056000, China
| | - Cheng Chen
- The Second Department of Oncology, Affiliated Hospital of Hebei Engineering University, Hebei, 056000, China
| | - Xiaoli Liu
- Department of Nephrology, Affiliated Hospital of Hebei Engineering University, No. 81 Congtai Road, Handan City, Hebei Province056000, China
| | - Taoxia Wang
- Department of Nephrology, Affiliated Hospital of Hebei Engineering University, No. 81 Congtai Road, Handan City, Hebei Province056000, China
| | - Shuning Feng
- Department of Nephrology, Affiliated Hospital of Hebei Engineering University, No. 81 Congtai Road, Handan City, Hebei Province056000, China
| | - Jianwei Li
- Department of Nephrology, Affiliated Hospital of Hebei Engineering University, No. 81 Congtai Road, Handan City, Hebei Province056000, China
| | - Guiying Li
- Department of Nephrology, Affiliated Hospital of Hebei Engineering University, No. 81 Congtai Road, Handan City, Hebei Province056000, China.
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10
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Dalga D, Verissimo T, de Seigneux S. Gluconeogenesis in the kidney: in health and in chronic kidney disease. Clin Kidney J 2023; 16:1249-1257. [PMID: 37529654 PMCID: PMC10387387 DOI: 10.1093/ckj/sfad046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Indexed: 08/03/2023] Open
Abstract
Chronic kidney disease (CKD) is a global health issue with increasing prevalence. Despite large improvements in current therapies, slowing CKD progression remains a challenge. A better understanding of renal pathophysiology is needed to offer new therapeutic targets. The role of metabolism alterations and mitochondrial dysfunction in tubular cells is increasingly recognized in CKD progression. In proximal tubular cells, CKD progression is associated with a switch from fatty acid oxidation to glycolysis. Glucose synthesis through gluconeogenesis is one of the principal physiological functions of the kidney. Loss of tubular gluconeogenesis in a stage-dependent manner is a key feature of CKD and contributes to systemic and possibly local metabolic complications. The local consequences observed may be related to an accumulation of precursors, such as glycogen, but also to the various physiological functions of the gluconeogenesis enzymes. The basic features of metabolism in proximal tubular cells and their modifications during CKD will be reviewed. The metabolic modifications and their influence on kidney disease will be described, as well as the local and systemic consequences. Finally, therapeutic interventions will be discussed.
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Affiliation(s)
- Delal Dalga
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Thomas Verissimo
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
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11
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Sato T, Kouzu H, Yano T, Sakuma I, Furuhashi M, Tohse N. Potential favorable action of sodium-glucose cotransporter-2 inhibitors on sudden cardiac death: a brief overview. Front Cardiovasc Med 2023; 10:1159953. [PMID: 37252114 PMCID: PMC10214280 DOI: 10.3389/fcvm.2023.1159953] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 04/21/2023] [Indexed: 05/31/2023] Open
Abstract
The primary pharmacological action of sodium-glucose co-transporter 2 (SGLT2) inhibitors is to inhibit the reabsorption of glucose and sodium ions from the proximal tubules of the kidney and to promote urinary glucose excretion. Notably, several clinical trials have recently demonstrated potent protective effects of SGLT2 inhibitors in patients with heart failure (HF) or chronic kidney disease (CKD), regardless of the presence or absence of diabetes. However, the impact of SGLT2 inhibitors on sudden cardiac death (SCD) or fatal ventricular arrhythmias (VAs), the pathophysiology of which is partly similar to that of HF and CKD, remains undetermined. The cardiorenal protective effects of SGLT2 inhibitors have been reported to include hemodynamic improvement, reverse remodeling of the failing heart, amelioration of sympathetic hyperactivity, correction of anemia and impaired iron metabolism, antioxidative effects, correction of serum electrolyte abnormalities, and antifibrotic effects, which may lead to prevent SCD and/or VAs. Recently, as possible direct cardiac effects of SGLT2 inhibitors, not only inhibition of Na+/H+ exchanger (NHE) activity, but also suppression of late Na+ current have been focused on. In addition to the indirect cardioprotective mechanisms of SGLT2 inhibitors, suppression of aberrantly increased late Na+ current may contribute to preventing SCD and/or VAs via restoration of the prolonged repolarization phase in the failing heart. This review summarizes the results of previous clinical trials of SGLT2 inhibitors for prevention of SCD, their impact on the indices of electrocardiogram, and the possible molecular mechanisms of their anti-arrhythmic effects.
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Affiliation(s)
- Tatsuya Sato
- Department of Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, Sapporo, Japan
- Department of Cardiovascular, Renal, and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hidemichi Kouzu
- Department of Cardiovascular, Renal, and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Toshiyuki Yano
- Department of Cardiovascular, Renal, and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Ichiro Sakuma
- Caress Sapporo Hokko Memorial Clinic, Sapporo, Japan
| | - Masato Furuhashi
- Department of Cardiovascular, Renal, and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Noritsugu Tohse
- Department of Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, Sapporo, Japan
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12
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Ji L, Lu Y, Li Q, Fu L, Luo Y, Lei T, Li L, Ye S, Shi B, Li X, Meinicke T. Efficacy and safety of empagliflozin in combination with insulin in Chinese patients with type 2 diabetes and insufficient glycaemic control: A phase III, randomized, double-blind, placebo-controlled, parallel study. Diabetes Obes Metab 2023. [PMID: 36864540 DOI: 10.1111/dom.15041] [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: 11/30/2022] [Revised: 02/17/2023] [Accepted: 02/27/2023] [Indexed: 03/04/2023]
Abstract
AIM To evaluate the efficacy and safety of empagliflozin in combination with insulin ± oral antidiabetic drugs (OADs) over 24 weeks, in Chinese patients with type 2 diabetes (T2D) who had insufficient glycaemic control. MATERIALS AND METHODS This was a randomized, double-blind, placebo-controlled, parallel group, multicentre phase III study. Adult patients with T2D and insufficient glycaemic control who received insulin ± up to two OADs were randomized (1:1:1) to receive empagliflozin 10 or 25 mg, or placebo for 24 weeks. The primary endpoint was change from baseline in HbA1c at week 24. RESULTS Of 219 randomized patients, 73 patients were in each treatment group; baseline characteristics were comparable among the groups. There was a significantly larger decrease from baseline in HbA1c (adjusted mean treatment difference -0.99 and -0.98 for in the empagliflozin 10 and 25 mg groups, respectively; P < .0001) with both doses of empagliflozin than with placebo. There were also significantly larger decreases from baseline in fasting plasma glucose, 2-hour postprandial glucose and body weight with both empagliflozin doses than with placebo. Among patients in the empagliflozin 10 mg, 25 mg and placebo groups, 17.8%, 9.6% and 11.0% reported confirmed hypoglycaemic events, respectively (nominal P = .2422 and .7661 in the empagliflozin 10 and 25 mg groups, respectively), and no Clinical Events Committee-confirmed diabetic ketoacidosis events were reported. CONCLUSIONS In Chinese patients with T2D, empagliflozin combined with insulin ± OADs improved glycaemic control and was well tolerated, without an increased risk of hypoglycaemia.
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Affiliation(s)
- Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, People's Republic of China
| | - Yibin Lu
- Department of Endocrinology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Qifu Li
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Liujun Fu
- Department of Endocrinology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, People's Republic of China
| | - Yong Luo
- Department of Endocrinology, Chongqing University Three Gerges Hospital, Chongqing, People's Republic of China
| | - Tao Lei
- Department of Endocrinology, Putuo District Central Hospital of Shanghai, Shanghai, People's Republic of China
| | - Ling Li
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China
| | - Shandong Ye
- Department of Endocrinology, The First Affiliated Hospital of USTC, Hefei, People's Republic of China
| | - Bimin Shi
- Department of Endocrinology, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Xiyan Li
- Biostatistics and Data Sciences, Boehringer Ingelheim (China) Investment Co. Ltd, Shanghai, People's Republic of China
| | - Thomas Meinicke
- Therapeutic Area Cardiovascular/Metabolism/Respiratory, Boehringer Ingelheim International GmbH, Ingelheim, Germany
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13
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Isidto R, Danguilan R, Naidas O, Vilanueva R, Arakama MH, Paraiso LM. Emerging Role of Sodium-Glucose Co-Transporter 2 Inhibitors for the Treatment of Chronic Kidney Disease. Int J Nephrol Renovasc Dis 2023; 16:43-57. [PMID: 36852177 PMCID: PMC9960786 DOI: 10.2147/ijnrd.s387262] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 12/24/2022] [Indexed: 02/25/2023] Open
Abstract
Chronic kidney disease is one of the leading causes of morbidity and mortality in the Philippines. It is associated with a growing health burden as many patients progress to end-stage renal disease. Until recently, therapeutic options for the management of chronic kidney disease were limited. Sodium-glucose co-transporter 2 inhibitors offer an alternative therapeutic approach for patients with chronic kidney disease. Several trials have shown renal benefits with sodium-glucose co-transporter 2 inhibitors in patients with cardiovascular disease with and without type 2 diabetes and across a range of estimated glomerular filtration rate levels. In the Philippines, the sodium-glucose co-transporter 2 inhibitors dapagliflozin and canagliflozin are approved for the prevention of new and worsening nephropathy in type 2 diabetes. With emerging treatment options, an urgent need exists for guidance on the management of chronic kidney disease within the Philippines. In this review, we focus on the putative renal-protective mechanisms of sodium-glucose co-transporter 2 inhibitors, including effects on tubuloglomerular feedback, albuminuria, endothelial function, erythropoiesis, uric acid levels, renal oxygen demand, and hypoxia. Furthermore, we discuss the findings of recent large clinical trials using sodium-glucose co-transporter 2 inhibitors in patients with chronic kidney disease and diabetic kidney disease, summarize safety aspects, and outline the practical management of patients with chronic kidney disease in the Philippines.
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Affiliation(s)
- Rey Isidto
- HealthLink Medical, Surgical, Dental Clinics and Diagnostic Center, Iloilo City, Iloilo, Philippines
| | - Romina Danguilan
- Department of Adult Nephrology, National Kidney and Transplant Institute, Quezon City, Manila, Philippines
| | - Oscar Naidas
- Department of Adult Nephrology, St. Luke’s Medical Center, Quezon City, Manila, Philippines
| | - Russell Vilanueva
- Department of Adult Nephrology, National Kidney and Transplant Institute, Quezon City, Manila, Philippines
| | - Mel-Hatra Arakama
- Department of Adult Nephrology, National Kidney and Transplant Institute, Quezon City, Manila, Philippines
| | - Layla Marie Paraiso
- Department of Adult Nephrology, National Kidney and Transplant Institute, Quezon City, Manila, Philippines
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14
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Azzane A, Farid O, Eddouks M. Antihyperglycemic and Antidyslipidemic Effects of Artemisia arborescens Aqueous Extract on Streptozotocin-induced Diabetic Rats. Cardiovasc Hematol Agents Med Chem 2023; 21:120-138. [PMID: 35469581 DOI: 10.2174/1871525720666220425094135] [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: 08/25/2021] [Revised: 12/09/2021] [Accepted: 01/26/2022] [Indexed: 06/14/2023]
Abstract
AIMS This study aimed to investigate the antidiabetic activity of Artemisia arborescens. BACKGROUND Artemisia arborescens is an aromatic, medicinal, and endemic plant mostly found in the Mediterranean region. This plant is widely used as alternative medicine. OBJECTIVE The study was designed to examine the antihyperglycemic and antihyperlipidemic activities of Artemisia arborescens aqueous extract (AEAA) in normal and streptozotocin (STZ)- induced diabetic rats. METHODS The effect of AEAA (40 mg/kg and 80 mg/kg) on plasma glucose levels and plasma lipid profile was investigated in normal and STZ-induced diabetic rats. The plasma glucose levels were determined after a single (6 hours) and subchronic oral administration (7 days), and plasma lipid profiles were evaluated after both acute and subchronic oral administration. Additionally, the glycogen content in the liver, extensor digitorum longus (EDL), and soleus muscles was measured using a standard method. Moreover, the aqueous extract was tested for its 1.1-diphenyl-2- picrylhydrazyl (DPPH) radical-scavenging activity. RESULTS In diabetic rats, AEAA oral administration (40 mg/kg and 80 mg/kg) produced a significant decrease in blood glucose levels after 7 days of oral administration (P<0.0001). Moreover, a significant decrease in plasma triglyceride levels was reported on the last day of treatment by AEAA (80 mg/kg) (P<0.05). Furthermore, a significant decrease in total cholesterol levels was observed after 7 days of AEAA oral administration in diabetic rats (P<0.01). Moreover, a significant increase in HDL-c concentration was noted after one week of AEAA (80 mg/kg) oral administration (P<0.001). In addition, AEAA oral administration (80 mg/kg) significantly increased the glycogen content in the liver and extensor digitorum longus (P<0.05). On the other hand, qualitative and quantitative phytochemical screenings revealed the presence of various compounds, such as polyphenols, flavonoids, and tannins. CONCLUSION In summary, the study demonstrates that Artemisia arborescens oral administration exhibited a significant antihyperglycemic effect on diabetic rats and revealed a significant amelioration in lipid profile and glycogen content.
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Affiliation(s)
- Amine Azzane
- Faculty of Sciences and Techniques, Errachidia, Moulay Ismail University, Meknes, BP 509, Boutalamine, 52000, Errachidia, Morocco
| | - Omar Farid
- Faculty of Sciences and Techniques, Errachidia, Moulay Ismail University, Meknes, BP 509, Boutalamine, 52000, Errachidia, Morocco
| | - Mohamed Eddouks
- Faculty of Sciences and Techniques, Errachidia, Moulay Ismail University, Meknes, BP 509, Boutalamine, 52000, Errachidia, Morocco
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15
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Chen X, Wang L, Li H, Huang W, Huang S, Zhao L, Guo W. Clinical benefit of sodium-glucose transport protein-2 inhibitors in patients with heart failure: An updated meta-analysis and trial sequential analysis. Front Cardiovasc Med 2022; 9:1067806. [PMID: 36531703 PMCID: PMC9755323 DOI: 10.3389/fcvm.2022.1067806] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 11/11/2022] [Indexed: 09/10/2024] Open
Abstract
To assess whether the current body of accumulated data can give convincing evidence in favor of sodium-glucose transport protein-2 inhibitor (SGLT-2i) in all types of heart failure (HF). We searched for randomized controlled trials contrasting the effectiveness of SGLT-2i to placebo or other hypoglycemic medications on clinicaltrials.gov, PubMed, and the Cochrane Library database. To gauge effect size, hazard ratios (HR) were employed as measurements. The composite outcome of cardiovascular death or hospitalization owing to HF was the primary endpoint. Eleven studies were included. In comparison to the control group, the data demonstrated that SGLT-2i is related with a decreased incidence of composite outcome (HR: 0.77, 95% CIs: 0.73-0.81, I 2 = 0%, P < 0.01), CV death (HR: 0.87, 95% CIs: 0.81-0.94, I 2 = 3%, P < 0.01), all-cause mortality (HR: 0.90, 95% CIs: 0.84-0.96, I 2 = 10%, P < 0.01), and hospitalization due to HF (HHF) (HR: 0.70, 95% CIs: 0.66-0.75, I 2 = 0%, P < 0.01). The trial sequential analysis found strong evidence of a decrease in the incidence of all clinical outcomes with SGLT-2i when compared to the control group. Subgroup analysis demonstrated that the association between SGLT-2i and clinical outcome was independent of population characteristics. We confirm that the present evidence supports the use of SGLT-2i in a wide range of HF patients. Systematic review registration [https://www.crd.york.ac.uk/prospero/#recordDetails], identifier [CRD42022333279].
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Affiliation(s)
- Xiehui Chen
- Longhua District Central Hospital, Shenzhen, China
| | - Lili Wang
- Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, China
| | - Huijun Li
- Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, China
| | - Weichao Huang
- Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, China
| | - Siquan Huang
- Shenzhen Longhua People’s Hospital, Shenzhen, China
| | - Lingyue Zhao
- Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China
| | - Wenqin Guo
- Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, China
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16
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Hu S, Lin C, Cai X, Zhu X, Lv F, Yang W, Ji L. Disparities in efficacy and safety of sodium-glucose cotransporter 2 inhibitor among patients with different extents of renal dysfunction: A systematic review and meta-analysis of randomized controlled trials. Front Pharmacol 2022; 13:1018720. [PMID: 36483741 PMCID: PMC9723253 DOI: 10.3389/fphar.2022.1018720] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 11/02/2022] [Indexed: 09/08/2023] Open
Abstract
Background: The pleiotropic efficacy of SGLT2is in patients with different eGFR levels has not been well-understood. This systematic review and meta-analysis assessed the disparities in the efficacy and safety of SGLT2i treatment across stratified renal function. Methods: We searched four databases from inception to December 2021. We included randomized controlled trials (RCTs) with reported baseline eGFR levels and absolute changes from baseline in at least one of the following outcomes: HbA1c, body weight, blood pressure, and eGFR. Continuous outcomes were evaluated as the weighted mean differences (WMDs) and 95% confidence intervals (CIs). Categorical outcomes were evaluated as odds ratios (ORs) and accompanying 95% CIs. Results: In total, 86 eligible RCTs were included. SGLT2is produces a substantial benefit in glycemic control, weight control, and blood pressure control even in patients with impaired renal function. HbA1c and weight reductions observed in SGLT2i users were generally parallel with the renal function levels, although there was an augmented weight reduction in severe renal dysfunction stratum [HbA1c: -0.49% (-0.58 to -0.39%) for normal renal function, -0.58% (-0.66 to -0.50%) for mild renal function impairment, -0.22% (-0.35 to -0.09%) for moderate renal function impairment, and -0.13% (-0.67 to 0.42%) for severe renal function impairment (p < 0.001 for subgroup differences); weight: -2.12 kg (-2.66 to -1.59 kg) for normal renal function, -2.06 kg (-2.31 to -1.82 kg) for mild renal function impairment; -1.23 kg (-1.59 to -0.86 kg) for moderate renal function impairment; -1.88 kg (-3.04 to -0.72 kg) for severe renal function impairment (p = 0.002 for subgroup differences)]. However, the blood pressure reduction observed in SGLT2i users was independent of renal function. When compared with the placebo, the occurrence of hypoglycemia was more frequent in patients with favorable renal function rather than in those with substantial renal dysfunction. Conclusion: The HbA1c and body weight reductions observed in SGLT2i users were generally parallel with their baseline eGFR levels, while blood pressure reductions in SGLT2i users were independent of their baseline eGFR levels. Consistently, when compared with the placebo, hypoglycemia was more frequent in patients with favorable renal function, where the HbA1c reduction was profound.
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Affiliation(s)
| | | | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
| | | | | | | | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
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17
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Akalestou E, Lopez-Noriega L, Tough IR, Hu M, Leclerc I, Cox HM, Rutter GA. Vertical Sleeve Gastrectomy Lowers SGLT2/Slc5a2 Expression in the Mouse Kidney. Diabetes 2022; 71:1623-1635. [PMID: 35594379 DOI: 10.2337/db21-0768] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 05/02/2022] [Indexed: 11/13/2022]
Abstract
Bariatric surgery improves glucose homeostasis, but the underlying mechanisms are not fully elucidated. Here, we show that the expression of sodium-glucose cotransporter 2 (SGLT2/Slc5a2) is reduced in the kidney of lean and obese mice following vertical sleeve gastrectomy (VSG). Indicating an important contribution of altered cotransporter expression to the impact of surgery, inactivation of the SGLT2/Slc5a2 gene by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 attenuated the effects of VSG, with glucose excursions following intraperitoneal injection lowered by ∼30% in wild-type mice but by ∼20% in SGLT2-null animals. The effects of the SGLT2 inhibitor dapaglifozin were similarly blunted by surgery. Unexpectedly, effects of dapaglifozin were still observed in SGLT2-null mice, consistent with the existence of metabolically beneficial off-target effects of SGLT2 inhibitors. Thus, we describe a new mechanism involved in mediating the glucose-lowering effects of bariatric surgery.
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Affiliation(s)
- Elina Akalestou
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, U.K
| | - Livia Lopez-Noriega
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, U.K
| | - Iain R Tough
- Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London, U.K
| | - Ming Hu
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, U.K
| | - Isabelle Leclerc
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, U.K
- Centre de Recherches du Centre hospitalier de l'Université de Montréal (CHUM), University of Montreal, Montreal, Quebec, Canada
| | - Helen M Cox
- Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London, U.K
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, U.K
- Centre de Recherches du Centre hospitalier de l'Université de Montréal (CHUM), University of Montreal, Montreal, Quebec, Canada
- Lee Kong Chian Imperial Medical School, Nanyang Technological University, Singapore
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18
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Abbad L, Prakoura N, Michon A, Chalghoumi R, Reichelt-Wurm S, Banas MC, Chatziantoniou C. Role of Periostin and Nuclear Factor-κB Interplay in the Development of Diabetic Nephropathy. Cells 2022; 11:cells11142212. [PMID: 35883655 PMCID: PMC9320904 DOI: 10.3390/cells11142212] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/11/2022] [Accepted: 07/12/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic nephropathy (DN) remains the most common reason for end-stage renal disease and a leading cause of kidney replacement therapy. Multifactorial pathophysiological mechanisms underlie the development of DN. Among the signalling pathways involved, nuclear factor-κB (NF-κB) plays a key role in pathogenesis triggering inflammation, oxidative stress and fibrosis. Recent evidence shows that periostin, a matricellular protein, is involved in the development of renal glomerular diseases through interaction with NF-κB signalling. The aim of the present study is to investigate the contribution of periostin and its interaction with NF-κB in DN development. To this end, we used the BTBR ob/ob mice model of diabetes type 2, and we applied transcriptomic analysis, immunostaining and methods quantifying protein and mRNA expressions. We found that increased periostin expression was correlated with decreased renal function, advanced stage renal damage and fibrosis, and NF-κB activation. Subsequently, we identified novel pathways and genes regulated by the NF-κB-periostin interaction which are involved in the mechanisms of progression of DN. Some of these genes, such as FGF1 and GDF15, have the potential to be new biomarkers and/or targets for the therapy of DN.
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Affiliation(s)
- Lilia Abbad
- Unite Mixte de Recherche Scientific 1155, Institut National de la Sante et de la Recherche Medicale, Tenon Hospital, 75020 Paris, France; (L.A.); (N.P.); (A.M.); (R.C.)
- Faculty of Medicine, Sorbonne University, 75020 Paris, France
| | - Niki Prakoura
- Unite Mixte de Recherche Scientific 1155, Institut National de la Sante et de la Recherche Medicale, Tenon Hospital, 75020 Paris, France; (L.A.); (N.P.); (A.M.); (R.C.)
- Faculty of Medicine, Sorbonne University, 75020 Paris, France
| | - Arthur Michon
- Unite Mixte de Recherche Scientific 1155, Institut National de la Sante et de la Recherche Medicale, Tenon Hospital, 75020 Paris, France; (L.A.); (N.P.); (A.M.); (R.C.)
- Faculty of Medicine, Sorbonne University, 75020 Paris, France
| | - Rym Chalghoumi
- Unite Mixte de Recherche Scientific 1155, Institut National de la Sante et de la Recherche Medicale, Tenon Hospital, 75020 Paris, France; (L.A.); (N.P.); (A.M.); (R.C.)
- Faculty of Medicine, Sorbonne University, 75020 Paris, France
| | - Simone Reichelt-Wurm
- Department of Nephrology, University Hospital Regensburg, D-93053 Regensburg, Germany; (S.R.-W.); (M.C.B.)
| | - Miriam C. Banas
- Department of Nephrology, University Hospital Regensburg, D-93053 Regensburg, Germany; (S.R.-W.); (M.C.B.)
| | - Christos Chatziantoniou
- Unite Mixte de Recherche Scientific 1155, Institut National de la Sante et de la Recherche Medicale, Tenon Hospital, 75020 Paris, France; (L.A.); (N.P.); (A.M.); (R.C.)
- Faculty of Medicine, Sorbonne University, 75020 Paris, France
- Correspondence:
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19
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Zhao L, Guo W, Huang W, Wang L, Huang S. Benefit of sodium-glucose cotransporter-2 inhibitors on survival outcome is related to the type of heart failure: A meta-analysis. Diabetes Res Clin Pract 2022; 187:109871. [PMID: 35413392 DOI: 10.1016/j.diabres.2022.109871] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 03/22/2022] [Accepted: 04/06/2022] [Indexed: 12/31/2022]
Abstract
AIMS This meta-analysis aimed to evaluate the efficacy of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in different types of heart failure (HF). METHODS Randomized controlled trials (RCTs) comparing SGLT-2 inhibitors with placebo in patients with HF were searched in PubMed, the Cochrane Library database, and clinicaltrials.gov. A random-effects model was used for evidence synthesis. The primary endpoint was cardiac death. RESULTS We included 13 studies (12 RCTs). In patients with HF with preserved ejection fraction (HFpEF), SGLT-2 inhibitors reduced the composite endpoint of cardiac death or rehospitalization because of HF (HHF) (HR: 0.78, 95% CI: 0.70-0.87, I2 = 0%, P < 0.001) and that of HHF (HR: 0.74; 95% CI: 0.64-0.85, I2 = 0%, P < 0.001) but not that of cardiac death (HR: 1.01, 95% CI: 0.80-1.28, I2 = 23.9%, P = 0.943). In patients with HF with reduced EF (HFrEF), SGLT-2 inhibitors reduced the composite endpoint of cardiac death or HHF (HR: 0.75, 95% CI: 0.69-0.82, I2 = 0%, P < 0.001) and the individual endpoints of cardiac death (HR: 0.84, 95% CI: 0.75-0.95, I2 = 0%, P = 0.007) and HHF (HR: 0.69, 95% CI: 0.62-0.77, I2 = 0%, P < 0.001). CONCLUSIONS SGLT-2 inhibitors reduced the risk of cardiac death in patients with HFrEF but not in those with HFpEF.
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Affiliation(s)
- Lingyue Zhao
- Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China
| | - Wenqin Guo
- Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, Shenzhen, China
| | - Weichao Huang
- Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, Shenzhen, China
| | - Lili Wang
- Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, Shenzhen, China
| | - Siquan Huang
- People's Hospital of Longhua District, Shenzhen, China.
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Burggraaf B, Pouw NMC, Fernández Arroyo S, van Vark-van der Zee LC, van de Geijn GJM, Birnie E, Huisbrink J, van der Zwan EM, de Herder WW, Mulder MT, Rensen PCN, Castro Cabezas M. Effects of dapagliflozin on postprandial lipid metabolism in type 2 diabetes mellitus. Eur J Endocrinol 2022; 186:597-605. [PMID: 35312632 DOI: 10.1530/eje-21-1270] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/21/2022] [Indexed: 11/08/2022]
Abstract
OBJECTIVES Sodium-glucose cotransporter 2 inhibitors (SGLT2i) modulate lipid metabolism and improve cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). The exact cardioprotective mechanism of SGLT2i is unclear. We evaluated the effects of SGLT2i on postprandial lipids, lipoprotein concentrations, glucose and fatty acids. DESIGN A placebo-controlled randomized, proof-of-concept study. METHODS Fourteen male patients with T2DM on intensive insulin regimen were randomly and double-blind allocated to 12 weeks dapagliflozin (10 mg) or placebo. Postprandial effects were assessed with an 8-h standardized oral fat loading test. RESULTS Mean glycated A1c did not change by dapagliflozin, but the mean daily insulin dose was significantly reduced. Although dapagliflozin did not affect fasting or postprandial levels of glucose and insulin, it increased the postprandial levels of glucagon. While fasting levels of free fatty acids and beta-hydroxybutyrate (bHBA) were unchanged, dapagliflozin significantly increased the postprandial bHBA response. This was seen in the context of increased postprandial glucagon levels by dapagliflozin, without influencing postprandial insulin or glucose levels. Dapagliflozin did not affect fasting or postprandial plasma cholesterol and triglycerides nor postprandial inflammatory markers. Fasting apolipoprotein B48 was decreased without affecting the postprandial response. Markers of inflammation and vascular function did not change. CONCLUSION Treatment with dapagliflozin of patients with T2DM led to a reduction of fasting chylomicron remnants and increased postprandial ketone bodies compared to placebo suggesting enhanced hepatic fatty acid oxidation. The latter may have been caused by decreasing the insulin-glucagon ratio. The beneficial clinical effects seen in the trials using dapagliflozin most likely are not due to effects on postprandial inflammation nor postprandial lipemia.
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Affiliation(s)
- Benjamin Burggraaf
- Department of Internal Medicine, Center for Endocrinology, Diabetes and Vascular Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands
| | - Nadine M C Pouw
- Department of Clinical Chemistry, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands
| | - Salvador Fernández Arroyo
- Departament de Medicina i Cirurgia, Unitat de Recerca Biomèdica, Universitat Rovira i Virgili, Tarragona, Spain
| | - Leonie C van Vark-van der Zee
- Division of Pharmacology, Vascular and Metabolic Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Gert-Jan M van de Geijn
- Department of Clinical Chemistry, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands
| | - Erwin Birnie
- Department of Statistics and Education, Franciscus Academy, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands
- Department of Genetics, University Medical Center Groningen, Groningen University, Groningen, the Netherlands
| | - Jeannine Huisbrink
- Department of Pharmacy, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands
| | - Ellen M van der Zwan
- Department of Clinical Chemistry, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands
| | - Wouter W de Herder
- Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Monique T Mulder
- Division of Pharmacology, Vascular and Metabolic Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Patrick C N Rensen
- Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Manuel Castro Cabezas
- Department of Internal Medicine, Center for Endocrinology, Diabetes and Vascular Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands
- Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands
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21
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Sohatee M, Holland J. Life-threatening complications for diabetic patients taking SGLT2 inhibitors when undergoing surgery: A poorly recognised problem? J Perioper Pract 2022; 32:234-238. [PMID: 35291825 DOI: 10.1177/17504589211024409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
A knowledge of perioperative problems and complications is an important requirement for surgeons. Diabetic patients are a particular group of patients that are specifically at risk of problems. These risks are not only related to the underlying pathophysiological process associated with the disease, but can also occur secondarily to medications used to manage the condition and require careful monitoring, and is of increased importance in the perioperative period. Although a number of medications have historically been used to manage diabetes, a relatively novel group of diabetic medications 'SGLT2 inhibitors' are now being used and have been shown to have many positive attributes, when considering the sequalae of diabetes. However, they have also been associated with significant perioperative problems, which are a consequence of euglycaemic ketoacidosis, a potentially life-threatening condition. Given the significant complications associated with these medications, it is important that practitioners should have an awareness of the problems related to their use. In addition, messages contained in safety releases pertaining to SGLT2 inhibitor use and their risks in patients undergoing surgery, may have been weakened due the timing of their publication in March 2020, during the first UK national lockdown amidst the Coronavirus pandemic.
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Affiliation(s)
- Mark Sohatee
- Trauma and Orthopaedics Department, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK
| | - James Holland
- Trauma and Orthopaedics Department, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK
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22
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Amole M, Leey-Casella J. Stopping Empagliflozin Unmasks Heart Failure. Fed Pract 2022; 38:e44-e45. [PMID: 35136342 DOI: 10.12788/fp.0144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
SGLT2 inhibitors have been shown to have a role in the management of heart failure in patients with type 2 diabetes mellitus, but there is a risk of exacerbation when discontinued.
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Affiliation(s)
| | - Julio Leey-Casella
- University of Florida College of Medicine, Gainesville.,Malcolm Randall Veterans Affairs Medical Center, Gainesville, Florida
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23
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Baig MA, Nogar J. Euglycemia despite a sodium glucose co-transporter 2 inhibitor overdose. World J Emerg Med 2022; 13:147-148. [DOI: 10.5847/wjem.j.1920-8642.2022.050] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 11/20/2021] [Indexed: 11/19/2022] Open
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24
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Verta R, Gurrieri M, Borga S, Benetti E, Pollicino P, Cavalli R, Thurmond RL, Chazot PL, Pini A, Rosa AC, Grange C. The Interplay between Histamine H 4 Receptor and the Kidney Function: The Lesson from H 4 Receptor Knockout Mice. Biomolecules 2021; 11:biom11101517. [PMID: 34680152 PMCID: PMC8533779 DOI: 10.3390/biom11101517] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/30/2021] [Accepted: 10/13/2021] [Indexed: 01/15/2023] Open
Abstract
Previous studies implicated the histamine H4 receptor in renal pathophysiology. The aim here is to elucidate the role of this receptor on renal function using H4 receptor knockout mice (H4R-/-). Healthy and diabetic H4R-/- mice compared to their C57BL/6J wild-type counterpart for renal function and the expression of crucial tubular proteins. H4R-/- and wild-type mice, matched for ages, showed comparable weight gain curves reaching similar median weight at the end of the study. However, H4R-/- mice displayed a higher basal glycemia. H4R-/- mice showed a lower urine 24 h outflow, and albumin-to-creatinine ratio (ACR) compared to wild-type mice. Consistently, H4R-/- mice presented a higher expression of megalin and a lower basal expression of the sodium-hydrogen exchanger (NHE)3 and aquaporin (AQP)2. According to these basal differences, diabetic H4R-/- mice developed more severe hyperglycemia and a higher 24 h urine volume, but a lower increase in ACR and decrease in urine pH were observed. These events were paralleled by a reduced NHE3 over-expression and megalin loss in diabetic H4R-/- mice. The AQP1 and AQP7 patterns were also different between H4R-/- and wild-type diabetic mice. The collected results highlight the role of the histamine H4 receptor in the control of renal reabsorption processes, particularly albumin uptake.
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Affiliation(s)
- Roberta Verta
- Department of Biotechnology and Health Sciences, University of Turin, C.So Dogliotti 14, 10126 Turin, Italy;
| | - Maura Gurrieri
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy; (M.G.); (S.B.); (E.B.); (R.C.)
| | - Sara Borga
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy; (M.G.); (S.B.); (E.B.); (R.C.)
| | - Elisa Benetti
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy; (M.G.); (S.B.); (E.B.); (R.C.)
| | - Paolo Pollicino
- Direzione Ricerca e Terza Missione, University of Turin, Via Bogino 9 Torino, 10123 Turin, Italy;
| | - Roberta Cavalli
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy; (M.G.); (S.B.); (E.B.); (R.C.)
| | - Robin L. Thurmond
- Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA;
| | - Paul L. Chazot
- Department of Biosciences and Wolfson Research Institute, Durham University, South Road, Durham DH1 3LE, UK;
| | - Alessandro Pini
- Department of Clinical and Experimental Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy;
| | - Arianna Carolina Rosa
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy; (M.G.); (S.B.); (E.B.); (R.C.)
- Correspondence: ; Tel.: +39-011-6707955
| | - Cristina Grange
- Department of Medical Sciences, University of Turin, C.So Dogliotti 14, 10126 Turin, Italy;
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Cheung YMM, McDonnell M, Hamnvik OPR. A targeted approach to phosphoinositide-3-kinase/Akt/mammalian target of rapamycin-induced hyperglycemia. Curr Probl Cancer 2021; 46:100776. [PMID: 34376311 DOI: 10.1016/j.currproblcancer.2021.100776] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/28/2021] [Accepted: 06/29/2021] [Indexed: 12/11/2022]
Abstract
Phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway inhibitors are a novel class of antineoplastic agent available for the treatment of various cancers. With improved cancer outcomes and survival, individuals are exposed to these antineoplastic therapies for longer periods of time and therefore, the consideration of adverse effects is of increasing importance. The PI3K/Akt/mTOR signaling pathway plays a critical role in regulating cellular processes such as growth and proliferation, but also regulates the metabolic effects of insulin such as glucose uptake and glycogen synthesis. Therefore, hyperglycemia and insulin resistance are frequently reported adverse effects. There are no recent consensus guidelines on the management of hyperglycemia secondary to PI3K/Akt/mTOR inhibitors, with the latest guidelines produced in 2012 - when many of these agents were still undergoing development. As we now have a greater understanding of the underlying mechanisms and patterns in which hyperglycemia is induced and access to an increasing array of glucose-lowering agents, an update of the previous guidelines accommodating these understandings and developments is timely. This review will provide a comprehensive summary of the current literature with regards to the incidence of hyperglycemia associated with each agent, as well as the different pathways and mechanisms in which hyperglycemia is induced. Our proposed up-to-date strategy for the specific management of PI3K/Akt/mTOR inhibitor-induced hyperglycemia will also aim to facilitate management of this complex oncological population.
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Affiliation(s)
- Yee-Ming Melody Cheung
- Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Medicine, Endocrine Unit, Austin Hospital, The University of Melbourne, Victoria, Australia
| | - Marie McDonnell
- Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Ole-Petter Riksfjord Hamnvik
- Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
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26
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Yasuma T, Okano Y, Tanaka S, Nishihama K, Eguchi K, Inoue C, Maki K, Uchida A, Uemura M, Suzuki T, D'Alessandro-Gabazza CN, Gabazza EC, Yano Y. Sodium-glucose co-transporter-2 inhibitor-associated euglycemic diabetic ketoacidosis that prompted the diagnosis of fulminant type-1 diabetes: A case report. World J Clin Cases 2021; 9:3163-3169. [PMID: 33969104 PMCID: PMC8080741 DOI: 10.12998/wjcc.v9.i13.3163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/26/2021] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Fulminant type 1 diabetes mellitus (FT1DM) is a subtype of type 1 diabetes mellitus characterized by an abrupt onset and a rapid and complete functional loss of islet β cells. It is a very rare disease generally associated with ketoacidosis and the absence of circulating pancreatic islet-related autoantibodies. Diabetic ketoacidosis with normal blood glucose levels has been reported during sodium-glucose co-transporter 2 (SGLT2) inhibitor therapy.
CASE SUMMARY The patient was a 43-year-old woman that consulted a medical practitioner for malaise, thirst, and vomiting. Blood analysis showed high blood glucose levels (428 mg/dL), a mild increase of hemoglobin A1c (6.6%), and increased ketone bodies in urine. The patient was diagnosed with type 2 diabetes mellitus. The patient was initially treated with insulin, which was subsequently changed to an oral SGLT2 inhibitor. Antibodies to glutamic acid decarboxylase were negative. Four days after receiving oral SGLT2 inhibitor, she consulted at Mie University Hospital, complaining of fatigue and vomiting. Laboratory analysis revealed diabetic ketoacidosis with almost normal blood glucose levels. The endogenous insulin secretion was markedly low, and the serum levels of islet-related autoantibodies were undetectable. We made the diagnosis of FT1DM with concurrent SGLT2 inhibitor-associated euglycemic diabetic ketoacidosis. The patient's general condition improved after therapy with intravenous insulin and withdrawal of oral medication. She was discharged on day 14 with an indication of multiple daily insulin therapy.
CONCLUSION This patient is a rare case of FT1DM that developed SGLT2 inhibitor-associated diabetic ketoacidosis with almost normal blood glucose levels. This case report underscores the importance of considering the diagnosis of FT1DM in patients with negative circulating autoantibodies and a history of hyperglycemia that subsequently develop euglycemic diabetic ketoacidosis following treatment with a SGLT2 inhibitor.
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Affiliation(s)
- Taro Yasuma
- Department of Diabetes, Metabolism, and Endocrinology and Immunology, Mie University, Tsu 514-8507, Japan
| | - Yuko Okano
- Department of Diabetes, Metabolism, and Endocrinology and Immunology, Mie University, Tsu 514-8507, Japan
| | - Soichiro Tanaka
- Department of Diabetes, Metabolism, and Endocrinology, Mie University, Tsu 514-8507, Japan
| | - Kota Nishihama
- Department of Diabetes, Metabolism, and Endocrinology, Mie University, Tsu 514-8507, Japan
| | - Kazuhito Eguchi
- Department of Diabetes, Metabolism, and Endocrinology, Mie University, Tsu 514-8507, Japan
| | - Chisa Inoue
- Department of Diabetes, Metabolism, and Endocrinology, Mie University, Tsu 514-8507, Japan
| | - Kanako Maki
- Department of Diabetes, Metabolism, and Endocrinology, Mie University, Tsu 514-8507, Japan
| | - Akihiro Uchida
- Department of Diabetes, Metabolism, and Endocrinology, Mie University, Tsu 514-8507, Japan
| | - Mei Uemura
- Department of Diabetes, Metabolism, and Endocrinology, Mie University, Tsu 514-8507, Japan
| | - Toshinari Suzuki
- Department of Diabetes, Metabolism, and Endocrinology, Mie University, Tsu 514-8507, Japan
| | | | - Esteban C Gabazza
- Department of Immunology, Mie University Faculty and Graduate School of Medicine, Tsu 514-8507, Japan
| | - Yutaka Yano
- Department of Diabetes, Mie University Graduate School of Medicine, Tsu 514-8507, Japan
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Sutthasupha P, Lungkaphin A. The potential roles of chitosan oligosaccharide in prevention of kidney injury in obese and diabetic conditions. Food Funct 2021; 11:7371-7388. [PMID: 32839793 DOI: 10.1039/d0fo00302f] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Obesity is closely associated with insulin resistance (IR). The most likely links between the two are obesity-mediated systemic low-grade chronic inflammation, endoplasmic reticulum stress and mitochondrial dysfunction, which are all known to contribute to the development of type 2 diabetes (T2DM) and eventually diabetic nephropathy (DN). Chitosan oligosaccharide (COS) is an oligomer of chitosan prepared by the deacetylation of chitin commonly found in exoskeletons of crustaceans such as shrimp and crab as well as the cell walls of fungi. COS has various biological effects including lipid lowering, anti-inflammation, anti-diabetes, and anti-oxidant effects. Therefore, COS is a potential new therapeutic agent for treatment of the obesity-induced DN condition. It is an abundant natural polymer and therefore freely available. This review includes information regarding the relationship between obesity, IR, T2DM, and DN as well as the potential usefulness of COS in controlling lipid and cholesterol metabolism, T2DM and kidney injury models in both in vivo and in vitro studies. However, evidence is limited regarding the effect of COS on the DN model. Further studies, especially in obesity-induced DN, are needed to support the mechanisms proposed in this review.
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Affiliation(s)
- Prempree Sutthasupha
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
| | - Anusorn Lungkaphin
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. and Functional Food Research Center for Well-being, Chiang Mai University, Chiang Mai University, Chiang Mai, Thailand
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El-Desouky EA, Abdel-Raoof AM, Abdel-Fattah A, Abdel-Zaher A, Osman AOE, Abdel-Monem AH, Morshedy S. Determination of linagliptin and empagliflozin by UPLC and HPTLC techniques aided by lean six sigma approach. Biomed Chromatogr 2021; 35:e5102. [PMID: 33629452 DOI: 10.1002/bmc.5102] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 01/05/2021] [Accepted: 02/05/2021] [Indexed: 01/10/2023]
Abstract
Two chromatographic techniques were developed and validated for simultaneous determination of the newly co-formulated antidiabetic combination linagliptin and empagliflozin in their pure form and film-coated tables. The first technique was UPLC; the separation and resolution of both analytes were achieved using a Zorbax eclipse plus C18 column applying an isocratic elution based on phosphate buffer pH 4-acetonitrile (65:35, v/v) as a running mobile phase at flow rate 1.5 ml/min and the effluent was monitored at 220 nm. Augmentation of Lean Six Sigma with UPLC and HPTLC methods had a major impact on the development of robust specifications to ensure that the quality at six sigma level has a high level of statistical confidence and target performance. On the chromatogram, empagliflozin and linagliptin appeared at retention times of 1.417 and 2.453 min, respectively. The second technique was HPTLC; both analytes were fairly well resolved and separated using a developing mobile phase composed of ethyl acetate-chloroform-acetonitrile (55:25:20 by volume). The values of retention factor (RF ) were 0.29 and 0.53 for linagliptin and empagliflozin, respectively. All variables were investigated to adjust the whole conditions.
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Affiliation(s)
- Ebrahim A El-Desouky
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt
| | - Ahmed M Abdel-Raoof
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt
| | - Ashraf Abdel-Fattah
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt
| | - Ahmed Abdel-Zaher
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt
| | - Ayman O E Osman
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt
| | - Ahmed H Abdel-Monem
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt
| | - Samir Morshedy
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Damanhour University, Beheira, Egypt
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29
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Determination of empagliflozin in the presence of its organic impurities and identification of two degradation products using UHPLC-QTOF/MS. Microchem J 2021. [DOI: 10.1016/j.microc.2020.105795] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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30
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Hu S, Lin C, Cai X, Zhu X, Lv F, Nie L, Ji L. The Urinary Glucose Excretion by Sodium-Glucose Cotransporter 2 Inhibitor in Patients With Different Levels of Renal Function: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 2021; 12:814074. [PMID: 35154011 PMCID: PMC8830597 DOI: 10.3389/fendo.2021.814074] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 12/28/2021] [Indexed: 01/10/2023] Open
Abstract
OBJECTIVE Previous evidence suggested that sodium-glucose cotransporter 2 inhibitor (SGLT2i)-mediated urinary glucose excretion (UGE) appeared to be reduced with a decrease in glomerular filtration rate. Thus, we conducted a systematic review and meta-analysis to compare SGLT2i-mediated UGE among individuals with different levels of renal function. METHODS We conducted systematic searches in PubMed, Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrial.gov from inception to May 2021. Clinical studies of SGLT2i with reports of UGE changes in predefined different levels of renal function were included. The results were expressed as pooled effect sizes with 95% confidence interval (CI). A random-effects model was used to calculate the pooled effect sizes. RESULTS In total, eight eligible studies were included. Significant differences were observed in the post-treatment UGE level among subgroups stratified by renal function (P <0.001 for subgroup difference), which were gradually decreased along with the severity of impaired renal function. Consistently, changes in UGE before and after SGLT2i treatment were also decreased along with the severity of impaired renal function [67.52 g/day (95%CI: 55.58 to 79.47 g/day) for individuals with normal renal function, 52.41 g/day (95%CI: 38.83 to 65.99 g/day) for individuals with mild renal function impairment, 35.11 g/day (95%CI: 19.79 to 50.43 g/day) for individuals with moderate renal function impairment, and 13.53 g/day (95%CI: 7.20 to 19.86 g/day) for individuals with severe renal function impairment; P <0.001 for subgroup differences]. CONCLUSIONS SGLT2i-mediated UGE was renal function dependent, which was decreased with the extent of renal function impairment.
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Affiliation(s)
- Suiyuan Hu
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
| | - Chu Lin
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
- *Correspondence: Xiaoling Cai, ; Linong Ji,
| | - Xingyun Zhu
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
| | - Fang Lv
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
| | - Lin Nie
- Department of Endocrinology and Metabolism, Beijing Airport Hospital, Beijing, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
- *Correspondence: Xiaoling Cai, ; Linong Ji,
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31
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Chai Q, Miao J, Liu M, Zhang Z, Meng Z, Wu W. Knockdown of SGLT1 prevents the apoptosis of cardiomyocytes induced by glucose fluctuation via relieving oxidative stress and mitochondrial dysfunction. Biochem Cell Biol 2020; 99:356-363. [PMID: 33259229 DOI: 10.1139/bcb-2020-0491] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Fluctuations in the concentration of glucose in the blood is more detrimental than a constantly high level of glucose with respect to the development of cardiovascular complications associated with diabetes mellitus (DM). Sodium glucose cotransporter 2 (SGLT2) inhibitors have been developed as antidiabetic drugs with cardiovascular benefits; however, whether inhibition of SGLT1 protects the diabetic heart remains to be determined. This study investigated the role of SGLT1 in rat H9c2 cardiomyocytes subjected to fluctuating levels of glucose and the underlying mechanisms. The results indicated that knockdown of SGLT1 restored cell proliferation and suppressed the cytotoxicity associated with fluctuating glucose levels. Oxidative stress was induced in H9c2 cells subjected to fluctuating glucose levels, but these changes were effectively reversed by knockdown of SGLT1, as manifested by reductions in the level of intracellular reactive oxygen species and increased antioxidant activity. Further study demonstrated that knockdown of SGLT1 attenuated the mitochondrial dysfunction in H9c2 cells exposed to fluctuating glucose levels, by restoring mitochondrial membrane potential and promoting mitochondrial fusion. In addition, knockdown of SGLT1 downregulated the expression of Bax, upregulated the expression of Bcl-2, and reduced the activation of caspase-3 in H9c2 cells subjected to fluctuating levels of glucose. Collectively, our results show that knockdown of SGLT1 ameliorates the apoptosis of cardiomyocyte caused by fluctuating glucose levels via regulating oxidative stress and combatting mitochondrial dysfunction.
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Affiliation(s)
- Qian Chai
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, P.R. China
| | - Jiajing Miao
- Department of Endocrinology, Affiliated Hospital of Jilin Medical College, Jilin 132013, P.R. China
| | - Meili Liu
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, P.R. China
| | - Ziying Zhang
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, P.R. China
| | - Ziang Meng
- Department of Urology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150001, P.R. China
| | - Weihua Wu
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, P.R. China
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Lee HS, Hwang JS. Impact of Type 2 Diabetes Mellitus and Antidiabetic Medications on Bone Metabolism. Curr Diab Rep 2020; 20:78. [PMID: 33247351 DOI: 10.1007/s11892-020-01361-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/26/2020] [Indexed: 12/25/2022]
Abstract
PURPOSE OF REVIEW This review focuses on the complex interactions between hyperglycemia and bone fragility and the effects of antidiabetic medications on bone metabolism. RECENT FINDINGS Type 2 diabetes (T2D) is associated with increased risk of bone fracture even in those with increased or normal bone mineral density (BMD). The pathophysiology of diabetic bone disease is not completely understood, but it is thought to be multifactorial and associated with complex cross talk among factors such as AGEs, IGF-1, enteric hormones, and pro-inflammatory cytokines. Treatment for T2D may have an impact on bone metabolism. Diabetic bone disease should be considered a serious complication of long-standing T2D.
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Affiliation(s)
- Hae Sang Lee
- Department of Pediatrics, Ajou University Hospital, Ajou University School of Medicine, Ajou University Hospital, San 5, Wonchon-dong, Yeongtong-gu, Suwon, 443-721, Korea
| | - Jin Soon Hwang
- Department of Pediatrics, Ajou University Hospital, Ajou University School of Medicine, Ajou University Hospital, San 5, Wonchon-dong, Yeongtong-gu, Suwon, 443-721, Korea.
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33
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Higashikawa T, Ito T, Mizuno T, Ishigami K, Kohori M, Mae K, Usuda D, Takeshima K, Takagi S, Izumida T, Yamada S, Kuroki K, Sangen R, Saito A, Iguchi M, Kamasaki Y, Nakahashi T, Fukuda A, Kanda T, Okuro M. Gender Differences in Cardiac Function Following Three-Month Administration of Tofogliflozin in Patients With Diabetes Mellitus. J Clin Med Res 2020; 12:530-538. [PMID: 32849941 PMCID: PMC7430877 DOI: 10.14740/jocmr4278] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 07/09/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Patients with type 2 diabetes mellitus (T2DM) are at increased risk for impairment in heart failure and diastolic relaxation while preserving ejection fraction (EF). Recently, several sodium glucose cotransporter-2 (SGLT2) inhibitors have demonstrated to decrease cardiovascular disease (CVD) events in elderly diabetic patients, although gender difference in the effect of SGLT2 inhibitors is unknown. The objective of the present study was to evaluate gender difference in the effect of tofogliflozin, one of the SGLT2 inhibitors, on CVD function in patients with diabetes mellitus. METHODS This was a retrospective study. Patients received 20 mg of tofogliflozin daily for 3 months. EF, ratio of early filling to atrial filling (E/A), a change in mitral inflow E and mitral e' annular velocities (E/e'), left atrial dimension (LAD) and maximal diameter of inferior vena cava (IVCmax), including various physiological parameters were measured between baseline, 1 month and 3 months after administration of tofogliflozin. Interaction between gender and time after administration was evaluated using mixed effect model. RESULTS The results showed significant decrease in E/e' (P < 0.01) and significant interaction between time and gender in E/A (P < 0.01), following administration of tofogliflozin for 3 months. EF was constantly higher significantly in women (P < 0.01). CONCLUSION It is concluded that 3-month administration of tofogliflozin decreased E/e' with gender difference in EF and E/A.
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Affiliation(s)
- Toshihiro Higashikawa
- Kanazawa Medical University Himi Municipal Hospital, 1130, Kurakawa, Himi, Toyama 935-8531, Japan
- Department of Geriatric Medicine, Kanazawa Medical University, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan
| | - Tomohiko Ito
- Kanazawa Medical University Himi Municipal Hospital, 1130, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Takurou Mizuno
- Kanazawa Medical University Himi Municipal Hospital, 1130, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Keiichiro Ishigami
- Kanazawa Medical University Himi Municipal Hospital, 1130, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Masaru Kohori
- Kanazawa Medical University Himi Municipal Hospital, 1130, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Kunihiro Mae
- Kanazawa Medical University Himi Municipal Hospital, 1130, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Daisuke Usuda
- Kanazawa Medical University Himi Municipal Hospital, 1130, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Kento Takeshima
- Kanazawa Medical University Himi Municipal Hospital, 1130, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Susumu Takagi
- Kanazawa Medical University Himi Municipal Hospital, 1130, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Toshihide Izumida
- Kanazawa Medical University Himi Municipal Hospital, 1130, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Shinya Yamada
- Kanazawa Medical University Himi Municipal Hospital, 1130, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Kengo Kuroki
- Kanazawa Medical University Himi Municipal Hospital, 1130, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Ryusho Sangen
- Kanazawa Medical University Himi Municipal Hospital, 1130, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Atsushi Saito
- Kanazawa Medical University Himi Municipal Hospital, 1130, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Masaharu Iguchi
- Kanazawa Medical University Himi Municipal Hospital, 1130, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Yuji Kamasaki
- Kanazawa Medical University Himi Municipal Hospital, 1130, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Takeshi Nakahashi
- Department of Geriatric Medicine, Kanazawa Medical University, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan
| | - Akihiro Fukuda
- Kanazawa Medical University Himi Municipal Hospital, 1130, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Tsugiyasu Kanda
- Kanazawa Medical University Himi Municipal Hospital, 1130, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Masashi Okuro
- Department of Geriatric Medicine, Kanazawa Medical University, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan
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Omar MA, Ahmed HM, Batakoushy HA, Abdel Hamid MA. New spectrofluorimetric analysis of empagliflozin in its tablets and human plasma using two level full factorial design. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2020; 235:118307. [PMID: 32247255 DOI: 10.1016/j.saa.2020.118307] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 03/23/2020] [Accepted: 03/24/2020] [Indexed: 06/11/2023]
Abstract
An efficient, accurate and sensitive spectrofluorimetric method was developed for analysis of empagliflozin (EGF) in pure form, dosage form and human plasma. The proposed procedure was based on formation of yellow fluorescent product between benzofurazan reagent and empagliflozin in slightly alkaline medium that is measured at 521 nm, when excitation at 455 nm. The present study was validated according to ICH guidelines and bioanalytical validated according to US-FDA guidance. The fluorescence intensity-concentration plot was linear over the range of 50-1000 ng ml-1 with limit of detection (LOD) and quantitation (LOQ) of 15.55 and 46.63 ng ml-1, respectively. The correlation (r) and determination (r2) coefficient was 0.9998 and 0.9997, respectively. Due to high sensitivity and selectivity of the proposed method, it is successfully used for analysis of empagliflozin in its dosage form and human plasma with good recoveries of 98.89% and 98.70%, respectively, without any interfering from matrix components. The corresponding regression equation, Y = 0.756X + 141.93, (r2 = 0.9994) for spiked plasma sample. Two level full factorial designs were used to study different experimental parameters that affect the reaction product and to get the optimum method conditions. The suggested method can be used in quality control lab as well as in pharmacokinetic studies of empagliflozin.
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Affiliation(s)
- Mahmoud A Omar
- Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Medinah, Saudi Arabia; Department of Analytical Chemistry, Faculty of Pharmacy, Minia University, Egypt
| | - Hytham M Ahmed
- Pharmaceutical Analysis Department, Faculty of Pharmacy, Menoufia University, Egypt.
| | - Hany A Batakoushy
- Pharmaceutical Analysis Department, Faculty of Pharmacy, Menoufia University, Egypt
| | - Mohamed A Abdel Hamid
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Tanta University, Egypt
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Kim H, Lee S, Cho J, Lee H, Yim HW, Yoon K, Kim H. Discontinuation rate and reason for discontinuation after sodium‐glucose cotransporter 2 inhibitor prescription in real clinical practice. J Clin Pharm Ther 2020; 45:1271-1277. [DOI: 10.1111/jcpt.13205] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 05/05/2020] [Accepted: 05/21/2020] [Indexed: 01/02/2023]
Affiliation(s)
- Hyunah Kim
- College of Pharmacy Sookmyung Women's University Seoul Korea
| | - Seung‐Hwan Lee
- Division of Endocrinology and Metabolism Department of Internal Medicine Seoul St. Mary's Hospital College of Medicine The Catholic University of Korea Seoul Korea
- Department of Medical Informatics College of Medicine The Catholic University of Korea Seoul Korea
| | - Jae‐Hyoung Cho
- Division of Endocrinology and Metabolism Department of Internal Medicine Seoul St. Mary's Hospital College of Medicine The Catholic University of Korea Seoul Korea
- Department of Medical Informatics College of Medicine The Catholic University of Korea Seoul Korea
| | - Hyunyong Lee
- Clinical Research Coordinating Center Catholic Medical Center The Catholic University of Korea Seoul Korea
| | - Hyeon Woo Yim
- Department of Preventive Medicine College of Medicine The Catholic University of Korea Seoul Korea
| | - Kun‐Ho Yoon
- Division of Endocrinology and Metabolism Department of Internal Medicine Seoul St. Mary's Hospital College of Medicine The Catholic University of Korea Seoul Korea
- Department of Medical Informatics College of Medicine The Catholic University of Korea Seoul Korea
| | - Hun‐Sung Kim
- Division of Endocrinology and Metabolism Department of Internal Medicine Seoul St. Mary's Hospital College of Medicine The Catholic University of Korea Seoul Korea
- Department of Medical Informatics College of Medicine The Catholic University of Korea Seoul Korea
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Hieshima K, Sugiyama S, Yoshida A, Kurinami N, Suzuki T, Ijima H, Miyamoto F, Kajiwara K, Jinnouchi K, Jinnouchi T, Jinnouchi H. Elevation of the renal threshold for glucose is associated with insulin resistance and higher glycated hemoglobin levels. J Diabetes Investig 2020; 11:617-625. [PMID: 31770476 PMCID: PMC7232275 DOI: 10.1111/jdi.13191] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 11/22/2019] [Accepted: 11/25/2019] [Indexed: 12/17/2022] Open
Abstract
AIMS/INTRODUCTION The renal threshold for glucose (RTg) corresponds to a blood glucose level of ~180 mg/dL; however, in hospitals, patients are often encountered who are hyperglycemic, but urine glucose test strip-negative, who remain negative for urine glucose even at blood glucose concentrations >180 mg/dL, implying a high RTg value. In this study, we aimed to identify factors determining high RTg in Japanese patients with type 2 diabetes mellitus. MATERIALS AND METHODS We estimated RTg (eRTg) using urinalysis data from 67 type 2 diabetes mellitus patients for whom the glucose infusion rate (GIR) was determined by hyperinsulinemic-euglycemic clamp. After allocating patients to two groups according to their baseline eRTg (<180 mg/dL or ≥180 mg/dL), we identified the factors affecting eRTg using simple and multiple linear regression analyses. RESULTS GIR, glycated hemoglobin (HbA1c), insulin use and dyslipidemia differed significantly between the groups. In simple regression analysis, GIR, HbA1c, body muscle-to-fat ratio and insulin use were significantly correlated with eRTg; and in multiple regression analysis, GIR and HbA1c remained independent negative and positive determinants, respectively, with the contribution of GIR being substantial. In receiver operating characteristic curve analysis, when GIR <5.7 was used as the insulin resistance threshold, the cut-off value of eRTg was 189 mg/dL (P = 0.0001). Furthermore, in receiver operating characteristic analysis using eRTg ≥189 mg/dL, the cut-off value for HbA1c was 8.0% (P = 0.0006). CONCLUSIONS High eRTg is associated with low GIR and high HbA1c, with GIR making a substantial contribution.
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Affiliation(s)
| | - Seigo Sugiyama
- Diabetes Care CenterJinnouchi HospitalKumamotoJapan
- Cardiovascular DivisionDiabetes Care CenterJinnouchi HospitalKumamotoJapan
| | | | | | | | - Hiroko Ijima
- Diabetes Care CenterJinnouchi HospitalKumamotoJapan
| | | | | | | | | | - Hideaki Jinnouchi
- Diabetes Care CenterJinnouchi HospitalKumamotoJapan
- Cardiovascular DivisionDiabetes Care CenterJinnouchi HospitalKumamotoJapan
- Division of Preventive CardiologyDepartment of Cardiovascular MedicineKumamoto University HospitalKumamotoJapan
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Araki E, Watada H, Uchigata Y, Tomonaga O, Fujii H, Ohashi H, Okabe T, Asano M, Thoren F, Kim H, Yajima T, Langkilde AM. Efficacy and safety of dapagliflozin in Japanese patients with inadequately controlled type 1 diabetes (DEPICT-5): 52-week results from a randomized, open-label, phase III clinical trial. Diabetes Obes Metab 2020; 22:540-548. [PMID: 31742898 PMCID: PMC7078973 DOI: 10.1111/dom.13922] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 11/10/2019] [Accepted: 11/14/2019] [Indexed: 12/16/2022]
Abstract
AIMS To investigate the safety and tolerability of 5 and 10 mg dapagliflozin added to insulin therapy over 52 weeks in Japanese patients with inadequately controlled type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS This randomized, open-label, parallel-group, multicentre phase III clinical trial was conducted from October 26, 2015 to June 15, 2017. The primary endpoint was the occurrence of adverse events such as hypoglycaemia and diabetic ketoacidosis. Secondary endpoints included changes in glycaemic parameters, total daily insulin dosage and body weight over time. The efficacy of dapagliflozin in patients stratified by body mass index (BMI) <25.0 and ≥25.0 kg/m2 was evaluated in a subgroup analysis. RESULTS In total, 151 patients received 5 mg (n = 76) or 10 mg (n = 75) dapagliflozin once daily for 52 weeks. Adverse events were observed in 88.2% and 73.3% of patients in the 5 and 10 mg dapagliflozin groups, respectively. Severe hypoglycaemia was reported in 2.6% (n = 2) and 6.7% (n = 5) of patients, and diabetic ketoacidosis in 2.6% (n = 2) and 1.3% (n = 1) of patients in the 5 and 10 mg dapagliflozin groups, respectively. The adjusted mean (95% confidence interval) changes in glycated haemoglobin at week 52 were -0.33% (-0.50, -0.15) and -0.36% (-0.53, -0.18) in the 5 and 10 mg dapagliflozin groups, respectively. There were no differences in efficacy parameters when stratified by BMI. CONCLUSIONS This study demonstrated the long-term safety and tolerability of dapagliflozin added to insulin therapy in Japanese patients with inadequately controlled T1DM.
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Affiliation(s)
- Eiichi Araki
- Department of Metabolic Medicine, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Hirotaka Watada
- Department of Metabolism and EndocrinologyJuntendo University Graduate School of MedicineTokyoJapan
| | - Yasuko Uchigata
- Diabetes Center, Tokyo Women's Medical University School of MedicineTokyoJapan
| | - Osamu Tomonaga
- Diabetes and Lifestyle Center, Tomonaga ClinicTokyoJapan
| | - Hitomi Fujii
- Internal Medicine, Tama‐center Mirai ClinicTokyoJapan
| | | | | | | | - Fredrik Thoren
- Global Medicine Development, AstraZeneca GothenburgMölndalSweden
| | - Hyosung Kim
- Research & Development, AstraZeneca K.K.OsakaJapan
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Higashikawa T, Ito T, Mizuno T, Ishigami K, Kohori M, Mae K, Usuda D, Takagi S, Sangen R, Saito A, Iguchi M, Kasamaki Y, Fukuda A, Kanda T, Okuro M. Effects of Tofogliflozin on Cardiac Function in Elderly Patients With Diabetes Mellitus. J Clin Med Res 2020; 12:165-171. [PMID: 32231752 PMCID: PMC7092764 DOI: 10.14740/jocmr4098] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 02/11/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Patients with type 2 diabetes mellitus (T2DM) are at increased risk for impairments in diastolic relaxation and heart failure with preserved ejection fraction (EF). Recent clinical data suggest that several sodium glucose transporter-2 (SGLT2) inhibitors are found to reduce cardiovascular disease (CVD) events in elderly diabetic patients, but the effect of tofogliflozin, one of the SGLT2 inhibitors, on CVD is unknown. We retrospectively investigated the effect of tofogliflozin on cardiac function in elderly patients with T2DM. METHODS Patients received 20 mg of tofogliflozin daily for 1 month. EF, ratio of early filling to atrial filling (E/A), a change in mitral inflow E and mitral e' annular velocities (E/e'), left atrial dimension (LAD) and maximal diameter of inferior vena cava (IVCmax) were measured between baseline and 1 month after the administration of tofogliflozin. RESULTS Body weight, systolic and diastolic blood pressures significantly decreased, while renin and aldosterone level significantly increased after 1 month of tofogliflozin treatment. Most of the physiological parameters and the level of serum electrolyte did not change significantly. E/A, E/e' and LAD significantly decreased, while no significant changes were observed in EF and IVCmax. The interactions of E/e' between time, gender and age were not significant. CONCLUSION The present study suggested that tofogliflozin improved left ventricular diastolic function irrespective of gender and age, while preserving IVC, renal function and electrolyte balance.
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Affiliation(s)
- Toshihiro Higashikawa
- Kanazawa Medical University Himi Municipal Hospital, Kurakawa, Himi, Toyama 935-8531, Japan
- Department of Geriatric Medicine, Kanazawa Medical University, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan
| | - Tomohiko Ito
- Kanazawa Medical University Himi Municipal Hospital, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Takurou Mizuno
- Kanazawa Medical University Himi Municipal Hospital, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Keiichirou Ishigami
- Kanazawa Medical University Himi Municipal Hospital, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Masaru Kohori
- Kanazawa Medical University Himi Municipal Hospital, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Kunihiro Mae
- Kanazawa Medical University Himi Municipal Hospital, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Daisuke Usuda
- Kanazawa Medical University Himi Municipal Hospital, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Susumu Takagi
- Kanazawa Medical University Himi Municipal Hospital, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Ryusho Sangen
- Kanazawa Medical University Himi Municipal Hospital, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Atsushi Saito
- Kanazawa Medical University Himi Municipal Hospital, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Masaharu Iguchi
- Kanazawa Medical University Himi Municipal Hospital, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Yuji Kasamaki
- Kanazawa Medical University Himi Municipal Hospital, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Akihiro Fukuda
- Kanazawa Medical University Himi Municipal Hospital, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Tsugiyasu Kanda
- Kanazawa Medical University Himi Municipal Hospital, Kurakawa, Himi, Toyama 935-8531, Japan
| | - Masashi Okuro
- Department of Geriatric Medicine, Kanazawa Medical University, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan
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Tiwari P, Katyal A, Khan MF, Ashraf GM, Ahmad K. Lead Optimization Resources in Drug Discovery for Diabetes. Endocr Metab Immune Disord Drug Targets 2020; 19:754-774. [PMID: 30834844 DOI: 10.2174/1871530319666190304121826] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/27/2018] [Accepted: 01/05/2019] [Indexed: 12/25/2022]
Abstract
BACKGROUND Diabetes, defined as a chronic metabolic syndrome, exhibits global prevalence and phenomenal rise worldwide. The rising incidence accounts for a global health crisis, demonstrating a profound effect on low and middle-income countries, particularly people with limited healthcare facilities. METHODS Highlighting the prevalence of diabetes and its socio-economic implications on the population across the globe, the article aimed to address the emerging significance of computational biology in drug designing and development, pertaining to identification and validation of lead molecules for diabetes treatment. RESULTS The drug discovery programs have shifted the focus on in silico prediction strategies minimizing prolonged clinical trials and expenses. Despite technological advances and effective drug therapies, the fight against life-threatening, disabling disease has witnessed multiple challenges. The lead optimization resources in computational biology have transformed the research on the identification and optimization of anti-diabetic lead molecules in drug discovery studies. The QSAR approaches and ADMET/Toxicity parameters provide significant evaluation of prospective "drug-like" molecules from natural sources. CONCLUSION The science of computational biology has facilitated the drug discovery and development studies and the available data may be utilized in a rational construction of a drug 'blueprint' for a particular individual based on the genetic organization. The identification of natural products possessing bioactive properties as well as their scientific validation is an emerging prospective approach in antidiabetic drug discovery.
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Affiliation(s)
- Pragya Tiwari
- Department of Biotechnology, MG Institute of Management and Technology, Lucknow-Kanpur Road, Lucknow, India
| | - Ashish Katyal
- Department of Biotechnology, Meerut Institute of Engineering and Technology, Meerut, India
| | - Mohd F Khan
- Department of Biotechnology, Utkarsh School of Management and Technology, Bareilly, India.,Department of Plant Science, MJP Rohilkhand University, Bareilly, India
| | - Ghulam Md Ashraf
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia.,Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Khurshid Ahmad
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan, Korea
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40
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Sugimoto K, Abe I, Minezaki M, Takashi Y, Ochi K, Fujii H, Ohishi H, Yamao Y, Kudo T, Ohe K, Abe M, Ohnishi Y, Shinagawa T, Mukoubara S, Kobayashi K. Investigation of efficacy and safety of low-dose sodium glucose transporter 2 inhibitors and differences between two agents, canagliflozin and ipragliflozin, in patients with type 2 diabetes mellitus. Drug Discov Ther 2020; 13:322-327. [PMID: 31956230 DOI: 10.5582/ddt.2019.01085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Sodium glucose transporter 2 inhibitors (SGLT2is), new antidiabetic agents, were reported to improve not only glycemic parameters but also metabolic and circulatory parameters. Whereas, several adverse events caused by SGLT2is were also reported. We aimed to investigate the changes of glycemic, metabolic, and circulatory parameters as well as safety with low-dose administration of two SGLT2is, canagliflozin and ipragliflozin, and also the difference between the two agents. 25 individuals with type-2 diabetes mellitus (T2DM) were recruited and administered with low-dose SGLT2is, canagliflozin (n = 10, 50 mg/day) and ipragliflozin (n = 15, 25 mg/day). We examined glycemic, metabolic, and circulatory parameters at baseline and 24 weeks after administration. All patients completed the study without complications. Compared with baseline, levels of glycated hemoglobin, fasting plasma glucose, and homeostasis model assessment of β-cell function improved significantly at 24 weeks after administration (p < 0.05). Levels of body weight, low-density lipoproteincholesterol, aspartate transaminase, γ-glutamyl transferase, and urinary excretion of albumin also improved significantly (p < 0.05). Moreover, systolic/diastolic blood pressure and levels of brain natriuretic peptide improved significantly (p < 0.05). The comparison of improvement ratio (values of improvement/values of basement) of each agent revealed that there was a significant difference between low-dose canagliflozin and low-dose ipragliflozin for brain natriuretic peptide (0.4404 vs. 0.0970, p = 0.0275). Hence, low-dose SGLT2is could be useful for patients of T2DM not only for hyperglycemia but also for metabolic and circulatory disorders without eliciting adverse events. In addition, with regard to the efficacy upon cardiovascular function, canagliflozin could be more suitable than ipragliflozin.
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Affiliation(s)
- Kaoru Sugimoto
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka, Japan
| | - Ichiro Abe
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka, Japan.,Department of Internal Medicine, Nagasaki Prefecture Iki Hospital, Iki, Nagasaki, Japan.,Department of Internal Medicine, Shinagawa Surgical Hospital, Iki, Nagasaki, Japan
| | - Midori Minezaki
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka, Japan.,Department of Internal Medicine, Nagasaki Prefecture Iki Hospital, Iki, Nagasaki, Japan
| | - Yuichi Takashi
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka, Japan.,Department of Internal Medicine, Nagasaki Prefecture Iki Hospital, Iki, Nagasaki, Japan
| | - Kentaro Ochi
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka, Japan.,Department of Internal Medicine, Nagasaki Prefecture Iki Hospital, Iki, Nagasaki, Japan
| | - Hideyuki Fujii
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka, Japan.,Department of Internal Medicine, Nagasaki Prefecture Iki Hospital, Iki, Nagasaki, Japan.,Department of Internal Medicine, Shinagawa Surgical Hospital, Iki, Nagasaki, Japan
| | - Hanako Ohishi
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka, Japan
| | - Yuka Yamao
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka, Japan
| | - Tadachika Kudo
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka, Japan
| | - Kenji Ohe
- Department of Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
| | - Makiko Abe
- Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan
| | - Yasushi Ohnishi
- Department of Internal Medicine, Nagasaki Prefecture Iki Hospital, Iki, Nagasaki, Japan
| | - Tomohiro Shinagawa
- Department of Internal Medicine, Shinagawa Surgical Hospital, Iki, Nagasaki, Japan
| | - Shigeaki Mukoubara
- Department of Internal Medicine, Nagasaki Prefecture Iki Hospital, Iki, Nagasaki, Japan
| | - Kunihisa Kobayashi
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka, Japan
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41
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Nakamura M, Nakade J, Toyama T, Okajima M, Taniguchi T. Severe intoxication caused by sodium-glucose cotransporter 2 inhibitor overdose: a case report. BMC Pharmacol Toxicol 2020; 21:5. [PMID: 31918741 PMCID: PMC6953132 DOI: 10.1186/s40360-019-0381-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 12/30/2019] [Indexed: 01/10/2023] Open
Abstract
Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors inhibit SGLT2, which is expressed in the proximal renal tubule, and thus reduce blood glucose levels by enabling the urinary excretion of excess glucose. SGLT2 inhibitors have been reported to suppress the complications of diabetes and reduce overall mortality. However, little is known about the types of symptoms that may occur in response to an overdose of an SGLT2 inhibitor. Here, we describe a case of intoxication caused by an overdose of an SGLT2 inhibitor. Case presentation An otherwise physically healthy adult woman ingested an overdose of ipragliflozin, an SGLT2 inhibitor, and a polypill of olmesartan medoxomil, and azelnidipine in a suicide attempt. Although her blood ipragliflozin concentration was very high (9516.3 ng/mL) upon hospital arrival, her initial blood glucose level was normal, and she did not exhibit symptoms such as hypoglycemia or polyuria. Moderate renal dysfunction associated with an estimated glomerular filtration rate of 42.3 mL/min/1.73 m2 was observed. Thirty-six hours after ingestion, her blood ipragliflozin concentration decreased to a level equivalent to that observed after a therapeutic dose and her renal function improved almost simultaneously. After improvement in her renal function, the osmotic diuretic effect of the drug progressed. Her blood glucose level declined slightly but was in the normal range due to glucose administration. During the clinical course, fatal hypoglycemia was not observed. Conclusions Our case showed that an overdose of an SGLT2 inhibitor caused toxic effects on renal function, but severe hypoglycemia was not observed. Additional cases of intoxication from SGLT2 inhibitors alone would be helpful to clarify the mechanism of intoxication.
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Affiliation(s)
- Miho Nakamura
- Intensive Care Unit, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.
| | - Junya Nakade
- Department of Hospital Pharmacy, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Tadashi Toyama
- Intensive Care Unit, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Masaki Okajima
- Intensive Care Unit, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Takumi Taniguchi
- Intensive Care Unit, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.,Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan
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42
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Kshirsagar RP, Kulkarni AA, Chouthe RS, Pathan SK, Une HD, Reddy GB, Diwan PV, Ansari SA, Sangshetti JN. SGLT inhibitors as antidiabetic agents: a comprehensive review. RSC Adv 2020; 10:1733-1756. [PMID: 35494673 PMCID: PMC9048284 DOI: 10.1039/c9ra08706k] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 12/18/2019] [Indexed: 12/12/2022] Open
Abstract
Diabetes is one of the most common disorders that substantially contributes to an increase in global health burden. As a metabolic disorder, diabetes is associated with various medical conditions and diseases such as obesity, hypertension, cardiovascular diseases, and atherosclerosis. In this review, we cover the scientific studies on sodium/glucose cotransporter (SGLT) inhibitors published during the last decade. Our focus on providing an exhaustive overview of SGLT inhibitors enabled us to present their chemical classification for the first time.
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Affiliation(s)
| | | | - Rashmi S Chouthe
- Srinath Institute of Pharmaceutical Education and Research Bajaj Nagar Waluj Aurangabad 431136 India
| | | | - Hemant D Une
- Y. B. Chavan College of Pharmacy Aurangabad Maharashtra India - 431001
| | - G Bhanuprakash Reddy
- Department of Biochemistry, National Institute of Nutrition (ICMR) Hyderabad Telangana India - 500007
| | - Prakash V Diwan
- Maratha Mandal Research Centre Belagavi Karnataka India - 590019
| | - Siddique Akber Ansari
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University Po Box 2454 Riyadh 11451 Saudi Arabia
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43
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Yehya A, Sadhu A. Sodium-Glucose Cotransporter 2 Inhibitor-Associated Prolonged Euglycemic Diabetic Ketoacidosis in Type 2 Diabetes: A Case Report and Literature Review. Clin Diabetes 2020; 38:112-116. [PMID: 31975762 PMCID: PMC6969664 DOI: 10.2337/cd19-0035] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Affiliation(s)
- Ahmad Yehya
- Division of Endocrinology, Diabetes & Metabolism, Houston Methodist Hospital, Houston, TX
| | - Archana Sadhu
- Division of Endocrinology, Diabetes & Metabolism, Houston Methodist Hospital, Houston, TX
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44
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Shahady E, Leahy JL. Sodium-Glucose Cotransporter 2 Inhibitor Protection Against Adverse Cardiovascular and Renal Outcomes in Patients With Type 2 Diabetes. Clin Diabetes 2019; 37:211-220. [PMID: 31371851 PMCID: PMC6640890 DOI: 10.2337/cd18-0064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
IN BRIEF New treatments for type 2 diabetes are required to demonstrate cardiovascular safety in dedicated cardiovascular outcomes trials (CVOTs). This article reviews available evidence on cardiovascular, renal, and safety outcomes from CVOTs and real-world analyses of sodium-glucose cotransporter 2 inhibitors, along with considerations for their use in clinical practice.
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Affiliation(s)
| | - John L. Leahy
- University of Vermont College of Medicine, Burlington, VT
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45
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Saito M, Kaibara A, Kadokura T, Toyoshima J, Yoshida S, Kazuta K, Ueyama E. Pharmacokinetic and pharmacodynamic modelling for renal function dependent urinary glucose excretion effect of ipragliflozin, a selective sodium-glucose cotransporter 2 inhibitor, both in healthy subjects and patients with type 2 diabetes mellitus. Br J Clin Pharmacol 2019; 85:1808-1819. [PMID: 31026084 PMCID: PMC6624389 DOI: 10.1111/bcp.13972] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 03/22/2019] [Accepted: 04/04/2019] [Indexed: 11/30/2022] Open
Abstract
AIMS To provide a model-based prediction of individual urinary glucose excretion (UGE) effect of ipragliflozin, we constructed a pharmacokinetic/pharmacodynamic (PK/PD) model and a population PK model using pooled data of clinical studies. METHODS A PK/PD model for the change from baseline in UGE for 24 hours (ΔUGE24h ) with area under the concentration-time curve from time of dosing to 24 h after administration (AUC24h ) of ipragliflozin was described by a maximum effect model. A population PK model was also constructed using rich PK sampling data obtained from 2 clinical pharmacology studies and sparse data from 4 late-phase studies by the NONMEM $PRIOR subroutine. Finally, we simulated how the PK/PD of ipragliflozin changes in response to dose regime as well as patients' renal function using the developed model. RESULTS The estimated individual maximum effect were dependent on fasting plasma glucose and renal function, except in patients who had significant UGE before treatment. The PK of ipragliflozin in type 2 diabetes mellitus (T2DM) patients was accurately described by a 2-compartment model with first order absorption. The population mean oral clearance was 9.47 L/h and was increased in patients with higher glomerular filtration rates and body surface area. Simulation suggested that medians (95% prediction intervals) of AUC24h and ΔUGE24h were 5417 (3229-8775) ng·h/mL and 85 (51-145) g, respectively. The simulation also suggested a 1.17-fold increase in AUC24h of ipragliflozin and a 0.76-fold in ΔUGE24h in T2DM patients with moderate renal impairment compared to those with normal renal function. CONCLUSIONS The developed models described the clinical data well, and the simulation suggested mechanism-based weaker antidiabetic effect in T2DM patients with renal impairment.
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46
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Han DG, Yun H, Yoon IS. A novel high-performance liquid chromatographic method combined with fluorescence detection for determination of ertugliflozin in rat plasma: Assessment of pharmacokinetic drug interaction potential of ertugliflozin with mefenamic acid and ketoconazole. J Chromatogr B Analyt Technol Biomed Life Sci 2019; 1122-1123:49-57. [PMID: 31153131 DOI: 10.1016/j.jchromb.2019.05.023] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 05/01/2019] [Accepted: 05/24/2019] [Indexed: 12/11/2022]
Abstract
Ertugliflozin (ERTU) is a novel, potent, and highly selective sodium glucose cotransporter 2 inhibitor that has been recently approved for the treatment of type 2 diabetes mellitus. We describe a novel bioanalytical method using high-performance liquid chromatography (HPLC) coupled with fluorescence detection for quantitative determination of ERTU in rat plasma. Acetonitrile-based protein precipitation method was used for sample preparation, and chromatographic separation was performed on a Kinetex® C18 column with an isocratic mobile phase comprising acetonitrile and 10 mM potassium phosphate buffer (pH 6.0). The eluent was monitored by a fluorescence detector at an optimized excitation/emission wavelength pair of 277/320 nm. The method was validated to demonstrate the selectivity, linearity (ranging from 4 to 2000 ng/mL), precision, accuracy, recovery, matrix effect, and stability in line with the current FDA guidelines. The newly developed method was successfully applied to investigate the pharmacokinetic interactions of ERTU with mefenamic acid (MEF) and ketoconazole (KET). The findings of the present study revealed that the pharmacokinetics of ERTU may be altered by concurrent administration of MEF and KET in rats. To our knowledge, the present study is the first to develop a validated bioanalytical method for quantification of ERTU using HPLC coupled with fluorescence detection and to assess the drug interaction potential of ERTU with non-steroidal anti-inflammatory (MEF) and azole antifungal (KET) drugs.
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Affiliation(s)
- Dong-Gyun Han
- Department of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan, South Korea
| | - Hwayoung Yun
- Department of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan, South Korea.
| | - In-Soo Yoon
- Department of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan, South Korea.
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47
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Pandey J, Tamrakar AK. SGLT2 inhibitors for the treatment of diabetes: a patent review (2013-2018). Expert Opin Ther Pat 2019; 29:369-384. [DOI: 10.1080/13543776.2019.1612879] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Jyotsana Pandey
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), New Delhi, India
| | - Akhilesh K Tamrakar
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), New Delhi, India
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48
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Wang C, Zhou Y, Kong Z, Wang X, Lv W, Geng Z, Wang Y. The renoprotective effects of sodium-glucose cotransporter 2 inhibitors versus placebo in patients with type 2 diabetes with or without prevalent kidney disease: A systematic review and meta-analysis. Diabetes Obes Metab 2019; 21:1018-1026. [PMID: 30565382 DOI: 10.1111/dom.13620] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Revised: 12/02/2018] [Accepted: 12/07/2018] [Indexed: 12/11/2022]
Abstract
AIMS We undertook a systematic review and meta-analysis to assess the efficacy and safety of sodium-glucose cotransporter 2 inhibitors (SGLT2is) concerning kidney outcomes in patients with type 2 diabetes mellitus (T2DM), with or without prevalent kidney disease. MATERIALS AND METHODS PubMed, Web of science, Embase and the Cochrane Library were systematically searched for randomized controlled trials (RCTs) to assess the efficacy and safety of treatment with SGLT2is versus placebo in patients with T2DM. The weighted mean difference (WMD) and its 95% confidence interval (CI) were applied for continuous variables, and the risk ratio (RR) and corresponding 95% CI were used for dichotomous outcomes. Patients were categorized according to whether the baseline mean estimated glomerular filtration rate (eGFR) was less or was more than 60 mL/min/1.73 m2 . RESULTS A total of 25 eligible studies with 43 721 participants were included. There was an initial and small decrease in eGFR during the early treatment period (WMD, -4.63; 95% CI, -6.08 to -3.19 mL/min/1.73 m2 ), which was noted at 1-6 weeks and gradually narrowed over time, with a decline in protection from eGFR in the long term (WMD, 3.82; 95% CI, 2.80-4.85 mL/min/1.73 m2 ). SGLT2is significantly delayed albuminuria progression (RR, 0.71; 95% CI, 0.66-0.76), promoted albuminuria regression (RR,1.71; 95% CI, 1.54-1.90), improved the composite of ≥40% decrease in eGFR, in the need for renal-replacement and in death from renal causes (RR, 0.57; 95% CI, 0.49-0.66), and reduced all-cause mortality (RR, 0.84; 95% CI, 0.75-0.94). At the same time, they significantly increased the risk of genital infection (RR, 3.43; 95% CI, 2.87-4.10) vs placebo in patients with T2DM. Meta-regression analyses showed that eGFR-preservation effects were not significantly associated with basic patient characteristics (age, BMI, HbA1c, eGFR level), but were influenced by drug administration (treatment duration, type, dosage of SGLT2is). Subgroup analyses showed that the relative effects on renal outcomes of SGLT2is vs placebo were similar across eGFR subgroups (P heterogeneity >0.05). CONCLUSIONS SGLT2is slowed eGFR decline, lowered albuminuria progression, improved adverse renal endpoints and reduced all-cause mortality, but increased risk of genital infections vs placebo in patients with T2DM. The indication of consistent renal benefits across categories of baseline eGFR levels may allow additional individuals to benefit from SGLT2is therapy.
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Affiliation(s)
- Chen Wang
- Department of Endocrinology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yue Zhou
- Department of Endocrinology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zili Kong
- Department of Endocrinology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiang Wang
- Department of Endocrinology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wenshan Lv
- Department of Endocrinology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhuang Geng
- Department of Endocrinology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yangang Wang
- Department of Endocrinology, Affiliated Hospital of Qingdao University, Qingdao, China
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49
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Zhao XC, Livingston MJ, Liang XL, Dong Z. Cell Apoptosis and Autophagy in Renal Fibrosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1165:557-584. [PMID: 31399985 DOI: 10.1007/978-981-13-8871-2_28] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Renal fibrosis is the final common pathway of all chronic kidney diseases progressing to end-stage renal diseases. Autophagy, a highly conserved lysosomal degradation pathway, plays important roles in maintaining cellular homeostasis in all major types of kidney cells including renal tubular cells as well as podocytes, mesangial cells and endothelial cells in glomeruli. Autophagy dysfunction is implicated in the pathogenesis of various renal pathologies. Here, we analyze the pathological role and regulation of autophagy in renal fibrosis and related kidney diseases in both glomeruli and tubulointerstitial compartments. Further research is expected to gain significant mechanistic insights and discover pathway-specific and kidney-selective therapies targeting autophagy to prevent renal fibrosis and related kidney diseases.
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Affiliation(s)
- Xing-Chen Zhao
- Division of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Man J Livingston
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, 30912, USA
| | - Xin-Ling Liang
- Division of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
| | - Zheng Dong
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, 30912, USA.
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50
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Nho IY, Kim HS, Kang NK, Lee MW, Kim SK, Park SO. Case of hyperosmolar hyperglycemic state by a sodium-glucose cotransporter 2 inhibitor. KOSIN MEDICAL JOURNAL 2018. [DOI: 10.7180/kmj.2018.33.3.402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus. SGLT2 cotransporters are responsible for reabsorption of 90 % of the glucose filtered by the kidney. The glucuretic effect resulting from SGLT2 inhibition contributes to reduce hyperglycaemia and also assists weight loss and blood pressure reduction. In this study, we presented the case of a 59-year-old male who developed hyperosmolar hyperglycemic state (HHS), possibly caused by a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a novel class of antihyperglycemic agents. This case highlights that HHS can develop in patients with diabetes treated with SGLT2 inhibitors
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