Oxidative Stress and NRF2/KEAP1/ARE Pathway in Diabetic Kidney Disease (DKD): New Perspectives

Biomolecules, Journal Year: 2022, Volume and Issue: 12(9), P. 1227 - 1227

Published: Sept. 2, 2022

Diabetes mellitus (DM) is one of the most debilitating chronic diseases worldwide, with increased prevalence and incidence. In addition to its macrovascular damage, through microvascular complications, such as Diabetic Kidney Disease (DKD), DM further compounds quality life these patients. Considering DKD main cause end-stage renal disease (ESRD) in developed countries, extensive research currently investigating matrix pathophysiology. Hyperglycemia, inflammation oxidative stress (OS) are mechanisms behind this disease. By generating pro-inflammatory factors (e.g., IL-1,6,18, TNF-α, TGF-β, NF-κB, MCP-1, VCAM-1, ICAM-1) activation diverse pathways PKC, ROCK, AGE/RAGE, JAK-STAT), they promote a pro-oxidant state impairment antioxidant system (NRF2/KEAP1/ARE pathway) and, finally, alterations filtration unit. Hitherto, wide spectrum pre-clinical clinical studies shows beneficial use NRF2-inducing strategies, NRF2 activators Bardoxolone methyl, Curcumin, Sulforaphane their analogues), other natural properties treatment. However, limitations regarding lack larger trials, solubility or delivery hamper implementation for use. Therefore, review, we will discuss mechanisms, especially NRF2/KEAP1/ARE involvement, while highlighting potential therapeutic approaches that target via OS.

Language: Английский

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Oxidative Stress: A Culprit in the Progression of Diabetic Kidney Disease

Antioxidants, Journal Year: 2024, Volume and Issue: 13(4), P. 455 - 455

Published: April 12, 2024

Diabetic kidney disease (DKD) is the principal culprit behind chronic (CKD), ultimately developing end-stage renal (ESRD) and necessitating costly dialysis or transplantation. The limited therapeutic efficiency among individuals with DKD a result of our finite understanding its pathogenesis. complex interactions between various factors. Oxidative stress fundamental factor that can establish link hyperglycemia vascular complications frequently encountered in diabetes, particularly DKD. It crucial to recognize essential integral role oxidative development diabetic complications, Hyperglycemia primary trigger an upsurge production reactive oxygen species (ROS), sparking stress. main endogenous sources ROS include mitochondrial production, NADPH oxidases (Nox), uncoupled endothelial nitric oxide synthase (eNOS), xanthine oxidase (XO), cytochrome P450 (CYP450), lipoxygenase. Under persistent high glucose levels, immune cells, complement system, advanced glycation end products (AGEs), protein kinase C (PKC), polyol pathway, hexosamine pathway are activated. Consequently, oxidant–antioxidant balance within body disrupted, which triggers series reactions downstream pathways, including phosphoinositide 3-kinase/protein B (PI3K/Akt), transforming growth beta/p38-mitogen-activated (TGF-β/p38-MAPK), nuclear kappa (NF-κB), adenosine monophosphate-activated (AMPK), Janus kinase/signal transducer activator transcription (JAK/STAT) signaling. might persist even if strict control achieved, be attributed epigenetic modifications. treatment remains unresolved issue. Therefore, reducing intriguing target. clinical trials have shown bardoxolone methyl, erythroid 2-related 2 (Nrf2) activator, blood glucose-lowering drugs, such as sodium-glucose cotransporter inhibitors, glucagon-like peptide-1 receptor agonists effectively slow down progression by Other antioxidants, vitamins, lipoic acid, Nox regulators, present promising option for In this review, we conduct thorough assessment both preclinical studies current findings from focus on targeted interventions aimed at manipulating these pathways. We aim provide comprehensive overview state research area identify key areas future exploration.

Language: Английский

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Lysophosphatidylcholine mediates fast decline in kidney function in diabetic kidney disease

Kidney International, Journal Year: 2021, Volume and Issue: 101(3), P. 510 - 526

Published: Nov. 30, 2021

Some patients with diabetic kidney disease (DKD) show a fast progression of dysfunction and are known as "fast decliner" (FD). Therefore, it is critical to understand pathomechanisms specific for decline. Here, we performed comprehensive metabolomic analysis stage G3 DKD identified increased urinary lysophosphatidylcholine (LPC) in This was confirmed by quantification LPC using mass spectrometry containing saturated fatty acids palmitic (16:0) stearic (18:0) FDs. The upsurge levels correlated decline estimated glomerular filtration rate after 2.5 years. To clarify pathogenic role FD, studied an accelerated rat model observed increase the urine tubulointerstitium progressed. These findings suggested that local dysregulation lipid metabolism resulted excessive accumulation this species kidney. Our vitro studies also LPC-mediated lipotoxicity cultured proximal tubular cells. induced droplets via activation peroxisome proliferator-activated receptor-δ followed upregulation droplet membrane protein perilipin 2 decreased autophagic flux, thereby inducing organelle stress subsequent apoptosis. Thus, may mediate serve target novel therapeutic approaches. see commentary on page 454Translational StatementOur prospective cohort animal utilizing revealed changes DKD. Imaging further dysregulated tubulointerstitium. LPC-treated cells showed abnormal metabolism, impaired flux through proliferator–activated receptor δ–perilipin axis, demonstrating pathophysiological LPC. results provide foundation elucidating pathogenesis developing new therapies preventing 454 prevalence increasing worldwide.1Cho N.H. Shaw J.E. Karuranga S. et al.IDF Diabetes Atlas: global estimates diabetes 2017 projections 2045.Diabetes Res Clin Pract. 2018; 138: 271-281Google Scholar Despite improvements glycemic control blood pressure management renin-angiotensin system blockade, current therapy cannot completely halt end-stage disease. Analysis Global Burden Disease study data incidence chronic 89%, 87%, death due 98%, disability-adjusted life years 62% from 1990 2016.2Xie Y. Bowe B. Mokdad A.H. al.Analysis highlights global, regional, national trends epidemiology 2016.Kidney Int. 94: 567-581Google Decomposition analyses approximately one-half driven burden Pathogenesis multifactorial includes both metabolic hemodynamic factors. Glomerular hyperfiltration, oxidative stress, hypoxia kidney, advanced glycation end products, intracellular signaling pathways, autophagy, epigenetic can result inflammation fibrosis DKD.3Sugahara M. Pak W.L.W. Tanaka T. al.Update diagnosis, pathophysiology, disease.Nephrology. 2021; : 491-500Google Previous focused damages However, accumulating evidence protection sodium glucose co-transporter (SGLT2) inhibition emphasizes crucial damage because SGLT2 exclusively localized tubules.4Tanaka Sugiura Saito H. al.Sodium–glucose cotransporter normalizes suppresses kidneys mice.Kidney 912-925Google Metabolic derangements Particularly, mitochondrial leads development DKD.5Galvan D.L. Long J. Green N. al.Drp1S600 phosphorylation regulates fission nephropathy mice.J Invest. 2019; 129: 2807-2823Google Scholar, 6Wang W. Wang al.Mitochondrial triggered hyperglycemia mediated ROCK1 podocytes endothelial cells.Cell Metab. 2012; 15: 186-200Google 7Qi Keenan H.A. Li Q. al.Pyruvate kinase M2 protect against pathology dysfunction.Nat Med. 2017; 23: 753-762Google Energy supply mitochondria majorly depends programmed enzyme systems acid β-oxidation Krebs cycle. On other hand, causes aberrant leading production metabolites toxic In patients, addition levels, dyslipidemia often currently thought contribute cell DKD.8Kume Maegawa Lipotoxicity, nutrient-sensing signals, autophagy nephropathy.JMA 2020; 3: 87-94Google Furthermore, lipotoxicity, which occurs cholesterol or sphingolipids, impact abnormalities DKD.9Mitrofanova A. Sosa M.A. Fornoni Lipid mediators insulin disease.Am J Physiol Ren Physiol. 317: F1241-F1252Google function, these decliners" (FDs).10Yoshida Kashiwabara K. Hirakawa al.Conditions, pathogenesis, early decliner Japan.BMJ Open Care. 8: 1-9Google It important FD mediator should be good individualize medical approach high-risk patients.11Tofte Persson F. Rossing P. Omics research disease: biomarker dimensions understandings?.J Nephrol. 33: 931-948Google Scholar,12Tuttle K.R. Bakris G.L. Bilous R.W. al.Diabetic report ADA consensus conference.Diabetes 2014; 37: 2864-2883Google study, plasma identify FD. experiments detailed methods described Supplementary Methods. clinical approved Institutional Review Board at University Tokyo Graduate School Medicine, Tokyo, Japan (approval number 10660) adhered Declaration Helsinki. All provided written informed consent participate before inclusion study. Animal were conducted Ina Research, Inc. (Nagano, Japan), accordance National Institutes Health guidelines Standards Proper Conduct Experiments, approval Kyowa Kirin Co., Ltd., Care Use Committee 20J0034). We prospectively recruited 150 Asian between January 2015 August Hospital DKD, whose (eGFR) values 30 60 ml/min per 1.73 m2 time consent. Most those type diabetes. Comorbidity, history, laboratory collected electronic records. baseline criteria follows: subjects aged 20 80 no coexistence nondiabetic cirrhosis, systemic cancer within past 1 year, organ transplantation, ingestion steroids month, controlled (systolic < 170 mm Hg hemoglobin A1c 9.5%). Plasma samples participants 10 months. Kidney function evaluated measuring eGFR over based equation Japanese populations: = 194 × serum creatinine−1.094 age−0.287 (for men) 0.739 women). A threshold median 10% year employed define calculated average change 4 points every months least square method. Participants who matched following excluded our analysis: insufficient (n 2) missed appearances follow-up period hospital transfer withdrawal agreement 15). validated association altered comparing 3 groups rats: unilateral nephrectomized spontaneously Torii (SDTF) rats (SDT fatty/Jcl, male; CLEA Japan, Inc.) fed 0.2% v/w saline (SDTF uNx; n 20); nonnephrectomized SDTF general (SDTF; 10); Sprague-Dawley (Jcl:SD, Inc.), genetically originated rats, healthy group (SD; 8). had free access Purina 5008 (Charles River Laboratories Japan) throughout At 6 weeks age, randomly divided into (20 + 10), right removed anesthesia isoflurane (Mylan, Inc.). One week later, continuously intake, all their status 11 operation (17 age). No animals died during observation period. obtained HK-2 American Type Culture Collection. 1:1 mixture Dulbecco's modified Eagle's medium Ham's F-12 nutrient (D8062; Sigma-Aldrich) fetal bovine (F7524; Sigma-Aldrich), 50 U/ml penicillin, mg/mL streptomycin 37 °C atmosphere 5% CO2. Human renal tubule epithelial (RPTECs; CC-2553; Lonza) Renal Epithelial Cell Growth Medium (CC-3191; 0.5% serum. For treatment cells, preincubated assay medium, contained 0.1% acid–free albumin (017-15141; Wako), overnight (855675C 855775C; Avanti Polar Lipids) preconjugated 5 minutes. applied related COI-STREAM project (Figure 1a). total 10.5% considered they >10% 1b). characteristics shown Table 1. Metabolomic 260 198 urine, respectively. Among metabolites, each significant differences non-FD (fold ratio > 0.5; P 0.05; S1). Spearman correlation coefficients. only 1c). analyzed experiments.Table 1Baseline DKDCharacteristicsValueNo.Age, yr70.3 ± 6.9133Male sex, %79.7133Systolic pressure, Hg139.6 15.9133Diastolic Hg71.2 10.3133BMI, kg/m225.5 3.6133HDL, mg/dl56.4 16.3129TG, mg/dl153.8 123.5133Fasting glucose, mg/dl131.7 32.6133HbA1c, %6.9 0.6131Hemoglobin, g/dl13.9 1.4133eGFR, m247.4 7.9133Serum creatinine, mg/dl1.2 0.2133ACR, mg/g creatinine68.7 126.996Urinary protein, creatinine1130.1 2049.252ACR, albumin-to-creatinine ratio; BMI, body index; disease; eGFR, rate; HbA1c, A1c; HDL, high-density lipoprotein; TG, triglyceride.Values expressed mean SD, unless otherwise indicated. table tab ACR, triglyceride. Values bioactive lipids associated cardiovascular diseases diabetes.13Schmitz G. Ruebsaamen Metabolism atherogenic lysophosphatidylcholine.Atherosclerosis. 2010; 208: 10-18Google major mammalian systems, such 14:0, 16:0, 16:1, 18:0, 18:1, 18:2, 20:3, 20:4, 20:5, 20:6, quantitatively measured compared internal standard. highly abundant >95% whereas detected <50% 2a Figure S1A). concentration higher (P 0.019 0.152, respectively; 2b). More important, 2c), but not 2d). Multiple regression (18:0), even adjusting (Supplementary S2). addition, positively triglycerides negatively lipoprotein S3). persisted S1B C). Logistic high (16:0), predicted 2e f S4). suggest Next, investigated whether equivalent occurred DKD: wild (SD), (SD diabetes: SDTF), (unilateral SDTF: uNx). dyslipidemia, particularly 3a–c). uNx injury involving creatinine clearance led ratio, injury, weight. effects more severe than rats; however, did exhibit exacerbated 3a d–f S2A B). Measurement concentrations elevated 3g) species. Notably, inversely 3h). Taken together, elevation LPC, indicated consistent observations play causative roles Increased without corresponding blood, derived quantified tissue rats. Both significantly 4a). 4b). contrast, liver substantially elevate S2C D). proportion components relative (both >30%) 4c). imaging around interstitial area wild-type SD glomerulus among 4d). markedly rather being consequence.Figure 4Lysophosphatidylcholine ectopically accumulated tissues nephrectomy (uNx) (a) Concentration uNx. compare representative accounting (b) coefficients (LPC [16:0] [18:0]) (c) Proportion (significant indicate comparisons kidney). (d) Mass (MS) cortex (left, hematoxylin eosin [HE] staining; middle, [16:0]; right, [18:0]). Black angles glomerulus. Bar =200 μm, color bars MS intensity normalized ion chromatogram. (e–g) Relative mRNA expression LDLR LOX-1 (e), genes (f), PLIN2 (g). (h) Immunohistochemistry labeled anti-PLIN2 antibody. μm. One-way variance, Sidak post hoc test, used. presented SEM. ∗P 0.05, ∗∗P 0.01, ∗∗∗P 0.005. NS, significant. optimize viewing image, please online version article www.kidney-international.org.View Large Image ViewerDownload Hi-res image Download (PPT) determine molecular mechanisms tissues. low-density (LDLR) lectin-like oxidized receptor-1 (LOX-1), responsible normal uptake, respectively, upregulated 4e). Moreover, β-oxidation–related genes, oxidation maintaining homeostasis, downregulated 4f). (PLIN2), main component droplets,14Heid H.W. Moll R. Schwetlick I. al.Adipophilin marker diverse types diseases.Cell Tissue Res. 1998; 294: 309-321Google 4g). Immunohistologic staining 4h). demonstrated susceptible (collectively termed "lipotoxicity"), address implications effect exposing (18:0). used RPTECs, primary immortalized human line, consistent. Cultured treated 5a). 5b). When inhibitor lysophospholipid acyltransferase (inhibits metabolism), CI-976,15Chambers Judson Brown W.J. unique (LPAT) antagonist, CI-976, affects secretory endocytic trafficking pathways.J Sci. 2005; 118: 3061-3071Google S3A supported hypothesis exposure exogenous lipoprotein, DKD.Figure 5Exposure Cells μM hours 5, group). Fluorescence images formation 90 24 6). fluorescence normalization nucleus. viability stimulus 4). Caspase 3/7 activity hours. luminescent (e) Percentage apoptotic (annexin V+ 7-amino-actinomycin D [7-AAD]+/–; (f) endoplasmic reticulum stress-related (g) Immunoblots c-Jun N-terminal (JNK) 3). FASL HRK (i) CHOP Comparisons unpaired Student t test test. Data BiP, binding immunoglobulin protein; CHOP, C/EBP homologous GADD34, growth arrest DNA gene; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GRP78, 78-kDa glucose-regulated LD, droplet; p-JNK, phosphorylated JNK. caused cytotoxicity dose-dependent manner 5c). caspase 5d) enhanced apoptosis 5e). An level cytosolic Ca2+ (ER) stress-mediated apoptosis16Orrenius Zhivotovsky Nicotera Regulation death: calcium-apoptosis link.Nat Rev Mol Biol. 2003; 4: 552-565Google S3C). Further supporting LPC-induced ER unfolded response, (CHOP), gene (GADD34), luminal (BiP/GRP78; 5f). structurally similar, bind long-chain acids. similar effects; potent effects. examined mechanism Treatment activated functions downstream response 5g). Activation Fas ligand (FASL) harakiri (HRK), activate proapoptotic 5h). signal induction expressions 5i). Considering initiates mitochondria-dependent apoptosis17Cunha D.A. Igoillo-Esteve Gurzov E.N. al.Death p53-upregulated modulator stress-mitochondrial dialog triggering lipotoxic rodent β-cell apoptosis.Diabetes. 61: 2763-2775Google linked dysfunction, reactive oxygen 6a). RPTECs concerns regarding cellular severely consumption 6b); moreover, adenosine triphosphate basal maximal respiration rates treatment. Mitochondrial permeability treatme

Language: Английский

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The Bidirectional Link Between Diabetes and Kidney Disease: Mechanisms and Management

Cureus, Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 20, 2023

The complex and mutually influential connection between diabetes mellitus chronic kidney disease (CKD) is a significant focal point in the current healthcare landscape. Diabetes, medical condition characterized by elevated blood glucose levels resulting from impaired insulin action or secretion, has become global epidemic. It poses considerable challenges to systems affects millions of individuals worldwide. Concurrently, CKD, gradual decline function, persistent health challenge. This narrative review explores relationship these two conditions, shedding light on their implications for public health, clinical practice, biomedical research. correlation not merely coincidental. Diabetes recognized as risk factor with are considerably more vulnerable developing renal complications. Diabetic nephropathy, distinct type closely associated diabetes, end-stage disease. imperative implement efficient management strategies regulate sugar prevent potential damage. On other hand, may contribute development diabetes. kidneys filtering selectively reabsorbing necessary. In compromised such metabolism can give rise resistance As result, plays dual role both preserving function preventing who at risk. coexistence patient presents challenges. Achieving effective requires meticulous balance glycemic control preservation function. Failing maintain this delicate equilibrium lead cardiovascular complications subsequent hospitalizations. comprehensive aims thoroughly examine pathophysiological mechanisms that connect will provide insights into manifestations diagnostic methods, explore various approaches managing condition, discuss crucial nutrition, delve pharmacological interventions, emphasize importance education self-care, shed emerging research areas. addition impacting individual outcomes, reciprocal systems, socioeconomic landscapes, policy. Comprehending interaction making well-informed judgments, improving care, approach address interconnected issues

Language: Английский

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Oxidative stress as a culprit in diabetic kidney disease

Life Sciences, Journal Year: 2023, Volume and Issue: 322, P. 121661 - 121661

Published: April 5, 2023

Language: Английский

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The role of inflammation in diabetic kidney disease

The Korean Journal of Internal Medicine, Journal Year: 2021, Volume and Issue: 36(4), P. 753 - 766

Published: July 1, 2021

Diabetic kidney disease (DKD) has been the leading cause of chronic for over 20 years. Yet, these two decades, clinical approach to this condition not much improved beyond administration glucose-lowering agents, renin-angiotensin-aldosterone system blockers blood pressure control, and lipid-lowering agents. The proportion diabetic patients who develop DKD progress end-stage renal remained nearly same. This unmet need treatment is caused by complex pathophysiology DKD, difficulty translating from bench bed, which further adds growing argument that a homogeneous disease. To better capture full spectrum in our design regimens, we diagnostic tools can distinguish subgroups within condition. For instance, typically placed broad category non-inflammatory However, genome-wide transcriptome analysis studies consistently indicate inflammatory signaling pathway activation DKD. review will utilize human data discussing potential redefining role inflammation We also comment on therapeutic targeted anti-inflammatory therapy

Language: Английский

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Metabolic Changes and Oxidative Stress in Diabetic Kidney Disease

Antioxidants, Journal Year: 2021, Volume and Issue: 10(7), P. 1143 - 1143

Published: July 19, 2021

Diabetic kidney disease (DKD) is a major cause of end-stage disease, and it crucial to understand the pathophysiology DKD. The control blood glucose levels by various glucose-lowering drugs, common use inhibitors renin–angiotensin system, aging patients with diabetes can alter course Moreover, metabolic changes associated atherosclerosis play role in etiology DKD largely attributed disruption cellular stress responses due changes, especially an increase oxidative stress. Therefore, many antioxidants have been studied as therapeutic agents. Recently, has found that NRF2, master regulator stress, plays pathogenesis bardoxolone methyl, activator attracted attention drug increases estimated glomerular filtration rate This review outlines altered organelles DKD, their involvement discusses strategies for developing agents, methyl.

Language: Английский

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Polyphenols and Their Metabolites in Renal Diseases: An Overview

Foods, Journal Year: 2022, Volume and Issue: 11(7), P. 1060 - 1060

Published: April 6, 2022

Kidney diseases constitute a worldwide public health problem, contributing to morbidity and mortality. The present study aimed provide an overview of the published data regarding potential beneficial effects polyphenols on major kidney diseases, namely acute injury, chronic disease, diabetic nephropathy, renal cancer, drug-induced nephrotoxicity. This consists bibliographical review including in vitro vivo studies dealing with individual compounds. An analysis polyphenol metabolome human urine was also conducted estimate those compounds that are most likely be responsible for protective polyphenols. biological can highly attributed modulation specific signaling cascades involved oxidative stress responses, anti-inflammation processes, apoptosis. There is increasing evidence afford great disease protection. However, this (especially when involved) should considered caution before its clinical translation, particularly due unfavorable pharmacokinetics extensive metabolization undergo body. Future research consider their metabolites indeed reach tissues.

Language: Английский

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Exploration of Some Bis‐Sulfide and Bis‐Sulfone Derivatives as Non‐Classical Aldose Reductase İnhibitors

ChemistrySelect, Journal Year: 2023, Volume and Issue: 8(5)

Published: Feb. 2, 2023

Abstract Aldose reductase (AR, ALR2; EC 1.1.1.21), an enzyme that converts glucose to fructose on the polyol pathway, is important member of Aldo‐keto superfamily. ALR2 part rate‐limiting step, which associated with diabetic complications in this process, and plays a role regulating reactive oxygen species induced by growth factors cytokines. Despite fact sulfides sulfones have been discovered variety other biological functions, current study, we assessed inhibitory potential derivatives bis‐sulfide ( 5 – i ) bis‐sulfone 6 order further our interest designing discovering powerful inhibitors. The results investigations showed all exhibit activity against ALR2, K I values ranging from 0.53±0.03 4.20±0.06 μM. Among these agents, 2,6‐bis((4‐chlorophenyl)(phenylthio)methyl)cyclohexan‐1‐one h ), 2,6‐bis((3‐nitrophenyl)(phenylthio)methyl)cyclohexan‐1‐one c 2,6‐bis((3‐chlorophenyl)(phenylthio)methyl)cyclohexan‐1‐one g exhibited prominent constants μM, 0.65±0.04 0.71±0.05 respectively, were found be more potent than epalrestat =0.79±0.01 μM) currently, only inhibitor (ALR2I) utilized treatment. Additionally, silico molecular docking experiments carried out explain how bis‐sulfides bis‐sulfones interacted target ALR2′s binding site. According ADME‐Tox compounds are predicted ALR2Is appropriate drug‐like characteristics. study‘s findings could exploited create innovative therapeutics prevent diabetes complications.

Language: Английский

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Clinical and preclinical evidence that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers prevent diabetic peripheral neuropathy

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Jan. 10, 2024

Abstract Given possible involvement of the central and peripheral angiotensin system in pain processing, we conducted clinical preclinical studies to test whether pharmacological inhibition would prevent diabetic neuropathy (DPN) accompanying type 2 diabetes mellitus (T2DM). In study, nociceptive sensitivity was determined leptin-deficient ob / mice, a T2DM model. A retrospective cohort study conducted, using medical records patients receiving antihypertensives at three hospitals for nearly decade. daily treatment with perindopril, an angiotensin-converting enzyme inhibitor (ACEI), or telmisartan, receptor blocker (ARB), but not amlodipine, L-type calcium channel (CaB), significantly inhibited DPN development without affecting hyperglycemia. enrolled 7464 were divided into groups ACEIs, ARBs others (non-ACEI, non-ARB antihypertensives). Bonferroni’s indicated later ARB ACEI than group. The multivariate Cox proportional analysis detected significant negative association prescription ACEIs β-blockers, CaBs diuretics, development. Thus, our suggests that is beneficial T2DM.

Language: Английский

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