Verapamil inhibits early acute liver failure through suppressing the NLRP3 inflammasome pathway.
Journal of cellular and molecular medicine
Acute liver failure (ALF) is a rare disease characterized by the sudden onset of serious hepatic injury, as manifested by a profound liver dysfunction and hepatic encephalopathy in patients without prior liver disease. In this paper, we aim to investigate whether verapamil, an antagonist of TXNIP, inhibits early ALF through suppressing the NLRP3 inflammasome pathway. Firstly, an ALF mouse model was induced by lipopolysaccharide (LPS)/D-galactosamine (GalN) treatment. The optimal concentration of verapamil in treating early ALF mice was determined followed by investigation on its mechanism in LPS/GalN-induced liver injury. Western blot analysis and co-immunoprecipitation were performed to determine the activation of the TXNIP/NLRP3 inflammasome pathway. Subsequently, overexpression of NLRP3 in mouse liver was induced by transfection with AAV-NRLP3 in vivo and in vitro to identity whether verapamil inhibited early ALF through suppressing the activation of NLRP3 inflammasome. We found that ALF was induced by LPS/GalN in mice but was alleviated by verapamil through a mechanism that correlated with suppression of the NLRP3 inflammasome pathway. Oxidative stress and inflammatory response were induced by intraperitoneal injection of LPS/GalN, but alleviated with injection of verapamil. Overexpression of NLRP3 via AAV in mouse liver in vivo and in vitro reduced the therapeutic effect of verapamil on LPS/GalN-induced ALF. Taken together, the TXNIP antagonist verapamil could inhibit activation of the NLRP3 inflammasome, inflammatory responses and oxidative stress to alleviate LPS/GalN-induced ALF.
10.1111/jcmm.16357
Verapamil Inhibits Ser202/Thr205 Phosphorylation of Tau by Blocking TXNIP/ROS/p38 MAPK Pathway.
Melone Mariarosa Anna Beatrice,Dato Clemente,Paladino Simona,Coppola Cinzia,Trebini Claudia,Giordana Maria Teresa,Perrone Lorena
Pharmaceutical research
PURPOSE:Oxidative stress is a hallmark of Alzheimer's Disease (AD) and promotes tau phosphorylation. Since Thioredoxin Interacting protein (TXNIP), the inhibitor of the anti-oxidant system of Thioredoxin, is up regulated in the hippocampus of AD patients, we investigated whether TXNIP plays a role in promoting tau phosphorylation and whether Verapamil, an inhibitor of TXNIP expression, prevents TXNIP downstream effects. METHODS:We analyzed TXNIP expression and tau phosphorylation in the hippocampus of the 5xFAD mice in the absence and presence of a pharmacological treatment with Verapamil. Using SH-SY5Y cells, we verified the causative role of TXNIP in promoting tau phosphorylation at Ser202/Thr205, by inducing TXNIP silencing. RESULTS:The amyloid beta peptide (Aβ) leads to TXNIP over-expression in SH-SY5Y cells, which in turns induces oxidative stress and the activation of p38 MAPK, promoting tau phosphorylation at Ser202/Thr205. Silencing of TXNIP abolishes Aβ-induced tau phosphorylation, p38 MAPK phosphorylation and subsequent tau phosphorylation. Verapamil prevents TXNIP expression as well as p38 MAPK and tau phosphorylation at Ser202/Thr205 in the hippocampus of the 5xFAD mice. CONCLUSIONS:Our study unveil a novel pathway involved in AD progression that is inhibited by Verapamil, shedding new light on the understanding of the therapeutic potential of Verapamil in AD.
10.1007/s11095-017-2276-2
Verapamil as an Adjunct Therapy to Reduce tPA Toxicity in Hyperglycemic Stroke: Implication of TXNIP/NLRP3 Inflammasome.
Molecular neurobiology
Thrombolytic therapy has remained quite challenging in hyperglycemic patients for its association with poor prognosis and increased hemorrhagic conversions. We recently showed that tissue plasminogen activator (tPA)-induced cerebrovascular damage is associated with thioredoxin-interacting protein (TXNIP) upregulation, which has an established role in the detrimental effects of hyperglycemia. In the present work, we investigated whether verapamil, an established TXNIP inhibitor, may provide protection against hyperglycemic stroke and tPA-induced blood-brain barrier (BBB) disruption. Acute hyperglycemia was induced by intraperitoneal administration of 20% glucose, 15 min prior to transient middle cerebral artery occlusion (tMCAO). Verapamil (0.15 mg/kg) or saline was intravenously infused with tPA at hyperglycemic reperfusion, 1 h post tMCAO. After 24 h of ischemia/reperfusion (I/R), mice were assessed for neurobehavioral deficits followed by sacrifice and evaluation of brain infarct volume, edema, and microbleeding. Alterations in TXNIP, inflammatory mediators, and BBB markers were further analyzed using immunoblotting or immunostaining techniques. As adjunctive therapy, verapamil significantly reduced tPA-induced BBB leakage, matrix metalloproteinase 9 (MMP-9) upregulation, and tight junction protein deregulation, which resulted in lesser hemorrhagic conversions. Importantly, verapamil strongly reversed tPA-induced TXNIP/NLRP3 (NOD-like receptor pyrin domain-containing-3) inflammasome activation and reduced infarct volume. This concurred with a remarkable decrease in high-mobility group box protein 1 (HMGB-1) and nuclear factor kappa B (NF-κB) stimulation, leading to less priming of NLRP3 inflammasome. This preclinical study supports verapamil as a safe adjuvant that may complement thrombolytic therapy by inhibiting TXNIP's detrimental role in hyperglycemic stroke.
10.1007/s12035-021-02384-z
Verapamil inhibits tumor progression of chemotherapy-resistant pancreatic cancer side population cells.
Zhao Lu,Zhao Yue,Schwarz Bettina,Mysliwietz Josef,Hartig Roland,Camaj Peter,Bao Qi,Jauch Karl-Walter,Guba Makus,Ellwart Joachim Walter,Nelson Peter Jon,Bruns Christiane Josephine
International journal of oncology
Tumor side population (SP) cells display stem-like properties that can be modulated by treatment with the calcium channel blocker verapamil. Verapamil can enhance the cytotoxic effects of chemotherapeutic drugs and multidrug resistance by targeting the transport function of the P-glycoprotein (P-gp). This study focused on the therapeutic potential of verapamil on stem-like SP tumor cells, and further investigated its chemosensitizing effects using L3.6pl and AsPC-1 pancreatic carcinoma models. As compared to parental L3.6pl cells (0.9±0.22%), L3.6pl gemcitabine-resistant cells (L3.6plGres) showed a significantly higher percentage of SP cells (5.38±0.99%) as detected by Hoechst 33342/FACS assays. The L3.6plGres SP cells showed stable gemcitabine resistance, enhanced colony formation ability and increased tumorigenicity. Verapamil effectively inhibited L3.6plGres and AsPC-1 SP cell proliferation in vitro. A pro-apoptotic effect of verapamil was observed in L3.6pl cells, but not in L3.6plGres cells, which was linked to their differential expression of P-gp and equilibrative nucleoside transporter-1 (ENT-1). In an orthotopic pancreatic cancer mouse model, both low and high dose verapamil was shown to substantially reduce L3.6plGres-SP cell tumor growth and metastasis, enhance tumor apoptosis, and reduce microvascular density.
10.3892/ijo.2016.3512
Pharmacokinetics of verapamil in diabetic rats induced by combination of high-fat diet and streptozotocin injection.
Chen G M,Hu N,Liu L,Xie S S,Wang P,Li J,Xie L,Wang G J,Liu X D
Xenobiotica; the fate of foreign compounds in biological systems
The aim of this study was to investigate effects of type 2 diabetes on the pharmacokinetics of verapamil after intravenous administration. Diabetes mellitus (DM) rats were induced by combination of high-fat diet (HFD) and streptozotocin. Plasma concentrations of verapamil in DM rats, rats fed with HFD, and control (CON) rats were measured after intravenous administration of 1 mg/kg verapamil and corresponding pharmacokinetic parameters were estimated. Area under the plasma concentration in DM rats was significantly smaller than that in CON rats. In vitro microsomal study showed that intrinsic clearance of verapamil in DM rats was significantly higher than those in CON rats. Compared to CON rats, higher intrinsic clearance was also observed in HFD rats. Western blot results demonstrated higher levels of CYP3A2 in DM and HFD rats, which was in line to activity of CYP3A. All the results gave a conclusion that diabetes may enhance metabolism of verapamil in rat, and the enhancement may partly result from induction of CYP3A.
10.3109/00498254.2011.558933
Preventing β-cell loss and diabetes with calcium channel blockers.
Xu Guanlan,Chen Junqin,Jing Gu,Shalev Anath
Diabetes
Although loss of functional β-cell mass is a hallmark of diabetes, no treatment approaches that halt this process are currently available. We recently identified thioredoxin-interacting protein (TXNIP) as an attractive target in this regard. Glucose and diabetes upregulate β-cell TXNIP expression, and TXNIP overexpression induces β-cell apoptosis. In contrast, genetic ablation of TXNIP promotes endogenous β-cell survival and prevents streptozotocin (STZ)- and obesity-induced diabetes. Finding an oral medication that could inhibit β-cell TXNIP expression would therefore represent a major breakthrough. We were surprised to discover that calcium channel blockers inhibited TXNIP expression in INS-1 cells and human islets and that orally administered verapamil reduced TXNIP expression and β-cell apoptosis, enhanced endogenous insulin levels, and rescued mice from STZ-induced diabetes. Verapamil also promoted β-cell survival and improved glucose homeostasis and insulin sensitivity in BTBR ob/ob mice. Our data further suggest that this verapamil-mediated TXNIP repression is conferred by reduction of intracellular calcium, inhibition of calcineurin signaling, and nuclear exclusion and decreased binding of carbohydrate response element-binding protein to the E-box repeat in the TXNIP promoter. Thus, for the first time, we have identified an oral medication that can inhibit proapoptotic β-cell TXNIP expression, enhance β-cell survival and function, and prevent and even improve overt diabetes.
10.2337/db11-0955
Diabetes pathogenic mechanisms and potential new therapies based upon a novel target called TXNIP.
Thielen Lance,Shalev Anath
Current opinion in endocrinology, diabetes, and obesity
PURPOSE OF REVIEW:Thioredoxin-interacting protein has emerged as a major factor regulating pancreatic β-cell dysfunction and death, key processes in the pathogenesis of type 1 and type 2 diabetes. Accumulating evidence based on basic, preclinical, and retrospective epidemiological research suggests that TXNIP represents a promising therapeutic target for diabetes. The present review is aimed at providing an update regarding these developments. RECENT FINDINGS:TXNIP has been shown to be induced by glucose and increased in diabetes and to promote β-cell apoptosis, whereas TXNIP deletion protected against diabetes. More recently, TXNIP inhibition has also been found to promote insulin production and glucagon-like peptide 1 signaling via regulation of a microRNA. β-Cell TXNIP expression itself was found to be regulated by hypoglycemic agents, carbohydrate-response-element-binding protein, and cytosolic calcium or the calcium channel blocker, verapamil. Retrospective studies now further suggest that verapamil use might be associated with a lower incidence of type 2 diabetes in humans. SUMMARY:TXNIP has emerged as a key factor in the regulation of functional β-cell mass and TXNIP inhibition has shown beneficial effects in a variety of studies. Thus, the inhibition of TXNIP may provide a novel approach to the treatment of diabetes.
10.1097/MED.0000000000000391
Prevention of Severe Hypoglycemia-Induced Brain Damage and Cognitive Impairment With Verapamil.
Jackson David A,Michael Trevin,Vieira de Abreu Adriana,Agrawal Rahul,Bortolato Marco,Fisher Simon J
Diabetes
People with insulin-treated diabetes are uniquely at risk for severe hypoglycemia-induced brain damage. Because calcium influx may mediate brain damage, we tested the hypothesis that the calcium-channel blocker, verapamil, would significantly reduce brain damage and cognitive impairment caused by severe hypoglycemia. Sprague-Dawley rats (10 weeks old) were randomly assigned to one of three treatments: ) control hyperinsulinemic (200 mU ⋅ kg ⋅ min)-euglycemic (80-100 mg/dL) clamps ( = 14), ) hyperinsulinemic-hypoglycemic (10-15 mg/dL) clamps ( = 16), or ) hyperinsulinemic-hypoglycemic clamps, followed by a single treatment with verapamil (20 mg/kg) ( = 11). Compared with euglycemic controls, hypoglycemia markedly increased dead/dying neurons in the hippocampus by 16-fold and cortex by 14-fold. Verapamil treatment strikingly decreased hypoglycemia-induced hippocampal and cortical damage, by 87% and 94%, respectively. Morris Water Maze probe trial results demonstrated that hypoglycemia induced a retention, but not encoding, memory deficit (noted by both abolished target quadrant preference and reduced target quadrant time). Verapamil treatment significantly rescued spatial memory as noted by restoration of target quadrant preference and target quadrant time. In summary, a one-time treatment with verapamil after severe hypoglycemia prevented neural damage and memory impairment caused by severe hypoglycemia. For people with insulin-treated diabetes, verapamil may be a useful drug to prevent hypoglycemia-induced brain damage.
10.2337/db18-0008
Current and future therapies for type 1 diabetes.
Diabetologia
In type 1 diabetes, insulin remains the mature therapeutic cornerstone; yet, the increasing number of individuals developing type 1 diabetes (predominantly children and adolescents) still face severe complications. Fortunately, our understanding of type 1 diabetes is continuously being refined, allowing for refocused development of novel prevention and management strategies. Hitherto, attempts based on immune suppression and modulation have been only partly successful in preventing the key pathophysiological feature in type 1 diabetes: the immune-mediated derangement or destruction of beta cells in the pancreatic islets of Langerhans, leading to low or absent insulin secretion and chronic hyperglycaemia. Evidence now warrants a focus on the beta cell itself and how to avoid its dysfunction, which is putatively caused by cytokine-driven inflammation and other stress factors, leading to low insulin-secretory capacity, autoantigen presentation and immune-mediated destruction. Correspondingly, beta cell rescue strategies are being pursued, which include antigen vaccination using, for example, oral insulin or peptides, as well as agents with suggested benefits on beta cell stress, such as verapamil and glucagon-like peptide-1 receptor agonists. Whilst autoimmune-focused prevention approaches are central in type 1 diabetes and will be a requirement in the advent of stem cell-based replacement therapies, managing the primarily cardiometabolic complications of established type 1 diabetes is equally essential. In this review, we outline selected recent and suggested future attempts to address the evolving profile of the person with type 1 diabetes.
10.1007/s00125-021-05398-3
The Effect of Verapamil on TXNIP Gene Expression, GLP1R mRNA, FBS, HbA1c, and Lipid Profile in T2DM Patients Receiving Metformin and Sitagliptin.
Malayeri Alireza,Zakerkish Mehrnoosh,Ramesh Farrokh,Galehdari Hamid,Hemmati Ali Asghar,Angali Kambiz A
Diabetes therapy : research, treatment and education of diabetes and related disorders
INTRODUCTION:Type 2 diabetes mellitus (T2DM) is the most common type of diabetes. A decrease in the number of pancreatic beta cells is a pathological sign of diabetes, and to date there is no drug treatment that targets damage to these cells. Pancreatic beta cells have a weak antioxidant system and are highly sensitive to oxidative stress reactions that occur within cells. Thioredoxin interacting protein (TXNIP) inhibits thioredoxin, which is part of the intracellular antioxidant system, thereby accelerating oxidative stress and apoptosis of pancreatic beta cells. Verapamil is a non-dihydropyridine calcium channel blocker. The efficacy of this drug to improve beta cell survival and glucose homeostasis by inhibiting TXNIP expression has been demonstrated in in vitro studies. Although several retrospective studies have shown a lower incidence of T2DM with verapamil treatment, no prospective intervention studies have determined the efficacy of this drug in patients with T2DM. METHODS:The aim of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy and safety of oral verapamil administration in T2DM patients. In this 90-day study, the effects of verapamil on fasting blood sugar (FBS), hemoglobin A1C (HbA1c), and the lipid profile were evaluated and compared with those of the placebo. RESULTS:There was a significant decrease in HbA1c (about 0.5%) in the verapamil group at the end of the intervention period. The effects of verapamil on TXNIP gene expression and glucagon-like peptide-1 receptor (GLP1R) mRNA were compared with those of the placebo (at baseline, after 15 and 30 days, and at the end of the study). During the first month of the study, decreased TXNIP gene expression and increased GLP1R mRNA were associated with the administration of verapamil when compared with the placebo, although the differences were not significant. CONCLUSION:Verapamil can lead to better control of T2DM by reducing TXNIP gene expression and increasing beta cell survival and, possibly, by other mechanisms. CLINICAL TRIAL REGISTRATION:IRCT registration no.: IRCT20180417039339N1 ( https://www.IRCT.ir ).
10.1007/s13300-021-01145-4
Predictors of development of diabetes mellitus in patients with coronary artery disease taking antihypertensive medications (findings from the INternational VErapamil SR-Trandolapril STudy [INVEST]).
Cooper-Dehoff Rhonda,Cohen Jerome D,Bakris George L,Messerli Franz H,Erdine Serap,Hewkin Ann C,Kupfer Stuart,Pepine Carl J,
The American journal of cardiology
Knowledge of predictors of diabetes mellitus (DM) development in patients with coronary artery disease (CAD) who use antihypertensive therapy could contribute to decreasing this adverse metabolic consequence. This is particularly relevant because the standard of care, beta blockers combined with diuretics, may contribute to adverse metabolic risk. The INternational VErapamil SR-trandolapril STudy compared a calcium antagonist-based (verapamil SR) and a beta-blocker-based (atenolol) strategy with trandolapril and/or hydrochlorothiazide added to control blood pressure (BP) in patients with CAD. The 16,176 patients without DM at entry were investigated with regard to newly diagnosed DM during follow-up. Newly diagnosed DM was less frequent in the verapamil SR versus atenolol strategy (7.0% vs 8.2%, hazard ratio 0.85, 95% confidence interval 0.76 to 0.95, p <0.01). Characteristics associated with risk for newly diagnosed DM included United States residence, left ventricular hypertrophy, previous stroke/transient ischemic attack, Hispanic ethnicity, coronary revascularization, hypercholesterolemia, greater body mass index, and higher follow-up systolic BP. Addition of trandolapril to verapamil SR decreased DM risk and addition of hydrochlorothiazide to atenolol increased risk. In conclusion, clinical findings associated with more severe vascular disease and Hispanic ethnicity identify a group at high risk for developing DM, whereas lower on-treatment BP and treatment with verapamil SR-trandolapril attenuated this risk.
10.1016/j.amjcard.2006.04.030
Treatments for diabetes mellitus type II: New perspectives regarding the possible role of calcium and cAMP interaction.
Carvalho Diego Soares,de Almeida Alexandre Aparecido,Borges Aurélio Ferreira,Vannucci Campos Diego
European journal of pharmacology
Diabetes mellitus (DM) is among the top ten causes of death worldwide. It is considered to be one of the major global epidemics of the 21st century, with a significant impact on public health budgets. DM is a metabolic disorder with multiple etiologies. Its pathophysiology is marked by dysfunction of pancreatic β-cells which compromises the synthesis and secretion of insulin along with resistance to insulin action in peripheral tissues (muscle and adipose). Subjects presenting insulin resistance in DM type 2 often also exhibit increased insulin secretion and hyperinsulinemia. Insulin secretion is controlled by several factors such as nutrients, hormones, and neural factors. Exocytosis of insulin granules has, as its main stimulus, increased intracellular calcium ([Ca]i) and it is further amplified by cyclic AMP (cAMP). In the event of this hyperfunction, it is very common for β-cells to go into exhaustion leading to failure or death. Several animal studies have demonstrated pleiotropic effects of L-type Ca channel blockers (CCBs). In animal models of obesity and diabetes, treatment with CCBs promoted restoration of insulin secretion, glycemic control, and reduction of pancreatic β-cell apoptosis. In addition, hypertensive individuals treated with CCBs presented a lower incidence of DM when compared with other antihypertensive agents. In this review, we propose that pharmacological manipulation of the Ca/cAMP interaction system could lead to important targets for pharmacological improvement of insulin secretion in DM type 2.
10.1016/j.ejphar.2018.04.002
Verapamil and beta cell function in adults with recent-onset type 1 diabetes.
Ovalle Fernando,Grimes Tiffany,Xu Guanlan,Patel Anish J,Grayson Truman B,Thielen Lance A,Li Peng,Shalev Anath
Nature medicine
Pancreatic beta cell loss is a key factor in the pathogenesis of type 1 diabetes (T1D), but therapies to halt this process are lacking. We previously reported that the approved antihypertensive calcium-channel blocker verapamil, by decreasing the expression of thioredoxin-interacting protein, promotes the survival of insulin-producing beta cells and reverses diabetes in mouse models. To translate these findings into humans, we conducted a randomized double-blind placebo-controlled phase 2 clinical trial ( NCT02372253 ) to assess the efficacy and safety of oral verapamil added for 12 months to a standard insulin regimen in adult subjects with recent-onset T1D. Verapamil treatment, compared with placebo was well tolerated and associated with an improved mixed-meal-stimulated C-peptide area under the curve, a measure of endogenous beta cell function, at 3 and 12 months (prespecified primary endpoint), as well as with a lower increase in insulin requirements, fewer hypoglycemic events and on-target glycemic control (secondary endpoints). Thus, addition of once-daily oral verapamil may be a safe and effective novel approach to promote endogenous beta cell function and reduce insulin requirements and hypoglycemic episodes in adult individuals with recent-onset T1D.
10.1038/s41591-018-0089-4
Effect of verapamil on bone mass, microstructure and mechanical properties in type 2 diabetes mellitus rats.
BMC musculoskeletal disorders
BACKGROUND:Verapamil was mainly used to treat hypertension, cardiovascular disease, inflammation and improve blood glucose in patients with diabetes, but its effects on bone mass, microstructure and mechanical properties were unclear. This study described the effects of verapamil on bone mass, microstructure, macro and nano mechanical properties in type 2 diabetic rats. METHODS:Rat models of type 2 diabetes were treated with verapamil at doses of 4, 12, 24 and 48 mg/kg/day by gavage respectively, twice a day. After 12 weeks, all rats were sacrificed under general anesthesia. Blood glucose, blood lipid, renal function and biochemical markers of bone metabolism were obtained by serum analysis, Micro-CT scanning was used to assess the microstructure parameters of cancellous bone of femoral head, three-point bending test was used to measure maximum load and elastic modulus of femoral shaft, and nano-indentation tests were used to measure indentation moduli and hardnesses of longitudinal cortical bone in femoral shaft, longitudinal and transverse cancellous bones in femoral head. RESULTS:Compared with T2DM group, transverse indentation moduli of cancellous bones in VER 24 group, longitudinal and transverse indentation moduli and hardnesses of cancellous bones in VER 48 group were significantly increased (p < 0.05). Furthermore, the effects of verapamil on blood glucoses, microstructures and mechanical properties in type 2 diabetic rats were dependent on drug dose. Starting from verapamil dose of 12 mg/kg/day, with dose increasing, the concentrations of P1NP, BMD, BV/TV, Tb. Th, Tb. N, maximum loads, elastic moduli, indentation moduli and hardnesses of femurs in rats in treatment group increased gradually, the concentrations of CTX-1 decreased gradually, but these parameters did not return to the level of the corresponding parameters of normal rats. Verapamil (48 mg/kg/day) had the best therapeutic effect. CONCLUSION:Verapamil treatment (24, 48 mg/kg/day) significantly affected nano mechanical properties of the femurs, and tended to improve bone microstructures and macro mechanical properties of the femurs, which provided guidance for the selection of verapamil dose in the treatment of type 2 diabetic patients.
10.1186/s12891-022-05294-w
Evaluating the antidiabetic effects of R-verapamil in type 1 and type 2 diabetes mellitus mouse models.
Chen Yu-Syuan,Weng Shao-Ju,Chang Shu-Hsien,Li Rou-Ying,Shane Guang-Tzuu,Hsu Jui-Pao,Yeh Sheng-Wen,Chang Ai-Ching,Lee Meng-Ju
PloS one
The global incidence of diabetes mellitus (DM) is increasing. Types 1 and 2 DM are associated with declining β-cell function. Verapamil (50% S-verapamil and 50% R-verapamil) can treat DM by downregulating thioredoxin-interacting protein (TXNIP), which induces islet β-cell apoptosis. However, it may also induce cardiovascular side effects as S-verapamil is negatively inotropic. In contrast, R-verapamil only weakly induces adverse cardiac effects. In this study, we aimed to determine the antidiabetic efficacy and cardiovascular safety of R-verapamil. We examined R- and S-verapamil binding through in vitro studies. Streptozotocin-induced type 1 and db/db type 2 DM mouse models were used to assess the antidiabetic efficacy of verapamil. IL-6, blood glucose (BG), Txnip expression, and β-cells were evaluated in streptozotocin-induced diabetic mice, while body weight, BG, and serum insulin were measured in the db/db mice. In the type 1 DM study, 100 mg/kg/day R-verapamil and racemic verapamil lowered BG, downregulated Txnip expression, and reduced β-cell apoptosis. In the type 2 DM study, the optimal R-verapamil dosage was 60 mg/kg/day and it lowered BG and raised serum insulin. However, efficacy did not increase with R-verapamil dosage. R-verapamil combined with metformin/acarbose improved BG and serum insulin more effectively than metformin/acarbose alone or verapamil combined with acarbose. R-verapamil had weaker cardiovascular side effects than S-verapamil. R-verapamil was 9.0× and 3.4× less effective than S-verapamil at inhibiting atrial inotropy and ileal contractility, respectively. It was also 8.7× weaker than S-verapamil as an agonist of somatostatin receptor type 2 (SSTR2), inhibiting ileal neurogenic contraction. Hence, R-verapamil may be an optimal DM treatment as it is safe, improves glycemic control, and preserves β-cell function both as monotherapy and in combination with metformin or acarbose. R-Verapamil has potential for delaying or arresting DM progression and improving patients' quality of life.
10.1371/journal.pone.0255405
Verapamil ameliorates proximal tubular epithelial cells apoptosis and fibrosis in diabetic kidney.
Song Yi,Guo Feng,Zhao Yanyan,Zhao Lin,Fan Xunjie,Zhang Yuanyuan,Liu Yanling,Qin Guijun
European journal of pharmacology
Diabetic kidney disease (DKD) is a severe complication of diabetes mellitus for which there is still no effective treatment. We previously showed that upregulation of thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of thioredoxin (TRX), accelerates the progression of DKD. In this study, we hypothesized whether verapamil, a calcium channel blocker and an established TXNIP inhibitor, might exert a renal-protective effect on DKD by regulating TXNIP expression. Herein, a systemic pharmacological network study was performed and multiple molecules and pathways targeted by verapamil on DKD were characterized. Furthermore, diabetic mice were induced by streptozotocin (STZ), and verapamil (100 mg/kg/day) or saline was intraperitoneally injected into the mice. After 16 weeks, mice were analyzed for blood glucose, blood pressure, and functional parameters followed by sacrifice and evaluation of renal tubular injury, alterations in TXNIP, apoptosis and fibrosis markers. Additionally, the effects of treatment with verapamil (50 μM, 100 μM, 150 μM) under high glucose conditions on the expression of TXNIP and signaling pathway components in proximal tubular epithelial cells (PTEC, HK-2 cells) were explored. According to these findings, we conclude that verapamil might serve as a potential agent for the prevention and treatment of DKD.
10.1016/j.ejphar.2021.174552
Verapamil: prevention and treatment of cardio-renal syndromes in diabetic hypertensive patients?
Lido P,Romanello D,Tesauro M,Bei A,Perrone M A,Palazzetti D,Noce A,Di Lullo L,Calò L,Cice G
European review for medical and pharmacological sciences
Patients with diabetes mellitus (DM) often present other chronic comorbidities including arterial hypertension (AH), chronic kidney disease (CKD), ischemic heart disease (IHD) and heart failure with preserved ejection fraction (HFpEF). The frequent association of the latter conditions is considered part of the spectrum of cardio-renal syndromes (CRS), a group of disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. Verapamil is a non-dihydropyridine calcium channel blocker (CCB) widely used in the treatment of hypertension, chronic stable angina, secondary prevention of reinfarction, paroxysmal supra-ventricular tachycardia and for rate control in atrial fibrillation/flutter. In addition to its antihypertensive and anti-ischemic actions verapamil exerts favorable effects also on glycemic control, proteinuric diabetic nephropathy, left ventricular diastolic dysfunction and sympathetic nervous system overactivity which may potentially benefit patients with DM and CRS. In this narrative review, we summarize the current evidence on the potential role of verapamil in the prevention and treatment of CRS in diabetic hypertensive patients.
10.26355/eurrev_202203_28217
Exploratory study reveals far reaching systemic and cellular effects of verapamil treatment in subjects with type 1 diabetes.
Nature communications
Currently, no oral medications are available for type 1 diabetes (T1D). While our recent randomized placebo-controlled T1D trial revealed that oral verapamil had short-term beneficial effects, their duration and underlying mechanisms remained elusive. Now, our global T1D serum proteomics analysis identified chromogranin A (CHGA), a T1D-autoantigen, as the top protein altered by verapamil and as a potential therapeutic marker and revealed that verapamil normalizes serum CHGA levels and reverses T1D-induced elevations in circulating proinflammatory T-follicular-helper cell markers. RNA-sequencing further confirmed that verapamil regulates the thioredoxin system and promotes an anti-oxidative, anti-apoptotic and immunomodulatory gene expression profile in human islets. Moreover, continuous use of oral verapamil delayed T1D progression, promoted endogenous beta-cell function and lowered insulin requirements and serum CHGA levels for at least 2 years and these benefits were lost upon discontinuation. Thus, the current studies provide crucial mechanistic and clinical insight into the beneficial effects of verapamil in T1D.
10.1038/s41467-022-28826-3
Verapamil Attenuated Prediabetic Neuropathy in High-Fat Diet-Fed Mice through Inhibiting TXNIP-Mediated Apoptosis and Inflammation.
Xu Lingling,Lin Xiaopu,Guan Meiping,Zeng Yanmei,Liu Yingshan
Oxidative medicine and cellular longevity
Diabetic neuropathy (DN) is a common and severe complication of diabetes mellitus. There is still a lack of an effective treatment to DN because of its complex pathogenesis. Thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of thioredoxin, has been shown to be associated with diabetic retinopathy and nephropathy. Herein, we aim to investigate the role of TXNIP in prediabetic neuropathy and therapeutic potential of verapamil which has been shown to inhibit TXNIP expression. The effects of mediating TXNIP on prediabetic neuropathy and its exact mechanism were performed using high-fat diet- (HFD-) induced diabetic mice and palmitate-treated neurons. Our results showed that TXNIP upregulation is associated with prediabetic neuropathy in HFD-fed mice. TXNIP knockdown improved DN in HFD-induced prediabetic mice. Mechanistically, increased TXNIP in dorsal root ganglion is transferred into the cytoplasm and shuttled to the mitochondria. In cytoplasm, TXNIP binding to TRX1 results in the increased oxidative stress and inflammation. In mitochondria, TXNIP binding to TRX2 induced mitochondria dysfunction and apoptosis. TXNIP isolated from TRX2 then shuttles to the cytoplasm and binds to NLRP3, resulting in further increased TXNIP-NLRP3 complex, which induced the release of IL-1 and the development of inflammation. Thus, apoptosis and inflammation of dorsal root ganglion neuron eventually cause neural dysfunction. In addition, we also showed that verapamil, a known inhibitor of calcium channels, improved prediabetic neuropathy in the HFD-fed mice by inhibiting the upregulation of TXNIP. Our finding suggests that TXNIP might be a potential target for the treatment of neuropathy in prediabetic patients with dyslipidemia.
10.1155/2019/1896041
The β-cell effect of verapamil-based treatment in patients with type 2 diabetes: a systematic review.
Carnovale Carla,Dassano Alice,Mosini Giulia,Mazhar Faizan,D'Addio Francesca,Pozzi Marco,Radice Sonia,Fiorina Paolo,Clementi Emilio
Acta diabetologica
AIMS:The possibility that verapamil has new beneficial effects in diabetic patients in terms of an improvement in glycometabolic control has been put forward recently in several studies. However, to date the issue is still under debate. We conducted the first systematic review examining the impact of verapamil-based treatment on glycometabolic outcomes, in type 2 diabetes (T2D) patients. METHODS:We searched the PubMed, MEDLINE, Embase, Cochrane and ClinicalTrials.gov up to 9 October 2018, for all studies evaluating whether verapamil-based treatment is associated with changes in glycated haemoglobin (HbA1c), fasting plasma glucose levels, glucose and C-peptide areas from baseline in humans, without restrictions for study type. RESULTS:Plasma glucose levels were lowered significantly by verapamil-based treatment in patients with T2D (mean change - 13 ± 5.29; P = 0.049); HbA1c values were instead not affected by the drug (mean change - 0.10 ± 0.12; P = 0.453). In five studies, groups exposed to verapamil achieved lower value of glycometabolic outcomes: comparison with values recorded in control groups showed a significant difference, in terms of both HbA1c and plasma glucose levels. CONCLUSIONS:Despite the fact that plasma glucose levels were lowered significantly by verapamil-based treatment in patients with T2D (the HbA1c values were not affected by the drug), the clinical significance of the glycometabolic response induced by verapamil-based treatment remains unclear due to the high variety of sample size and type of studies presently available. Further experimental and clinical trials are needed to clarify unambiguously the role of verapamil in metabolic control.
10.1007/s00592-019-01370-1