Calcium channel blocker use is associated with lower fasting serum glucose among adults with diabetes from the REGARDS study

Hafez

et al. 2018

Endocrine Regulations

Objective. We aimed to assess the protective role of verapamil, L-type calcium channel blockers, against early lung damage in diabetic rats. Lung injury has recently been recognized as a consequent complication of diabetes mellitus. Hyperglycemia induces inflammatory changes in lung tissue early in the disease. Methods. Twenty four adult male rats were grouped into control, diabetic, diabetic treated with verapamil, and verapamil control. Streptozotocin (STZ) was used to induce diabetes. Oxidative parameters and antioxidative mechanisms were assessed in lung homogenate. Tumor necrosis factor alpha (TNFα) protein was measured as a pro-inflammatory mediator. Signal transducer and activator of transcription 3 (STAT3) gene expression and nuclear erythroid factor 2 (Nrf2) immunoexpression were screened. Results. The lung showed oxidative damage and inflammatory infiltration in STZ diabetic rats early at 2 weeks. The parameters significantly improved in lung tissue treated with verapamil. Histopathology of the lung tissue confirmed the results. Inhibition of STAT3/TNFα pathway was involved in the protection offered by verapamil. Activation of Nrf2 together with an increasing antioxidant capacity of diabetic lung significantly ameliorates the injury induced by diabetes. Conclusions. Verapamil afforded protection in diabetic lung injury. The protection was mediated by the anti-inflammatory and antioxidant effects of verapamil.

mentioning

confidence: 89%

STAT3 and Nrf2 pathways modulate the protective effect of verapamil on lung injury of diabetic rats

Hafez

et al. 2018

Endocrine Regulations

“…The idea is based on the assumption that newly diagnosed T1DM patients do not have comprehensive β-cell loss and the residual β-cells can be saved from further impairment by reducing the levels of TXNIP. This view was reinforced by a recent study in which diabetic subjects that received verapamil had fasting serum glucose levels significantly lower than their peers who were not receiving verapamil [ 98 ]. Remarkably, verapamil was very effective in subjects with T1DM or late-stage T2DM (both conditions characterized by β-cell death) but no effect was seen in subjects with early-stage T2DM (characterized by insulin resistance but no beta cell loss) [ 98 ].…”

Section: Txnip Is a Potential Therapeutic Targetmentioning

confidence: 99%

“…This view was reinforced by a recent study in which diabetic subjects that received verapamil had fasting serum glucose levels significantly lower than their peers who were not receiving verapamil [ 98 ]. Remarkably, verapamil was very effective in subjects with T1DM or late-stage T2DM (both conditions characterized by β-cell death) but no effect was seen in subjects with early-stage T2DM (characterized by insulin resistance but no beta cell loss) [ 98 ]. This comes as a surprise because TXNIP is a significant player in regulating insulin sensitivity of peripheral tissues and reduced insulin sensitivity is hallmark of T2DM.…”

Section: Txnip Is a Potential Therapeutic Targetmentioning

confidence: 99%

TXNIP in Metabolic Regulation: Physiological Role and Therapeutic Outlook

Alhawiti

Mahri

Aziz

et al. 2017

CDT

174

160

Background & Objective: Thioredoxin-interacting protein (TXNIP) also known as thioredoxin binding protein-2 is a ubiquitously expressed protein that interacts and negatively regulates expression and function of Thioredoxin (TXN). Over the last few years, TXNIP has attracted considerable attention due to its wide-ranging functions impacting several aspects of energy metabolism. TXNIP acts as an important regulator of glucose and lipid metabolism through pleiotropic actions including regulation of β-cell function, hepatic glucose production, peripheral glucose uptake, adipogenesis, and substrate utilization. Overexpression of TXNIP in animal models has been shown to induce apoptosis of pancreatic β-cells, reduce insulin sensitivity in peripheral tissues like skeletal muscle and adipose, and decrease energy expenditure. On the contrary, TXNIP deficient animals are protected from diet induced insulin resistance and type 2 diabetes.Summary:Consequently, targeting TXNIP is thought to offer novel therapeutic opportunity and TXNIP inhibitors have the potential to become a powerful therapeutic tool for the treatment of diabetes mellitus. Here we summarize the current state of our understanding of TXNIP biology, highlight its role in metabolic regulation and raise critical questions that could help future research to exploit TXNIP as a therapeutic target.

“…In addition, verapamil was also recently proposed to act on thioredoxin-interacting protein (TNIXP), thereby rescuing pancreatic b cell degradation in mouse models of diabetes [44]. The proposed utilization of verapamil in diabetes is currently in phase II of clinical trials (Clin-icalTrials.gov Identifier: NCT02372253) and related population studies revealed that in blood serum of verapamil-treated diabetics glucose levels are reduced in comparison to nonverapamil users with diabetes [45]. In light of our studies, an examination of the role of autophagy in this context would certainly be worthwhile, especially since autophagy has been shown to contribute to b-cell viability [46].…”

Section: Discussionmentioning

confidence: 99%

Verapamil treatment induces cytoprotective autophagy by modulating cellular metabolism

et al. 2017

Verapamil, an L-type calcium channel blocker, has been used successfully to treat cardiovascular diseases. Interestingly, we have recently shown that treatment of cancer cells with verapamil causes an effect on autophagy. As autophagy is known to modulate chemotherapy responses, this prompted us to explore the impact of verapamil on autophagy and cell viability in greater detail. We report here that verapamil causes an induction of autophagic flux in a number or tumor cells and immortalized normal cells. Moreover, we found that inhibition of autophagy in COLO 205 cells, via treatment with the chloroquine (CQ) or by CRISPR/Cas9-mediated disruption of the autophagy genes Atg7 and Atg5, causes an upregulation of apoptotic markers in response to verapamil. In search of a mechanism for this effect and because autophagy can often mitigate metabolic stress, we examined the impact of verapamil on cellular metabolism. This revealed that in normal prostate cells, verapamil diminishes glucose and glycolytic intermediate levels leading to adenosine 5'-triphosphate (ATP) depletion. In contrast, in COLO 205 cells it enhances aerobic glycolysis and maintains ATP. Importantly, we found that the autophagic response in these cells is related to the activity of l-lactate dehydrogenase A (LDHA, EC 1.1.1.27), as inhibition of LDHA reduces both basal and verapamil-induced autophagy and consequently decreases cell viability. In summary, these findings not only identify a novel mechanism of cytoprotective autophagy induction but they also highlight the potential of using verapamil together with inhibitors of autophagy for the treatment of malignant disease. ENZYMES: l-lactate dehydrogenase (LDHA, EC 1.1.1.27).