Cardiotoxin‐I: An Unexpectedly Potent Insulinotropic Agent

Abstract

Insulin secretion from pancreatic β-cells is a complex process, involving the integration and interaction of multiple external and internal stimuli, in which glucose plays a major role. Understanding the physiology leading to insulin release is a crucial step toward the identification of new targets. In this study, we evaluated the presence of insulinotropic metabolites in Naja kaouthia snake venom. Only one fraction, identified as cardiotoxin-I (CTX-I) was able to induce insulin secretion from INS-1E cells without affecting cell viability and integrity, as assessed by MTT and LDH assays. Interestingly, CTX-I was also able to stimulate insulin secretion from INS-1E cells even in the absence of glucose. Although cardiotoxins have been characterized as potent hemolytic agents and vasoconstrictors, CTX-I was unable to induce direct hemolysis of human erythrocytes or to induce potent vasoconstriction. As such, this newly identified insulin-releasing toxin will surely enrich the pool of existing tools to study β-cell physiology or even open a new therapeutic avenue.

Peptide Fraction pOh2 Exerts Antiadipogenic Activity through Inhibition of C/EBP-αand PPAR-γExpression in 3T3-L1 Adipocytes

“…Peptide fraction 2, which showed major adipogenesis-inhibiting activity, was further purified by analytical HPLC. Absorbance was monitored at 220 nm [33]. …”

Multifunctional Toxins in Snake Venoms and Therapeutic Implications: From Pain to Hemorrhage and Necrosis

“…Despite the shared three-finger fold, the 3FTXs have diverse targets and biological activities. For example, αneurotoxins inhibit muscle acetylcholine receptors (nAChR) (Changeux, 1990), κ-neurotoxins inhibits neuronal AChR (Grant and Chiappinelli, 1985), muscarinic toxins inhibit muscarinic receptors (Marquer et al, 2011), fasciculins inhibit acetylcholinesterase (AChE) (Marchot et al, 1998), calciseptine modulates L-type calcium channels (De Weille et al, 1991;Garcia et al, 2001), cardiotoxins interact non-specifically with phospholipids (Konshina et al, 2017), or induce insulin secretion (Nguyen et al, 2012), mambin interacts with platelet receptors (McDowell et al, 1992), exactin inhibits Factor X (Girish and Kini, 2016), β-cardiotoxins inhibit β-adrenoreceptors (Rajagopalan et al, 2007), MTα inhibits α-adrenoreceptors (Koivula et al, 2010), mambalgins inhibit ASIC channels (Diochot et al, 2012), Tx7335 that activates potassium channels (Rivera- Torres et al, 2016) and calliotoxin activates voltagegated sodium channels (Na V ) (Yang et al, 2016). Their toxic biological effects include flaccid or spastic paralysis due to the inhibition of AChE and ACh receptors (Grant and Chiappinelli, 1985;Changeux, 1990;Marchot et al, 1998;Marquer et al, 2011), and activation of Na V 1.4 (Yang et al, 2016) and L-type calcium channels (Garcia et al, 2001) in the periphery, necrosis through the action of cardiotoxins (cytotoxins) (Konshina et al, 2017), alteration of the cardiac rate through modulation of αand β-adrenoreceptors (Rajagopalan et al, 2007;Koivula et al, 2010), and altered homeostasis through inhibition of platelet aggregation (McDowell et al, 1992) and Factor X (Girish and Kini, 2016).…”

Revisiting the Therapeutic Potential of Bothrops jararaca Venom: Screening for Novel Activities Using Connectivity Mapping

“…“Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both” [ 186 ]. Insulin secretion is modulated by the action of different hormonal and neural stimuli [ 95 , 187 , 188 ], such as through the activation of G-protein-coupled receptors [ 189 ], but also through modulation of ion channel activity [ 190 , 191 ].…”

“…It is well known that toxins from venomous animals are able to target a great diversity of G-protein-coupled receptors, such as glucagon receptor family as well as affect membrane excitability through ionic channels modulation [ 95 , 134 , 192 ]. Thus, the identification of antidiabetic activity was not surprising since insulinotropic properties of snake venoms have already been reported for some components such as PLA 2 , serine endopeptidases, disintegrins [ 96 ], crotamine [ 97 , 193 ], and cardiotoxin [ 95 ]. In the case of PLA 2 , the increase in insulin secretion is likely related to cytosolic Ca 2+ [ 98 , 99 , 100 ].…”