Disruption of Glucose Homeostasis in Prey: Combinatorial Use of Weaponized Mimetics of Somatostatin and Insulin by a Fish-Hunting Cone Snail

Venomous animals have evolved diverse molecular mechanisms to incapacitate prey and defend against predators. The majority of venom components characterized to date disrupt the nervous, locomotor, and cardiovascular system or causes tissue damage and degradation1. The discovery that certain species of fish-hunting cone snail use weaponized insulins to induce hypoglycemic shock in prey provided an unusual example for the use of toxins that target glucose homeostasis2. Here, we show that, in addition to insulins, the deadly fish hunter, Conus geographus, uses a selective agonist of the somatostatin receptor 2 (SSTR2) that potently blocks the release of the insulin-counteracting hormone glucagon, thereby exacerbating insulin-induced hypoglycemia in prey. The native toxin, Consomatin nG1, exists in several proteoforms that contain a minimized vertebrate somatostatin-like core motif connected to a heavily glycosylated N-terminal region. We demonstrate that the toxin’s N-terminal tail aligns with a glycosylated somatostatin peptide previously identified from fish pancreas and plays an important role in activating the fish SSTR2. Collectively, these findings provide a stunning example of chemical mimicry, highlight the combinatorial nature of venom components, and establish glucose homeostasis as an effective target for prey capture.

有毒动物演化出多样的分子机制，用以使猎物丧失行动能力并抵御捕食者。迄今已被表征的绝大多数毒液组分，可破坏猎物的神经、运动与心血管系统，或引发组织损伤与降解[1]。此前有研究发现，部分猎食性芋螺会借助武器化胰岛素使猎物产生低血糖休克，这为靶向葡萄糖稳态的毒素应用提供了一个罕见案例[2]。本研究表明，除胰岛素外，致命的猎食性芋螺物种地理芋螺（Conus geographus）还会分泌一种生长抑素受体2（somatostatin receptor 2, SSTR2）的选择性激动剂，该激动剂可强效阻断拮抗胰岛素的胰高血糖素的释放，进而加剧猎物体内胰岛素诱导的低血糖症状。天然毒素Consomatin nG1存在多种蛋白质变体，其包含一个简化的脊椎动物生长抑素样核心基序，并连接至一个高度糖基化的N端区域。我们证实，该毒素的N端尾巴与此前从鱼胰腺中鉴定出的糖基化生长抑素肽序列高度匹配，且在激活鱼类SSTR2的过程中发挥关键作用。综上，这些发现为化学拟态提供了极具代表性的案例，凸显了毒液组分的组合特性，并确立了葡萄糖稳态作为猎食的有效靶向靶点。