Mimicking gastric bypass glucotonic effect: the role of atypical PKC activation and GLUT1

Bariatric surgery has demonstrated a significant therapeutic impact in reducing obesity and achieving euglycemia in diabetic patientspatients with diabetes. We previously demonstrated that iIntestinal glucotonic transformation, defined as increased intestinal serum glucose uptake and secretion into the lumen, has anplays a vital important role in bypass surgeryies. Altered transcriptomes were evaluated in variable intestinal glucotonic models and big-data artificial intelligence AI-based drug discovery systems. We found noted that protein kinase C (PKC) activation mimics the intestinal transcriptome changes alterations observed in during intestinal glucotonic transformation. Among PKC subfamilies, atypical PKC promotes GLUT1- mediated intestinal glucotonic transformation without inducing oncogenic proliferation. Intestinal aPKC activation through via the transposon expression vector induces serum glucose uptake into intestinal tissue and excretion into the lumeinal space. . Prostratin, a non-tumorigenic phorbol ester, was found observed to activate aPKC and induce a similar glucotonic effect. Taken together, our study results highlightCollectively, we identified a a new chemical compound and target molecular pathways that may provide a distinct and effective approach to to treating diabetes .减重代谢手术（Bariatric surgery）已被证实可显著改善肥胖症状，并帮助糖尿病患者实现血糖正常化。我们此前的研究表明，肠糖稳态转化（intestinal glucotonic transformation）——即肠道血清葡萄糖摄取增加并向肠腔分泌的过程——在减重旁路手术中发挥关键作用。我们在多种肠糖稳态转化模型中评估了转录组变化，并结合基于大数据人工智能的药物发现系统开展分析。研究发现，蛋白激酶C（Protein Kinase C, PKC）的激活可模拟肠糖稳态转化过程中观察到的肠道转录组改变。在PKC亚家族中，非典型PKC（atypical PKC, aPKC）可介导GLUT1依赖的肠糖稳态转化，且不会引发致癌性增殖。通过转座子表达载体激活肠道aPKC，可诱导肠道组织摄取血清葡萄糖并将其排泄至肠腔。普罗司他汀（Prostratin）作为一种非致瘤性佛波酯，被证实可激活aPKC并诱导相似的糖稳态转化效应。综上，本研究鉴定出一种新型化合物及潜在分子通路，可为糖尿病的治疗提供全新且有效的策略。