Atypical protein kinase C activation drives intestinal glucose excretion in diabetes mellitus.

Abstract

Intestinal glucose excretion, defined as increased intestinal serum glucose uptake and secretion into the lumen, influences bariatric surgery-associated glycaemic control. Here, we investigate molecular mechanisms that activate intestinal glucose excretion. We evaluate altered transcriptomes in variable intestinal glucose excretion models and big data-based drug discovery systems. We show that protein kinase C (PKC) activation mimics transcriptome alterations observed during intestinal glucose excretion. Among PKC subfamilies, atypical PKC (aPKC) facilitates glucose transporter 1 (GLUT1)-mediated intestinal glucose excretion without inducing oncogenic proliferation. Intestinal aPKC activation via transposon expression vector induces serum glucose uptake into intestinal tissues and excretion into the lumen. Prostratin, a non-tumorigenic phorbol ester, activates aPKC and induces a similar effect on intestinal glucose excretion. We identify the prostratin and aPKC/GLUT1 signalling pathways as putative targets for treating diabetes, providing insights into the future development of antidiabetic and weight-loss drugs.