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

Summary

This mechanistic study shows that activating atypical PKC in the intestine drives GLUT1-mediated uptake of circulating glucose and its secretion into the lumen, recapitulating intestinal glucose excretion. Pharmacologic activation with prostratin replicated the effect without oncogenic proliferation, nominating the aPKC/GLUT1 axis as a therapeutic target for diabetes and weight loss.

Key Findings

• PKC activation reproduced transcriptomic signatures of intestinal glucose excretion.
• Atypical PKC (aPKC) facilitated GLUT1-mediated intestinal glucose excretion without inducing proliferative signals.
• Genetic activation of intestinal aPKC increased serum glucose uptake into tissue and excretion into the lumen.
• Prostratin activated aPKC and induced intestinal glucose excretion, highlighting a druggable pathway.

Clinical Implications

Targeted activation of intestinal aPKC/GLUT1 could be explored to lower glycemia and body weight; however, human safety, dose, and long-term metabolic effects require rigorous clinical evaluation.

Limitations

• Entirely preclinical with no human intervention data.
• Long-term metabolic, microbiome, and safety consequences of sustained intestinal glucose excretion are unknown.

Future Directions

First-in-human studies of intestinal aPKC modulators (e.g., prostratin analogs), dose–response and safety profiling, and biomarker development to monitor intestinal glucose flux.