Abstract
The present study investigated the influence of epigallocatechin-3-gallate (EGCG) and its autoxidation products on insulin sensitivity in db/db mice. Compared to EGCG, autoxidation products of EGCG alleviated diabetic symptoms by suppressing the deleterious renal axis of the renin-angiotensin system (RAS), activating the beneficial hepatic axis of RAS, and downregulating hepatic and renal SELENOP and TXNIP. A molecular weight fraction study demonstrated that polymeric oxidation products were of essential importance. The mechanism of action involved coating polymeric oxidation products on the cell surface to protect against cholesterol loading, which induces abnormal RAS. Moreover, polymeric oxidation products could regulate RAS and SELENOP at doses that were far below cytotoxicity. The proof-of-principal demonstrations of EGCG-derived polymeric oxidation products open a new avenue for discovering highly active polymeric oxidation products based on the oxidation of naturally occurring polyphenols to manage diabetes and other diseases involving abnormal RAS.