Plumieride ameliorates type 2 diabetes and colitis by regulating intestinal functions

Plumeria rubra L. has been traditionally used to alleviate symptoms of intestinal disorders. Plumieride (PR), a major iridoid glycoside isolated from Plumeria rubra L., possesses a rare spirocyclic structure featuring a 5/5-spiro junction annulated to a six-membered ring. This unique structure sets it apart within the iridoid group and is linked to a variety of pharmacological activities. However, there is limited research on the mechanisms underlying PR's activity.

Our work aims at elucidating PR's therapeutic effects and the mechanisms mediating its treatment of intestinal-related diseases, with particular emphasis on how its pharmacodynamic properties support its ethnopharmacological use.

PR was extracted from Plumeria rubra L., and the rest of the derivatives, including plumieride aglycone (PR-a), were modified based on PR. All of the compounds were characterized using nuclear magnetic resonance (NMR) spectroscopy. In vivo, the pharmacokinetic assessment was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). db/db diabetic mice were employed to assess PR's hypoglycemic effects, while mice exhibiting colitis resulting from dextran sulfate sodium (DSS) treatment were used to evaluate its anti-inflammatory properties. In vitro, the specific mechanisms of PR-a were investigated using intestinal L cells (STC-1) and bone marrow-derived macrophages (BMDMs), along with RT-qPCR and Western blot analysis.

Pharmacokinetic analysis indicated that PR accumulated in the gut after oral administration, providing a material basis for its direct action on intestinal targets. PR treatment effectively alleviated hyperglycemia in db/db mice, partly through stimulating intestinal glucagon-like peptide-1 (GLP-1) secretion, and attenuated DSS-induced colitis by reducing intestinal oxidative stress and inflammatory signaling. PR-a, a metabolite of PR, was suggested to be the active form modulating the intestinal function through stimulating calcium signaling in intestinal endocrine cells and regulation of the nuclear factor erythroid 2-related factor 2 (NRF2) and NRF2-independent NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathways in macrophages. Additionally, 26 structurally diverse derivatives of PR were synthesized to explore structure-activity relationships, identify bioactive congeners, and optimize pharmacological potency.

PR ameliorates type 2 diabetes (T2D) and colitis through gut-related mechanisms involving endocrine regulation, anti-oxidative effects, and anti-inflammatory actions. By mechanistically linking the gut accumulation of PR and the activity of its potential active in vivo metabolite PR-a to the traditional uses of Plumeria rubra, this study suggests PR and PR-a as promising candidates for treating intestinal function-related disorders pending further validation of their efficacy and safety, providing a theoretical basis for their structural modification, development, and application.