Short-chain fatty acids (SCFAs), such as propionic and
butyric acids have been touted as potential therapeutic interventions that can ameliorate diabetic pathogenesis. However, SCFAs are low-molecular-weight (LMW) compounds that have limited clinical use due to unfavorable pharmacokinetics, off-target effects, poor palatability and unpleasant odor. Hence, to improve the therapeutic utilization of SCFAs, the
enzyme metabolizable block copolymers, [poly(
ethylene glycol)-b-poly(vinyl
ester)s], possessing
propionate and
butyrate esters were synthesized, which formed stable nanoparticles by self-assembling under physiological conditions. In this study, the therapeutic efficacy of
propionic acid- and
butyric acid-based self-assembling nanoparticles (PNP/BNP) was evaluated in a mouse model of
type 2 diabetes mellitus through ad libitum drinking. The conventional
antidiabetic drug,
exenatide- and BNP-treated mice showed the highest
glucose tolerance, whereas LMW SCFAs remained ineffective in normalizing
glucose homeostasis. The better efficacy of BNP over the LMW SCFAs was attributable to (i) higher consumption of BNP than the LMW SCFAs by the mice (good palatability and odorless), (ii) prolonged residence time of BNP (48 h) in the gastro-intestinal tract (muco-adhesion) contributing to intestinal
enzyme-mediated sustained release of
butyric acid, and (iii) negligible off-target effects (no abrupt rise in the bloodstream). The aforementioned data suggest that SCFA-based nanoparticles are more potential therapeutic interventions than LMW SCFAs for
metabolic diseases such as diabetes.