Betulinic acid enhances glucose uptake in 3T3L1 adipocytes after long term treatment

The metabolic syndrome including hyperglycaemia and insulin resistance is on the rise worldwide and consequently also cardiovascular diseases and Diabetes Mellitus Type 2. Currently used drugs for these indications are effective, but possess side effects when used chronically. Nature could provide a variety of compounds with undiscovered potential to treat and prevent these disorders.

In this study, we tested betulinic acid (BA), a naturally occurring pentacyclic triterpenoid, in two diabetes-related assays, namely inhibition of the Protein Tyrosine Phosphatase 1B (PTP1B) in vitro and 2-deoxy-D-glucose (3H-DOG) uptake in 3T3L1 adipocytes.

We found no inhibition of PTP1B activity by BA despite its close structural similarity to ursolic acid, a known natural PTP1B inhibitor. However, in differentiated 3T3L1 adipocytes, BA (10µM) elicited a 1.8-fold increase of the basal glucose (3H-DOG) uptake rate after 48 hours of treatment. The observed increase in glucose uptake was further enhanced by insulin stimulation and not accompanied by a decrease in cell viability as evident by unaltered cell morphology under the microscope and lack of procaspase 3 cleavage shown by immunoblots. Interestingly, incubation of RAW264.7 macrophages and immortalized human umbilical vein endothelial cells (HUVECs) with 10µM BA also increased their basal glucose uptake rate approximately 1.4-fold and 1.7-fold, respectively.

Given the vast number of so far reported anti-fungal, anti-viral, anti-bacterial and anti-cancer properties of BA [1], our data indicate that BA may be successfully repurposed also for metabolic disorders (hyperglycemia), and warrant further investigations concerning the underlying mode of action.

Keywords: adipocytes, hyperglycemia, triterpenoids, metabolic syndrome

References: [1] Mullauer FB et al. (2010) Anticancer Drugs 21(3):215–227