Olive-derived elenolic acid surpasses metformin and rivals liraglutide in managing blood glucose and obesity in a mouse model of type 2 diabetes.

Abstract

Obesity and type 2 diabetes (T2D) are among the most common metabolic diseases that are associated with increased risk of noncommunicable diseases globally. Elenolic acid (EA), derived from olives, was shown to possess potent acute effects on obesity and diabetes that were associated with increased gut hormone secretion. Here, we investigate the long-term effects of EA in two mouse models of obesity and diabetes. In diet-induced obese mice, oral administration of EA (50 mg/kg/day) for 7 weeks, normalized fasting blood glucose (from 176.6±4.5 mg/dL to 120.8±4.0 mg/dL), and restored glucose tolerance and insulin sensitivity to levels comparable to lean mice. These improvements were associated with increased circulating peptide YY and gastric inhibitory polypeptide concentrations, downregulation of hypothalamic agouti-related peptide (AgRP), reduced food intake (∼20%), and weight loss. Acutely, EA slowed gastric emptying rate by about 50% and increased glucagon like peptide-1 levels. In db/db mice, EA reduced non-fasting blood glucose from 459.0±51.1 mg/dL to 208.9±10.3 mg/dL, an effect comparable to liraglutide and greater than metformin. EA also lowered fasting blood glucose levels similar to liraglutide and significantly below those observed with metformin. Moreover, EA-treated mice exhibited less weight gain than those receiving either drug. These effects were accompanied by decreased AgRP expression and increased c-fos activation. These results suggest that EA is a novel, multi-target agent with therapeutic potential for treating T2D and obesity.