Objectives: Insulin resistance and progressive decline in functional β-cell mass are two key factors for developing type 2 diabetes (T2D), which is largely driven by overweight and obesity, a significant obstacle for effective metabolic control in many patients with T2D. We recently found that elenolic acid (EA), a small molecule derived from olive can directly stimulate intestinal GLP-1 and peptide YY (PYY) secretion from L-cells and improves obesity and hyperglycemia in diet-induced obese (DIO) mice. In this study, we further explored the underlying mechanism and compared its metabolically beneficial efficacy with that of metformin.
Methods: HepG2 cells, primary human myotubes or CHO-cells overexpressed with insulin receptor were incubated with EA, insulin or both to examine the activation of insulin signaling pathway. The metabolic and anti-hyperglycemic effects of EA, metformin or both in vivo were assessed using mouse models of T2D.
Results: Here, we report that EA is a novel multi-target agent that also acts like insulin to activate Akt phosphorylation in insulin sensitive tissues and greatly stimulates glucose uptake in human skeletal muscle cells. In addition, EA directly suppresses glucose production in liver cells. Oral administration of EA completely reversed diet-induced hyperglycemia, liver weight gain, hepatic steatosis, triglyceride accumulation, and elevated alanine aminotransferase levels in obese mice. Similarly, EA also exerts potent anti-diabetic and anti-obesity actions in db/db mice, and its blood glucose-lowering effect is comparable with that of liraglutide but is better than that of metformin in db/db mice. In addition, EA significantly reduced food intake and promoted weight loss, which are associated with improved circulating levels of PYY and GLP-1 and the downregulation of agouti-related peptide in the hypothalamus.
Conclusions: These results demonstrate for the first time that EA could be a novel therapeutic agent for treating both obesity and T2D.
Funding Sources: The work was supported by National Institutes of Health (R01DK134401-01A1), diabetes action research and education foundation, and SJ Ritchey Research Grants (to D. Liu).
https://nutrition2024.eventscribe.net/index.asp?presTarget=2742404
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