The prevalence of type 2 diabetes (T2D) has been rising dramatically in many countries around the world. The main signatures of T2D are insulin resistance and dysfunction of β-cells. While there are several pharmaceutical therapies for T2D, no effective treatment is available for reversing the functional decline of pancreatic β-cells in T2D patients. It has been well recognized that glucagon-like peptide-1 (GLP-1), which is an incretin hormone secreted from intestinal L-cells, plays a vital role in regulating glycemic homeostasis via potentiating glucose-stimulated insulin secretion and promoting β-cell function. We found that genipin, a natural compound from Elli, can directly target intestinal L-cells, leading to the secretion of GLP-1. Incubation of the cells with genipin elicited a rapid increase in intracellular Ca2+. Inhibition of PLC ablated genipin-stimulated Ca2+ increase and GLP-1 secretion, suggesting that genipin-induced GLP-1 release from cells is dependent on the PLC/Ca2+ pathway. In vivo, acute administration of genipin stimulated GLP-1 secretion in mice. Chronically, treatment with genipin via oral gavage at 50 mg/kg/day for 6 weeks reversed hyperglycemia and insulin resistance in high-fat-diet (HFD)-induced obese mice. Moreover, genipin alleviated the impaired lipid metabolism and decreased lipid accumulation in the liver of obese mice. These results suggest that naturally occurring genipin might potentially be a novel agent for the treatment of T2D and diet-induced fatty liver disease.

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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. Thus, agents that simultaneously ameliorate obesity and act on multiple pathophysiological components could be more effective for treating T2D. Here, we report that elenolic acid (EA), a phytochemical, is such a dual-action agent. we show that EA dose-dependently stimulates GLP-1 secretion in mouse clonal L-cells and isolated mouse ileum crypts. In addition, EA induces L-cells to secrete peptide YY (PYY). EA induces a rapid increase in intracellular [Ca2+]i and the production of inositol trisphosphate in L-cells, indicating that EA activates phospholipase C (PLC)-mediated signaling. Consistently, inhibition of (PLC) or Gαq ablates EA-stimulated increase of [Ca2+]i and GLP-1 secretion. In vivo, a single dose of EA acutely stimulates GLP-1 and PYY secretion in mice, accompanied with an improved glucose tolerance and insulin levels. Oral administration of EA at a dose of 50 mg/kg/day for 2 weeks normalized the fasting blood glucose and restored glucose tolerance in high-fat diet-induced obese (DIO) mice to levels that were comparable to chow-fed mice. In addition, EA suppresses appetite, reduces food intake, promotes weight loss, and reverses perturbated metabolic variables in obese mice. These results suggest that EA could be a dual-action agent as an alternative or adjuvant treatment for both T2D and obesity.

Insulin resistance and progressive decline in functional β-cell mass are two key factors for developing T2D, which is largely driven by overweight and obesity, a significant obstacle for effective metabolic control in many patients with T2D. Thus, agents that simultaneously ameliorate obesity and promote insulin sensitivity and β-cell function could be more effective for treating T2D. Here, we report that elenolic acid (EA), a small molecule, is such a dual-action agent. Oral administration of EA restored glucose homeostasis and other metabolic disorders in diet-induced obese mice, which were associated with increased circulating GLP-1, PYY, and GIP concentrations. EA slowed gastric emptying, downregulated hypothalamic agouti-related peptide, and reduced food intake and obesity in obese mice. EA also exerted potent anti-hyperglycemic effect in db/db mice that was comparable to that of liraglutide but greater than that of metformin, and it was more effective in promoting weight loss relative to these two drugs. Mechanistically, EA directly stimulated GLP-1 and PYY secretion from L-cells, and its induction of GLP-1 release is mediated via Gαq/phospholipase C-mediated pathway. EA also directly suppresses glucose production in liver cells. These results suggest that EA is a novel, dual-action agent for developing drug to treat both T2D and obesity.

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