J Ethnopharmacol. 2015 Jul 21;170:98-105. doi: 10.1016/j.jep.2015.05.003.

An extract of Artemisia dracunculus L. stimulates insulin secretion from β cells, activates AMPK and suppresses inflammation.

Aggarwal S1, Shailendra G2, Ribnicky DM3, Burk D4, Karki N5, Qingxia Wang MS5.
  • 1William Hansel Cancer Prevention Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA. Electronic address: sita.aggarwal@pbrc.edu.
  • 2Department of Experimental Pathology, Mayo Clinic, Rochester, MN 55905, USA.
  • 3Department of Plant Biology and Pathology, Rutgers University, New Brunswick, NJ 08901-8521, USA.
  • 4Cell Biology and Bio-imaging, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA.
  • 5William Hansel Cancer Prevention Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA.

 

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia dracunculus L. (Russian tarragon) is a perennial herb belonging to the family Compositae and has a history of medicinal use in humans, particularly for treatment of diabetes.

AIM OF THE STUDY: In this study a defined plant extract from A. dracunculus L. (termed PMI-5011) is used to improve beta(β) cells function and maintain β cell number in pancreatic islets as an alternative drug approach for successful treatment of diabetes.

MATERIALS AND METHODS: Mouse and human pancreatic beta cells were treated with defined plant extract of A. dracunculus L. (PMI-5011) to understand the mechanism(s) that influence beta cell function and β cell number.

RESULTS: We found that the PMI-5011 enhances insulin release from primary β cells, isolated mouse and human islets and it maintains β cell number. Insulin released by PMI-5011 is associated with the activation of AMP-activated protein kinase (AMPK), and protein kinase B (PKB). Furthermore, PMI-5011 suppresses LPS/INFγ-induced inflammation and inflammatory mediator(s) in macrophages. PMI-5011 inhibited Nitric oxide (NO) production and expression of inducible nitric oxide synthase (iNOS) at the protein level and also attenuated pro-inflammatory cytokine (IL-6) production in macrophages.

CONCLUSION: PMI-5011 has potential therapeutic value for diabetes treatment via increasing insulin release from β cells and decreases capacity of macrophages to combat inflammation.

KEYWORDS: Botanical(s); Diabetes; Inflammation; Insulin secretion; Islets; Pancreatic beta (β) cells

PMID: 25980421

 

Supplements:

Diabetes is a group of diseases marked by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. Insulin is the hormone that allows glucose to enter body cells and when it is absent, glucose builds up in the bloodstream leading to a condition called hyperglycemia. Insulin-secreting beta cells are present with other hormone-secreting cells as little clusters in the pancreas called the pancreatic islets. In adults, type 2 diabetes accounts for about 90% to 95% of all diagnosed cases of diabetes. It usually begins as insulin resistance, a disorder in which the cells do not use insulin properly. As the need for insulin rises, the pancreas’ beta cells gradually lose their ability to produce this hormone. Newer Insulin therapy has improved the control of diabetes; however complications from this method still persist. Intensive insulin therapy results in tighter glycemic control and has better outcomes as far as complications are concerned when compared to conventional insulin therapy; however, there is increased risk of hypoglycemia associated with intensive insulin therapy. Thus, even with insulin therapy, glycemic level varies significantly in the diabetic population. Because of the shortcomings of insulin therapy, the development of alternative drugs from natural resources such as traditional medicinal plants for long term normalization of glycemic control in Type 2 Diabetes is imperative. It has been previously shown that the active compounds in certain foods we consume and/or in traditional medicinal plants may increase or protect the function of insulin [1, 2]. We hypothesized that the use of a purified extract from the plant called Artemisia dracunculus L. (Russian tarragon) could improve beta cell function. The Artemisia dracunculus L. extract described as “PMI-5011” is an alcoholic extract of the plant and has been shown previously to improve whole body glucose disposal [3-7]. We asked the question, … “Can a purified, well defined extract of Artemisia dracunculus L. (PMI-5011) trigger insulin release from pancreatic beta cells?” To answer this question, we utilized mouse and human pancreatic beta cells and the defined plant extract PMI-5011 to understand the mechanism(s) that influence beta cell mass and function. Our data clearly demonstrates that PMI-5011 can induce insulin release from pancreatic beta cells above the basal level (Figure 1).

 

 

SA fig1

Figure 1.Visualization of insulin in NIT-1, a pancreatic beta cell line obtained from American Type Culture Collection, VA, USA. (a;b) NIT-1 cells in control medium and (c) medium containing PMI-5011 (30 µg/mL).Images captured by confocal microscopy. NIT-cells, DIC; Red stain: Localization of insulin; Blue Stain: Localization of cell nucleus.

 

 

We then asked if PMI-5011 is toxic to beta cells. Our data suggested that up to 72 h incubation with 5011 does not kill beta cells and, instead facilities an increase in beta cell mass [8].

Other well accepted and acknowledged risk factors associated with diabetes are inflammation and disruptions in normal cellular energy balance. Therefore, we investigated the mechanism of action of PMI-5011 in beta cells and macrophages cells that play a critical role in the inflammation response. Chronic inflammation can stimulate the pancreatic resident macrophages to secrete pro-inflammatory cytokines such as IL-6, or TNFα, which can lead to islet dysfunction. We found that macrophages exposed to PMI-5011 secreted less IL-6 and produced less nitric oxide when challenged with pro-inflammatory lipopolysaccharide. Additionally, we observed activation of cellular energy targets such as activated protein kinase (AMPK) and cell survival targets such as AKT.

 

SA fig2.png

Figure 2. Schematic representation of mechanistic action of PMI-5011; activates cellular energy targets and cell survival targets in beta cells and inhibits inflammatory markers in macrophages. In conclusion protects beta cells function.

 

Our data clearly demonstrate that the botanical extract, PMI-5011, can help restore beta cell mass, maintain insulin production, and reduce inflammation response in vitro. This suggests that PMI-5011 could potentially serve as an alternative mechanism to traditional insulin therapy for better glycemic control and help to improve the quality of life of people with type II diabetes.

Importance of the study: Our experimental data lends further support to the idea that botanicals and botanical extracts have the potential to improve the function of beta cells in vitro. Further studies are in progress to examine the effects of these botanical compounds in animal models with a focus towards improving efficacy, potency, and safety.

 

Grant Support and Acknowledgments: This work was supported in part by P50AT002776-02 from the National Centre for Complementary and Alternative Medicine (NCCAM) and the Office of Dietary Supplements (ODS) which funds the Botanical Research Centre at Pennington Biomedical and in part by the Hansel/Downey Research Fund, the Pennington Biomedical Research Foundation and by Louisiana State University, LA. We thank Dr. William Cefalu, Botanical Research Centre of Pennington Biomedical Research Centre, Baton Rouge, LA and The Biotech Centre of Rutgers University, Rutgers, The State University of New Jersey. This work utilized the facilities of the Cell Biology and Bioimaging Core that are supported in part by COBRE (NIH P20-GM103528) and NORC (NIH 2P30-DK072476) center grants from the National Institutes of Health.

 

Contact

Sita Aggarwal, Ph.D.

Adjunct- Assistant Professor

William Hansel Cancer Prevention Laboratory

Pennington Biomedical Research Center

6400 Perkins Road

Baton Rouge, LA-70808

Ph# 225-763-2931 (office)

Fax# 225-763-3030

 

References

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  7. Wang ZQ, Ribnicky D, Zhang XH, Zuberi A, Raskin I, Yu Y, Cefalu WT: An extract of Artemisia dracunculus L. enhances insulin receptor signaling and modulates gene expression in skeletal muscle in KK-A(y) mice. J Nutr Biochem 2011, 22(1):71-78.
  8. Aggarwal S, Shailendra G, Ribnicky DM, Burk D, Karki N, Qingxia Wang MS: An extract of Artemisia dracunculus L. stimulates insulin secretion from beta cells, activates AMPK and suppresses inflammation. J Ethnopharmacol 2015, 170:98-105.

 

 

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