Validation des effets antidiabétiques de Rhododendron groenlandicum, une plante médicinale des Cri de la Baie James, dans le modèle in vitro et in vivo : élucidation des mécanismes d’action et identification des composés actifs

Diabetes is a metabolic syndrome characterized by chronic hyperglycemia due to a defect in insulin secretion, insulin action (sensitivity), or both. More than one million Canadians are currently living with diabetes. The prevalence of this disease is at least three times higher among indigenous people than in the general Canadian population. Our team studied the potential effects of certain anti-diabetic medicinal plants used by the Cree nation of Eeyou Istchee (James Bay, Quebec) where compliance to western treatment is low due in part to the cultured disconnect of the latter. Using an ethnobotanical approach, we identified 17 medicinal plants used by this population to treat symptoms of diabetes. Among these plants, the ethanol extract of Rhododendron groenlandicum (Labrador Tea) showed strong anti-diabetic potential in several cell lines, including adipocytes (3T3-L1) where it induced differentiation probably by stimulating the peroxisome proliferator-activated receptor gamma (PPAR γ). Such stimulation has been shown to improve insulin resistance, a mechanism used by a class of anti-diabetic drugs, the thiazolidinediones.  The aim of the present study is to validate the effectiveness and the safety of R. groenlandicum in vivo in a mouse model of insulin resistance, to elucidate the mechanisms by which it exerts its effects and to identify the active principles responsible for its activity. Isolation and identification of active constituents of R. groenlandicum were performed using a fractionation approach guided by the increase of triglyceride content in the adipocyte (3T3-L1). In vivo studies were performed on a DIO (diet induced obesity) mouse model. The ethanolic extract of R. groenlandicum was incorporated into the high fat diet (35% energy derived from lipids) at three different doses (125, 250 and 500 mg / kg) over a period of 8 weeks. Western immunoblot analysis was performed on different tissues (liver, skeletal muscle, adipose tissue) collected at the end of the study.  Quercetin, catechin and epicatechin were identified as the active compounds responsible for the anti-diabetic effect of R. groenlandicum. Alone, catechin and epicatechin activate adipogenesis only at high concentrations (125-150 M) while quercetin inhibits it.  In vivo, treatment of DIO mice with R. groenlandicum diminished weight gain by 6 %, reduced blood glucose by 13%, insulin plasma by 65% and prevented hepatic steatosis (triglycerides levels decreased by 42%) without significant toxicity. Western blot analysis showed that R. groenlandicum increased Glut 4 protein content in skeletal muscle by activating the insulin dependent pathway implicating Akt. Effects of R. groenlandicum on hepatic steatosis seems to involve both pathways; the insulin dependent Akt and insulin independent AMPK pathways. This correlated with decreased SREBP-1 hepatic content, a transcription factor involved in de novo lipogenesis, and with a reduction of inflammation (decrease in the activity of IKK alpha / beta).  Taken together, these results support the therapeutic potential of Rhododendron groenlandicum and its active compounds in the treatment and prevention of type 2 diabetes. We validated the safety and efficacy of this plant from traditional Cree medicine. It could represent an alternative treatment of type 2 diabetes in a population that has a poor compliance to pharmacological treatments.

Keyphrases: Labrador tea, Type 2 diabetes, Insulin resistance, DIO, DIO, Akt, Akt, AMPK, AMPK, Glut4, Glut4, PPAR γ, PPAR γ, SREBP-1, SREBP-1, Natural health products