Étude des propriétés antidiabétiques de Nigella sativa : sites d’action cellulaires et moléculaires

Nigella sativa or black cumin is a medicinal plant and a popular condiment. The seeds of N. sativa are widely used in the traditional medicine of North African countries for the treatment of diabetes. However, the cellular and molecular mechanisms of action through which the plant exerts its hypoglycemic effect remain unclear. The aim of our study is to determine the effect of N. sativa on insulin secretion, glucose transport and signaling pathways involved in the regulation of glucose homeostasis and metabolism. We carried out in vitro murine cell-based bioassays (βTC pancreatic β cells, C2C12 myoblasts, H4IIE hepatocytes and 3T3-L1 adipocytes) and in vivo studies in normoglycemic rats and diabetic Meriones shawi (rodent). In pancreatic β cells, N. sativa increased cell proliferation as well as basal and glucose stimulated insulin secretion. It also enhanced glucose uptake in muscle cells by 50%. Moreover, the increase of glucose uptake in fat cells reached levels up to 400%. The experiments using Western immunoblot analysis showed that N. sativa stimulated insulin-dependent (Akt and ERK) as well as -independent (AMPK) pathways in C2C12 cells. In 3T3-L1 cells, the increase of glucose uptake was attributed to the activation of the peroxisome proliferator activated receptor γ (PPARγ) pathway. Similarly to C2C12 cells, N. sativa activated Akt and 5' adenosine monophosphate-activated protein kinase (AMPK) in hepatocytes. This activation of AMPK was associated with an uncoupling effect on mitochondrial oxidative phosphorylation.  In diabetic Meriones, N. sativa gradually decreased fasting blood glucose and the glycemic response to an oral glucose load (OGTT) to values similar to normal animals at the end of treatment. Improved lipid profile is observed in both animal models. At the molecular level, N. sativa increased muscle glucose transporter 4 (Glut4) content and acetyl-coenzyme A carboxylase (ACC) phosphorylation in soleus muscle and liver in diabetic Meriones shawi. In normal rats, the plant extract induced a stimulation of insulin signaling pathways (Akt and ERK) in the liver.  In conclusion, N. sativa has an insulinotropic effect on pancreatic β cells. Our study has revealed for the first time that N. sativa exerts its antidiabetic activity by a combination of insulino-mimetic and insulin-sensitizing effects, thereby increasing glucose uptake in peripheral tissues. This effect of N. sativa is linked to the stimulation of insulin-dependent and -independent (AMPK) pathway in skeletal muscle and liver, while in adipose tissue, the effect was attributed to the activation of PPARγ. Finally, the in vivo study confirms the antidiabetic and antihyperlipidemic effects of N. sativa. Our original contribution lies in the demonstration that the in vivo antidiabetic action of N. sativa is exerted though the same mechanisms identified by our in vitro studies. These data support the soundness of the ethnobotanical use of this plant for the treatment of diabetes and its associated dyslipidemia. Moreover, the pleiotropic actions of N. sativa make it a very promising alternative or complementary treatment for diabetes, which calls for immediate high quality clinical trials.

Keyphrases: Nigella sativa, Meriones shawi, AMPK, Glut4, Nigella sativa, Diabetes, Insulin resistance, Meriones shawi, AMPK, Insulin secretion, Skeletal muscle, Mitochondrial respiratory, Fat tissue, Glut4