Possible mechanisms of the hypoglycaemic effect of artesunate: Gender implication

Abstract

Background Artesunate is an antimalarial drug that affects glucose homeostasis but the mechanism of its glucose-modulating effect is not fully understood especially with gender implication, which is the information this study sought to provide. Methods Twenty-five (25) male and 25 female rats were separately and blindly allocated into five identical groups (n = 5/group). Group I (control) received 0.2 ml/kg distilled water. Groups II and III both received 2.90 mg/kg artesunate on day one, but 1.45 mg/kg from day two till day five and day fifteen respectively. Groups IV and V both received 8.70 mg/kg artesunate on day one, but 4.35 mg/kg artesunate from day two till day five and day fifteen respectively. Results In male rats, the blood glucose was reduced by low and high doses of artesunate at 5 days but increased by high dose at 15 days. Glucose was reduced in female rats but unchanged in male rats by low dose artesunate at 15 days. Artesunate increased glycogen concentration at short duration which normalised at long duration in both genders. Artesunate increased G6P concentration only in male rats at 15 days but reduced G6Pase activity in male and female rats (except in those that received low and high doses of artesunate for 15 days). Artesunate increased insulin only in male rats treated with low dose artesunate for 5 days. Artesunate increased cortisol concentration in male but reduced it in female rats. Artesunate decreased glucagon concentration except in female rats treated with high dose for 5 days. Artesunate increased oestrogen concentration in male rats that received low dose artesunate for 5 days but reduced it in female rats that received high dose for 15 days. Except in male rats that received high dose of artesunate for 15 days where testosterone was increased, artesunate did not affect testosterone concentration in all other male and female groups Conclusions The present study suggests that artesunate causes reduction in plasma glucose by reducing plasma glucagon concentrations and inhibiting liver glycogenolysis via inhibition of G6Pase activity in both sexes. In addition, increase in plasma insulin concentration contributed to the reduction in blood glucose caused by artesunate in male but not female rats; and artesunate-induced increase in G6P, a substrate for G6PD, could enhance NADPH generation and antioxidant enzyme activation in male rats.

Effect of Acute Caffeine Exposure on Blood Glucose and Hepatic Glycogen Content in Normal and Thyroidectomized Male Wistar Rats

“…Caffeine caused significant increased blood glucose level in normal and thyroidectomized rats of this study. This effect is in consonance with the well documented effect of acute caffeine exposure (Oyebola and Alada, 1993;Dekker et al, 2007;Salahdeen and Alada, 2009;Alagbonsi et al, 2016;Shi et al, 2016;Reis et al, 2018) on blood glucose in normal rats. Caffeine increases blood glucose through its stimulation of adrenal gland release of adrenaline (Battram et al, 2005), hence studies have linked acute caffeine consumption, increased plasma adrenaline and decreased insulin sensitivity (Dekker et al, 2007).…”

“…The lack of total abolishment of the caffeine-induced increased blood glucose in the thyroidectomized rats of the current study may be linked with the interaction of caffeine with adenosine receptor, caffeine is a potent non-selective adenosine receptor antagonist and exerts most of its biological activities by blocking all types of adenosine receptors (Ribeiro and Sebastião, 2010). Agonist of adenosine receptors have been shown to decrease blood glucose and their blockade increases blood glucose (Alagbonsi et al, 2016) therefore, caffeine may utilize the adenosine receptor blockade pathway independently of its direct stimulation of adrenaline release to increase blood glucose level. Earlier reports have shown that adenosine receptor expression is greatly increased in hypothyroid rats (Baños et al, 2002) thus, their blood glucose lowering effect may be effectively blocked by caffeine administration in the thyroidectomized rats hence providing additional pathway for caffeine induction of high blood glucose level in the thyroidectomized rats.…”

“…Acute exposure to caffeine increased blood glucose, hampered insulin sensitivity, induced adrenaline and cortisol stimulated hepatic glucose production and reduced glucose uptake and utilization by peripheral tissues (Dekker et al, 2007;Salahdeen and Alada, 2009;Alagbonsi et al, 2016;Shi et al, 2016;Reis et al, 2018). Physiologically, increased blood glucose is channeled into increased glucose utilization and storage as glycogen.…”

Progress on the study of the anticancer effects of artesunate (Review)

“…ART is metabolized to docosahexaenoic acid (DHA) as it enters the body (16)(17)(18). ART induces the generation of ROS, increasing malondialdehyde levels and decreasing the levels antioxidants such as superoxide dismutase and catalase, thereby causing alkylation of the proteins of the Plasmodium parasite (19). At present, ART is mainly used for the treatment of malaria of all types (20), for immune regulation (in type 1 diabetes in NOD mice) (21), as well as for liver (22), breast (23) and lung (24-26) cancer.…”