Management of glucose homeostasis and dyslipidemia

Read Also

The growing evidence that AMPK regulates the coordination of anabolic and catabolic metabolic processes represents an attractive therapeutic target for intervention in many conditions of disordered energy balance, including obesity, type 2 diabetes, and the metabolic syndrome (Winder and Hardie, 1999). Support for this idea came from in vivo treatment with AICAR of various animal models of insulin resistance, causing improvement of metabolic disturbances, at least partly by lowering blood glucose levels and increasing insulin sensitivity (Bergeron et al., 2001, Buhl et al., 2002, Iglesias et al., 2002, Song et al., 2002, Pold et al., 2005, Fiedler et al., 2001). Chronic treatment with AICAR was also shown to reduce plasma TG levels and adiposity in obese animals (Bergeron et al., 2001, Buhl et al., 2002, Song et al., 2002). Furthermore, similar beneficial metabolic effects have been also obtained by direct AMPK activation in the liver by overexpression of AMPK-CA or by the use of the AMPK activator A-769662, leading to decreased plasma glucose, plasma TG levels and adiposity in diabetic, obese and high fat fed mice (Cool et al., 2006, Foretz et al., 2005, Yang et al., 2008). These results suggest that direct targeting of the liver is crucial for improving glucose and lipid metabolism, thereby preventing and treating type 2 diabetes. Accordingly, it appears that the major effect of intravenous AICAR infusion in type 2 diabetic patients was on the liver with inhibition of hepatic glucose output and decreased blood glucose levels (Boon et al., 2008). However, as liver samples were not collected in this study, one can only speculate on the role of hepatic AMPK in this therapeutic effect of AICAR. Indeed, inhibition of hepatic glucose output could have resulted from AMPK-independent effects, such as inhibition of fructose-1,6-bisphosphatase by ZMP accumulation in the liver [(Vincent et al., 1991) and see above] Furthermore, AICAR administration could also stimulate hepatic fatty acid oxidation and/or inhibit whole body lipolysis, thereby reducing plasma non-esterified fatty acids (NEFA) concentration (Boon et al., 2008). Unexpectedly, the effect of AICAR infusion on skeletal muscle glucose uptake was not evident and no changes in AMPK activity were detected in skeletal muscle. Similarly, in another study performed in healthy humans, AMPK activity was not modified in skeletal muscle after AICAR infusion (Cuthbertson et al., 2007), reinforcing the role of the liver in the action of AICAR.

Several reports indicate that metformin and TZDs can reduce risk for type 2 diabetes in people with glucose intolerance (Knowler et al., 2002). Interestingly, these two drugs have been reported to activate AMPK which is now considered as a new target for the management of insulin-resistant state. Consistent with these data, AMPK now appears to be activated by a multitude of natural products such as polyphenols and traditional Chinese medicine able to reduce blood glucose levels in obese and diabetic animal models (table 1). Pathophysiology and management of type 2 diabetes are complex. Increased concentrations of NEFA and inflammatory cytokines (e.g., tumor necrosis factor a [TNFa] and interleukin 6 [IL-6]) released by expanded visceral adipose tissue are crucial mechanisms involved in the alteration of insulin signaling cascade (Stumvoll et al., 2005). Adiponectin is another important key of the pathophysiology of type 2 diabetes. Adiponectin has favourable effects on insulin resistance, hepatic steatosis and inflammation (Kadowaki et al., 2006). It is now well established that circulating levels of adiponectin are decreased in individuals with obesity and insulin resistance, suggesting that its deficiency may have a causal role in the etiopathogenesis of these diseases and their consequences. Thus, adiponectin replacement or restoration of endogenous secretion in humans may represent a promising approach to prevent and/or treat obesity, insulin resistance and the metabolic syndrome. The chronic effects of adiponectin on insulin resistance were investigated in vivo by generating adiponectin transgenic mice. Globular adiponectin transgenic ob/ob mice showed partial amelioration of insulin resistance and diabetes (Yamauchi et al., 2003) and full length adiponectin showed suppression of insulin-mediated endogenous glucose production (Yamauchi et al., 2002). Interestingly, it has been shown that metabolic and insulin-sensitizing effects of TZDs are in part mediated through increase in adiponectin availability. Indeed, TZDs metabolic effects are abolished in lipoatrophic mice suggesting that adipose tissue is an essential key of TZDs action (Chao et al., 2000). In addition, TZDs can markedly enhance the expression and secretion of adiponectin in vitro and in vivo through the activation of its promoter and also by blocking the suppressive effect of TNFa on the production of adiponectin. Even if the intracellular adiponectin signaling is not yet completely described, it is clearly demonstrated that adiponectin activates hepatic AMPK (Yamauchi et al., 2002). In consequence, TZDs probably activate AMPK by an indirect mechanism, through increase of adiponectin levels. This is suggested by the reduction of AMPK activation by rosiglitazone in adiponectin KO mice (Nawrocki et al., 2006). A possible similar mechanism of action could concern AICAR (but not metformin) which increase the expression of adiponectin in human adipose tissue as TZDs (Lihn et al., 2004).