Increased malonyl-CoA and diacylglycerol content and reduced AMPK activity accompany insulin resistance induced by glucose infusion in muscle and liver of rats

Abstract

Glucose infusion in rats for 1-4 days results in insulin resistance and increased triglyceride, whole tissue long-chain fatty acyl-CoA (LCA-CoA), and malonyl-CoA content in red skeletal muscle. Despite this, the relation between these alterations and the onset of insulin resistance has not been defined. We aimed to 1) identify whether the changes in these lipids and of diacylglycerol (DAG) precede or accompany the onset of insulin resistance in glucose-infused rats, 2) determine whether the insulin resistance is associated with alterations in AMP-activated protein kinase (AMPK), and 3) assess whether similar changes occur in liver and in muscle. Hyperglycemia (17-18 mM) was maintained by intravenous glucose infusion in rats for 3 or 5 h; then euglycemia was restored and a 2-h hyperinsulinemic clamp was performed. Significant (P < 0.01) muscle and liver insulin resistance first appeared in red quadriceps and liver of the glucose-infused group at 5 h and was associated with a twofold increase in DAG and malonyl-CoA content and a 50% decrease in AMPK and acetyl-CoA carboxylase (ACC) phosphorylation and AMPK activity. White quadriceps showed qualitatively similar changes but without decreases in AMPK or ACC phosphorylation. Triglyceride mass was increased at 5 h only in liver, and whole tissue LCA-CoA content was not increased in liver or either muscle type. We conclude that the onset of insulin resistance induced by glucose oversupply correlates temporally with increases in malonyl-CoA and DAG content in all three tissues and with reduced AMPK phosphorylation and activity in red muscle and liver. In contrast, it was not associated with increased whole tissue LCA-CoA content in any tissue or triglyceride in muscle, although both are observed at later times.

Aging impairs insulin-stimulated glucose uptake in rat skeletal muscle via suppressing AMPKα

“…Furthermore, it was demonstrated recently that altered expression or activity of AMPK might play a key role in the onset of both high-fat and high-glucose induced insulin resistance (Kraegen et al, 2006;Liu et al, 2006). In the present study, we demonstrated AMPK might also participate in aging-related fat oxidation insufficiency and insulin resistance.…”

“…Recently, Kraegen EW and colleagues reported that four days of glucose infusion induced a significant decrement of AMPK activities in rats' muscles and liver, accompanied with impaired insulin signaling and glucose disposal, indicating a possible role of AMPK in glucotoxicity (Kraegen et al, 2006). Our previous study also demonstrated that impaired expression and activity of AMPK, and accordingly insufficient intracellular fatty acid oxidation, might also participate in high-fat associated insulin resistance (lipotoxicity) (Liu et al, 2006).…”

Infusion of a Lipid Emulsion Modulates AMPK and Related Proteins in Rat Liver, Muscle, and Adipose Tissues

“…Recently, it has been shown that increased FA availability stimulates AMPK activity in skeletal muscle both in vitro and in vivo (10,(24)(25)(26)(27). Likewise, a diminished AMPK phosphorylation in the liver was also supported by previous works showing that TG accumulation in the liver is in association with decreased AMPK activation (27,28). Similarly, our results show that lipid oversupply produced differing effects on AMPK activation in different tissues.…”

Effect of age and moderate food restriction on insulin sensitivity in Wistar rats: role of adiposity

“…Quadriceps muscle is mainly constituted by type 2a and 2b fibers, which are mainly glycolytic and have a low capacity for using fatty acids as fuel, a fact that might explain the accumulation of triglycerides in this tissue in 24-month-old rats, which are characterized by increased serum triglyceride concentration (Escrivá et al 1997). As reported by others (Kiens 2006, Kraegen et al 2006, muscle insulin resistance is rather associated with cellular levels of malonyl-CoA, fatty acyl CoA, diacylglycerol, or ceramide, than with triglyceride accumulation. Thus, more experimental work is needed to clarify the differences in mechanism underlying the differences in insulin sensitivity between oxidative and glycolytic muscles with ageing.…”