Abstract
This study tested whether the glycogen-accumulating effect of chronic in vivo pharmacological 5′AMP-activated protein kinase (AMPK) activation could improve glycemic control under conditions of insulin deficiency. Male Wistar rats were rendered diabetic through the administration of streptozotocin (STZ) and then treated for 7 consecutive days with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). Subsequently, glycogen content and synthesis, glucose oxidation, and fatty acid oxidation (FAO) were determined in oxidative and glycolytic skeletal muscles. Glycemia, insulinemia, glucagonemia, and circulating triglycerides (TG) and non-esterified fatty acids (NEFAs) were measured after AICAR treatment. Insulin was almost undetectable in STZ rats and these animals were severely hyperglycemic. Glycogen content was markedly low mainly in glycolytic muscles of STZ rats and AICAR treatment restored it to control values. No differences were found among all muscles studied with regards to the content and phosphorylation of Akt/protein kinase B and glycogen synthase kinase 3. Even though glycogen synthase content was reduced in all muscles from STZ rats, insulin-induced dephosphorylation/activation of this enzyme was preserved and unaffected by AICAR treatment. Glucagon and NEFAS were 2- and 7.4-fold fold higher in STZ rats than controls, respectively. AICAR did not affect hyperglycemia and hyperglucagonemia in STZ rats; however, it normalized circulating NEFAs and significantly increased FAO in glycolytic muscles. In conclusion, even though AICAR-induced AMPK activation enhanced glycogen accumulation in glycolytic muscles and normalized circulating NEFAs and TG levels, the hyperglycemic effects of glucagon likely offset the potentially glucose-lowering effects of AICAR, resulting in no improvement of glycemic control in insulin-deficient rats.
Highlights
Skeletal muscle accounts for,40% of total body mass in a reference adult male and,30% in a reference adult female [1] and has the capacity to store up to 1 to 2% of its weight in glycogen [2]
Insulin was almost undetectable in the blood of STZ rats (Figure 1B), which is in line with the severe hyperglycemia found in these animals (Figure 1A)
Insulin was almost undetectable in the blood of STZ rats and this was accompanied by marked reductions in glycogen content in SOL, extensor digitorum longus (EDL), and EPI muscles
Summary
Skeletal muscle accounts for ,40% of total body mass in a reference adult male and ,30% in a reference adult female [1] and has the capacity to store up to 1 to 2% of its weight in glycogen [2]. It has been estimated that muscle glycogen synthesis accounts for the majority of whole-body glucose uptake and virtually the entire nonoxidative glucose metabolism [3]. These features make the skeletal muscle a crucial compartment for the regulation and maintenance of whole-body glucose homeostasis. Glucose uptake and glycogen synthesis in skeletal muscles are closely linked and tightly regulated processes that require the recruitment of glucose transporter 4 (GLUT4) from intracellular vesicular structures to the cell surface and activation of glycogen synthase (GS), respectively [4]. There are insulin-independent mechanisms that promote the recruitment of GLUT4 to the plasma membrane (e.g. muscle contractions) and increase intracellular glucose availability and regulate glycogen synthesis [4]
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