Pioglitazone stimulates AMP-activated protein kinase signalling and increases the expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation in human skeletal muscle in vivo: a randomised trial

Abstract

Aims/hypothesis The molecular mechanisms by which thiazolidinediones improve insulin sensitivity in type 2 diabetes are not fully understood. We hypothesised that pioglitazone would activate the adenosine 5′-monophosphate-activated protein kinase (AMPK) pathway and increase the expression of genes involved in adiponectin signalling, NEFA oxidation and mitochondrial function in human skeletal muscle. Methods A randomised, double-blind, parallel study was performed in 26 drug-naive type 2 diabetes patients treated with: (1) pioglitazone (n=14) or (2) aggressive nutritional therapy (n=12) to reduce HbA1c to levels observed in the pioglitazone-treated group. Participants were assigned randomly to treatment using a table of random numbers. Before and after 6 months, patients reported to the Clinical Research Center of the Texas Diabetes Institute for a vastus lateralis muscle biopsy followed by a 180 min euglycaemic–hyperinsulinaemic (80 mU m−2 min−1) clamp. Results All patients in the pioglitazone (n=14) or nutritional therapy (n=12) group were included in the analysis. Pioglitazone significantly increased plasma adiponectin concentration by 79% and reduced fasting plasma NEFA by 35% (both p<0.01). Following pioglitazone, insulin-stimulated glucose disposal increased by 30% (p<0.01), and muscle AMPK and acetyl-CoA carboxylase (ACC) phosphorylation increased by 38% and 53%, respectively (p<0.05). Pioglitazone increased mRNA levels for adiponectin receptor 1 and 2 genes (ADIPOR1, ADIPOR2), peroxisome proliferator-activated receptor gamma, coactivator 1 gene (PPARGC1) and multiple genes involved in mitochondrial function and fat oxidation. Despite a similar reduction in HbA1c and similar improvement in insulin sensitivity with nutritional therapy, there were no significant changes in muscle AMPK and ACC phosphorylation, or the expression of ADIPOR1, ADIPOR2, PPARGC1 and genes involved in mitochondrial function and fat oxidation. No adverse (or unexpected) effects or side effects were reported from the study. Conclusions/interpretations Pioglitazone increases plasma adiponectin levels, stimulates muscle AMPK signalling and increases the expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation. These changes may represent an important cellular mechanism by which thiazolidinediones improve skeletal muscle insulin sensitivity.

Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier

“…5C). Consistent with previous reports (34)(35)(36), treatment of patient myotubes with 10 μM pioglitazone increased phosphorylation of AMP-activated protein kinase (AMPK) (Fig. 5D).…”

Adenosine Monophosphate-Activated Protein Kinase (AMPK) as a New Target for Antidiabetic Drugs: A Review on Metabolic, Pharmacological and Chemical Considerations

“…PGC-1 regulates the expression of several genes that are involved in mitochondrial bioenergetics [127]. Moreover, TZD also increase the expression of super oxide dismutase-2 (SOD2) and quinone oxidoreductase-1 (NQO1), providing an efficient antioxidant defense against elevated levels of reactive oxygen species [128]. Importantly, in vitro experiments suggest that TZD-dependent activation of AMPK-dependent pathways in insulin sensitive tissue is not exclusively mediated by adiponectin.…”

ACC2 gene polymorphisms, metabolic syndrome, and gene-nutrient interactions with dietary fat

“…In addition, cellular ACC2 activity depends on phosphorylation status (41)(42)(43)(44), and insulin is known to activate ACC activity by promoting dephosphorylation ( 52 ). Recent data has shown reduced ACC phosphorylation in conjunction with increased insulin-stimulated glucose disposal in T2DM patients following insulin-sensitizing therapy ( 53 ). The authors of that study hypothesized that increased expression of genes involved in fat oxidation and mitochondrial function, such as ACC, may lead to reduced production of lipotoxic metabolites that have the potential to improve insulin signaling and augment insulin sensitivity.…”