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PPAR β activation restores the high glucose‐induced impairment of insulin signalling in endothelial cells
Author(s) -
Quintela A M,
Jiménez R,
Piqueras L,
GómezGuzmán M,
Haro J,
Zarzuelo M J,
Cogolludo A,
Sanz M J,
Toral M,
Romero M,
PérezVizcaíno F,
Duarte J
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12646
Subject(s) - medicine , insulin , endocrinology , protein kinase b , chemistry , insulin resistance , phosphorylation , reactive oxygen species , pdk4 , glucose uptake , mitochondrial ros , oxidative stress , pyruvate dehydrogenase complex , biology , biochemistry , enzyme
Background and Purpose PPARβ enhances insulin sensitivity in adipocytes and skeletal muscle cells, but its effects on insulin signalling in endothelial cells are not known. We analysed the effects of the PPAR β/δ ( PPAR β) agonists, GW 0742 and L 165041, on impaired insulin signalling induced by high glucose in HUVECs and aortic and mesenteric arteries from diabetic rats. Experimental Approach Insulin‐stimulated NO production, Akt ‐ Ser 473 and eNOS ‐ Ser 1177 phosphorylation, and reactive oxygen species ( ROS ) production were studied in HUVECs incubated in low‐ or high‐glucose medium. Insulin‐stimulated relaxations and protein phosphorylation in vessels from streptozotocin ( STZ )‐induced diabetic rats were also analysed. Key Results HUVECs incubated in high‐glucose medium showed a significant reduction in insulin‐stimulated production of NO . High glucose also reduced insulin‐induced Akt ‐ Ser 473 and eNOS ‐ Ser 1177 phosphorylation, increased IRS ‐1‐Ser 636 and ERK 1/2‐ Thr 183 ‐ Tyr 185 phosphorylation and increased ROS production. The co‐incubation with the PPAR β agonists GW 0742 or L 165041 prevented all these effects induced by high glucose. In turn, the effects induced by the agonists were suppressed when HUVEC were also incubated with the PPAR β antagonist GSK 0660, the pyruvate dehydrogenase kinase ( PDK )4 inhibitor dichloroacetate or after knockdown of both PPAR β and PDK 4 with siRNA . The ERK 1/2 inhibitor PD 98059, ROS scavenger catalase, inhibitor of complex II thenoyltrifluoroacetone or uncoupler of oxidative phosphorylation, carbonyl cyanide m‐chlorophenylhydrazone, also prevented glucose‐induced insulin resistance. In STZ diabetic rats, oral GW 0742 also improved insulin signalling and the impaired NO ‐mediated vascular relaxation. Conclusion and Implications PPAR β activation in vitro and in vivo restores the endothelial function, preserving the insulin‐ Akt ‐ eNOS pathway impaired by high glucose, at least in part, through PDK 4 activation.