Abstract 1087: Diet-Induced Insulin Resistance Causes Isoform-Specific Abnormalities of Akt Signaling in Arterial Wall of Pigs
Background: Akt exists in 3 isoforms with distinct primary functions: Akt1 (physiologic growth, cell survival, eNOS activation), Akt2 (glucose metabolism), and Akt3 (cell proliferation/hypertrophy). Normally, each isoform is phosphorylated in response to insulin. Insulin resistance is associated with defective insulin signaling through the PI3K/Akt pathway and vascular dysfunction manifested by hypertension and endothelial dysfunction. In this study, we investigated whether isoform-specific defects in Akt signaling develop in arterial walls of pigs with insulin resistance.
Methods: Micropigs (n=16) were assigned to low-fat, no added sugar chow or to chow supplemented with coconut oil and fructose for 7 mo. The latter group developed insulin resistance (elevated fasting blood glucose and insulin, abnormal intravenous glucose tolerance tests), obesity, dyslipidemia and hypertension, recapitulating clinical features of the metabolic syndrome. Under anesthesia, pigs received an insulin bolus (10 u/kg, IV) and were euthanized 10 min later. Aortic lysates were analyzed for PI3K activity and phosphorylation of total Akt, Akt isoforms, p38 and JNK MAP kinases. Aortic intima-media thickness was measured.
Results: Insulin-stimulated PI3K activity was lower in aortas of insulin-resistant pigs compared with control pigs (p<0.01). Total Akt and total pAkt did not differ between groups; however, pronounced differences in isoform-specific Akt phosphorylation after insulin were identified: In insulin-resistant pigs, aortic pAkt1 was 53% lower (p=0.01) and pAkt2 was 21% lower (p=0.03) than in control pigs. In contrast, pAkt3 was 7% (p NS) higher in insulin-resistant pigs. Phospho/total p38 and JNK did not differ between groups. No atherosclerotic lesions were evident in any aortas, and intima-media thickness was equal in both groups.
Conclusion: Pigs with insulin resistance and features of the metabolic syndrome develop isoform-specific defects of insulin-stimulated Akt phosphorylation in arterial wall: pAkt1 and pAkt2 are attenuated while pAkt3 and MAP kinases are unaffected. These imbalances occur after a short duration of insulin resistance, preceding abnormalities of arterial structure, but accompanied by elevated blood pressure.