Type 2 diabetes is characterized by insulin resistance, hyperinsulinemia and hepatic overproduction of glucose and lipids. Insulin increases lipogenic enzyme expression by activating Akt and aPKC which activate SREBP-1c; this pathway is hyperactivated in insulin-resistant states. Insulin suppresses gluconeogenic enzyme expression by Akt-dependent phosphorylation/inactivation of FoxO1 and PGC-1α; this pathway is impaired in insulin-resistant states by aPKC excess, which displaces Akt from scaffolding-protein WD40/ProF, where Akt phosphorylates/inhibits FoxO1. But how PGC-1α and FoxO1 are coordinated in insulin action and resistance is uncertain. Here, in normal mice, we found, along with Akt and aPKC, insulin increased PGC-1α association with WD40/ProF by an aPKC-dependent mechanism. However, in insulin-resistant high-fat-fed mice, like FoxO1, PGC-1α phosphorylation was impaired by aPKC-mediated displacement of Akt from WD40/ProF, as aPKC inhibition diminished its association with WD40/ProF, and simultaneously restored Akt association with WD40/ProF and phosphorylation/inhibition of both PGC-1α and FoxO1. Moreover, in high-fat-fed mice, in addition to activity, PGC-1α expression was increased, not only by FoxO1 activation, but also, as found in human hepatocytes, by a mechanism requiring aPKC and SREBP-1c, which also increased expression and activity of PKC-ι. In high-fat-fed mice, inhibition of hepatic aPKC, not only restored Akt association with WD40/ProF and FoxO1/PGC-1α phosphorylation, but also diminished expression of SREBP-1c, PGC-1α, PKC-ι and gluconeogenic and lipogenic enzymes, and corrected glucose intolerance and hyperlipidemia. Conclusion: Insulin suppression of gluconeogenic enzyme expression is facilitated by coordinated inactivation of FoxO1 and PGC-1α by WD40/ProF-associated Akt; but this coordination also increases vulnerability to aPKC hyperactivity, which is abetted by SREBP-1c-induced increases in PGC-1α and PKC-ι.

2型糖尿病的特征是胰岛素抵抗，高胰岛素血症以及肝脏中葡萄糖和脂质的过量生产。胰岛素通过激活SREBP-1c的Akt和aPKC来增加脂肪酶的表达。在胰岛素抵抗状态下，该途径被过度激活。胰岛素通过Akt依赖性FoxO1和PGC-1α的磷酸化/失活抑制糖原异生酶的表达。在apkC过量的情况下，该途径在胰岛素抵抗状态中受损，从而使Akt脱离了脚手架蛋白WD40 / ProF，而Akt磷酸化/抑制了FoxO1。但是PGC-1α和FoxO1如何在胰岛素作用和抗药性上协调尚不确定。在这里，在正常小鼠中，我们发现胰岛素与Akt和aPKC一起通过aPKC依赖性机制增加了与WD40 / ProF的PGC-1α缔合。但是，在胰岛素抵抗性高脂喂养的小鼠中，例如FoxO1，APKC介导的Akt从WD40 / ProF的置换取代了aktc介导的Akt的置换，削弱了pGC-1α的磷酸化，因为aPKC抑制作用减弱了其与WD40 / proF的结合，同时恢复了akt与WD40 / ProF的结合以及PGC-1α和FoxO1的磷酸化/抑制。此外，在高脂喂养的小鼠中，除活性外，PGC-1α的表达不仅通过FoxO1激活而增加，而且，如在人肝细胞中发现的那样，还通过需要aPKC和SREBP-1c的机制而增加。 PKC-1的表达和活性。在高脂饮食小鼠中，抑制肝aPKC不仅恢复了与WD40 / ProF和FoxO1 /PGC-1α磷酸化相关的Akt结合，而且还减少了SREBP-1c，PGC-1α，PKC-1和糖原异生性和脂生性的表达酶，纠正​​糖耐量异常和高脂血症。结论：WD40 / ProF相关的Akt通过协同失活FoxO1和PGC-1α来促进胰岛素抑制糖异生酶的表达。但是这种协调也增加了对aPKC过度活跃的脆弱性，这是由SREBP-1c诱导的PGC-1α和PKC-1的增加所诱使的。