| First Author | Chaudhari A | Year | 2017 |
| Journal | F1000Res | Volume | 6 |
| Pages | 1600 | PubMed ID | 29983910 |
| Mgi Jnum | J:288803 | Mgi Id | MGI:6430356 |
| Doi | 10.12688/f1000research.12418.2 | Citation | Chaudhari A, et al. (2017) Hepatic deletion of p110alpha and p85alpha results in insulin resistance despite sustained IRS1-associated phosphatidylinositol kinase activity. F1000Res 6:1600 |
| abstractText | Background: Class IA phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is an integral mediator of insulin signaling. The p110 catalytic and p85 regulatory subunits of PI3K are the products of separate genes, and while they come together to make the active heterodimer, they have opposing roles in insulin signaling and action. Deletion of hepatic p110alpha results in an impaired insulin signal and severe insulin resistance, whereas deletion of hepatic p85alpha results in improved insulin sensitivity due to sustained levels of phosphatidylinositol (3,4,5)-trisphosphate. Here, we created mice with combined hepatic deletion of p110alpha and p85alpha (L-DKO) to study the impact on insulin signaling and whole body glucose homeostasis. Methods: Six-week old male flox control and L-DKO mice were studied over a period of 18 weeks, during which weight and glucose levels were monitored, and glucose tolerance tests, insulin tolerance test and pyruvate tolerance test were performed. Fasting insulin, insulin signaling mediators, PI3K activity and insulin receptor substrate (IRS)1-associated phosphatidylinositol kinase activity were examined at 10 weeks. Liver, muscle and white adipose tissue weight was recorded at 10 weeks and 25 weeks. Results: The L-DKO mice showed a blunted insulin signal downstream of PI3K, developed markedly impaired glucose tolerance, hyperinsulinemia and had decreased liver and adipose tissue weights. Surprisingly, however, these mice displayed normal hepatic glucose production, normal insulin tolerance, and intact IRS1-associated phosphatidylinositol kinase activity without compensatory upregulated signaling of other classes of PI3K. Conclusions: The data demonstrate an unexpectedly overall mild metabolic phenotype of the L-DKO mice, suggesting that lipid kinases other than PI3Ks might partially compensate for the loss of p110alpha/p85alpha by signaling through other nodes than Akt/Protein Kinase B. |
