Hepatic deletion of p110α and p85α results in insulin resistance despite sustained IRS1-associated phosphatidylinositol kinase activity

Abstract

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 p110α results in an impaired insulin signal and severe insulin resistance, whereas deletion of hepatic p85α results in improved insulin sensitivity due to sustained levels of phosphatidylinositol (3,4,5)-trisphosphate. Here, we created mice with combined hepatic deletion of p110α and p85α (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 p110α/p85α by signaling through other nodes than Akt/Protein Kinase B.

PI3Kinases in Diabetes Mellitus and Its Related Complications

“…Actually, mice that are genetically heterozygous for both PI3K α and PI3K β develop glucose intolerance, probably in response to a reduced interaction between IRS-1 and PI3K [14]. All tissues responsible for most glucose uptake from the blood are involved, since ablation of a Class I A PI3K in either muscle or liver produce the same glucose-intolerant phenotype, although through different mechanisms [15,16]. In particular, deletion of all regulatory subunits of Class I A PI3K in muscles impairs downstream signaling in response to insulin or to insulin growth factor-1 (IGF-1), resulting in reduced glucose uptake and higher glucose plasma levels when challenged by insulin [15].…”

“…However, fasting glucose was not affected in these mice, because of whole-body metabolic adjustments, consisting in increased adiposity and circulating lipid levels, as observed in diabetic patients. In contrast, deletion of PI3K α in the liver, which similarly impairs downstream signaling in response to insulin in this organ, results in reduced adiposity [16], highlighting how insulin-induced PI3K signaling in specific organs can have different whole-body metabolic effects.…”

Hepatic deletion of p110α and p85α results in insulin resistance despite sustained IRS1-associated phosphatidylinositol kinase activity

“…Dataset 4: Raw data for metabolic procedures and measurements and gene expression shown in Figure 4 . DOI, 10.5256/f1000research.12418.d205910 42 …”