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Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase
1Department of Internal Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Japan.
Abstract:
The hallmark of type 2 diabetes, the most common metabolic disorder, is a defect in insulin-stimulated glucose transport in peripheral tissues. Although a role for phosphoinositide-3-kinase (PI3K) activity in insulin-stimulated glucose transport and glucose transporter isoform 4 (Glut4) translocation has been suggested in vitro, its role in vivo and the molecular link between activation of PI3K and translocation has not yet been elucidated. To determine the role of PI3K in glucose homeostasis, we generated mice with a targeted disruption of the gene encoding the p85alpha regulatory subunit of PI3K (Pik3r1; refs 3-5). Pik3r1-/- mice showed increased insulin sensitivity and hypoglycaemia due to increased glucose transport in skeletal muscle and adipocytes. Insulin-stimulated PI3K activity associated with insulin receptor substrates (IRSs) was mediated via full-length p85 alpha in wild-type mice, but via the p50 alpha alternative splicing isoform of the same gene in Pik3r1-/- mice. This isoform switch was associated with an increase in insulin-induced generation of phosphatidylinositol(3,4,5)triphosphate (PtdIns(3,4,5)P3) in Pik3r1-/- adipocytes and facilitation of Glut4 translocation from the low-density microsome (LDM) fraction to the plasma membrane (PM). This mechanism seems to be responsible for the phenotype of Pik3r1-/- mice, namely increased glucose transport and hypoglycaemia. Our work provides the first direct evidence that PI3K and its regulatory subunit have a role in glucose homeostasis in vivo.
Insights
Mice lacking the p85alpha regulatory subunit of phosphoinositide-3-kinase (PI3K) exhibit enhanced insulin sensitivity and hypoglycemia. This is due to increased glucose transport in muscle and fat cells, mediated by an alternative splicing isoform of PI3K.
Area of Science:
- Metabolic disorders
- Molecular biology
- Diabetes research
Background:
- Type 2 diabetes is characterized by impaired insulin-stimulated glucose transport.
- The role of phosphoinositide-3-kinase (PI3K) in glucose transport in vivo remains unclear.
- Understanding PI3K's role is crucial for elucidating mechanisms of glucose homeostasis.
Purpose of the Study:
- To investigate the in vivo role of PI3K's p85alpha regulatory subunit in glucose homeostasis.
- To determine the molecular link between PI3K activation and glucose transporter 4 (Glut4) translocation.
- To identify the specific PI3K isoforms involved in insulin signaling.
Main Methods:
- Generation of knockout mice lacking the p85alpha regulatory subunit of PI3K (Pik3r1-/-).
- Assessment of insulin sensitivity, glucose transport, and hypoglycemia in Pik3r1-/- mice.
- Analysis of PI3K activity, phosphatidylinositol(3,4,5)triphosphate (PtdIns(3,4,5)P3) generation, and Glut4 translocation.
Main Results:
- Pik3r1-/- mice displayed increased insulin sensitivity and hypoglycemia.
- Skeletal muscle and adipocytes in these mice showed elevated glucose transport.
- An alternative splicing isoform (p50 alpha) of the p85alpha subunit mediated PI3K activity, increasing PtdIns(3,4,5)P3 and facilitating Glut4 translocation.
Conclusions:
- The p85alpha regulatory subunit of PI3K plays a critical role in regulating glucose homeostasis in vivo.
- Alternative splicing of the p85alpha subunit influences insulin signaling and glucose transport.
- This study provides direct evidence for PI3K's involvement in preventing hypoglycemia and maintaining glucose balance.