# Role of PI 3-Kinase Isoforms in Insulin Action

> **NIH NIH R01** · JOSLIN DIABETES CENTER · 2020 · $441,331

## Abstract

Project Summary/Abstract
 This is a revised competitive renewal of NIH grant DK055545 which is focused on the role of
phosphatidylinositol 3-kinase (PI3K) in insulin action and insulin resistance. PI 3-kinase is a critical node in
insulin's metabolic actions. Alterations in PI3K have been implicated in cancer, diabetes and many other
disorders. In previous work under this grant we have used both in vitro and in vivo approaches to define the
role of this enzyme in insulin action and insulin resistance. We have shown that regulation of PI3K depends
both on the nature of the different regulatory subunits; the stoichiometry between regulatory and catalytic
subunits; the ability of PI 3-kinase to serve as a site for divergence of downstream signaling; and alterations in
PI3K activity in disease states. We have also identified new links between the PI 3-kinase pathway and other
signaling pathways, including important links between the p85 regulatory subunits and several pathways
involved in insulin resistance, such as activation of the stress kinases JNK and p38, regulation of the PIP3
phosphatase PTEN, and a novel link between PI 3-kinase, endoplasmic reticulum (ER) stress and the unfolded
protein response (UPR) created by the interaction between p85α and XBP-1s, facilitating XBP-1s transport into
the nucleus and thus modifying the ER stress response. Another exciting recent development has been the
identification of a mutation in p85α in patients with SHORT syndrome, a syndrome characterized by insulin
resistance and partial lipodystrophy. Recently, we have created a knock-in mouse bearing this mutation to
study its effects in vivo. We have also begun to characterize the different roles of the two major catalytic
subunits of PI3K (p110α and p110β) in insulin signaling and mitochondrial homeostasis through knockout in
vivo and in vitro. This has led to new hypotheses about the unique roles of the different catalytic and regulatory
subunits of PI 3-kinase, which allow these proteins to serve as both sites of divergence in the insulin signaling
pathway and sites of positive and negative regulation in physiological and pathological states.
 In the next five years, we propose to expand upon these observations by defining at both the molecular
and physiological levels how different signals are generated by the p110α and p110β catalytic subunits of PI 3-
kinase, the specific signaling complexes involved, and the link between PI3K and mitochondrial homeostasis.
In addition, we will expand our studies on the regulatory subunits focusing defining the regions of p85α that
interact with XBP-1s creating crosstalk between the PI 3-kinase pathway and ER stress. We will also further
define how mutations in the p85α regulatory subunit can have a dominant negative effect and result in severe
insulin resistance. Together, these studies will help complete our understanding of the role of the PI3K system
and its different catalytic and regulatory subunits in insulin acti...

## Key facts

- **NIH application ID:** 9920716
- **Project number:** 5R01DK055545-21
- **Recipient organization:** JOSLIN DIABETES CENTER
- **Principal Investigator:** C RONALD KAHN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $441,331
- **Award type:** 5
- **Project period:** 1999-06-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920716

## Citation

> US National Institutes of Health, RePORTER application 9920716, Role of PI 3-Kinase Isoforms in Insulin Action (5R01DK055545-21). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9920716. Licensed CC0.

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