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PID1 regulates insulin-dependent glucose uptake by controlling intracellular sorting of GLUT4-storage vesicles.

ABSTRACT: The phosphotyrosine interacting domain-containing protein 1 (PID1) serves as a cytosolic adaptor protein of the LDL receptor-related protein 1 (LRP1). By regulating its intracellular trafficking, PID1 controls the hepatic, LRP1-dependent clearance of pro-atherogenic lipoproteins. In adipose and muscle tissues, LRP1 is present in endosomal storage vesicles containing the insulin-responsive glucose transporter 4 (GLUT4). This prompted us to investigate whether PID1 modulates GLUT4 translocation and function via its interaction with the LRP1 cytosolic domain. We initially evaluated this in primary brown adipocytes as we observed an inverse correlation between brown adipose tissue glucose uptake and expression of LRP1 and PID1. Insulin stimulation in wild type brown adipocytes induced LRP1 and GLUT4 translocation from endosomal storage vesicles to the cell surface. Loss of PID1 expression in brown adipocytes prompted LRP1 and GLUT4 sorting to the plasma membrane independent of insulin signaling. When placed on a diabetogenic high fat diet, systemic and adipocyte-specific PID1-deficient mice presented with improved hyperglycemia and glucose tolerance as well as reduced basal plasma insulin levels compared to wild type control mice. Moreover, the improvements in glucose parameters associated with increased glucose uptake in adipose and muscle tissues from PID1-deficient mice. The data provide evidence that PID1 serves as an insulin-regulated retention adaptor protein controlling translocation of LRP1 in conjunction with GLUT4 to the plasma membrane of adipocytes. Notably, loss of PID1 corrects for insulin resistance-associated hyperglycemia emphasizing its pivotal role and therapeutic potential in the regulation of glucose homeostasis.

SUBMITTER: Fischer AW

PROVIDER: S-EPMC6624118 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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PID1 regulates insulin-dependent glucose uptake by controlling intracellular sorting of GLUT4-storage vesicles.

Fischer Alexander W AW Albers Kirstin K Schlein Christian C Sass Frederike F Krott Lucia M LM Schmale Hartwig H Gordts Philip L S M PLSM Scheja Ludger L Heeren Joerg J

Biochimica et biophysica acta. Molecular basis of disease 20190321 6

The phosphotyrosine interacting domain-containing protein 1 (PID1) serves as a cytosolic adaptor protein of the LDL receptor-related protein 1 (LRP1). By regulating its intracellular trafficking, PID1 controls the hepatic, LRP1-dependent clearance of pro-atherogenic lipoproteins. In adipose and muscle tissues, LRP1 is present in endosomal storage vesicles containing the insulin-responsive glucose transporter 4 (GLUT4). This prompted us to investigate whether PID1 modulates GLUT4 translocation an ...[more]

PMID: 30904610

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Project description:Impaired insulin-mediated glucose uptake characterizes cardiac muscle in humans and animals with insulin resistance and diabetes, despite preserved or enhanced phosphatidylinositol 3-kinase (PI3K) and the serine-threonine kinase, Akt-signaling, via mechanisms that are incompletely understood. One potential mechanism is PI3K- and Akt-mediated activation of mechanistic target of rapamycin (mTOR) and ribosomal protein S6 kinase (S6K), which may impair insulin-mediated activation of insulin receptor substrate (IRS)1/2 via inhibitory serine phosphorylation or proteasomal degradation. To gain mechanistic insights by which constitutive activation of PI3K or Akt may desensitize insulin-mediated glucose uptake in cardiomyocytes, we examined mice with cardiomyocyte-restricted, constitutive or inducible overexpression of a constitutively activated PI3K or a myristoylated Akt1 (myrAkt1) transgene that also expressed a myc-epitope-tagged glucose transporter type 4 protein (GLUT4). Although short-term activation of PI3K and myrAkt1 increased mTOR and S6 signaling, there was no impairment in insulin-mediated activation of IRS1/2. However, insulin-mediated glucose uptake was reduced by 50-80%. Although longer-term activation of Akt reduced IRS2 protein content via an mTORC1-mediated mechanism, treatment of transgenic mice with rapamycin failed to restore insulin-mediated glucose uptake, despite restoring IRS2. Transgenic activation of Akt and insulin-stimulation of myrAkt1 transgenic cardiomyocytes increased sarcolemmal insertion of myc-GLUT4 to levels equivalent to that observed in insulin-stimulated wild-type controls. Despite preserved GLUT4 translocation, glucose uptake was not elevated by the presence of constitutive activation of PI3K and Akt. Hexokinase II activity was preserved in myrAkt1 hearts. Thus, constitutive activation of PI3K and Akt in cardiomyocytes impairs GLUT4-mediated glucose uptake via mechanisms that impair the function of GLUT4 after its plasma-membrane insertion.

Dataset Information

PID1 regulates insulin-dependent glucose uptake by controlling intracellular sorting of GLUT4-storage vesicles.

Publications

PID1 regulates insulin-dependent glucose uptake by controlling intracellular sorting of GLUT4-storage vesicles.

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