PXD034052

PXD034052 is an original dataset announced via ProteomeXchange.

Title	Identification of Small molecule Insulin Sensitizers for the Treatment of Insulin Resistance.
Description	Type 2 diabetes (T2D) is major cause of mortality and morbidity. The key manifestations of this disease are insulin resistance (IR), hyperglycemia and hyperinsulinemia. Secretion of insulin from the endocrine pancreas is triggered by elevated circulating glucose and acts on skeletal muscle and adipose tissues to remove excess glucose from the blood (1). This is achieved through a series of intracellular events that trigger the translocation of vesicles containing the glucose transporter 4 (GLUT4) to the surface of skeletal muscle cells and adipocytes (2,3). This process is impaired in patients with IR or T2D and insulin fails to promote GLUT4 translocation, thus resulting in inefficient glucose uptake in storage tissue and hyperglycemia (4). Chronic hyperglycemic condition increases the risk of cardiovascular disease, stroke, neuropathy, and death (5). Previously developed insulin sensitizer like thiazolidinediones (TZDs) have proven effective in improving glycemic control, however, they significantly increase the risk of cardiovascular disease due to their agonist activity at PPAR(6-8). Consequently, identifying insulin sensitizers that restore insulin-stimulated GLUT4 translocation in diabetic patients without targeting PPAR is urgently needed. The discovery of such molecules has been challenging due to the lack of a GLUT4 translocation assay amenable to high throughput screening (HTS). For this reason, we have developed a new luminescence based HTS assay that allows real time monitoring of GLUT4 translocation in mammalian cells and further adapted the assay to measure GLUT4 translocation in live mice. Using this assay, we identified a new insulin sensitizer which greatly improves insulin-dependent glucose uptake in storage tissues and glucose tolerance in insulin resistant rodents. This new insulin sensitizers acts through interaction with the Unc119 family of proteins which are known to facilitate the transport of specific cargos (9) but had not yet been implicated in insulin action or GLUT4 translocation. This study identifies new PPAR-independent insulin sensitizers with in-vivo efficacy and identify Unc119 proteins as new targets for the treatment of T2D.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:48:28.953.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jonathan Van Vranken
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2022-05-25 01:01:51	ID requested
1	2024-07-03 02:03:24	announced
⏵ 2	2024-10-22 06:48:29	announced	2024-10-22: Updated project metadata.

10.1016/j.chembiol.2023.06.012;

Yin TC, Van Vranken JG, Srivastava D, Mittal A, Buscaglia P, Moore AE, Verdinez JA, Graham AE, Walsh SA, Acevedo MA, Kerns RJ, Artemyev NO, Gygi SP, Sebag JA, Insulin sensitization by small molecules enhancing GLUT4 translocation. Cell Chem Biol, 30(8):933-942.e6(2023) [pubmed]

submitter keyword: small molecule drug,Diabetes

Julien Sebag
contact affiliation	Department of Molecular Physiology and Biophysics, University of Iowa, Iowa city, IA
contact email	Julien-sebag@uiowa.edu
lab head
Jonathan Van Vranken
contact affiliation	Harvard Medical School
contact email	van@hms.harvard.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/07/PXD034052

PRIDE project URI

• PRIDE
  1. PXD034052
     1. Label: PRIDE project
     2. Name: Identification of Small molecule Insulin Sensitizers for the Treatment of Insulin Resistance.