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A Broad Network of Dysregulated Protein Phosphorylation Underlies Muscle Insulin Resistance in Type 2 Diabetes

ABSTRACT: Skeletal muscle insulin resistance is the earliest defect in type 2 diabetes (T2D), preceding and predicting disease development. Whether this represents the underlying primary defect in T2D or effects of changes in hormones or circulating metabolites is unknown. To address this question, we have developed a “disease-in-a-dish” model by differentiating iPS cells from T2D patients and controls into myoblasts (iMyo) and studied their function in vitro. We find that T2D iMyos exhibit multiple defects mirroring human disease including altered insulin signaling through the IRS/AKT pathway, decreased insulin-stimulated glucose uptake, and reduced mitochondrial oxidation. In addition, using global phosphoproteomics we find that T2D alters phosphorylation of a large network of targets of mTOR, S6K, PKC and other kinases including proteins involved in regulation of Rho-GTPases, mRNA splicing/processing, vesicular trafficking, gene transcription and chromatin remodeling. This cell-autonomous dysregulated phosphorylation network reveals a new dimension in the mechanism underlying insulin resistance in T2D.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Myoblast

SUBMITTER: Ashokkumar Jayavelu

LAB HEAD: C. Ronald Kahn

PROVIDER: PXD015430 | Pride | 2020-08-27

REPOSITORIES: Pride

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