Editors' ChoiceDiabetes

Signal autonomy: Skeletal muscle in diabetes

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Science Translational Medicine  30 Sep 2020:
Vol. 12, Issue 563, eabe6026
DOI: 10.1126/scitranslmed.abe6026

Abstract

Skeletal muscle from individuals with type 2 diabetes has a cell-autonomous phosphoprotein signature.

Type 2 diabetes (T2DM) is a worldwide health problem and contributes to substantial morbidity and premature mortality. Although hyperglycemia clinically defines T2DM, insulin resistance precedes the development of hyperglycemia by many years. Insulin resistance affects tissues such as skeletal muscle, where glucose uptake is less than anticipated for a given concentration of circulating insulin. Skeletal muscle insulin resistance is thought to be a key contributor to the development of T2DM, but whether systemic or cell autonomous factors underly its development is a subject of contention. Batista and colleagues aimed to understand whether there are primary, cell-autonomous contributors to insulin resistance in skeletal muscle in the setting of T2DM.

The investigators performed skeletal muscle biopsies on individuals with T2DM and healthy controls and, from these biopsies, derived induced pluripotent stem cell lines in vitro. They then differentiated the stem cell lines into skeletal muscle myoblasts to study insulin signaling and glucose metabolism. They found that the differentiated myoblasts from individuals with T2DM demonstrated impaired insulin signaling, glucose uptake, and glycolytic function compared with myoblasts derived from controls. Through global phosphoproteomics, they found that the differentiated myoblasts derived from individuals with T2DM did not have impaired phosphorylation of the entire insulin signaling cascade compared with controls. Instead, in basal and insulin-stimulated conditions, they found defects in phosphorylation of some proteins, along with enhanced dephosphorylation of others and increased phosphorylation of more. Although some of these differences were observed in classical insulin signaling pathways, the authors found that the T2DM phosphoprotein signature also involved Rho GTPases, mRNA splicing, vesicular trafficking, gene transcription, and chromatin remodeling pathways.

The results presented by Batista and co-investigators provide new insights into potential cell-autonomous mechanisms underlying the development of insulin resistance and T2DM. Some caveats to these findings are that T2DM is a heterogeneous disease that likely has different underlying pathophysiologies in different populations, and so the results may not be generalizable to a global population. Additionally, the cells were derived from individuals with T2DM; therefore, whether the phosphoprotein signature was the cause or consequence of T2DM cannot be determined from these studies.

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