The insulin-signaling network in human adipocytes, normally and in diabetes: role of signaling through ERK1/2
2014 (English)Manuscript (preprint) (Other academic)
Insulin acutely controls metabolism in adipocytes, but also nuclear transcription through the “mitogenic” signaling pathway mediated by Map-kinases ERK1/2 (ERK). The cellular metabolic response to insulin is attenuated in insulin resistance and type 2 diabetes, but whether this involves also signaling through ERK is unclear. Based on experimental data from primary mature human adipocytes from diabetic and nondiabetic individuals, we demonstrate a network-wide, model-based analysis of insulin signaling through ERK to phosphorylation of transcription factor Elk1 integrated with signaling for “metabolic” control. We use minimal modeling to analyze the idiosyncratic phosphorylation dynamics of ERK, i.e. a slow phosphorylation response that returns to basal in response to insulin, and conclude that sequestration of ERK is the simplest explanation to data. We also demonstrate a significant cross-talk between ERK and mTORC1 signaling to ribosomal protein S6 for control of protein synthesis. A reduced sensitivity and reduced maximal phosphorylation of ERK in response to insulin in the diabetic state can be explained by the same mechanisms that generate insulin resistance in the control of metabolism.
Place, publisher, year, edition, pages
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-104724OAI: oai:DiVA.org:liu-104724DiVA: diva2:698669