A Single Mechanism Can Explain Network-wide Insulin Resistance in Adipocytes from Obese Patients with Type 2 Diabetes*

Elin Nyman, Meenu Rohini Rajan, Siri Fagerholm, Cecilia Brännmark, Gunnar Cedersund, Peter Strålfors

The response to insulin is impaired in type 2 diabetes. Much information is available about insulin signaling, but understanding of the cellular mechanisms causing impaired signaling and insulin resistance is hampered by fragmented data, mainly obtained from different cell lines and animals. We have collected quantitative and systems-wide dynamic data on insulin signaling in primary adipocytes, and compared cells isolated from healthy and diabetic individuals. Mathematical modeling and experimental verification identified mechanisms of insulin control of the Map-kinases ERK1/2. We found that in human adipocytes insulin stimulates phosphorylation of the ribosomal protein S6, and hence protein synthesis, about equally via ERK1/2 and mTORC1. Using mathematical modeling we examined the signaling network as a whole, and show that a single mechanism can explain the insulin resistance of type 2 diabetes throughout the network, involving signaling both through IRS1, PKB, mTOR, and via ERK1/2 to the nuclear transcription factor Elk1. The most important part of the insulin resistance mechanism is an attenuated feedback from the protein kinase mTORC1 to IRS1, which spreads signal attenuation to all parts of the insulin-signaling network. Experimental inhibition of mTORC1 using rapamycin in adipocytes from non-diabetic individuals induced and thus confirmed the predicted network-wide insulin resistance.