Editors' ChoiceDiabetes

Fat weighing down the insulin receptor

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Science Translational Medicine  02 Nov 2016:
Vol. 8, Issue 363, pp. 363ec173
DOI: 10.1126/scitranslmed.aaj2088

Although most think of type 2 diabetes (T2D) as a disease of glucose metabolism dysfunction, abnormal lipid metabolism is actually the underlying cause of this common disease. Under conditions of energy excess, the liver and skeletal muscle accumulate intermediates in the lipid biosynthetic pathway that can negatively affect insulin action. In particular, accumulation of diacylglycerol (DAG) lipids in the plasma membrane can activate atypical protein kinase C-ε (PKCε), which then acts to serine phosphorylate proteins in the insulin signaling pathway, resulting in a blunting of insulin action. Most work to date has focused on PKC-mediated effects that occur downstream of the insulin receptor. Now, Petersen et al. provide strong evidence that proximal PKCε-driven phosphorylation of the insulin receptor itself is a key driver of insulin resistance.

Leveraging powerful mass spectrometry approaches, Petersen et al. identified Threonine1160 of the insulin receptor (INSR) as a PKCε substrate in the liver. Using classic site-directed mutagenesis approaches followed by transfection in HeLa cell, the authors demonstrated that a phosphomimetic INSR (T1160E, which mimics phosphorylation) impairs the receptor’s kinase activity, whereas phosphodeficient INSR (T1160A, which prevents phosphorylation) was not able to be negatively regulated by PKCε. Furthermore, Petersen et al. created a knock-in mouse model that expresses exclusively the phosphodeficient INSR (T1150A) and found that InsrT1150A mice were protected against high fat diet−induced hepatic insulin resistance. These data provide the first evidence that PKCε-driven phosphorylation of Thr1150 in mice is involved in the pathogenesis of insulin resistance in the liver. This work provides additional evidence supporting a central role for PKCε as a mediator of insulin resistance and provides key molecular insights into conserved mechanisms by which lipid metabolism drives T2D.

M. C. Petersen et al., Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance. J. Clin. Invest. 10.1172/JCI86013 (2016). [Full Text]

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