Research ArticleMetabolism

SHP2 drives inflammation-triggered insulin resistance by reshaping tissue macrophage populations

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Science Translational Medicine  28 Apr 2021:
Vol. 13, Issue 591, eabe2587
DOI: 10.1126/scitranslmed.abe2587

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Inflaming insulin resistance

Patients with the developmental disorder Noonan syndrome (NS) may be prone to insulin resistance. Studying the hyperactivation of tyrosine phosphatase SHP2 associated with this disease, Paccoud et al. now pinpoint an inflammatory origin of insulin resistance. Hyperactivation of SHP2 associated with glucose intolerance and insulin resistance in patients with NS. In a hyperactive SHP2 mouse model, bone marrow–derived and liver-resident macrophages shifted toward a proinflammatory profile, leading to altered systemic glucose homeostasis. Small-molecule targeting of SHP2 in wild-type diet-induced obese mice reduced inflammation in metabolic tissues and improved insulin sensitivity, hinting at the potential of targeting SHP2 for metabolic syndrome.

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