Obesity induces systemic insulin resistance via endothelium-specific insulin receptor inhibition

Abstract

Insulin resistance is a key component of the pathogenesis and progression of obesity-associated type 2 diabetes mellitus (T2DM). The insulin receptor is expressed in endothelial cells and insulin acts on blood vessels to increase blood flow to metabolic tissues. Endothelial insulin resistance was already known to be reduced in people with T2DM compared with healthy individuals, but the mechanisms of this insulin resistance and its contribution to T2DM development were unclear. Now, a paper in Science has determined that the peptide hormone adrenomedullin has a role in inducing vascular insulin resistance in the context of obesity.

Adrenomedullin was found to inhibit insulin signalling, thereby preventing insulin-induced eNOS phosphorylation, a process that leads to vasodilation. Under healthy conditions, this vasodilation increases blood perfusion of metabolic tissues such as the skeletal muscle, adipose tissue and liver, enabling increased delivery of oxygen and nutrients. Inhibition of insulin signalling was mediated by the G protein subunit Gα_s and protein kinase A (PKA), which increased activity of PTP1B, a key regulator of insulin sensitivity, via insulin receptor dephosphorylation. Knockout of adrenomedullin, knockdown of Gα_s or chemical inhibition of PKA all led to increased insulin receptor phosphorylation and subsequent increased insulin signalling.