Adrenomedullin hormone contributes to insulin resistance in obesity-associated type 2 diabetes

Adrenomedullin hormone contributes to insulin resistance in obesity-associated type 2 diabetes

The hormone adrenomedullin disrupts insulin signaling in blood vessel cells and contributes to systemic insulin resistance in obesity-associated type 2 diabetes, according to a new study. Blocking the effects of adrenomedullin restores insulin function and improves glucose control in a mouse model, suggesting a potential new target for the treatment of obesity-related metabolic diseases.

Diabetes is a leading cause of morbidity, mortality and healthcare expenditure worldwide. Insulin resistance primarily affects key metabolic cells, including those in skeletal muscle, adipose tissue, and the liver. Endothelial cells within blood vessels also express insulin receptors, and endothelial insulin signaling is thought to play a critical role in metabolic regulation. Previous research has suggested that endothelial insulin resistance may contribute to the systemic insulin resistance of type 2 diabetes. However, the precise mechanisms underlying endothelial insulin resistance remain unclear, and its direct role in type 2 diabetes remains to be definitively established.

Haaglim Cho and colleagues found that plasma levels of the hormone adrenomedullin and complement factor H (CFH) - a protein that enhances the effects of adrenomedullin - were increased in the blood of obese mice and humans. According to Choet al.In the findings in human endothelial cells, adrenomedullin inhibits insulin signaling by triggering a cascade that deactivates the insulin receptor, suggesting that higher levels of adrenomedullin and CFH in obesity contribute to insulin resistance in blood vessels. The authors reinforce these results, showing that treating lean mice with adrenomedullin caused insulin resistance and poor glucose control, mimicking obesity. This effect was abolished in mice that lacked adrenomedullin receptors in their blood vessels, confirming that the hormone acts through these receptors.

Furthermore, blocking adrenomedullin signaling improved insulin function in blood vessels, improved muscle blood flow, and prevented insulin resistance in obese mice, highlighting its central role in obesity-related metabolic disorders.

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