Blood vessel insulin sensitivity may be the key to understanding how obesity turns into diabetes

In the United States, two of every five adults are considered obese, a major risk factor for developing type 2 diabetes. Obesity is defined by excess body fat, while type 2 diabetes is a disease in which the body – mainly muscle, fat, and liver – loses its ability to respond to insulin. Both obesity and diabetes increase the risk for diseases such as cancer, cardiovascular disease, and dementia, but high blood sugar in type 2 diabetes can lead to severe nerve and vascular complications. Preventing the transition from obesity into type 2 diabetes is a crucial checkpoint in maintaining health. 

In a collaborative study from multiple institutions, scientists have discovered a hormone that may explain how obesity can cause type 2 diabetes by looking in an unexpected place: blood vessels. Previous studies have shown that obesity drives inflammation to cause insulin resistance. The new study provides an alternate mechanism where endothelial cells, the cells that compose our blood vessels, regulate insulin sensitivity by determining how much insulin can get to target tissues. They identified a hormone, adrenomedullin, elevated in obese humans and mice. This elevation does not occur in mice whose fat cells cannot produce adrenomedullin, indicating that adrenomedullin is released from fat. Adrenomedullin dampens insulin signaling in endothelial cells, and mice treated with adrenomedullin become insulin resistant. Inversely, mice that genetically lack the ability to respond to adrenomedullin in endothelial cells have increased blood flow compared to their obese counterparts and are protected from becoming obese while eating an obesity-inducing diet. Treatment with a drug that prevents adrenomedullin action restores insulin sensitivity to obese mice. 

This study provides a novel mechanism through which obesity can cause type 2 diabetes and proposes a new therapy to treat insulin resistance. While most researchers have typically studied the final target tissues of insulin action, these scientists investigated how insulin reaches those targets. This endothelial-minded approach may aid future studies on other hormones that, like insulin, have to pass through endothelial cells prior to their primary targets. 

This study was led by Haaglim Cho, a Project Leader at the Max Planck Institute for Heart and Lung Research, in Bad Nauheim, Germany.

Managing Correspondent: Samuel Lapp

Press Article: Obesity-Linked Hormone Adrenomedullin Disrupts Insulin Signaling (Genetic Engineering & Biotechnology News)

Original Journal Article: Endothelial insulin resistance induced by adrenomedullin mediates obesity-associated diabetes (Science) 

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