Stress Hormones Take Center Stage in Obesity-Related Diabetes

A collaborative study led by Rutgers Health has found that stress hormones—not necessarily impaired insulin signaling—may be the principal cause of obesity-related diabetes. These insights, published in the journal Cell Metabolism, have the potential to redefine how researchers understand and treat insulin resistance triggered by obesity.

“We have long been interested in the core mechanisms through which obesity leads to diabetes,” explains Christoph Buettner, chief of endocrinology, metabolism, and nutrition at Rutgers Robert Wood Johnson Medical School and senior author of the study. “Given that the diabetes epidemic costs the U.S. more than $300 billion each year, finding the root cause is absolutely critical.”

Challenging Conventional Wisdom

For years, scientists believed that excess weight directly disrupts how insulin signals within liver and fat cells, sparking the onset of diabetes. The new findings paint a different picture: overeating and obesity activate the body’s sympathetic nervous system—often called the “fight or flight” response—leading to elevated levels of the stress hormones norepinephrine and epinephrine. These hormones counteract insulin’s effects even when insulin signaling at the cellular level remains intact.

One telling observation emerged when normal mice began overeating: within days, their norepinephrine levels jumped, revealing just how fast increased food intake revs up the sympathetic nervous system.

Blocking Stress Hormones Prevents Metabolic Disease

To delve deeper, the researchers used specially engineered mice identical to normal mice in all but one aspect: they could not produce the stress hormones catecholamines outside of their brains and central nervous systems. When fed a high-fat, high-sugar diet, these mice consumed just as many calories, gained just as much weight, yet did not develop metabolic disease.

“We were delighted to see that these mice ate just as much,” Buettner says. “Their improved insulin sensitivity and lack of metabolic disease can’t be attributed to eating less or avoiding obesity. It’s because they couldn’t produce the stress hormones that antagonize insulin, so the usual insulin resistance never took hold.”

This observation sheds light on why some people with obesity develop diabetes while others do not. It also helps explain why stress, even in the absence of major weight gain, can worsen diabetes.

“A wide range of stressors—financial difficulties, marital problems, living in unsafe areas, experiencing discrimination, or even physical stress from heavy drinking—can intensify diabetes and overlap with obesity’s metabolic stress,” Buettner adds. “Our discovery that stress hormones largely drive metabolic disease in obesity shows these stressors share a fundamental biological pathway.”

Rethinking Insulin Resistance

Although researchers have long known that stress hormones can counter insulin’s actions, this study positions these hormones as the main agent behind insulin resistance in obesity. Stress hormones increase blood glucose and lipids, while insulin lowers them. The new work reveals that insulin’s signaling remains operational—its “braking” effect on blood sugar and fat release is still present—but the stress hormones “press the gas pedal” so firmly that insulin’s regulatory powers are overwhelmed.

“Some colleagues are surprised that insulin resistance can appear while insulin signaling still functions,” Buettner says. “However, stress signaling follows a different pathway from insulin signaling. So, while insulin still tells cells to slow sugar and fat release, stress hormones ramp up production through separate routes, effectively overpowering insulin’s effects.”

Potential New Therapeutic Approaches

These findings hint that drugs targeting stress hormones—also called catecholamines—could help prevent or treat diabetes. However, current blood pressure medications that block some catecholamine receptors have not shown marked benefits against diabetes. Researchers suspect that may be because they do not target the right receptors or they alter brain and body processes in complex ways.

Buettner and lead author Kenichi Sakamoto, an assistant professor of endocrinology at Robert Wood Johnson Medical School, plan to confirm their findings in human trials. They also aim to explore the sympathetic nervous system’s role in other types of diabetes, including Type 1 diabetes.

“We want to investigate whether short-term overeating—like the five to ten pounds some of us gain over the holidays—raises insulin resistance through heightened sympathetic nervous system activation,” says Buettner.

Ultimately, these new insights could spark a fresh direction for tackling insulin resistance, diabetes, and metabolic disorders—shifting the focus to reducing stress hormones rather than exclusively targeting insulin signaling.

“Our hope is that this study offers a fresh perspective on what drives insulin resistance,” Buettner says. “It might also explain why so many current therapies, other than insulin itself, don’t directly enhance cellular insulin signaling. We need a new approach, and this could be the key.”