Stress hormones may be the key to understanding how obesity causes diabetes, researchers reveal

A groundbreaking study from Rutgers Health, in collaboration with several institutions, suggests that stress hormones, rather than impaired cellular insulin signalling, might be the primary cause of obesity-related diabetes. This research, published in Cell Metabolism, challenges the traditional view of how obesity-induced insulin resistance develops and introduces novel perspectives on potential treatment approaches.

“We have been interested in the basic mechanisms of how obesity induces diabetes. Given that the cost of the diabetes epidemic in the U.S. alone exceeds $300 billion per year, this is a critically important question,” said Christoph Buettner, chief of endocrinology, metabolism, and nutrition at Rutgers Robert Wood Johnson Medical School and the senior author of the study.

Challenging Long-Standing Beliefs About Obesity and Diabetes

Historically, scientists have attributed the development of diabetes in people with obesity to disrupted insulin signalling within liver and fat cells. However, this new study offers an alternative explanation, highlighting the role of the body’s sympathetic nervous system (SNS) – commonly associated with the “fight or flight” response. According to the researchers, overeating and obesity stimulate this system, leading to increased levels of the stress hormones norepinephrine and epinephrine, which seem to interfere with insulin’s effects. Importantly, they observed that this interference occurs even when cellular insulin signalling remains intact.

Through experiments on mice, the researchers found that overeating rapidly increases the stress hormone norepinephrine within days, indicating just how quickly excess food can stimulate the SNS.

The Role of Stress Hormones in Disease Development

To better understand how this hormone surge influences disease progression, the researchers used a new type of genetically engineered mice that are identical to regular mice except for one critical difference: they are unable to produce catecholamines, the primary stress hormones, outside their brain and central nervous system.

The study showed that when these genetically modified mice were fed an obesity-inducing, high-fat and high-sugar diet, they gained just as much weight as their regular counterparts. Yet, they did not develop metabolic diseases typically associated with obesity.

“We were delighted to see that our mice ate as much because it indicates that the differences in insulin sensitivity and their lack of metabolic disease are not due to reduced food intake or reduced obesity but due to the greatly reduced stress hormones. These mice cannot increase stress hormones that counteract insulin; hence, insulin resistance does not develop during obesity development.”

Explaining the Variation in Diabetes Development

The findings may provide insight into why some people living with obesity develop diabetes while others do not, and why stressful conditions can worsen diabetes, even without significant weight gain. Buettner noted: “Many types of stress – financial stress, marital stress, the stress associated with living in dangerous areas or suffering discrimination or even the physical stress that comes from excessive alcohol consumption — all increase diabetes and synergize with the metabolic stress of obesity.”

He added, “Our finding that even obesity principally induces metabolic disease via increased stress hormones provides new insight into the common basis for all these factors that increase the risk of diabetes. Stress and obesity, in essence, work through the same basic mechanism in causing diabetes, through the actions of stress hormones.”

A Paradigm Shift in Understanding Insulin Resistance

While it has long been recognised that catecholamines can impair insulin action, this study suggests that heightened activity of these stress hormones might be the fundamental driver of insulin resistance in obesity. Stress hormones increase glucose and lipid levels in the bloodstream, while insulin typically works to lower them. The study reveals that insulin signalling remains intact in many cases of insulin resistance associated with obesity. Instead, the heightened presence of stress hormones acts like an “accelerated gas pedal,” pushing blood sugar and fat levels up, despite insulin’s continued attempts to reduce them.

“Some colleagues are at first surprised that insulin resistance can exist even though cellular insulin signalling is intact,” Buettner explained. “But let’s not forget that the gas pedal effects of stress hormones are exerted through very different signalling pathways than insulin signalling. That explains why the ability of insulin to ‘brake’ and reduce the release of sugar and fat into the bloodstream is impaired even though insulin signalling is intact because stress signalling is predominant.”

Potential for New Treatments

These findings open the door to considering medications that reduce catecholamines – encompassing all stress-related hormones produced by the SNS and adrenal glands – as a possible treatment for diabetes. However, medicines currently used to block catecholamines for high blood pressure have not shown significant benefits for diabetes, possibly due to their inability to target the relevant receptors or their complex interactions within the brain and body.

Buettner and Kenichi Sakamoto, the study’s first author and an assistant professor of endocrinology at Robert Wood Johnson Medical School, are now preparing to validate these findings in human studies. They are also exploring the role of the SNS in other forms of diabetes, including Type 1 diabetes. “We would like to study if short-term overfeeding, as some of us experience during the holidays by gaining five to 10 pounds, increases insulin resistance with heightened sympathetic nervous system activation,” Buettner said.

A New Direction for Diabetes and Metabolic Disease Research

Ultimately, this research could lead to a new focus on reducing stress hormones as a therapeutic strategy to tackle insulin resistance, diabetes, and metabolic diseases, shifting away from targeting insulin signalling alone.

“We hope this paper provides a different take on insulin resistance,” Buettner concluded. “It may also explain why none of the drugs currently used to treat insulin resistance, except insulin itself, directly increases cellular insulin signalling.”

By highlighting the potential for stress hormone reduction to prevent or treat diabetes, these findings represent a substantial step forward in understanding and addressing the complex relationship between obesity and diabetes.