Researchers identify link between stress and type 2 diabetes

When faced with danger, animals have to react fast. Heart rates climb, muscles tense, and the body prepares to fight or flee. At the same time, less urgent activities like eating get put on hold. Scientists have long known that hormones such as adrenaline and cortisol help drive these changes, but new research uncovers something unexpected: a direct brain-to-liver circuit that mobilizes glucose during stressful moments.

Published in the scientific journal Nature Communications, this work shows how the medial amygdala, a brain region best known for processing fear and social cues, plays a surprising role in controlling blood sugar. The findings also reveal how repeated stress can blunt this system, leaving the body prone to metabolic problems such as obesity and type 2 diabetes.

To study the link between stress and metabolism, researchers at the Mount Sinai Hospital and Mount Sinai School of Medicine turned to mice. They exposed them to two stressors: being held still and smelling a territorial rival’s scent. Both situations caused glucose in the blood to surge and reduced food intake. Stress also raised levels of several hormones and molecules linked to energy balance, including corticosterone, glucagon, and glycerol.

Even just five minutes of stress was enough to spike glucose and corticosterone. That quick reaction showed how efficiently the body can shift gears when danger strikes.

When scientists examined the brain, the medial amygdala stood out. Neurons in this region lit up during stress but not during harmless activities, like exploring a new cage. Calcium imaging confirmed that these neurons activated right before and during stressful experiences, not during ordinary movements.

The next question was whether these amygdala neurons directly controlled glucose levels. To test this, scientists activated the neurons in calm mice using advanced tools like chemogenetics, which switches on neurons with a designer drug, and optogenetics, which uses light.

The result was striking: glucose levels shot up, even without stress. The change happened independently of classic stress hormones like adrenaline and corticosterone. Blocking corticosterone had no effect, proving that the brain alone could spark the glucose release.

Activating the medial amygdala also briefly reduced eating, regardless of whether the mice were hungry or full. Interestingly, it did not cause fearful or anxious behavior. That meant the circuit could mimic the body’s stress-related metabolism without triggering the feeling of stress itself.

To learn where the signals traveled, the team traced connections from the amygdala to other brain regions. They found strong links to the ventromedial hypothalamus (VMH), an area involved in energy regulation. A smaller set of neurons connected to the bed nucleus of the stria terminalis (BNST).

When the animals were restrained, neurons projecting from the amygdala to the VMH became highly active, while those projecting to the BNST did not. Fiber photometry—a way of measuring brain activity in real time—confirmed that the amygdala-to-VMH pathway lit up during stress.

This pointed to a dedicated route: from the medial amygdala to the VMH, and then onward to the liver through the sympathetic nervous system.

Tracing experiments showed that signals from the VMH reached neurons connected to the liver. These routes included sympathetic nerve cells, such as those in the coeliac ganglia, which regulate organ function. When the amygdala-to-VMH circuit was switched on, genes in the liver that promote glucose production became more active.

In pyruvate tolerance tests, which measure how efficiently the liver makes glucose, the mice showed enhanced gluconeogenesis. Labeling experiments with carbon-13 confirmed that glucose precursors in the liver were processed more rapidly.

In short, activating this brain pathway essentially turned the liver into a glucose pump, ready to flood the bloodstream with fuel.

While a burst of glucose is helpful in short emergencies, life rarely offers only brief stress. The researchers wanted to know what happens when stress keeps coming back.

When mice were repeatedly exposed to social stress through territorial odors, the first exposure triggered strong amygdala activity and glucose spikes. But with repeated exposures, both brain activity and glucose surges dropped off. The same pattern appeared when restraint stress was applied twice a day for five days.

This desensitization suggests the stress circuit becomes less responsive over time. Yet this “burnout” of the system is not harmless. Mice with reduced activity in this circuit ended up with higher baseline glucose and greater weight gain—even though they didn’t eat more food. A high-fat diet worsened the effects, reducing glucose tolerance and altering liver receptor expression in ways that favored excess glucose release.

This research highlights a brand-new way stress connects to metabolism. Rather than relying only on hormones like cortisol, the brain can directly command the liver to produce glucose. In emergencies, that mechanism makes sense, giving the body immediate energy to deal with threats. But when stress happens again and again, the circuit weakens. Instead of protecting you, it sets the stage for chronic high blood sugar, weight gain, and greater risk of type 2 diabetes.

“The results of this study not only change how we think about the role of stress in diabetes, but also how we think about the role of the amygdala,” said Sarah Stanley, associate professor at Mount Sinai and one of the study leaders. “Previously, we thought the amygdala only controls our behavioral response to stress—now, we know it controls bodily responses, too.”

For decades, most studies of glucose regulation in the brain have focused on the hypothalamus and brain stem. Those regions oversee hunger, thirst, and digestion. Finding that the amygdala—a region best known for emotions—can also regulate blood sugar represents a major shift.

Co-author Paul J. Kenny, chair of neuroscience at the Icahn School of Medicine at Mount Sinai, emphasized the broad reach of the findings. If the same circuit operates in humans, it could explain why long-term stress worsens metabolic health. It might also open the door to therapies that protect people at risk for diabetes by targeting the brain-liver connection.

Note: The article above provided above by The Brighter Side of News.

Like these kind of feel good stories? Get The Brighter Side of News' newsletter.