Chronic stress and fatty diet disrupt brain-liver circuit leading to diabetes

Bottom line: This study discovered a circuit in the brain that connects stress with increased glucose and therefore may link stress to type 2 diabetes. In stressful situations, this circuit from the amygdala to the liver naturally provides a burst of energy. When introducing chronic stress and a fatty diet, researchers observed a disruption in the circuit's output, specifically, an excess of glucose production in the liver. Long-term elevations in glucose can cause hyperglycemia and increase the risk of developing type 2 diabetes.

Why this study is unique: This is the first time researchers have described the connection between the medial amygdala in the brain-a specific area of the amygdala that responds to stress-and liver glucose production. The study, conducted in an animal model, represents a new way of targeting diabetes and shows how important stress is as a driver of diabetes and increased mortality.

To date, most studies have focused on how the hypothalamus and brain stem regulate blood glucose. These are regions in the brain that are homeostatic, controlling functions like hunger, thirst, and digestion. Showing that the amygdala, an area traditionally associated with emotion, also controls blood glucose is a major shift in thinking.

Why the study is important: These findings have significant consequences for how we think about preventative medicine and the causes of illness, including stress and social determinants of health. People admitted to the hospital with abnormal glucose responses (too high or too low) experience significantly higher rates of complications and death. Additionally, it has been demonstrated that chronic stress is linked to an increased risk of type 2 diabetes, which affects 500 million people worldwide.

How the research was conducted: To understand how stress changes brain activity in the amygdala, researchers monitored neural activity in the medial amygdala in mice. They found that many different types of stress, from social stress to visual stress, increased the medial amygdala activity and as expected, increased the mice's blood glucose.

They then switched on the medial amygdala neural activity in unstressed mice, which reproduced the same rise in glucose associated with stress, without causing stress-induced changes in behavior. This suggests that the circuit from the medial amygdala governs the glucose responses to stress.

Researchers then traced the neuronal connections from the medial amygdala through the hypothalamus to the liver, which showed that stress switched on the neurons connecting the medial amygdala and the hypothalamus, resulting in an increase in glucose released from the liver.

Results: The study showed that exposure to a range of acute stressors rapidly increases circulating blood glucose by 70 percent. At the time of the stress exposure, medial amygdala neuron activity was increased about twofold. Because this change in activity occurred before the change in blood glucose, we hypothesized that the medial amygdala could be driving this increase in glucose. To test this, researchers switched on medial amygdala neurons in unstressed mice, resulting in a 50 percent increase in blood glucose.

To determine the mechanism through which neural activity in the medial amygdala increased blood glucose, we used viruses to identify and map the neural circuits involved and found that medial amygdala neurons have major connections through the hypothalamus to the liver. When we switched on the amygdala connections to the hypothalamus, the amount of glucose released from the liver almost doubled.

Furthermore, researchers found that a combination of repeated stress and fatty diet altered the circuit between the medial amygdala and liver, resulting in long-term increased glucose, even when the mice were no longer exposed to stress. The research shows that, when exposed to repeated stressors, this circuit became desensitized, resulting in a decreased neural and glucose response to subsequent stress, pushing the mice toward diabetes.

These findings suggest that repeated stress disrupts the medial amygdala-to-hypothalamus-to-liver circuit, increasing liver glucose release.

What this study means for doctors and patients: This study gives clinicians a better understanding of the mechanisms linking stress and glucose control, opening new avenues to develop treatments to help reduce the risk of diabetes and improve glucose control for individuals with diabetes, particularly in individuals with elevated stress levels. By understanding the neural circuits through which stress controls glucose, we can identify therapies that help to regulate blood glucose and mitigate the risk of type two diabetes.

What the next steps are for this work: These findings suggest further research is required to study the medial amygdala-to-hypothalamus-to liver circuit in more detail, examine the types of neural cells involved, and observe how short-term and long-term stress changes the circuit structure and gene expression.

Additional research can also help understand if taking steps to reduce stress will reverse the disruption in the circuit, lowering the risk of diabetes and returning the circuit to healthy function.

Quotes: "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. Previously, we thought the amygdala only controls our behavioral response to stress-now, we know it controls bodily responses, too. The impact of stress on diabetes is enormous. But it's not just diabetes: stress has broader impacts on many other conditions. This means that addressing the social determinants that contribute to stress may improve health, including diabetes" says Dr. Stanley.

Funding: This work was supported by the American Diabetes Association "Pathway to Stop Diabetes" Grant, and in part by grants from the National Institutes of Health and Department of Defense.