Scientists have found that hyperbrain cells are the cause of increased blood sugar in diabetes, challenging routine understanding of the disease and potentially opening up new avenues of treatment. The finding, published on May 15 in the Journal of Clinical Research, suggests that a specific group of neurons in the hypothalamus plays a crucial role in diabetes development, unlike their effects on body weight or food intake.
In a study using diabetic mice, researchers at the University of Washington found that hyperactivity AGRP neurons in the brain were silenced within a few months without affecting weight or eating habits. This finding suggests that diabetes treatment targeting these neurons may also help patients treat blood sugar without losing weight.
“These neurons play an important role in hyperglycemia and type 2 diabetes,” said Dr. Michael Schwartz, a subject author of the paper. “He pointed out that this finding is “a departure from the traditional concept that leads to diabetes.”
Challenging traditional perspectives
Traditionally, type 2 diabetes is understood as a peripheral disease caused by insulin resistance in tissues such as muscles and liver, often associated with obesity and lifestyle factors. The role of the brain in diabetes development has received less attention.
But increasing evidence has prompted scientists to reconsider this view. Researchers have previously shown that injecting a protein called fibroblast growth factor 1 (FGF1) directly into the brain normalizes blood sugar in diabetic mice.
Can hyperactivity AGRP neurons become the key? To find out, the team used genetic techniques to silence these neurons in obese diabetic mice.
The results were surprising: blood sugar levels dropped from the diabetes range (above 200 mg/dl) to the normal range (about 140 mg/dl) and remained stable throughout the 10-week study period. However, food intake, weight, fat mass, and energy consumption remain the same.
Brain Candy Connection
To permanently inactivated AGRP neurons, the researchers injected a virus into the toxobaric nucleus of the hypothalamus where these neurons are located, which carries tetanus toxin. Toxins prevent neurons from communicating with other cells, but do not kill them.
When examining physiological changes in normalized blood sugar, the team discovered several interesting patterns:
- Plasma insulin levels have significantly decreased, indicating increased insulin sensitivity
- Increased liver glycogen content indicates better liver glucose processing
- Lower plasma corticosterone (mouse equivalent cortisol) levels
- Increased plasma lactate levels may support enhanced hepatic glucose absorption
Interestingly, the researchers found no changes in liver fat content or glycogenic gene expression, indicating an improved effect of blood sugar control compared to traditional diabetes treatments.
Separate obesity from diabetes
Perhaps the most surprising aspect of this study is how AgRP neurons normalize blood sugar without affecting weight or food intake. This challenges the assumption that obesity and diabetes are inevitably linked.
“Although these neurons are important for controlling blood sugar in diabetes, they are not important in causing obesity in these mice,” the researchers noted in the report.
What makes this finding particularly interesting is that it suggests that different brain circuits may control metabolism and dietary behaviors respectively. This could explain why some diabetes treatments require weight loss even without substantial weight loss, while others require weight loss to improve blood sugar control.
Impact on human therapy
Can these discoveries be transformed into humans? Although mouse studies do not always predict human results, there are interesting links to current diabetes treatment.
Schwartz notes that popular GLP-1 receptor agonists, such as Ozempic, are known to inhibit AGRP neurons. “The extent to which this effect leads to the antidiabetic effects of these drugs is unclear,” he said, suggesting how these drugs can go beyond the underlying mechanisms of weight loss.
This study also relates to growing evidence that the brain plays an important role in metabolic regulation. Several studies have shown that interventions targeting the central nervous system can profoundly affect glucose metabolism throughout the body.
Looking to the future
More research is needed to understand how these neurons become overactive in the first place and how they safely regulate their activity in humans. However, these findings suggest that targeted diabetes therapy may be independent of weight loss.
How does such a treatment work? They may involve drugs specifically designed to inhibit the activity of AGRP neurons, or existing drugs that use these neurons as part of their mechanisms.
As researchers continue to reveal the role of the brain in diabetes, these findings challenge our different thinking about this common disease. Rather than viewing type 2 diabetes as a peripheral metabolic disease driven by obesity, we may need to partially view it as a brain dysfunction—a multi-active neuron that drives hyperglycemia independently of body weight.
This shift in perspective could ultimately lead to more effective treatments for diseases that affect hundreds of millions of people around the world.
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