How Overeating Leads to Type 2 Diabetes: The Role of Neurotransmitters

How Overeating Leads to Type 2 Diabetes: The Role of Neurotransmitters

People with obesity have a tenfold increased risk of developing diabetes compared to lean people. Researchers trying to get to the bottom of this phenomenon have found an answer in the same system that controls the body's fight-or-flight response. The results 1, conducted in mice, challenge long-held assumptions about how overeating can lead to disease.

The study suggests that consuming a high-fat diet triggers a surge in neurotransmitters throughout the body, leading to the rapid breakdown of fatty tissue in the liver - a process normally triggered by the release of insulin is controlled. The release of high levels of fatty acids has been linked to a range of health problems, from diabetes to liver failure 2.

Previously, researchers thought that the main problem with obesity-related diabetes lies in faulty insulin activity, meaning the body does not stop the dangerous release of fatty acids. But the latest study shows that instead of a malfunctioning "brake system," there is a separate lever - neurotransmitters in the liver and other tissues - that are pressing hard on the accelerator, explains Martina Schweiger, a biochemist at the University of Graz, Austria. “This is actually a paradigm shift.”

The study was published October 21 in Cell Metabolism.

Insulin resistance

More than 890 million people worldwide are of obesity affected, the one great risk of developing diabetes and other metabolic disorders. Researchers have known for a long time that... disease progresses, when insulin is no longer able to lower blood sugar levels. Christoph Buettner and Kenichi Sakamoto, both physiologists at Rutgers University in New Brunswick, New Jersey, and their colleagues wanted to better understand the nature of this insulin resistance.

Buettner had long studied the role of insulin in the brain in regulating metabolism 3. So his team focused on the sympathetic nervous system, which transports neurotransmitters like norepinephrine to tissues throughout the body. The researchers used a mouse model in which they deleted a gene that expresses a key enzyme for producing these neurotransmitters. The gene was deleted only in the mouse's limbs and some organs, but not in the brain, to ensure it remained viable.

The modified mice were fed a high-fat diet containing lard, coconut oil and soybean oil. Over a period of more than two months, both the modified and unmodified mice ate similar amounts of food, gained comparable amounts of weight and exhibited similar insulin signaling activity, which describes the cascade of events that occurs after insulin binds to its target receptor on a cell.

However, the modified mice did not show increased adipose tissue breakdown and insulin resistance, and ultimately did not exhibit increased signs of fatty liver disease and tissue inflammation. In contrast, the unmodified mice developed insulin resistance, which can lead to diabetes. They also showed increased signs of inflammation and liver disease.

Signals in the brain

The results suggest that neurotransmitters are responsible for creating insulin resistance and related problems, says Buettner. He and his colleagues are now exploring the role of these neurotransmitters in other conditions, such as insulin resistance caused by menopause.

“This study is pretty well-founded,” says Schweiger, but “there are still some pieces of the puzzle missing.” The question of how the high-fat diet triggers the increase in neurotransmitters remains to be clarified.

She adds that additional work is needed to better understand the implications of the findings for people. So far, drugs that block the activity of neurotransmitters in the sympathetic nervous system have shown no benefit in obese people. It may be possible that targeting these drugs to specific tissues, avoiding the brain, might be more promising, Buettner says.

1. Sakamato, K. et al. Cell Metab. https://doi.org/10.1016/j.cmet.2024.09.012 (2024).

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2. Saponaro, C., Gaggini, M., Carli, F. & Gastaldelli., A. Nutrients 13, 9453–9474 (2015).

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3. Sherer, T. et al. Journal of Biological Chemistry 287, 33061–33069 (2012).

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