A University of Geneva study found that a high-protein “paleolithic diet” can be effective in weight management and diabetes stabilization. However, the study pointed out significant risks, including increased ammonium production, which can lead to severe neurological damage and, in extreme cases, coma. The study highlights the importance of understanding one’s metabolic health, particularly glutamate dehydrogenase function, before adopting such a diet.
The UNIGE study highlights the potential toxic risks associated with high-protein diets, which can lead to serious neurological damage.
High-protein diets, also known as “paleolithic diets”, are becoming increasingly popular. Researchers from the University of Geneva (UNIGE) investigated their effects in a mouse model. Although these diets have proven effective in weight management and diabetes stabilization, they also come with potential risks. High protein intake can significantly increase ammonium production, overloading the liver. Elevated ammonium levels can cause neurological damage and, in extreme cases, lead to coma. Biochemistry Journaladvises caution when adopting such a diet.
Type 2 diabetes is a metabolic disease that is on the rise. A sedentary lifestyle and an overly nutritious diet causes the damaged pancreas to struggle to regulate blood sugar levels. Current treatments help slow the progression of the disease but do not cure diabetes. Weight loss is often an important part of treatment.
“Diets high in animal and plant proteins, known as Paleolithic diets, can be used to stabilize type 2 diabetes and regulate body weight,” explains Pierre Meckler, a professor in the Department of Cellular Physiology and Metabolism at the Yale University School of Medicine, who led the study. These diets are inspired by the meat-based diets of pre-agricultural times. “But what effect do they have on the body? Are they harmless? That’s what we’ve started to ask.”
A liver under pressure
Ammonium is a normal waste product of protein breakdown and is essentially removed by the liver’s glutamate dehydrogenase (GDH). An excess of protein puts a strain on the GDH enzyme. To study the effects of a high-protein diet, Pierre Meckler’s team fed healthy mice and mice lacking the GDH enzyme in their liver a diet with a protein content that mimicked the so-called Paleolithic diet.
The scientists observed that in healthy mice, despite the increased production of ammonium due to the protein excess, the liver was able to manage this excess thanks to the action of the GDH enzyme, detoxifying the ammonium before it could cause damage. “In contrast, in mice lacking the GDH enzyme, the liver is unable to eliminate the toxic excess of ammonium derived from proteins. You don’t need to wait weeks or months – a few days of dietary changes are enough to observe a significant impact,” explains Karolina Ruczkowska, former PhD student at the Department of Cell Physiology and Metabolism at the UNIGE Faculty of Medicine and lead author of the study.
Caution is required
These results suggest that a high-protein diet can lead to a harmful ammonium excess if the GDH enzyme is dysfunctional. Ammonium that is not removed by the liver can lead to severe disorders, especially of the nervous system. Evaluating GDH activity with a blood test can help to avoid a protein overload on the metabolism of people with a deficiency of the GDH enzyme. “It is therefore important to be well informed before starting a high-protein diet”, concludes Pierre Maechler.
Reference: “Dietary protein loading affects energy and nitrogen balance requiring hepatic glutamate dehydrogenase to maintain physical activity” Karolina Luczkowska, Yan Zhou, Angela M. Ramos-Lobo, Thierry Brun, Pierre Maechler, June 13, 2024, Biochemistry Journal.
DOI: 10.1016/j.jbc.2024.107473
