Impact of Semaglutide on Growth in Malnourished Mice

In recent years, a group of drugs called GLP-1 receptor agonists (GLP-1RAs) has become important in treating type 2 diabetes and obesity. By 2024, seven GLP-1RAs have been approved in the United States for diabetes treatment. One well-known GLP-1RA is Semaglutide, which has been designed to stay in the body longer and resist breakdown better than other medications in its class. Semaglutide helps control blood sugar levels by increasing Insulin production when blood sugar levels rise and supporting the health and growth of insulin-producing cells in the pancreas. Beyond managing blood sugar, semaglutide also reduces hunger and helps people lose weight, making it a popular choice for treating obesity in both adults and children.

#Growth Regulation in Mammals

In mammals, growth is mainly controlled by hormones, specifically Growth Hormone (GH) and insulin-like growth factor 1 (IGF-1). Research in mice has shown that GLP-1RAs can influence growth by affecting the cells that create bone. Studies have found that GLP-1 and GLP-1RAs can enhance IGF-1 receptor levels, support bone health, and even directly activate IGF-1 receptors. Furthermore, both short-term and long-term GLP-1RA treatments in healthy adults have been linked to increased levels of GH in the bloodstream. This raises the question of whether GLP-1RAs, like semaglutide, could also have an effect on the GH/IGF-1 system.

#The Effects of Protein Malnutrition

While semaglutide's effects on obesity have been well studied, less research has focused on its impact during periods of nutritional stress, such as protein malnutrition. Protein malnutrition can cause significant changes in energy balance and insulin production, leading to poor blood sugar control. Children with chronic protein malnutrition often experience growth issues, such as stunted growth, which is defined by being shorter than expected for their age. Because researching human subjects is challenging, scientists often use mouse models to study the effects of malnutrition on growth and metabolism.

#Investigating Semaglutide's Effects on Malnutrition

Despite the known effects of GLP-1RAs, the role of semaglutide in energy balance and growth during periods of protein malnutrition has not been thoroughly studied. In this context, researchers aimed to examine how semaglutide influences blood sugar control and growth in a mouse model of juvenile protein malnutrition, and whether this medication could help counteract the negative effects of malnutrition. The findings indicated that semaglutide influences Glucose metabolism differently based on the diet and negatively affects the growth of malnourished mice but not those on a regular diet. Moreover, the effects on linear growth appeared to be unrelated to the hormone system (GH/IGF-1), while liver analysis suggested that semaglutide might be impacting the body's rhythms and heat production.

#Animal Study Methods

In the study, male mice around three weeks old were obtained and placed on different diets: a regular diet rich in protein or a modified version low in protein. The mice were weighed weekly and received injections of semaglutide or a salt solution for several weeks. Afterward, they were fasted for a short period, and then the scientists collected blood and body measurements.

The researchers also performed tests to see how well the mice reacted to glucose by giving them a sugar solution and measuring blood sugar levels at various times. This helped them understand how well the mice could manage their blood sugar after consuming sugar.

#Examining Insulin Production

One important aspect of diabetes management is how the pancreas produces insulin, the hormone that helps regulate blood sugar levels. The scientists isolated insulin-producing cells from the mice's pancreases to study how they responded to glucose. By observing the changes in insulin production in response to glucose, the researchers could better understand the effects of semaglutide.

#The Impact of Semaglutide on Glucose Levels

The study found that protein malnutrition led to lower fasting blood sugar and insulin levels. However, the effects of semaglutide treatment on these measurements were not significant. Nevertheless, the medication did improve the mice's ability to tolerate glucose, showing that it enhanced their response to sugar intake, regardless of their diet. Interestingly, the treatment did not boost the overall production of insulin in the body.

#Changes in Pancreatic Islet Cells

Investigating the structure and function of insulin-producing cells (islets) showed that semaglutide treatment caused a reduction in the size of islets in mice on a normal diet but not in malnourished mice. This suggests that semaglutide impacts islet development based on dietary conditions. Additionally, it was found that the isolated pancreatic cells from malnourished mice showed better insulin production when exposed to glucose after being treated with semaglutide, although this did not explain the observed insulin levels in the blood after sugar consumption.

#Growth Implications of Semaglutide Treatment

The study revealed that chronic protein malnutrition greatly affected growth, with malnourished mice being noticeably smaller and lighter. While semaglutide did not change growth in mice on a normal diet, it significantly decreased growth in malnourished mice. These malnourished mice receiving semaglutide were shorter, lighter, and showed reduced growth rates compared to their untreated counterparts.

Surprisingly, semaglutide did not decrease food intake in either group of mice, indicating that the reduced growth in malnourished mice was not due to a lack of food consumption. Moreover, semaglutide changed the weight of fat tissues but did not impact lean mass in malnourished mice.

#Hormonal Growth Factors

The primary hormones affecting growth, GH and IGF-1, were found to be reduced in malnourished mice. Despite this, the introduction of semaglutide did not alter hormone levels or impair hormone production even further. This suggests that the growth issues seen in malnourished mice treated with semaglutide are not directly linked to the hormone system.

#Changes in Liver Gene Activity

To understand more about how semaglutide affects the body, researchers analyzed the activity of genes in the livers of malnourished mice treated with semaglutide. They noticed significant changes in gene expression, suggesting the drug impacts biological functions in the liver. Notably, many of the altered genes were linked to the body's internal clock and heat production processes.

#Understanding Circadian Rhythms and Thermogenesis

The findings indicated that semaglutide treatment was associated with changes in the body's internal rhythms, which can influence how energy is used and stored. Alterations in these processes could explain why semaglutide treatment reduced growth in malnourished mice, potentially by increasing energy expenditure and reducing the body's ability to grow properly. While previous studies have shown that semaglutide can affect energy usage in obese mice, the effects in malnourished states appear to differ.

#Conclusion

This research highlights important details about the impact of semaglutide treatment in juvenile mice, specifically regarding how it affects growth and metabolism based on dietary conditions. While semaglutide is effective for weight loss and blood sugar control, it also presents unique challenges when used in growing organisms dealing with protein malnutrition. Understanding these effects is crucial for ensuring that GLP-1RAs are used safely and effectively, particularly in vulnerable populations such as children who may not be receiving adequate nutrition. Future studies are essential to further explore the mechanisms through which semaglutide acts so that its benefits and risks can be fully understood.