Oral diabetes drug semaglutide fights obesity in mice: A game-changer for human treatment?

By Neha MathurSep 3 2023Reviewed by Benedette Cuffari, M.Sc.

In a recent study published in the journal Nutrients, researchers investigate the metabolic effects of oral semaglutide in diet-induced obese (DIO) mice.

Study: Oral Semaglutide under Human Protocols and Doses Regulates Food Intake, Body Weight, and Glycemia in Diet-Induced Obese Mice. Image Credit: myskin / Shutterstock.com

Background

Semaglutide, an oral form of glucagon-like peptide-1 receptor agonist (GLP-1RA), is one of the first type 2 diabetes (T2D) drugs shown to mitigate obesity. These observations led to the approval of three, seven, and 14 mg doses of semaglutide for clinical use in humans.

The PIONEER 1 study showed that seven and 14 mg oral semaglutide significantly reduced hemoglobin A1C (HbA1C) and body weight (BW) at 26 and 52 weeks of treatment, respectively, in T2D patients. Moreover, 14 mg oral semaglutide reduced body fat mass and energy intake of T2D patients within 12 weeks and increased satiety in people eating high-calorie breakfasts. Oral semaglutide was also found to be more effective in reducing body weight than dulaglutide and liraglutide, both of which are also GLP-1RAs.

Due to differences in their gastrointestinal (GI) tract, oral semaglutide absorption might vary in humans and laboratory animals. Thus, an appropriate experimental model is needed to elucidate the mechanisms of oral semaglutide in humans.

About the study

In the present study, researchers selected a DIO murine model to test the metabolic effects of injected oral semaglutide doses reported in humans, including food intake (FI), BW, and blood glucose (BG) levels. Oral semaglutide doses included 0.05 mg/kg, 0.12 mg/kg, 0.23 mg/kg, and 0.7 mg/kg, which were equivalent to three, seven, 14, and 42 mg human doses, respectively.

Four-week-old male DIO mice weighing between 50-55 g were separated into three groups with seven mice each. The first and second groups received oral semaglutide 0.23 mg/kg, which was equivalent to a 14 mg human dose in 0.5 or 0.1 mL distilled water (DW), respectively. Controls received 0.23 mg/kg semaglutide with 0.5 mL DW. 

For the next set of experiments, DIO mice aged 32 weeks were separated into two groups of seven animals each according to their BG levels. These mice were injected with 0.23 mg/kg oral semaglutide in 0.1 mL DW in test groups and 0.5 mL DW in control groups.

In another set of experiments, DIO mice aged 32 weeks were also divided into five groups of six animals, each based on their daily FI. The four test groups received 0.05 mg/kg, 0.12 mg/kg, 0.23 mg/kg, and 0.7 mg/kg oral semaglutide in 0.1 mL DW, whereas the control group received only 0.5 mL DW.

DIO mice aged 36 weeks were also divided into three groups based on their BW and FI. The two test group animals received oral semaglutide at 0.23 and 0.7 mg/kg dosages in 0.1 mL DW, whereas controls received 0.5 mL DW.

Mice were deprived from food and water at 16:00 and 18:00, respectively, before receiving oral semaglutide or DW at 19:30. After 30 minutes, which was defined as “injection-refed” time, mice regained access to food and water. 

Blood samples were collected 30 minutes before the injection of oral semaglutide to quantify BG levels. Total FI was also measured at one, two, four, 12, and 20 hours after injection-refed time and BG levels at one, two, four, 12, and 24 hours post-injection-refed.

Additional mice also received oral semaglutide once daily for three days, during which their daily FI and BW were measured at 16:00. FI was also measured in the light phase (LP) between 8:00 and 16:00 before fasting, as well as between 20:00 and 8:00 the next day, which was defined as the dark phase (DP).

Study findings

In humans, oral semaglutide is adequately absorbed when administered early in the morning in less than 120 mL water after overnight fasting and drinking-restricted state, followed by an additional fasting and drinking-restricted state of 30 minutes after taking the drug.

The current study demonstrated that oral semaglutide in 0.1 mL DW lowered glycemia, FI, and BW in DIO mice. However, its administration in a five times larger DW volume of 0.5 mL prevented its effect on FI. These observations suggest that oral semaglutide should be administered in a small volume of water for successful absorption in the stomach of mice. 

Oral semaglutide consistently decreased daily FI and progressively reduced BW gain in DIO mice. When injected once daily for three days, this treatment also reduced LP and daily FI between days one and three, as well as BW gain on days two to three of treatment. This dose-dependent effect of oral semaglutide requires more investigation, as trials are already evaluating a higher oral semaglutide dose of 50 mg for treating obese subjects.

Conclusions

Oral semaglutide at a dose of 0.23 mg/kg after fasting and water deprivation rapidly decreased BG levels and total FI in DIO mice, ultimately reaching significant levels four hours after injection-refed time.  

A key finding of this study is the utility of the DIO murine model, as it successfully reproduced the metabolic effects of oral semaglutide reported in humans. Thus, the DIO animal model appears to be suitable for exploring the mechanism of action of oral semaglutide in future studies evaluating this treatment for obesity and T2D.