Ketogenic diet but not free-sugar restriction alters glucose tolerance, lipid metabolism, peripheral tissue phenotype, and gut microbiome: RCT.

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• Neither sugar nor carbohydrate-restricted diets were found to significantly affect energy expenditure or physical activity.

• Both 12-week sugar and carbohydrate-restricted diets resulted in reductions in body mass and cholesterol.

• Ketogenic carbohydrate restriction may not deliver the expected cardiometabolic health benefits typically associated with weight loss. Instead, reducing free sugar intake could be a more effective dietary approach for improving overall cardiometabolic health in many individuals.

• A carbohydrate-restricted diet providing less than 8% of total energy intake negatively influenced glucose tolerance, lipid metabolism, peripheral tissue phenotype, and gut microbiome composition.

Introduction

A randomised controlled trial was conducted to evaluate the effect of restricted dietary sugars (LOWSUG), or restricted carbohydrates (Ketogenic diet; LOWCHO), on free-living physical activity energy expenditure (PAEE) over 12 weeks in healthy adults. These two diets were each compared to a control diet with moderate sugar and carbohydrates (MODSUG).

Methods

Fifty-three participants were randomly assigned to one of the three dietary groups - LOWSUG, LOWCHO or MODSUG - for 12 weeks. Circulating biochemical profiles, diurnal glycemia, and muscle glycogen concentrations were assessed at baseline, 4 and 12 weeks. Participants in the LOWSUG group consumed less than 5% of their total energy intake from sugars, while those in the LOWCHO group consumed less than 8% of their energy from carbohydrates. Of the 60 participants initially enrolled, 53 (88%) completed the trial.

Results

Impact of LOWSUG

• Body mass was significantly reduced at both weeks 4 and 12 compared to the MODSUG group (p= 0.05; p=0.04, respectively).

• Total cholesterol was lowered at week 12  in the LOWSUG group compared to MODSUG (p= 0.001).

• By week 12, there was an 18% reduction in Akt (protein kinase B) compared to MODSUG (p=0.02), which coincided with increased glycogen concentrations at both weeks 4 and 12 (p=0.03; p= 0.004, respectively).

• LOWCHO altered gut microbiota beta diversity (p=0.04) and reduced the abundances of Bifidobacterium at weeks 4 and 12 (p=0.04;p= 0.01), while also changing metabolic pathway abundances at weeks 4 and 12 (p=0.02;p=0.04), and decreasing serum propionate at week 4 (p=0.03), with no changes in gut permeability markers or overall microbiome alpha diversity.

Impact of LOWCHO

• Body mass was significantly reduced at both weeks 4 and 12 compared to the MODSUG group (p< 0.001 for both time points).

• Increases were observed in low-density lipoproteins (LDLs), and very-low-density lipoproteins VLDLs, along with a reduction in total lipid high-density lipoprotein (HDL) particles (all p<0.05 vs. MODSUG).

• The ketogenic diet increased apolipoprotein B (apoB) concentrations (p=0.006) and fasting triacylglycerol concentrations at week 4 (p = 0.04) compared to MODSUG.

• Respiratory expenditure rate (RER) was significantly reduced at weeks 4 and 12 in the fasted state (p=0.004; p=0.04), postprandial state (p =0.005; p=0.01), and during exercise (p< 0.001; p= 0.001) compared to MODSUG.

• Skeletal muscle pyruvate dehydrogenase kinase 4 (PDK4) protein levels were elevated at week 4 (p= 0.04),  while insulin receptor (INSR), adenosine monophosphate-activated protein kinase (AMPK), glucose transporter 4 (GLUT4), and perilipin 1 (PLIN) were decreased at week 12 (p= 0.006, p =0.02, p=0.03, and p=0.02, respectively), compared to MODSUG.

• Gut microbial beta diversity was altered, with a significant reduction in the abundance of bifidobacterium observed at both weeks 4 and 12 (p=0.04).

Conclusion

This RCT demonstrated that sugar restriction led to weight loss, improved cholesterol profiles, and beneficial metabolic changes, including reduced Akt levels and increased glycogen storage. In contrast, carbohydrate restriction also reduced weight but negatively impacted lipid markers, metabolic proteins, and gut microbiota composition.

• This study found that both sugar and carbohydrate-restricted diets reduce body mass and cholesterol levels – an important consideration for targeted strategies by clinicians

• A ketogenic diet, restricting carbohydrates to below 8% of energy intake, affected glucose tolerance, increased apolipoprotein levels and reduced bifidobacterium abundance. As such, clinicians should be aware that a ketogenic diet may not be appropriate for all clients. Monitoring lipid panels, glucose intolerance and gastrointestinal symptoms may therefore be useful.

• This study demonstrated that carbohydrate restriction can positively influence certain cardiometabolic markers. However, further research is warranted to explore the effects of ketogenic diets in populations with prediabetes, metabolic syndrome and cardiovascular disease.

• Carbohydrate restriction was associated with reduced GLUT4, AMPK, and insulin receptors. Consequently, additional research is needed to examine how ketogenic diets may influence exercise-induced adaptations, particularly those related to insulin sensitivity and metabolic flexibility.