Exploring the Potential of the Ketogenic Diet in Managing Metabolic Syndrome: Mechanisms, Strategies, and Future Research Directions

Jiping Chen¹Jiawei Yao^2*

• ¹Shandong University, Jinan, China
• ²Guangdong Vocational Academy of Art, foshan, China

Metabolic syndrome (MetS) is a multifaceted condition characterized by a cluster of risk factors, including hypertension, elevated fasting blood glucose levels, increased waist circumference (WC), elevated triglyceride (TG) levels, and reduced high-density lipoprotein (HDL) cholesterol levels (1)(2)(3)(4)(5).Conventional treatments for MetS typically involve pharmacological interventions and physical activity (6,7). The former, such as oral hypoglycaemic and lipid-lowering drugs, are effective in controlling blood glucose and lipid levels, but have some side effects and dependence (8,9). The latter are helpful for weight control and improving insulin sensitivity, but these methods are often difficult to adhere to in the long term (10). Therefore, exploring more effective alternative treatment options has become an urgent need.In recent years, the ketogenic diet (KD)-a low-carbohydrate, high-fat nutritional regimen-has attracted considerable attention (11). Specifically, KD promotes fat burning by increasing ketone body (KB) levels (e.g., β-hydroxybutyrate (β-BHB)), improves insulin sensitivity, regulates lipid metabolism, and reduces chronic low-grade inflammatory responses, which in turn alleviates the symptoms of MetS (12,13). However, most current studies have focused on short-term effects in specific populations, leaving a gap in data from multicentre, large-scale clinical trials that encompass diverse ethnicities, age groups, and lifestyles (14)(15)(16). Future research should focus on the effects of the KD on various aspects of MetS, especially its adaptation in different populations. In addition, exploring optimised regimens such as cyclical KD, as well as combining them with other therapeutic options, may provide more effective avenues for the treatment of MetS. MetS is a group of closely related metabolic abnormalities that typically include obesity, insulin resistance, hyperglycemia, and hyperlipidemia (17). Treatment for MetS does not focus on a single health indicator; instead, it aims to reduce the overall metabolic burden through comprehensive interventions (18). assessed the metabolic health of low-fiber carbohydrates in patients with bipolar disorder (20). In contrast to the effects of KD, increased intake of low-fiber carbohydrates was associated with increased prevalence of MetS and higher BMI in this primary cohort. These findings suggest that the KD is highly effective in improving metabolic health, particularly in patients with psychiatric disorders.Another 52-week study assessed the effects of an Asian KD (AKD) on individuals with MetS (16).Participants were randomly assigned to three groups: the whole egg intake AKD group (Yolk-AKD), the yolk-free AKD group (White-AKD), and a balanced low-caloric diet group (BLC). The resultsshowed that the AKD group experienced significant improvements in weight, WC, and insulin sensitivity compared to the BLC group, with the Yolk-AKD group exhibiting the most pronounced weight loss. HDL cholesterol levels increased significantly in the AKD group, while TG levels decreased, indicating that AKD is efficacious in improving blood lipid profiles. Although low-density lipoprotein (LDL) increased, the improvement in HDL level helped to balance overall blood lipids.Furthermore, the AKD group exhibited lower levels of inflammation-related hormones, including a significant reduction in interleukin-6, tumor necrosis factor-alpha (TNF-α), and monocyte chemoattractant protein-1, underscoring its positive impact on metabolic health.It is worth noting that a single dietary intervention has obvious limitations in understanding the comparative analysis of the KD with other dietary interventions, especially in the context of MetS.Therefore, in order to show the differences and advantages of the KD versus other dietary regimens in improving various aspects of MetS, Castaldo et al. investigated the effects of combining a KD with a Mediterranean diet for the treatment of obesity (14). The results showed that the KD resulted in significant reductions in body weight and abdominal fat, along with improvements in blood glucose levels, lipid profiles, and liver function. While the Mediterranean diet phase also improved metabolic health to some extent compared to KD, a rebound in blood glucose and lipid levels was observed, indicating lower resilience. Overall, the combined approach of the ketogenic and Mediterranean diets proved highly effective in enhancing body weight reduction and metabolic health and lowering cardiovascular risks in patients with obesity. Subsequently, Genco et al. examined the impact of combining a very low-calorie KD with an intragastric balloon (Orbera) on weight loss outcomes in patients with obesity (21). The study included 80 patients with obesity who were randomly assigned to two groups after four months from the start of study: one group followed a KD with an intragastric balloon (Group A), while the other adhered to a low-calorie diet (LCD) with an intragastric balloon (Group B). The results revealed that, Group A experienced significantly greater weight loss than Group B (8 kg vs. 3 kg), with a total weight loss of 19 kg in Group A compared to 12 kg in Group B (p < 0.05). This study demonstrated that an intervention programme combining a KD with an intragastric balloon not only enhances weight loss but also has important clinical significance in improving various metabolic indices in MetS, suggesting its potential in the comprehensive management of MetS.In addition, Ghorbanian et al. investigated the effects of a KD and aerobic exercise (AE) on the metabolic health of middle-aged men with MetS (15). The results revealed that the AE+KD group experienced significant reductions in body weight, BMI, and body fat percentage, alongside substantial decreases in retinol binding protein 4 levels. The AE intervention also led to significant reductions in fatty acid binding protein 5 levels. Furthermore, the AE+KD group demonstrated notable improvements in insulin resistance and increased insulin sensitivity. Recent studies have shown that dietary patterns with increased protein intake trigger the release of anorexigenic hormones, such as glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), and peptide YY (PYY), which collectively contribute to reduced appetite. This mechanism is particularly relevant in the management of MetS, where appetite control is essential for weight management. Hall et al. examined the effects of casein and whey proteins on appetite and gastrointestinal hormone secretion (22). Their findings revealed that whey protein notably elevated plasma amino acid levels, stimulating the secretion of CCK and GLP-1, thereby enhancing satiety. In a similar vein, Lejeune et al. investigated the impact of a high-protein (HP) diet versus an adequate-protein diet on 24-hour satiety, energy expenditure, and substrate metabolism (23). Although energy intake did not differ substantially between the two diets, energy expenditure and fat oxidation were elevated in the HP diet, suggesting that HP diets may play a crucial role in improving insulin sensitivity and long-term weight management, thereby addressing multiple aspects of MetS.KD influences blood pressure through the renin-angiotensin-aldosterone (RAA) system. For instance, Belany et al. investigated the effects of a low-calorie, low-fat diet (LFD) compared to a KD on the human body, specifically focusing on aldosterone and renin (24). The study revealed that after six weeks of intervention, aldosterone levels rose significantly in the KD group, while no notable changes were observed in the LFD group. Specifically, aldosterone levels in the KD group increased by 88% and 144%, which may be attributed to the elevated concentration of KBs. Moreover, despite the rise in aldosterone, cardiovascular metabolic risks, including blood pressure and blood glucose levels, remained unaffected in the KD group. Despite elevated aldosterone, blood pressure and blood glucose levels were not adversely affected in the KD group, suggesting that the KD may have a potentially protective role in the management of MetS, particularly for blood pressure and cardiovascular health. 26). This demonstrates the potential of the KD in the short-term management of MetS, but more clinical studies are needed to validate its long-term effects and safety.In addition to this, MetS is usually accompanied by chronic low-grade systemic inflammation that is closely associated with MetS features such as insulin resistance, abdominal fat accumulation, and dyslipidaemia (27). It has been found that one of the main mechanisms by which the KD modulates inflammation is by promoting an increase in the level of circulating β-BHB, the primary KB, which can inhibit the inflammatory response through multiple pathways (28). β-BHB inhibits the expression of pro-inflammatory genes (e.g., TNF-α, IL-1β, and NF-κB) by up-regulating anti-inflammatory genes, such as NF-κBIA and MAP3K8, thereby reducing the release of inflammatory factors (28)(29)(30)(31)(32). In addition, KD directly affects lipid profile and insulin sensitivity by limiting the intake of digestible carbohydrates. Specific mechanisms include decreasing insulin secretion, promoting lipolysis, and increasing KB levels, thereby improving insulin signaling (33,34). Through these mechanisms, the KD not only helps to alleviate inflammation associated with MetS but also significantly improves metabolic indices such as body weight, blood glucose, blood lipids, and blood pressure, thus providing an important adjunctive role in the treatment of MetS. (3) the mechanisms by which the KD influences gut microbiota and metabolic pathways in the management of MetS.