Summary:
Obesity is closely linked to metabolic diseases such as dyslipidemia, prediabetes and excess liver fat, all of which increase the risk of type 2 diabetes and cardiovascular disease. These conditions are driven largely by insulin resistance in the liver and skeletal muscle. Although weight loss reliably improves insulin response, the macronutrient composition of a diet can also influence metabolic health independently of weight change. Popular diets such as the ketogenic, Mediterranean and very‑low‑fat plant diets, differ in their carbohydrate, fat and protein content, yet it is unclear which is more weight loss conducive. This randomised clinical trial examined whether these three diets have diet‑specific cardiometabolic effects when participants with unhealthy obesity achieve similar weight loss. All meals were provided to ensure adherence, and each group lost approximately 10% of body weight. This design allowed the investigators to isolate the metabolic impact of diet composition rather than differences in calorie intake for weight loss. Across all groups, weight loss improved skeletal muscle insulin sensitivity, fasting glucose, insulin resistance and several cardiovascular risk markers. However, this study found that the ketogenic diet produced the largest improvements in liver‑related metabolic outcomes. Liver fat also decreased in all groups, but the reduction was greatest with the ketogenic diet. The ketogenic diet caused large reductions in 24‑hour glucose and insulin exposure, increased insulin response and showed sustained elevations in ketones. Despite its high saturated‑fat content, the ketogenic diet did not worsen cholesterol markers. This study therefore demonstrated that while weight loss improves metabolic health regardless of diet, macronutrient composition meaningfully shapes the magnitude of the metabolic change. The ketogenic diet produced the most improvements in liver insulin sensitivity, liver fat, glucose regulation and several cardiovascular risk markers.
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Abstract:
The influence of diet macronutrient content on the cardiometabolic effects of weight loss in people with metabolically unhealthy obesity (prediabetes and hepatic steatosis) has important clinical implications. We evaluated the cardiometabolic effects of moderate (∼10%) weight loss induced by three popular diets with markedly different macronutrient composition (very-low-carbohydrate ketogenic, Mediterranean, and very-low-fat plant-forward). Weight loss increased muscle insulin sensitivity by ∼50% in all groups but caused a two-to-three-fold greater increase in hepatic insulin sensitivity in the very-low-carbohydrate group than the other groups (p < 0.001). Intrahepatic triglyceride content, hepatic de novo lipogenesis, glycated hemoglobin, and 24-h serial plasma glucose and insulin decreased most in the very-low-carbohydrate group. There were no differences among groups in LDL-cholesterol, apolipoprotein B, or 24-h plasma triglyceride concentrations. These results demonstrate that a very-low-carbohydrate diet has greater cardiometabolic benefits, particularly in hepatic metabolic function, than matched 10% weight loss induced by a Mediterranean or very-low-fat diet in people with metabolically unhealthy obesity.
Article Publication Date: 27/08/2026
DOI: 10.1016/j.cmet.2026.07.020
