When participants lost roughly the same amount of weight, changing the balance of carbohydrates, fats, and protein produced strikingly different metabolic responses, particularly in the liver.
Study: Effect of diet macronutrient content on the cardiometabolic response to weight loss: A randomized clinical trial. Image Credit: Explode / Shutterstock
A recent randomized controlled trial (RCT) published in the journal Cell Metabolism suggests that dietary macronutrient composition may influence cardiometabolic responses to weight loss. Participants adhering to the very-low-carbohydrate ketogenic diet (KD) demonstrated greater reductions in liver fat compared with those following the Mediterranean and very-low-fat plant-forward diets.
These findings could inform diet planning and nutrition research to help improve health outcomes through dietary modification, particularly among people with metabolically unhealthy obesity, defined in this study as obesity with prediabetes and hepatic steatosis.
Obesity is associated with metabolic diseases such as atherogenic dyslipidemia, prediabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). Strategies designed to improve the cardiometabolic health of such individuals may help lower the associated disease burden. In particular, interventions that can improve skeletal muscle and liver responses to insulin and/or decrease resistance to the hormone may help reduce obesity-associated metabolic dysfunction.
Recent studies suggest that the macronutrient composition of a diet may affect metabolic health independently of weight loss itself. In many previous diet studies, uncertain dietary adherence and unequal weight loss between groups have made it difficult to determine whether metabolic benefits reflect diet composition or weight loss itself.
About the study
In the present RCT, researchers compared the effects of dietary macronutrient composition on cardiometabolic responses to moderate weight loss. To do so, they evaluated cardiometabolic biomarkers among people with metabolically unhealthy obesity who lost approximately 10% of body weight after roughly five months of following the carbohydrate-restricted KD, Mediterranean diet (MedDiet), or fat-restricted plant-forward (PF) diet.
In total, 55 individuals were randomized to the KD, MedDiet, and PF diet groups, of whom 42 completed the study and were analyzed. Each final group comprised five men and nine women with a mean age of 43 years and an initial body mass index (BMI) of nearly 39 kg/m2. The team provided all study food and arranged weekly dietitian follow-ups to ensure dietary adherence. They assessed body composition, hepatic lipogenesis, oral glucose tolerance, pancreatic beta (β)-cell function, and blood pressure.
At baseline and after the dietary interventions, the researchers measured plasma lipid, triglyceride, glucose, and cytokine concentrations in blood samples collected from participants. They also assessed circulating hormone levels, including insulin, glucagon, and C-peptide. To evaluate how skeletal muscles respond to insulin, the researchers administered insulin and a glucose tracer while maintaining stable blood glucose levels. In a sensitivity analysis of the two primary insulin-sensitivity outcomes, they used linear mixed models to test for diet-by-time interactions using all available data from the 55 randomized participants.
Results
Dietary adherence, evaluated as the proportion of meals and snacks logged as consumed, exceeded 95% across groups. Weight reduction increased insulin responsiveness in the muscles by nearly 50% across groups. Hepatic insulin sensitivity also increased across groups, but the improvement was two to three times greater among KD followers than among those following the other diets.
Weight loss reduced hepatic triglyceride content across groups, but the decrease was more pronounced in the KD group (67%) than in the other groups (approximately 45%). Likewise, 24-hour plasma glucose exposure decreased the most in the KD group (20%) compared with the other groups (approximately 8.0%). While 24-hour plasma insulin exposure decreased across groups, the greatest decrease was observed in the KD group (74%), compared with the MedDiet (44%) and PF (27%) diet groups. Insulin clearance rate also increased the most in the KD group.
Fasting plasma glucose, insulin, mean very-low-density lipoprotein (VLDL) particle size, and the lipoprotein-insulin resistance (LP-IR) index were reduced to the greatest extent in the KD group. The Matsuda index of whole-body insulin responsiveness increased in all groups, with a greater increase in the KD group than in the MedDiet group. Hepatic de novo lipogenesis and glycated hemoglobin (HbA1c) also declined more with KD, while LDL cholesterol, apolipoprotein B, and 24-hour plasma triglycerides did not differ significantly among diets.
Prediabetes remission occurred in 50% of KD participants, compared with 29% in the MedDiet group and 7% in the PF group. However, all other outcomes beyond the two primary insulin-sensitivity endpoints were exploratory and were not adjusted for multiple comparisons.
The KD group participants demonstrated an increase in the estimated glomerular filtration rate (eGFR) values and decreases in cystatin C, tumor necrosis factor-α (TNF-α), and plasminogen activator inhibitor-1 (PAI-1) concentrations. Of interest, urinary 8-isoprostane concentration, an indicator of oxidative stress, also decreased among KD followers but not among participants in the other group, indicating a diet-specific change in this oxidative stress marker.
KD followers also demonstrated increased urinary nitrogen excretion, whereas those following the MedDiet and PF diets demonstrated decreases. Similarly, plasma glucagon concentrations rose by 52% among KD followers but fell by approximately 30-40% in the other groups. The plasma glucagon-to-insulin ratio increased more than threefold among KD followers but remained largely unchanged in the other groups. The sensitivity analysis of the two primary insulin-sensitivity outcomes yielded results similar to those of the primary analysis. There were no serious adverse events in any study group.
Conclusion
The study findings suggest that a very-low-carbohydrate ketogenic diet, when paired with about 10% weight loss, may produce greater improvements in some cardiometabolic measures among people with metabolically unhealthy obesity similar to those studied.
The macronutrient composition may influence cardiometabolic health beyond the effects of weight reduction alone. If confirmed in further studies with larger sample sizes, this very-low-carbohydrate ketogenic approach may affect circulating insulin, glucose, and glucagon concentrations and alter pathways related to liver fat metabolism. Whether these changes translate into lower cardiometabolic disease risk requires further investigation, particularly among people with metabolic dysregulation.
The study also could not determine whether less severe carbohydrate restriction without ketosis would produce the same effects or whether similar hepatic benefits would occur if the diet were introduced during weight maintenance.
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