Weight-independent effects of VLCarb on free-living glucose control in individuals at risk for TD2

Background and aims: Very low-carbohydrate (VLCarb) diets have shown great potential in the treatment of metabolic disease. Whether the metabolic benefits of VLCarb diets are solely dependent on body weight loss or can be attributed to its macronutrient composition has not been established. This study evaluates the metabolic effects of a VLCarb diet compared to an energy-matched Mediterranean (MED) diet in overweight individuals with abnormal glycemic control. Materials and methods: Twenty-two subjects with overweight/obesity (BMI>27 kg/m2) and abnormal glycemic control were assigned to a 4-week VLCarb diet (carbohydrate 20%, lipid 50%, protein 30%) and an energy-matched 4-week MED diet (carbohydrate 50%, lipid 20%, protein 30), in a randomized cross-over design. Routine biochemical analyses, mixed meal tolerance tests (MMTT), and 14-day continuous glucose monitoring (CGM) were performed at the end of each diet. Adherence to dietary prescriptions was evaluated by self-reported food diary analysis. Subjects with poor adherence to the VLCarb diet were excluded (n=5). Results: A total of 17 subjects completed the assessments (carbohydrate 29%, lipid 42%, protein 26%), (age 54.7±6.8 years, 47% women, BMI 30.5±0.9 kg/m, HbA1c 39.9±1.0 mmol/mol). VLCarb and MED diets induced a similar weight loss (BMI change -0.8 [-0.6; -1] vs -0.8 [-0.6; -1.1] kg/m2; p=0.714). They also induced comparable improvements in fasting glucose ([-5.1±2.4] vs [-4.6±3.1] mg/dl; p=0.854) and HbA1c (-1.7 [-1.1; -2.3] vs -1.6 [-1.0; -2.2] mmol/mol; p=0.746). At MMTT, there were no differences in plasma glucose (AUC p=0.173), in insulin profiles (AUC p=0.556), nor in markers of insulin resistance. In contrast, free-living glycemic control improved significantly more after the VLCarb diet, with lower mean glucose (85.9±3.3 vs 93.8±3.9 mg/dl; p=0.019) and estimated HbA1c levels (4.6 ±0,1 vs 4.9±0.1%; p=0.027), compared with the MED diet. Conclusion: Energy restriction with a VLCarb diet is not superior to MED diet in improving glucose homeostasis parameters. However, the VLCarb diet improved CGM-derived variables of free-living glycemic control, compared with the Med diet, regardless of body weight loss. This benefit is likely dependent on the low glycemic load of the VLC diet, reducing postprandial hyperglycemia, and could be missed at traditional fasting or post-standardized load measures.