Introduction: In humans with obesity, we found equivalent weight loss yet greater improvements in glucose tolerance in the intermittent fasting plus early time restricted eating (iTRE) vs caloric restriction (CR). This sub-analysis explored metabolic profiles in iTRE (post-fasting and feeding days) vs CR.
Methods: A randomised controlled trial was conducted in adults at elevated risk of diabetes (n=209, BMI 34.8±4.7kg/m2), with those from iTRE (30% energy requirements before 12pm with 20h fast on 3 days/week; usual diet on other days) and CR (70% energy requirements daily) included in this analysis. Fasting plasma glucose, insulin, non-esterified fatty acids (NEFA), triglycerides and polar metabolome were assessed after 12h fasts at baseline and month 6 (6A) for both groups, and again after 12h fast for CR or 20h fast for iTRE (6B). Between group effects at 6A and within group effects in iTRE (6A vs 6B) were examined by linear mixed model adjusted for baseline.
Results: Higher glucogenic amino acids, lactic acid and lower pentoses and sugar-derived acids (FDR<0.05) were found in iTRE vs CR following identical 12h overnight fasts, with top enriched pathways related to redox defence, glycolysis/gluconeogenesis, pyruvate metabolism and pentose phosphate pathway. The 20h fast induced reversals in these metabolites, and increased ketogenic amino acids, branched-chain amino acids, ketone bodies and metabolic intermediates of the citrate cycle (FDR<0.05), along with expected reductions in fasting glucose and insulin and increases in NEFA and triglycerides. Pathways related to amino acid degradation and biosynthesis, citrate cycle, and nicotinate/nicotinamide metabolism were further enriched post 20h fasting.
Conclusion: iTRE results in greater suppression of carbohydrate oxidation and upregulation of amino acid catabolism and redox defence vs CR. A distinct switch from 12h to 20h fasts reversed these metabolic processes alongside upregulated lipid-driven oxidative metabolism. Such shifts in metabolic profile may potentially enhance metabolic flexibility and contribute to the greater improvements in glucose tolerance over CR.