Effects of Dietary Carbohydrate Amount and Glycemic Index on Blood Lipidomic Signatures and Diurnal Postprandial Glucose Responses: The OmniCarb Trial

We investigated whether lowering dietary carbohydrate content and glycemic index (GI) levels altered deep lipidomic profiles and whether these changes were associated with improved diurnal postprandial glucose response (PPGR). In the OmniCarb trial, 59 adults completed 5-week controlled feeding interventions (low carbohydrate/low GI vs. high carbohydrate/high GI) and 12-h meal tests. Comprehensive lipidomic profiling was performed to measure lipid species and lipid class-specific fatty acids (FAs) at the end of each intervention. We found that lowering carbohydrate content and GI levels significantly decreased triacylglycerols (TAGs) and phosphatidylcholines, while increasing lactosylceramides and phosphatidylethanolamines (PEs). Of 731 lipid species analyzed, 521 (71%) were significantly modified, including TAGs (n = 398), PEs (n = 45), and ceramides. Of 199 FAs analyzed across and within lipid classes, 89 showed significant changes (false discovery rate-adjusted P < 0.05), including decreases in saturated FAs (total and TAG FA12:0 and FA14:0) and palmitoleic acid and increases in very-long-chain saturated FAs, when lowering carbohydrate and GI levels. Between-diet changes in six total FAs and 17 lipid class-specific FAs were associated with half-day PPGR changes; greater decreases in joint FA score changes were linked to improved PPGRs. Our study suggests the potential importance of dietary carbohydrate-responsive lipidomic signatures in explaining individual variability in half-day PPGRs and may encourage future intervention studies to target these signatures. ARTICLE HIGHLIGHTS: High-glycemic index (GI) carbohydrate diets increase postprandial glucose response (PPGR) and diabetes risk; however, the pathways underlying individual variability in diurnal PPGRs to diets differing in carbohydrate content and GI remain unclear. We examined the effect of lowering dietary carbohydrate content and GI levels on comprehensive lipidomic pathways and tested whether these changes were associated with improved half-day PPGRs. Five-week controlled feeding interventions altered multiple lipid species and lipid class-specific fatty acids toward more favorable profiles, and composite fasting blood fatty acid scores derived from comprehensive targeted lipidomic profiling were associated with improved 12-h PPGRs. These lipidomic signatures explain individual variability in PPGRs and provide targets for future intervention studies.