Fasting and postprandial plasma metabolite responses to a 12-wk dietary intervention in tissue-specific insulin resistance: a secondary analysis of the PERSonalized glucose Optimization through Nutritional intervention (PERSON) randomized trial

Background: We previously showed that dietary intervention effects on cardiometabolic health were driven by tissue-specific insulin resistance (IR) phenotype: individuals with predominant muscle IR (MIR) benefited more from a low-fat, high-protein, and high-fiber (LFHP) diet, whereas individuals with predominant liver insulin resistance (LIR) benefited more from a high-monounsaturated fatty acid (HMUFA) diet. Objectives: To further characterize the effects of LFHP and HMUFA diets and their interaction with tissue-specific IR, we investigated dietary intervention effects on fasting and postprandial plasma metabolite profile. Methods: Adults with MIR or LIR (40–75 y, BMI 25–40 kg/m²) were randomly assigned to a 12-wk HMUFA or LFHP diet (n = 242). After the exclusion of statin use, 214 participants were included in this prespecified secondary analysis. Plasma samples were collected before (T = 0) and after (T = 30, 60, 120, and 240 min) a high-fat mixed meal for quantification of 247 metabolite measures using nuclear magnetic resonance spectroscopy. Results: A larger reduction in fasting VLDL-triacylglycerol (TAG) and VLDL particle size was observed in individuals with MIR following the LFHP diet and those with LIR following the HMUFA diet, although no longer statistically significant after false discovery rate (FDR) adjustment. No IR phenotype-by-diet interactions were found for postprandial plasma metabolites assessed as total area under the curve (tAUC). Irrespective of IR phenotype, the LFHP diet induced greater reductions in postprandial plasma tAUC of the larger VLDL particles and small HDL particles, and TAG content in most VLDL subclasses and the smaller LDL and HDL subclasses (for example, VLDL-TAG tAUC standardized mean change [95% CI] LFHP = −0.29 [−0.43, −0.16] compared with HMUFA = −0.04 [−0.16, 0.09]; FDR-adjusted P for diet × time = 0.041). Conclusions: Diet effects on plasma metabolite profiles were more pronounced than phenotype-by-diet interactions. An LFHP diet may be more effective than an HMUFA diet for reducing cardiometabolic risk in individuals with tissue-specific IR, irrespective of IR phenotype. Am J Clin Nutr 20xx;x:xx. This trial was registered at the clinicaltrials.gov registration (https://clinicaltrials.gov/study/NCT03708419?term=NCT03708419&rank=1) as NCT03708419 and CCMO registration (https://www.toetsingonline.nl/to/ccmo_search.nsf/fABRpop?readform&unids=3969AABCD9BA27FEC12587F1001BCC65) as NL63768.068.17.