Dairy Milk Casein and Whey Proteins Differentially Alter the Postprandial Lipidome in Persons with Prediabetes: A Comparative Lipidomics Study.

Dairy milk, likely through its bioactive proteins, has been reported to attenuate postprandial hyperglycemia-induced oxidative stress responses implicated in cardiovascular diseases (CVDs). However, how its major proteins, whey and casein, alter metabolic excursions of the lipidome in persons with prediabetes is unclear. Therefore, the objective of this study was to examine whey or casein protein ingestion on glucose-induced alternations in lipidomic responses in adults (17 males and 6 females) with prediabetes. In this clinical study, participants consumed glucose alone, glucose + nonfat milk (NFM), or glucose with either whey (WHEY) or casein (CASEIN) protein, and plasma samples were collected at multiple time points. Lipidomics data from plasma samples was acquired using an ultra-high-performance liquid chromatography-high-resolution mass spectrometry-based platform. Our results indicated that glucose ingestion alone induced the largest number of changes in plasma lipids. WHEY showed an earlier and stronger impact to maintain the stability of the lipidome compared with CASEIN. WHEY protected against glucose-induced changes in glycerophospholipid and sphingolipid (SP) metabolism, while ether lipid metabolism and SP metabolism were the pathways most greatly impacted in CASEIN. Meanwhile, the decreased acyl carnitines and fatty acid (FA) 16:0 levels could attenuate lipid peroxidation after protein intervention to protect insulin secretory capacity. Diabetes-associated lipids, the increased phosphatidylethanolamine (PE) 34:2 and decreased phosphatidylcholine (PC) 34:3 in the NFM-T, elevated PC 35:4 and decreased CE 18:1 to a CE 18:2 ratio in the WHEY-T, decreased lysophosphatidylcholine (LPC) 22:6 and LPC 22:0/0:0 in the CASEIN-T, and decreased PE 36:1 in the CASEIN-T, indicating a decreased risk for prediabetes. Collectively, our study suggested that dairy milk proteins are responsible for the protective effect of non-fat milk on glucose-induced changes in the lipidome, which may potentially influence long-term CVD risk.