Dynamic multi-omics profiling of islet and gut hormonal secretion and peripheral crosstalk in response to various nutrient loads.

Postprandial metabolism is a complex and dynamic process involving diverse biomolecules, with islet and gut hormones playing crucial roles. However, how these hormones interact with biomolecules after nutrient intake and coordinate with peripheral insulin resistance (IR) remains elusive. This study characterizes postprandial multi-omics dynamics under mixed meals and four distinct macronutrient loads, investigating hormone secretion patterns, associated responsive molecules, and their relationships with IR. Postprandial multi-omics data significantly elucidate insulin and glucagon secretion, highlighting differences from the fasting state, while glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are exclusively explained postprandially. Hormone secretion and molecular responses exhibit substantial heterogeneity among macronutrients. Postprandial multi-omics better predict IR, particularly with hepatic enrichment. Protein load shows the strongest association with both hepatic and muscular IR, while butter mostly connects with systemic IR. Several identified molecules mediate interactions between IR and islet α and β cell function, providing a molecular basis for advancing precision nutrition therapies in metabolic diseases.