Interactions between Intestinal Homeostasis and NAD⁺ Biology in Regulating Incretin Production and Postprandial Glucose Metabolism

The intestine has garnered attention as a target organ for developing new therapies for impaired glucose tolerance. The intestine, which produces incretin hormones, is the central regulator of glucose metabolism. Glucagon-like peptide-1 (GLP-1) production, which determines postprandial glucose levels, is regulated by intestinal homeostasis. Nicotinamide phosphoribosyltransferase (NAMPT)-mediated nicotinamide adenine dinucleotide (NAD⁺) biosynthesis in major metabolic organs such as the liver, adipose tissue, and skeletal muscle plays a crucial role in obesity- and aging-associated organ derangements. Furthermore, NAMPT-mediated NAD⁺ biosynthesis in the intestines and its upstream and downstream mediators, adenosine monophosphate-activated protein kinase (AMPK) and NAD⁺-dependent deacetylase sirtuins (SIRTs), respectively, are critical for intestinal homeostasis, including gut microbiota composition and bile acid metabolism, and GLP-1 production. Thus, boosting the intestinal AMPK–NAMPT–NAD⁺–SIRT pathway to improve intestinal homeostasis, GLP-1 production, and postprandial glucose metabolism has gained significant attention as a novel strategy to improve impaired glucose tolerance. Herein, we aimed to review in detail the regulatory mechanisms and importance of intestinal NAMPT-mediated NAD⁺ biosynthesis in regulating intestinal homeostasis and GLP-1 secretion in obesity and aging. Furthermore, dietary and molecular factors regulating intestinal NAMPT-mediated NAD⁺ biosynthesis were critically explored to facilitate the development of new therapeutic strategies for postprandial glucose dysregulation.