Natural and Non-Nutritive Sweeteners: Comprehensive Bioactive Profiles, Extraction Methodologies, Health Implications, and Industrial Applications in Metabolic Disease Management

Excessive consumption of refined sucrose andhigh-fructose corn syrup has driven a global surge innoncommunicable metabolic disorders, including type 2diabetes mellitus, cardiovascular disease, non-alcoholicfatty liver disease, and clinical obesity. In response,human nutrition, pharmacology, and food engineeringhave increasingly shifted focus toward natural and nonnutritive sweeteners as therapeutic and functionalalternatives. This comprehensive manuscript delivers anexhaustive review of natural sugar sources (date palm,grapes, sweet sorghum, raw sugarcane, honey, agavesyrup, sugar beet, and maple syrup), non-nutritive highintensity natural sweeteners (thaumatin, glycyrrhizin,monk fruit mogrosides, and steviol glycosides), semisynthetic flavonoid derivatives (neohesperidindihydrochalcone), and rare nutritive carbohydrates andpolyols (D-tagatose, D-allulose, trehalose, erythritol,mannitol, and maltitol). We evaluate their molecularstructures, green and conventional extraction protocols,microencapsulation technologies, receptor-level sweetsynergy mechanisms, and broad-spectrum biologicalactivities including antioxidant, anti-inflammatory,hepatoprotective, and immunomodulatory effects.Furthermore, this manuscript examines detailed casestudies, including the hepatoprotective mechanisms ofNHDC against Paraquat-induced acute liver injury,longitudinal epidemiological evaluations of artificialsweetener exposure and type 2 diabetes risk in theNutriNet-Santé cohort, the dual metabolic paradox ofsynthetic sweeteners in glycemic control, the neurobehavioural reward dysregulation driving hyperphagiain obesity, a crossover clinical trial comparing honey,sucrose, and HFCS55, and the ethnopharmacologicalsynergistic co-administration of Stevia rebaudiana withsaxagliptin. Ultimately, this work synthesizes currentscientific evidence, addresses technological formulationhurdles, and establishes a strategic roadmap forintegrating functional natural sweeteners intomainstream food science and clinical metabolicmanagement.