Absence of meal-induced insulin sensitization (AMIS) results in a predictable progression of dysfunctions, including postprandial hyperglycemia, compensatory hyperinsulinemia, resultant hyperlipidemia, increased oxidative stress, and obesity, progressing to syndrome X and diabetes. To one year of age, rats show a slow development of AMIS, but this can be potentiated by addition of a low-dose sucrose supplement to the diet. Provision of a synergistic antioxidant cocktail consisting of S-adenosylmethionine, vitamin E, and vitamin C (Samec) attenuates the rate and extent of development of AMIS in both normal aging animals and in aging animals on the sucrose diet. Adiposity, assessed from weighed regional fat masses and from bioelectrical impedance to estimate whole-body adiposity, correlated strongly with AMIS (r2 = 0.7-0.8). Rats given the sucrose supplement had accelerated AMIS and developed fasting hyperinsulinemia and postprandial hyperglycemia, hyperlipidemia, hyperinsulinemia, and adiposity. Samec completely compensated for the negative impact of this sucrose supplement and attenuated development of the associated dysfunctions. AMIS is explained by the HISS (hepatic insulin-sensitizing substance) hypothesis, which is outlined in the paper.