INTRODUCTION: Storage of nutrient energy from a meal is partitioned in the body approximately equally by insulin (with its known actions on the liver and adipose tissue) and hepatalin (released from the liver with its glycogenic action selectively in skeletal muscle, heart, and kidneys). During healthy pregnancy, there is a late stage mixed insulin resistance involving both insulin and hepatalin. In pregnant rats on a high sucrose diet, hepatalin-dependent insulin resistance (HDIR) develops with unaffected direct insulin action. Compensatory hyperinsulinemia maintains blood glucose level with resultant hypertriglyceridemia and adiposity. Previously, in male Sprague Dawley sucrose-supplemented rats, aged for one year, HDIR and the associated cardiometabolic consequences were prevented by using a targeted synergistic antioxidant cocktail composed of S-Adenosyl-Methionine, vitamin E and vitamin C (SAMEC). The current study tested the hypothesis that SAMEC would confer protection against sucrose-induced HDIR in virgin and pregnant rats. METHODS: Post-prandial insulin sensitivity was quantified using the rapid insulin sensitivity test (RIST). Sucrose supplementation (35% sucrose in water) was used to induce HDIR in female rats. Eight weeks of normal or SAMEC diet with or without sucrose supplementation was used as an intervention to determine the extent of protection against HDIR by SAMEC in virgin and pregnant rats. RESULTS AND DISCUSSION: SAMEC administered with the sucrose diet prevented the development of HDIR resulting in normal plasma glucose, insulin, and triglyceride concentrations in both virgin and pregnant groups, and attenuated sucrose-induced fat mass gain in virgin rats. The direct insulin action was unimpaired. CONCLUSION: SAMEC preserves hepatalin-dependent glucose uptake in virgin and pregnant rats on sucrose supplementation, thus can be used as a preventative in obesity and gestational diabetes.