The goal of this dissertation was to investigate the impact of changing dietary carbohydrate (CARB) intakes within recommended dietary guidelines on metabolic outcomes specifically associated with glycemic regulations and carbohydrate metabolism. This research utilized both human and animal studies to examine changes in metabolism across a wide range of dietary CARB to protein ratios. My hypothesis was that increasing dietary CARB intake from the minimum RDA level to the upper range of the DRI recommendations will require a shift in glycemic regulation from liver oriented regulations associated with gluconeogenesis (GNG) to regulation by insulin-dependent glucose uptake in peripheral tissues to maintain glucose homeostasis. The first objective was to compare relative efficacy of two isocaloric human weight loss diets on post-prandial insulin in response to a meal and fasted TAG in free living overweight or obese adults. The test diets were the commonly recommended high CARB, low protein (CHO; 55% of energy from carbohydrates and 15% of energy from protein) diet versus a moderate CARB, moderate protein (PRO) diet (40% and 30% of energy, respectively. The PRO diet resulted in greater fat mass and weight loss, with marked improvement in the post-prandial insulin response and reduced serum TAG compared to the CHO diet. These results support use of PRO diets with moderate CARB and moderate protein over conventional CHO diets with high CARB and low protein for decreasing risks for obesity, MetS, T2DM, and CVD. The second objective of this research was to investigate changes in gene expression of enzymes associated with glucose regulation using adult rats trained to eat three meals per day. Similar to the human study, the test diets differed in ratios of CARB and protein, but these diets also differed in fat content. Metabolic dysregulation occurred among diets with the most pronounced changes seen in the diet with high CARB and low protein. Results indicate upregulation of enzymes involved in gluconeogenesis (GNG), fructose metabolism, lipogenesis, the integrated stress response, and increased liver glycogen consistent with metabolic adaptations necessary to maintain glycemic control. This study also demonstrated that reducing dietary fat by replacement with CARB produced transcriptional changes to increase lipogenesis and fat storage. Overall within recommended ranges of CARB and protein intakes there are significant adaptations required at the gene to maintain plasma glucose homeostasis with the most robust difference seen in a high CARB diet when protein is limited. The third objective evaluated differential tissue responses in gene expression and metabolic signaling in liver, muscle, and adipose tissue associated with diets containing 58%, 40%, or 25% of energy as CARB. These diets represent high (HC), moderate (MC), and low (LC) CARB amounts within the acceptable macronutrient distribution range for the DRI. This study was designed to identify the range of metabolic adaptations required to maintain glucose homeostasis across the recommended dietary range of CARB. While plasma glucose was maintained within normal range, as dietary CARB increased in the diet, there was a progression of saturation of hepatic glucose regulations including increased post-prandial glycogen, decreased GNG capacity (decreased expression of PEPCK) with increased lipogenic activity (increased FAS expression) in addition to the corresponding SREBP1c expression in liver. This increase in dietary CARB then exceeded skeletal muscle utilization of glucose, becoming reliant on adipose uptake of glucose: increased glucose uptake into muscle in addition to patterns observed in insulin signaling elements and FAS expression in adipose tissue. Though optimal macronutrient content remains unknown, increases in physiologic ranges of CARB in the diet produce huge shifts in metabolism while maintaining glucose homeostasis. (Abstract shortened by UMI.) [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]