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Although weight loss can be achieved by any means of energy restriction, current dietary guidelines have not prevented weight regain or population-level increases in obesity and overweight. Many high-carbohydrate, low-fat diets may be counterproductive to weight control because they markedly increase postprandial hyperglycemia and hyperinsulinemia. Many high-carbohydrate foods common to Western diets produce a high glycemic response [high-glycemic-index (GI) foods], promoting postprandial carbohydrate oxidation at the expense of fat oxidation, thus altering fuel partitioning in a way that may be conducive to body fat gain. In contrast, diets based on low-fat foods that produce a low glycemic response (low-GI foods) may enhance weight control because they promote satiety, minimize postprandial insulin secretion, and maintain insulin sensitivity. This hypothesis is supported by several intervention studies in humans in which energy-restricted diets based on low-GI foods produced greater weight loss than did equivalent diets based on high-GI foods. Long-term studies in animal models have also shown that diets based on high-GI starches promote weight gain, visceral adiposity, and higher concentrations of lipogenic enzymes than do isoenergetic, macronutrientcontrolled, low-GI-starch diets. In a study of healthy pregnant women, a high-GI diet was associated with greater weight at term than was a nutrient-balanced, low-GI diet. In a study of diet and complications of type 1 diabetes, the GI of the overall diet was an independent predictor of waist circumference in men. These findings provide the scientific rationale to justify randomized, controlled, multicenter intervention studies comparing the effects of conventional and low-GI diets on weight control.

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Summary Epidemiologic studies indicate that the risks for major age-related debilities including CHD, diabetes, and age-related macular degeneration (AMD) are diminished in people who consume lower glycemic index (GI) diets but lack of a unifying physiobiochemical mechanism that explains the salutary effect is a barrier to implementing dietary practices that capture the benefits of consuming lower GI diets. We established a simple murine model of age-related retinal lesions that precede AMD (hereafter called AMD-like lesions). We found that consuming a higher GI diet promotes these AMD-like lesions. However, mice that consumed the lower vs. higher GI diet had significantly reduced frequency (p<0.02) and severity (p<0.05) of hallmark age-related retinal lesions such as basal deposits. Consuming higher GI diets was associated with >3 fold higher accumulation of advanced glycation end products (AGEs) in retina, lens, liver and brain in the age-matched mice, suggesting diet-induced systemic glycative stress that is etiologic for lesions. Data from live cell and cell free systems show that the ubiquitin-proteasome system (UPS) and lysosome/autophagy pathway (LPS) are involved in the degradation of AGEs. Glycatively-modified substrates were degraded significantly slower than unmodified substrates by the UPS. Compounding the detriments of glycative stress, AGE-modification of ubiquitin and ubiquitin conjugating enzymes impaired UPS activities. Furthermore, ubiquitin conjugates and AGEs accumulate and are found in lysosomes when cells are glycatively stressed or the UPS or LPS/autophagy are inhibited indicating that the UPS and LPS interact with one another to degrade AGEs. Together these data explain why AGEs accumulate as glycative stress increases.