Dietary regulation of endogenous glucose metabolism Peter H. Bisschop, M.D. (Academic Medical Center, Amsterdam, The Netherlands) Increased food intake in industrialized countries has led to a dramatic increase in obesity, insulin resistance and type 2 diabetes mellitus. Especially high-fat diets are believed to contribute to insulin resistance and alterations in glucose metabolism. To get a clear understanding of the direct effects of dietary carbohydrates and fat, hypercaloric diets need to be distinguished from eucaloric diets to exclude confounding by obesity. In this lecture, recent studies will be discussed that have addressed the direct effects of varying dietary carbohydrate to fat ratios in otherwise eucaloric, strictly controlled diets on endogenous glucose metabolism and insulin sensitivity. Postabsorptive glucose production appears to be a function of the carbohydrate content of previous meals. The effect of dietary carbohydrate content on postabsorptive glucose production is fully accounted for by changes in glycogenolysis, whereas the rate of postabsorptive gluconeogenesis is relatively insensitive to these dietary effects. Since glucose metabolism is directly controlled by insulin, diet-induced changes in insulin sensitivity could also contribute to alterations in glucose metabolism. In lean, healthy subjects insulin-stimulated glucose uptake is not affected by short-term, eucaloric changes in carbohydrate and fat intake. In contrast, a low dietary carbohydrate to fat ration readily induces hepatic insulin resistance, mostly likely related to hepatic steatosis. Whether the above-mentioned dietary effects can be extrapolated to subjects with overt insulin resistance remains to be determined. In summary, eucaloric high-fat/low-carbohydrate diets reduce endogenous glucose production without affecting peripheral insulin sensitivity and might prove useful in controlling endogenous glucose metabolism. Before low-carbohydrate/high-fat can be implemented for controlling glycemia, long-term follow-up studies are needed to exclude potential adverse effects on lipid metabolism and risk factors for cardiovascular disease.