How is it that eating too much eventually leads to insulin resistance, diabetes and a shorter life? Just as scientists are making progress in uncovering the biomechanisms of calorie restriction, they are also showing how excess food causes its predictable effects: "For quite some time now, scientists suspected the so-called hexosamine pathway - a small side business of the main sugar processing enterprise inside a cell - to be involved in the development of insulin resistance. ... For the first time we have a real understanding of how the insulin signaling system is turned on and off ... researchers believe that the hexosamine pathway acts as fuel gauge, protecting the body's cells against the toxic effects of too much glucose and other high-energy molecules. Excessive quantities of nutrients - the result of a lifestyle where food is plentiful and exercise is optional - [dampen] the insulin response, paving the way for a relentless progression of insulin resistance. ... the enzyme OGT [is] the last in a line of enzymes that shuttle sugars through the hexosamine pathway. ... when [researchers] put OGT into overdrive in the livers of mice, the animals developed insulin resistance and abnormal blood lipid levels, emphasizing the importance of the hexosamine pathway for the development of insulin resistance, the first step towards full-blown type 2 diabetes." A step on a path you can choose not to follow, needless to say.