The effect of D-ribose (ribose) on insulin secretion and plasma glucose has been investigated since 1957, when the effect of insulin on the transport of various sugars, including ribose, across cell membranes was first studied. Over the decades, research has consistently shown that oral or intravenous ribose administration produces a transient, asymptomatic, and dose dependant decrease in plasma blood glucose to a nadir that is reached 30- to 75-minutes post-administration, before returning to baseline levels in approximately 60- to 120-minutes once administration is discontinued. The mechanism of this blood glucose lowering effect has not been fully elucidated, but several have been studied and more than one appear to contribute to the effect. Suggested mechanisms include direct stimulation of insulin secretion by the pancreas, indirect stimulation of insulin secretion by the liver and other tissues, a saturation of carbohydrate receptors in the liver and various tissues affecting insulin release, increased glucose utilization or decreased glucose production resulting from rising levels of blood ribose, and the competition in the liver for the enzyme phosphoglucomutase responsible for glycogen recruitment. Increased glucose utilization does not appear to materially contribute to the mechanism. Instead, the blood glucose lowering effect of ribose appears to result from a combination of factors including indirect stimulation of pancreatic insulin secretion, stimulation of humoral effectors causing secretion of minor, but important, amounts of insulin from tissues in the hepatic-portal pathway, and delayed glucose recruitment in the liver, likely due to competition for phosphoglucomutase activity.