Insulin secretion and insulin action are major factors in the determination of glucose tolerance, and insulinopenia and insulin resistance cause glucose intolerance and/or NIDDM. Because glucose itself can enhance glucose disposal and suppress endogenous glucose production independent of a change in insulin, it is necessary to consider an additional factor in determination of glucose tolerance: glucose effectiveness. This phenomenon represents the ability of glucose per se, under basal insulin conditions, to enhance glucose disposal and to suppress endogenous glucose production. Glucose effectiveness has been measured in many studies in which glucose disposal and output have been quantified at basal insulin but with widely varying glycemia. The effect of glucose on glucose disposal in humans is such that a 100 mg/dl increase in plasma glucose (at basal insulin) will increase glucose disposal by 1.63 mg• min'-kg'. Similarly, the same 100 mg/dl increment in glucose alone will suppress endogenous glucose output by 0.79 mg• min'• kg'. Thus, two-thirds of glucose effectiveness in humans is the disposal effect [1.63/(1.63+ 0.79)] and the remaining third is the effect to suppress the liver. Having numerical values for glucose effectiveness makes it possible to calculate the importance of hyperglycemia per se relative to the importance of insulin to disposition of a glucose load. In normal individuals,~ 50% of the glucose disposal during an oral glucose tolerance test (OGTT) is due to glucose effectiveness and not to the dynamic insulin response. In the insulin-resistant obese individual, 83% of glucose disposal occurs independent of the dynamic insulin response; in NIDDM, because of severe insulin resistance and relative insulinopenia, 99% of glucose uptake after a carbohydrate meal is due to glucose effectiveness. Thus, glucose effectiveness is a component equal to or greater than insulin itself in the determination of glucose tolerance. Glucose effectiveness can be assessed from the intravenous glucose tolerance test (IVGTT) by using the so-called minimal model approach; the sensitivity parameter that is calculated, the glucose effectiveness index (5G) represents the sum, or whole-body, effect of hyperglycemia to enhance glucose disposal and to suppress endogenous glucose production. Using the model, SG has been measured multiple times in humans: the average from 18 independent studies is 0.024 min" 1. Physical activity and training almost double SG; states of glucose intolerance are characterized by reduced SG. For example, SG is down 33% in offspring of two parents with NIDDM, down by 50% in subjects with impaired glucose tolerance, and reduced as much as 60% in subjects on a very-low-calorie diet. A hallmark of states of reduced SG appears to be the insulinopenic state, although this hypothesis requires further validation. Whether reduced glucose effectiveness is a true inheritable defect that can enhance risk for and contribute to the onset of NIDDM remains to be investigated. Recent evidence that glucose can