1 Department of Information Engineering, University of Padua, Padua, Italy; 2 San Raffaele Scientific Institute, Milan, Italy; 3 Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, California; and 4 Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota Submitted 16 August 2006 ; accepted in final form 27 February 2007 Assessment of insulin secretion in humans under physiological conditions has been a challenge because of its complex interplay with insulin action and hepatic insulin extraction. The possibility of simultaneously assessing -cell function, insulin sensitivity, and hepatic insulin extraction under physiological conditions using a simple protocol is appealing, since it has the potential to provide novel insights regarding the regulation of fasting and postprandial glucose metabolism in diabetic and nondiabetic humans. In this Perspective, we review data indicating that an oral glucose tolerance test (OGTT) or a meal test is able to accomplish this goal when interpreted with the oral -cell minimal model. We begin by using the well-established intravenous minimal model to highlight how the oral minimal model was developed and how the oral assessment parallels that of an intravenous glucose tolerance test (IVGTT). We also point out the unique aspects of both approaches in relation to their ability to assess different aspects of the -cell secretory cascade. We review the ability of the oral model to concurrently measure insulin sensitivity and hepatic insulin extraction, thereby enabling it to quantitatively portray the complex relationship among -cell function, hepatic insulin extraction, and insulin action. In addition, data from 204 individuals (54 young and 159 elderly) who underwent both IVGTT and meal tolerance tests are used to illustrate how these different approaches provide complementary but differing insights regarding the regulation of -cell function in humans. glucose tolerance; disposition index; oral glucose tolerance test; meal; intravenous glucose tolerance test Address for reprint requests and other correspondence: C. Cobelli, Dept. of Information Engineering, Univ. of Padua, Via Gradenigo 6/B, 35131 Padua, Italy (e-mail: cobelli{at}dei.unipd.it )