Although the plasma insulin response to the development of insulin resistance typically is increased during the natural history of T2DM (Figure 25.2), this does not mean that the β cell is functioning normally. To the contrary, studies have demonstrated that the onset of β-cell failure occurs much earlier and is more severe than previously appreciated. In the San Antonio Metabolism (SAM) study and the Veterans Administration Genetic Epidemiology Study (VAGES), a large number of subjects with NGT (n=318), IGT (n=259), and T2DM (n=201) were studied [55–58]. All subjects had an OGTT with plasma glucose and insulin concentrations measured every 15 min to evaluate overall glucose tolerance and β-cell function and a euglycemic insulin clamp to measure insulin sensitivity. Simply measuring the plasma insulin response to a glucose challenge does not provide a valid index of β-cell function . The β cell responds to an increment in glucose (ΔG) with an increment in insulin (ΔI) . Thus, a better measure of β-cell function is ΔI/ΔG. However, the β cell also recognizes the severity of insulin resistance and adjusts its secretion of insulin to offset the defect in insulin action [46,59–61]. Thus, the gold standard for measuring β-cell function is the insulin secretion/insulin resistance (ΔI/ΔG ÷ IR), or so-called disposition, index. Although subjects with IGT have an increase in the absolute plasma insulin concentration, this should not be interpreted to mean that the β cells in these individuals are functioning normally.
Figure 25.3 depicts the insulin secretion/insulin resistance index (ΔI/ΔG ÷ IR) in NGT, IGT, and T2DM subjects as a function of the 2-h plasma glucose concentration during the OGTT. Subjects in the upper tertile of “normal” glucose tolerance (2-h PG=120–139mg dL−1) have lost\ two thirds of their β-cell function (see first arrow in Figure 25.3), while subjects in the upper tertile of IGT (2-h PG=180–199mg dL−1) have lost 80–85% of their β-cell function (see second arrow in Figure 25.3). Similar results have been presented in other publications [22,23,25,31,62]. In biomedical phenomena, most reactions take place as a log function. Figure 25.3 depicts the natural log of the 2-h plasma glucose concentration during the OGTT as a function of the natural log of the insulin secretion/insulin resistance (β-cell function) index. These two variables are strongly and linearly related (r=0.91, p<0.00001). There are no cut points that distinguish NGT from IGT or IGT from T2DM. Rather, glucose intolerance is a continuum, and subjects simply move up and down this curve as a function of the insulin secretion/insulin resistance index. Therefore, the current diagnostic criteria  for IGT and T2DM are quite arbitrary and glucose tolerance should be viewed as a continuum of risk. The higher the 2-h plasma glucose concentration, even within the range of IGT, the greater is the risk for microvascular complications.
The previous discussion has focused on β-cell function and clearly demonstrates that β-cell health is severely impaired well before the onset of T2DM and even before the development of IGT. Even more ominous are studies demonstrating a significant reduction in β-cell mass in prediabetic (IFG/IGT) individuals [64–66]. In a postmortem analysis, these investigators demonstrated that as individuals progress from NGT to impaired fasting glucose (IFG), there was a 50% decline in β-cell volume, suggesting a significant loss of β-cell mass long before the onset of T2DM. With the progression to overt diabetes, there was a further loss of β-cell volume. Although β-cell volume should not be equated with β-cell mass, these results indicate that significant loss of β-cell mass occurs long before the onset of T2DM, according to current diagnostic criteria . Multiple other studies have also demonstrated a significant loss of β-cell mass before the onset of diabetes with a further decrease in β-cell mass with progression to overt diabetes [64–68].
In summary, at the upper tertile of IGT [55–58,62], individuals have lost over 80% of their β-cell function, while the results of autopsy studies [64–66] indicate that subjects with “prediabetes” have experienced a significant loss of β-cell mass. In humans this presents a major problem since no therapeutic intervention has been shown to increase β-cell number.