Disposition Index, Glucose Effectiveness, and Conversion to Type 2 Diabetes: The Insulin Resistance Atherosclerosis Study (IRAS)

OBJECTIVE

Disposition index (DI) and glucose effectiveness (S_G) are risk factors for diabetes. However, the effect of DI and S_G on future diabetes has not been examined in large epidemiological studies using direct measures.

RESEARCH DESIGN AND METHODS

Insulin sensitivity index (S_I), acute insulin response (AIR), and S_G were measured in 826 participants (aged 40–69 years) in the Insulin Resistance Atherosclerosis Study (IRAS) by the frequently sampled intravenous glucose tolerance test. DI was expressed as S_I × AIR. At the 5-year follow-up examination, 128 individuals (15.5%) had developed diabetes.

RESULTS

The area under the receiver operating characteristic curve of a model with S_I and AIR was similar to that of DI (0.767 vs. 0.774, P = 0.543). In a multivariate logistic regression model that included both DI and S_G, conversion to diabetes was predicted by both S_G (odds ratio × 1 SD, 0.61 [0.47–0.80]) and DI (0.68 [0.54–0.85]) after adjusting for demographic variables, fasting and 2-h glucose concentrations, family history of diabetes, and measures of obesity. Age, sex, race/ethnicity, glucose tolerance status, obesity, and family history of diabetes did not have a significant modifying impact on the relation of S_G and DI to incident diabetes.

CONCLUSIONS

The predictive power of DI is comparable to that of its components, S_I and AIR. S_G and DI independently predict conversion to diabetes similarly across race/ethnic groups, varying states of glucose tolerance, family history of diabetes, and obesity.Both insulin sensitivity and first-phase insulin secretion are independent determinants of conversion to diabetes in different ethnic groups and varying states of glucose tolerance, family history of diabetes, and obesity (1). First-phase insulin secretion compensates for the worsening of insulin sensitivity (2). In studies using direct methods, such as the frequently sampled intravenous glucose tolerance test (FSIGTT) with minimal model analysis, this relationship is hyperbolic (2) and similar across glucose tolerance categories (3). Known as the disposition index (DI), the product of measures of insulin sensitivity and first-phase insulin secretion, it has been shown to predict conversion to diabetes (4–6). The evidence, however, comes from studies that have enrolled relatively few participants or targeted persons from a single ethnic group. Since direct methods have demanding technical requirements, the product of measures of insulin sensitivity and insulin secretion derived from the oral glucose tolerance test has attracted interest. This product has been shown to have a modest correlation with minimal model–derived DI, to decrease as glucose tolerance status deteriorates, and to predict the development of diabetes independent of other risk factors including fasting and 2-h glucose concentrations (7,8). It includes the incretin effect and therefore may not always follow the hyperbolic law (7–9). The hyperbolic paradigm of the minimal model–derived DI has also been criticized (10). Furthermore, its predictive power has not been tested for large epidemiological studies.In addition to the insulin-dependent component of glucose tolerance (or DI), the insulin-independent component (glucose effectiveness [S_G]) has already been explored in mice (11) and humans (12). S_G is the capacity of glucose to enhance its own cellular uptake and to suppress endogenous glucose production. Although reduced in individuals with impaired glucose tolerance (IGT) and diabetes (4,13), S_G contributes to glucose tolerance even in conditions of significant insulin resistance, including diabetes (13). Reduced S_G has also been described in healthy individuals following the infusion of cortisol or glucagon, individuals in states of very low caloric intake, women with polycystic ovary syndrome, and the elderly (13–15). Contrary to the insulin sensitivity index (S_I), S_G may not be influenced by exercise (16) or weight loss interventions (17). In relatively small studies, S_G has been shown to predict future diabetes (4,5,18), but its contribution to the development of diabetes remains largely unknown.Since the hyperbolic paradigm has not been tested in large epidemiological studies, our first objective was to analyze the risk of future diabetes associated with minimal model-derived DI relative to its components, S_I, and acute insulin response (AIR). The second objective was to assess the relative contribution of the insulin-independent component of glucose tolerance, S_G, to the development of diabetes. To meet these aims, we used data from the Insulin Resistance Atherosclerosis Study (IRAS), a multicenter observational epidemiological study of different ethnic groups and varying states of glucose tolerance (19).