In cross-sectional analyses, SG and its components, BIE and GEZI, are directly related to glucose tolerance. SG and GEZI are not as severely compromised in subjects with significant deterioration of glucose tolerance (including those with type 2 diabetes) as are BIE, insulin sensitivity, and insulin secretion. Age, BMI, and AIR are independent correlates of SG and GEZI. SI also is an independent correlate of SG because of the strong relationship between SI and BIE. In longitudinal analysis, weight gain and worsening AIR correlate with declines in SG and GEZI. Worsening SI also is related to SG decline. SG and GEZI significantly decline in individuals with NGT whose glycemic status deteriorates. Changes in SG and GEZI are more modest in individuals who already have IGT or diabetes, but BIE deterioration may occur at all stages of glucose tolerance.
is an important determinant of glucose metabolism (5
) and an independent predictor of the development of diabetes (3
). Some studies have described that SG
is reduced in people with IGT and diabetes (6
may be similar in these two groups of individuals (7
seems to be higher in the first-degree offspring of individuals with type 2 diabetes who are more insulin resistant than matched subjects without any family history of diabetes (17
). In addition, the ability of glucose to enhance its own utilization may not be impaired in diabetic subjects who are insulin resistant (18
). Our larger sample size has allowed us to carry out a more comprehensive assessment on the relation of SG
and its components to glucose tolerance. BIE has a significant deterioration with worsening of glucose tolerance. It is not lower in individuals with isolated IFG because the decrease in insulin sensitivity is compensated with an increase in fasting insulin concentration. SG
and GEZI have steady declines as glucose tolerance worsens but remain preserved, to a large extent, in states of significant insulin resistance, including diabetes. Consequently, the body seems to protect its last resort for glucose utilization when there is a severe impairment of glucose tolerance.
We have previously reported that African Americans and Hispanics have lower insulin sensitivity and higher insulin secretion than non-Hispanic whites, but SG
did not differ significantly by ethnic group (19
). In a study among 32 individuals of African descent, Osei et al. (20
) have described that SG
is preserved in those with IGT or diabetes despite having more insulin resistance and β-cell dysfunction. Our results indicate SG
and both SG
components deteriorate as glucose tolerance worsens in all three race/ethnic groups. The absence of statistical differences in SG
in African Americans with isolated IFG or isolated IGT relative to counterparts with NGT may be attributed to sample size. GEZI is significantly lower in African Americans with isolated IFG, and there is no interaction effect of race/ethnicity on the relationship between SG
and GEZI to glucose tolerance.
Cnop et al. (21
) already have described longitudinal changes in SG
in 33 first-degree relatives of non-Hispanic whites with type 2 diabetes. These individuals tended to be insulin resistant, which is a common trait in offspring of diabetic individuals. During the follow-up period, there was a significant deterioration in β-cell function but without a significant decline in either SI
. Among the 16 individuals with NGT at baseline, baseline SG
was lower in individuals who progressed to IGT, but the change in SG
during the period of observation was not statistically significant. Cnop et al. (21
) recommended additional studies with larger sample sizes because a drop in SG
occurred in some individuals whose glucose tolerance status progressed to IGT. These results are not inconsistent with our article. In our large epidemiological study, SG
declines as glucose tolerance worsens, particularly early in the disease process.
Physical inactivity has been associated with lower SI
). Dietary fat has been linked to worsening of glucose tolerance in epidemiological studies (22
). However, there is no evidence that isoenergetic replacement of saturated fat with monounsaturated fat or carbohydrates improves insulin sensitivity in studies with randomized diets (23
). In our population, which is characterized by high rates of obesity, glucose tolerance abnormalities, and inactivity, diet and physical activity are not related to SG
. Insulin secretion, an important determinant of glucose tolerance status, tends to increase with weight gain and deterioration of insulin sensitivity (2
). Although not declined in the whole IRAS cohort, longitudinal changes in SG
occur in parallel with those in adiposity, insulin sensitivity, and β-cell function. BIE partially explains the relationship between insulin sensitivity and SG
In most tissues, glucose uptake is regulated by the expression of specific glucose transporter proteins at the plasma membrane. Two of them, GLUT-1 and GLUT-4, are of particular importance for whole-body glucose homeostasis. Expressed in insulin-responsive tissues, GLUT-4 is located in intracellular membrane compartments in the basal non–insulin-stimulated state (24
). GLUT-4 is translocated to the cell’s surface by insulin and exercise and accounts for the insulin-dependent glucose uptake. Intracellular GLUT-4 depletion and interference in its translocation in response to insulin occurs in insulin-resistant states (25
). GLUT-1 is much more widely distributed. GLUT-1 is located in the plasma membrane in the basal state and may account, at least partially, for the insulin-independent glucose uptake (17
). There is experimental evidence that exercise training, inflammation, and insulin resistance are associated with an increase in GLUT-1 content in skeletal muscle (24
). Thus, upregulation of GLUT-1 could mediate the preservation of SG
in states of severe impairment of glucose tolerance.
In conclusion, SG declines in subjects whose glycemic status worsens, but our study cannot determine whether glucose uptake by tissues and suppression of endogenous glucose production by the liver are equally affected in each of the glucose tolerance categories. Age, adiposity, insulin resistance, and β-cell dysfunction largely explain the relationship of SG to plasma glucose levels. The deterioration of BIE, the basal insulin effect component of SG, is a steady process throughout the entire range of fasting and 2-h glucose levels and is driven by insulin resistance. BIE partially accounts for the relationship between SG and insulin sensitivity. The decline of GEZI, the ability of glucose to promote its own disappearance independently of the BIE, is more prominent in the initial stages of the disease process leading to diabetes. It already is manifested in individuals with isolated IFG and IGT in men and women and across race/ethnic groups. Longitudinal changes in GEZI concur with weight and β-cell function changes.