Insulin resistance is a poor predictor of type 2 diabetes in individuals with no family history of disease

Abstract

In normoglycemic offspring of two type 2 diabetic parents, low insulin sensitivity (S(I)) and low insulin-independent glucose effectiveness (S(G)) predict the development of diabetes one to two decades later. To determine whether low S(I), low S(G,) or low acute insulin response to glucose are predictive of diabetes in a population at low genetic risk for disease, 181 normoglycemic individuals with no family history of diabetes (FH-) and 150 normoglycemic offspring of two type 2 diabetic parents (FH+) underwent i.v. glucose tolerance testing (IVGTT) between the years 1964-82. During 25 +/- 6 years follow-up, comprising 2,758 person years, the FH- cohort (54 +/- 9 years) had an age-adjusted incidence rate of type 2 diabetes of 1.8 per 1,000 person years, similar to that in other population-based studies, but significantly lower than 16.7 for the FH+ cohort. Even when the two study populations were subdivided by initial values of S(I) and S(G) derived from IVGTT's performed at study entry, there was a 10- to 20-fold difference in age-adjusted incidence rates for diabetes in the FH- vs. FH+ individuals with low S(I) and low S(G). The acute insulin response to glucose was not predictive of the development of diabetes when considered independently or when assessed as a function of S(I), i.e., the glucose disposition index. These data demonstrate that low glucose disposal rates are robustly associated with the development of diabetes in the FH+ individuals, but insulin resistance per se is not sufficient for the development of diabetes in individuals without family history of disease and strongly suggest a familial factor, not detectable in our current measures of the dynamic responses of glucose or insulin to an IVGTT is an important risk factor for type 2 diabetes. Low S(I) and low S(G), both measures of glucose disposal, interact with this putative familial factor to result in a high risk of type 2 diabetes in the FH+ individuals, but not in the FH- individuals.

Figure 1

Distribution of the S_I index (Left) and S_G (Right) assessed by the Bergman Minimal Model and measured at study entry are presented in individuals with no family history of diabetes (FH−, solid line) and offspring of two diabetic parents (FH+, dashed line).

Figure 2

Distribution of S_I and S_G by Bergman Minimal Model analysis measured at study entry in individuals with no family history of diabetes (FH−, black) or with family history of diabetes (FH+, gray). Low and high S_I and S_G were defined in both groups by the median S_I and S_G, respectively, in the offspring of two type 2 diabetic parents (FH+) cohort.

Figure 3

Comparison of the cumulative risk of type 2 diabetes in individuals with no family history of diabetes (FH−, black) and offspring of two diabetic parents (FH+, gray) according to S_I and S_G at study entry with low and high S_I and S_G defined by median values in the offspring of two type 2 diabetic parents.

Figure 4

Distribution of fasting insulin (Left) and AIRg (Right) during an IVGTT performed at study entry, are demonstrated for the two populations FH+ and FH−.

Figure 5

Incidence rates of type 2 diabetes in individuals with no family history of diabetes (FH−) and offspring of two diabetic parents (FH+) are shown according to fasting insulin (Left) and AIRg (Right) at study entry with low and high of each insulin parameter defined by median value of that parameter in the offspring of two type 2 diabetic parents at study entry.

Figure 6

The logarithmic regression is shown between S_I and the AIRg at study entry for individuals with no family history of diabetes (FH−) (Left) and for individuals with two parents with type 2 diabetes (FH+) (Right). Individuals who subsequently developed diabetes are shown by dark circles; individuals who did not develop disease during longitudinal evaluation are shown by light circles. In both panels, the solid line represents the regression relationship of the FH− cohort; in Right, the relationship of the FH+ cohort is shown by dotted line.

Figure 7

The effect of obesity on the age-adjusted incidence rates for type 2 diabetes in FH− and FH+ groups are shown. On the left, the incidence rates are shown for all individuals in each cohort, and on the right, a subgroup analysis is shown for nonobese (BMI <30) FH− and FH+ subjects.