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From the Clinical Research Centers |
Endocrinology Section, John L. McClellan Memorial Veterans Affairs Hospital (S.C.E., K.W.), Little Rock, Arkansas 72205; the Department of Medicine, and University of Arkansas for Medical Sciences (S.C.E., K.W.), Little Rock, Arkansas 72204; the Department of Human Genetics, University of Utah School of Medicine (S.J.H.), Salt Lake City, Utah 84112; and the Division of Metabolism, Endocrinology, and Nutrition, University of Washington, and Veterans Administration Puget Sound Health Care System (S.E.K.), Seattle, Washington 98195
Address all correspondence and requests for reprints to: Steven C. Elbein, M.D., Endocrinology 111J/LR, John L. McClellan Memorial Veterans Hospital, 4700 West 7th Street, Little Rock, Arkansas 72205. E-mail: sce{at}nidgene1.uams.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Many investigators have demonstrated insulin resistance directly or indirectly in relatives of diabetic individuals. Warram and colleagues demonstrated slower glucose removal rates and hyperinsulinemia (3), and Martin et al. (4) demonstrated lower insulin sensitivity indexes (SI) and low glucose effectiveness (Sg) in normoglycemic offspring of two diabetic parents 2 decades before the development of type 2 diabetes. Haffner et al. suggested that insulin resistance was present in Mexican Americans by finding hyperinsulinemia in the offspring of a type 2 diabetic parent (5). Similar conclusions were reached in extensive studies of Pima Indians (6, 7). Furthermore, in both Pima Indians (8) and our own studies (9), insulin sensitivity or fasting and postchallenge insulin levels appeared to be controlled by major genes.
Although most studies have emphasized the early and predictive role of insulin resistance in the pathogenesis of type 2 diabetes, others proposed an important role for ß-cell dysfunction. Pimenta et al. (10) demonstrated a 20%–25% reduction in first and second phase insulin release in first degree relatives of type 2 diabetic patients, without significant differences in insulin sensitivity. These researchers and others (11) suggested heterogeneity among first degree relatives, with 15% showing insulin resistance compared with matched controls. Vaag et al. (12) found significantly decreased first phase insulin release in monozygotic twins of type 2 diabetic patients with both impaired (IGT) and normal glucose tolerance (NGT) compared with control individuals. O’Rahilly and colleagues (13) found impairment of ß-cell function without insulin resistance in relatives of type 2 diabetic patients classified as intolerant by continuous glucose infusion compared with that in glucose-tolerant relatives. Among Pima Indians, diminished insulin secretion helped predict later type 2 diabetes when considered in the context of obesity or insulin resistance (7).
The failure of these studies to resolve the relative roles of insulin sensitivity and insulin secretion in the pathogenesis of type 2 diabetes might result from at least two factors. First, most investigators studied unrelated members of different families selected using differing ascertainment criteria. Thus, genetic heterogeneity may explain the discrepant conclusions. Second, few studies have considered insulin secretion in the context of insulin sensitivity (14, 15). Consequently, many earlier studies overestimated the pancreatic ß-cell response (15). In the present study, we sought to directly examine the role of insulin secretion in the early pathogenesis of type 2 diabetes and to address the potential deficiencies of earlier studies. We examined members of a relatively homogeneous Caucasian population using a uniform ascertainment criteria that placed all family members at high risk of type 2 diabetes, and we used the hyperbolic relationship of first phase insulin release (AIRglucose) and the insulin sensitivity index (SI) to define an index of ß-cell compensation to insulin sensitivity as the product of SI and AIRglucose (SI x AIRglucose) (14, 15). Although it is based only on first phase insulin secretion, this product appears to be a good measure of glucose tolerance and provides a constant that defines an individual’s response to insulin sensitivity (14). We hypothesized that among these families selected for high risk of type 2 diabetes and relatively uniform ethnic background, SI x AIRglucose is familial. We tested this hypothesis by performing tolbutamide-modified, iv glucose tolerance tests (16) on 120 nondiabetic members of 26 families selected for at least 2 diabetic siblings with disease onset before age 65 yr. Among those tested were 26 members with IGT diagnosed by WHO criteria (17). We show that SI x AIRglucose as a measure of insulin secretion, is highly heritable and has a high genetic correlation with diabetes status, thus validating this parameter as an inherited measure of ß-cell function.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We studied a total of 120 members of 55 sibships representing 26 families and 3 spouses whose children were also studied. Families were selected for at least a sibling pair with type 2 diabetes. Diabetic onset was before age 65 yr, and only families in which the grandparents were of Northern European extraction were studied. All family members underwent a standard 75-g oral glucose tolerance test at a prior visit and were classified as NGT, IGT, or diabetic by WHO criteria (17). Only nondiabetic individuals underwent further study. A total of 272 individuals from 87 sibships and 35 families were nondiabetic in the earlier oral glucose tolerance test and were either the sibling or offspring of a type 2 diabetic individual, and thus eligible for participation in the frequently sampled iv glucose tolerance test (FSIGT). A total of 120 of these eligible family members agreed to participate in the second study. These individuals were not significantly different from all eligible family members, except that a higher proportion had IGT. NGT individuals did not differ from other eligible NGT family members with regard to fasting or 2-h glucose levels. In addition to the 120 family members, we tested 3 spouses whose children were also tested and who were thus included in the heritability analysis. All study subjects provided written informed consent before study under a protocol approved by the University of Utah institutional review board.
Study protocol
Patients were studied after an overnight fast at the University of Utah General Clinical Research Center. Menstruating women were studied during the follicular phase of their menstrual cycles. No subjects engaged in regular aerobic athletics. Height was determined by the mean of three measures by a stadiometer, weight was measured by calibrated digital scale, and blood pressure was determined using the mean of two measures after 5 min of rest.
A tolbutamide-modified FSIGT was performed on all subjects, as described previously (18). Briefly, 20 min after initiating iv lines in both arms, 3 baseline samples were withdrawn. Glucose at a dose of 11.4 g/m2 body surface area was then administered iv over 60 s, and samples were withdrawn at 2, 3, 4, 5, 6, 8, 10, 14, and 19 min. At 20 min after initiation of glucose administration, tolbutamide (125 mg/m2) was administered iv over 30 s, and sampling was continued at 22, 24, 27, 30, 40, 50, 70, 90, 120, 150, and 180 min. Patients with a previous diagnosis of IGT, whose glucose level continued to change between 150–180 min, or whose glucose level at 180 min differed by more than 0.56 mmol/L from the baseline underwent additional sampling at 210 and 240 min. We have shown that this 25-sample protocol retains the precision of the 33-sample protocol (19). Glucose and insulin were measured by Penn Medical Laboratories using protocols described previously (18). The computer program MINMOD (16, 20) was used to calculate the SI and Sg at basal insulin. The AIRglucose was calculated as the mean of the insulin response above baseline from 2–10 min after glucose administration.
To account for the effect of insulin sensitivity to modulate AIRglucose, we calculated the product SI x AIRglucose based on the hyperbolic relationship between SI and AIRglucose in humans (14, 20). Because insulin is a unit in both SI and AIRglucose, the effect of any difference in insulin assays between laboratories is negated. Thus, SI x AIRglucose is independent of the specific laboratory. Using this assumption, we also assigned a percentile rank for SI x AIRglucose based on the published random sample of a healthy population under age 45 yr and with varying body mass index (BMI) values tested in Seattle, WA (14).
Statistical analysis
Comparison of SI x AIRglucose as a
percentile score with expected normal values was conducted using the
2 test with 120 family members (SPSS
statistical package, SPSS, Inc., Chicago, IL). Differences
between IGT and NGT family members were tested using the nonparametric
Mann-Whitney U test.
To determine the heritability of insulin secretion, we performed a multivariate analysis of diabetes status, SI, AIRglucose, and SI x AIRglucose using likelihood analysis. For this analysis, all family members of families in which at least one individual underwent FSIGT testing were included. For individuals who did not undergo FSIGT testing, values of SI, AIRglucose, and SI x AIRglucose were considered unknown, and only the diabetes status was included in the analysis. When IGT individuals were included, they were considered nondiabetic for this analysis.
Maximum likelihood analysis
We used a maximum likelihood method to estimate heritability, as
described in detail below. The traits in the model were SI,
AIRglucose, SIx AIRglucose, and
diabetes. We assumed that the variance of each trait was due to the
additive effects of a polygenic genetic component and random
environmental factors specific to the individual. For any two traits i
and j, the model parameters were the heritability of trait i
(hi2), the genetic correlation between traits i
and j (
gij), and the environmental correlation between
traits i and j (eij). Heritability
(hi2) is the proportion of the trait variance
that is genetic. The genetic correlation (gij) between
two traits is the correlation between the genetic portion of the
variance for each trait, whereas the environmental correlation
(eij) is the correlation between the proportion of the
variance attributed to environmental factors.
To estimate the three parameters of the model (h2,
g, and e) for each of four traits, we
tested the hypotheses of most interest. First, we tested the hypothesis
of no heritability for each trait (hi2 = 0).
When this null hypothesis was rejected, we tested the hypothesis that
genetic and environmental correlations for each pair of traits were
both 0 (g = e = 0). When this null
hypothesis was rejected, we tested the hypothesis that the genetic and
environmental correlations were equal for each pair of traits
(g = e). Finally, we tested the
hypotheses that for each pair of traits, either the environmental or
the genetic correlation was 0 (g = 0 or e
= 0). For each hypothesis, we compared the likelihood of the model with
the values of the parameters fixed (for example, heritability of
SI fixed at 0) to the model when all parameters were
allowed to vary. A hypothesis was rejected if the model differed
significantly from the most general model (all parameters estimated).
Hypotheses were tested by computing 2
statistics as twice the natural logarithm of the ratio of the maximized
likelihood of the general model to the maximized likelihood of the
model with some parameters constrained to fixed values. The values of
the parameters given in Results were taken from the
maximized likelihood of the model that did not differ significantly
from the general model but in which the fewest parameters were
estimated. However, not all possible constraints were included in the
final model, and a different set of constraints might also produce a
model that does not differ significantly from the general model. Thus,
estimates of h2, g, and e
might differ if other constraints were used.
The likelihood was calculated using the computer programs of the
Pedigree Analysis Package (21) and was maximized using NPSOL (22).
Because we ascertained on a diabetic sibling pair, we corrected for
this ascertainment bias by dividing the likelihood by the probability
of a sibling pair diagnosed with type 2 diabetes. To estimate the
liability for diabetes in the model, we assumed that an unmeasurable
quantitative liability variable underlies diabetes susceptibility (23).
The liability variable distributed as a normal density. The population
incidence for each age interval determined a point on the liability
scale such that the weighted sum of the areas between adjacent points
under the normal curve equaled the diabetes incidence for the age
interval, with younger ages corresponding to higher liability. For an
affected individual, the probability equaled the integral of the normal
curve between the two points on the liability scale bracketing the age
at onset. For an unaffected individual, the probability equaled the
integral of the normal curve from -
to the point on the
liability scale marking the upper end of the age range bracketing the
age when the subject was last known to be free of diabetes. Each
individual was classified as obese or not, and the appropriate gender-
and obesity-specific incidence figures were used (24).
We assumed that liability to type 2 diabetes, SI, AIRglucose, and SI x AIRglucose distributed as a quadrivariate normal density (25), following natural logarithm transformation of SI and AIRglucose and using the normal deviate corresponding to the percentile score for SI x AIRglucose. In addition, for each SI and AIRglucose, the mean, SD, and linear effects of age and BMI were estimated simultaneously with the other parameters of the model.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, and the characteristics
of the members with IGT and NGT on previous testing are shown in Table 2. Three spouses who also underwent FSIGT
testing were included for heritability analysis because their children
were studied, but are excluded from these tables. Although all
individuals were offspring or siblings of families with a type 2
diabetic sibling pair, we found a broad range of both SI
and AIRglucose that encompassed normal values, even among
family members with IGT.
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), thus
demonstrating that within this high risk population, both insulin
resistance and impaired insulin secretion characterize the IGT
state.
Based on the observed deficiency in insulin secretion among IGT
individuals, we estimated heritability of SI,
AIRglucose, and SI x
AIRglucose for both the full population and when these
indexes were considered known only for NGT individuals. For each
analysis, heritability and both genetic and environmental
correlations between indexes and diabetes were determined
for the model with the fewest estimated parameters that was not
significantly different from the model in which all parameters were
estimated. These data are summarized in Table 3. Beside type 2 diabetes, which showed 100%
heritability in these families, SI x
AIRglucose was the most heritable index, with 67%
heritability in the full population and 70% heritability when only NGT
individuals were included. The lower 95% confidence interval for these
estimates was 61% for the complete sample and 62% for the NGT
individuals. Both AIRglucose and SI showed
lower heritabilities (38% in all individuals; 33% and 29%,
respectively, in NGT individuals). Both SI x
AIRglucose and SI showed strong negative
genetic correlations with diabetes under both analyses
(g = -87% for the complete sample), thus suggesting
shared genetic susceptibility for diabetes and both SI and
SIx AIRglucose. In this analysis,
AIRglucose alone showed neither environmental nor genetic
correlation with diabetes status (Table 4).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Our study is unique in several respects. Our families were chosen for a specific ethnic background and for particularly high risk for type 2 diabetes with at least two siblings with diabetes onset before age 65 yr. We have specifically avoided bilineal families such as those examined by Warram et al. (3), and our families may carry a different genetic risk than either bilineal families or families with only a single diabetic member. In contrast to other studies, we examined a relatively large number of members (mean, 4.6; range, 1–11) of only 26 families, including nondiabetic members with both NGT and IGT and with different relationships to the diabetic members. Among the family members tested, we found a broad range of values for both insulin sensitivity (SI) and insulin secretion (SI x AIRglucose). When expressed as a percentile score from normal individuals, family members encompassed the full spectrum from 1–100%. Thus, as might be expected for an inherited disorder, not all individuals with a family history of diabetes show defects in either insulin sensitivity or insulin secretion. This fact may help explain some of the discrepancies in studies that have intensively studied small numbers of relatives of diabetic individuals. In the setting of heterogeneity, any smaller study is subject to sampling artifacts, and different conclusions may reflect the effects of random sampling.
We have chosen SI x AIRglucose rather than simply AIRglucose as our primary measure of insulin secretion. As might be expected if SI x AIRglucose is a more precise measure of ß-cell function, this index is more heritable than AIRglucose and is strongly correlated with diabetes. In contrast, the correlation of uncorrected AIRglucose with diabetes was not significantly different from 0. To our knowledge, this is the first demonstration that SI x AIRglucose is familial. Our data thus provide additional evidence that SI x AIRglucose is a more useful index of insulin secretion than AIRglucose or other measures of insulin secretion that are not corrected for insulin sensitivity.
Although familiality of insulin secretion was suggested in earlier studies of first degree relatives (10, 26), these studies did not seek to directly demonstrate heritability by examining multiple members of larger families. In contrast, Sakul et al. (28) recently reported a heritability analysis based on families rather than individuals. Our studies differ in several respects. They examined Pima Indians rather than Caucasians. Because their families were not selected on a diabetic sibling pair, they did not include an ascertainment correction. Finally, they examined each parameter individually rather than in a multivariate analysis, and they corrected AIRglucose by including a euglycemic clamp-derived measure of insulin sensitivity as a covariate rather than calculating an index of insulin secretion based on the hyperbolic relationship. This latter correction should be mathematically equivalent to our correction using the hyperbolic relationship of SI and AIRglucose, however. Despite the differences in our populations and study methods, the estimate of heritability for AIRglucose corrected for insulin sensitivity from Sakul et al. (70% heritability for the 10 min value) was remarkably similar to our value for SI x AIRglucose (67% with all individuals, 70% excluding IGT). Both studies thus suggest that AIRglucose when corrected for insulin sensitivity is a highly heritable trait.
An intriguing aspect of our analysis was the genetic correlation estimated between diabetes status, SI, and SI x AIRglucose. The strong negative correlation between diabetes and SI suggested that individuals with low SI are at highest risk for diabetes, a conclusion that is consistent with the findings of Warram et al. (3) in offspring of two diabetic parents. However, a low measure of insulin secretion corrected for the SI was even more strongly correlated with diabetes, with a genetic correlation estimated at -87%. This was in striking contrast to the failure of AIRglucose to correlate with diabetes. These data argue strongly for the superiority of SI x AIRglucose as an inherited and predictive measure of insulin secretion in family members at risk for type 2 diabetes.
We have used a maximum likelihood approach to estimate the familiarity
of the four traits under study. Our parameter estimates do have
limitations. First, the estimated heritability may reflect shared,
environmental effects that would increase the apparent heritability and
would not be included in the estimate of e, which
reflects random environmental effects specific to the individual.
Because shared environmental effects are likely among family members,
the estimate of heritability may be better stated as an estimate of
familiality (28). Second, we compared a limited number of models in
which the parameters values were set (constrained) to the more general
model in which all parameters were estimated. We tested models in which
the heritability was 0, each correlation between the traits was set at
0, and the random environmental and polygenic components of the
correlation of the variance were set as equal. A different set of
constraints might have lead to a different model with other parameters
that were not significantly different from the general model, and thus
slightly different estimates. Third, our data are based on families
ascertained for diabetes, which is highly correlated with
SI x AIRglucose. Although we have corrected
for that ascertainment, our study design may have resulted in inflated
heritabilities that were not adequately accounted for in our
ascertainment correction. Finally, although we simultaneously estimated
the effects of age and BMI with the other parameters of the model, we
have shown that BMI has nonlinear effects on SI (14) and
SI x AIRglucose (Elbein, S. C.,
unpublished data). Because BMI is also familial, our estimates of
heritability may include some effect of BMI despite our attempts to
correct for these effects.
We have previously examined a group of 16 large families from this population for segregation of fasting insulin level and insulin level 1 h after a 75-g oral glucose challenge (9). In that study, we suggested autosomal inheritance of both fasting and postchallenge insulin levels, thus indirectly suggesting the segregation of insulin sensitivity. Several other investigators have also suggested that insulin resistance is familial. Martin et al. (4) showed significant intraclass correlations of SI in families with two diabetic parents. Several analyses of Pima Indians have also suggested inheritance of insulin resistance (6, 8, 28). In their most recent analysis, Sakul et al. found a familiality of insulin action from 0.45–0.61 depending on the insulin concentration tested. Our analysis of heritability of SI shows a somewhat lower estimate of heritability of 38% when all individuals were included in this multivariate model, although our estimate was as high as 56% when SI was examined individually (data not shown), as in the study of Sakul et al. (28).
In conclusion, we have demonstrated high heritability of insulin secretion in Caucasian families with two diabetic siblings when insulin secretion is determined from the hyperbolic relationship of acute insulin response to glucose and insulin sensitivity. The highly familial nature of this parameter and the strong negative correlation of SI x AIRglucose with diabetes suggest that this will be a valuable quantitative trait in the search for genes causing type 2 diabetes. In contrast, although AIRglucose alone showed high heritability in a univariate analysis (data not shown), in the multivariate analysis this variable showed lower heritability and no genetic correlation with diabetes. Our data are consistent with those from recent studies in Pima Indians (28), where one potential locus controlling AIRglucose has been mapped to chromosome 1 (29).
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Acknowledgments |
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Footnotes |
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Received July 23, 1998.
Revised October 4, 1998.
Revised November 17, 1998.
Accepted November 17, 1998.
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H. Wang, W. S. Chu, C. Hemphill, and S. C. Elbein Human Resistin Gene: Molecular Scanning and Evaluation of Association with Insulin Sensitivity and Type 2 Diabetes in Caucasians J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2520 - 2524. [Abstract] [Full Text] [PDF]
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 S. C. Elbein Perspective: The Search for Genes for Type 2 Diabetes in the Post-Genome Era Endocrinology, June 1, 2002; 143(6): 2012 - 2018. [Abstract] [Full Text] [PDF]
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S. C. Elbein, W. Chu, Q. Ren, C. Hemphill, J. Schay, N. J. Cox, C. L. Hanis, and S. J. Hasstedt Role of Calpain-10 Gene Variants in Familial Type 2 Diabetes in Caucasians J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 650 - 654. [Abstract] [Full Text] [PDF]
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N. G. Knowles, M. A. Landchild, W. Y. Fujimoto, and S. E. Kahn Insulin and Amylin Release Are Both Diminished in First-Degree Relatives of Subjects With Type 2 Diabetes Diabetes Care, February 1, 2002; 25(2): 292 - 297. [Abstract] [Full Text] [PDF]
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S.C. Elbein and S.J. Hasstedt Quantitative Trait Linkage Analysis of Lipid-Related Traits in Familial Type 2 Diabetes: Evidence for Linkage of Triglyceride Levels to Chromosome 19q Diabetes, February 1, 2002; 51(2): 528 - 535. [Abstract] [Full Text] [PDF]
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R. N. Bergman, M. Ader, K. Huecking, and G. Van Citters Accurate Assessment of {beta}-Cell Function: The Hyperbolic Correction Diabetes, February 1, 2002; 51(90001): S212 - 220. [Abstract] [Full Text] [PDF]
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J. J. Meier, K. Hucking, J. J. Holst, C. F. Deacon, W. H. Schmiegel, and M. A. Nauck Reduced Insulinotropic Effect of Gastric Inhibitory Polypeptide in First-Degree Relatives of Patients With Type 2 Diabetes Diabetes, November 1, 2001; 50(11): 2497 - 2504. [Abstract] [Full Text] [PDF]
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S. E. Kahn The Importance of {beta}-Cell Failure in the Development and Progression of Type 2 Diabetes J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4047 - 4058. [Full Text] [PDF]
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S. Colilla, N. J. Cox, and D. A. Ehrmann Heritability of Insulin Secretion and Insulin Action in Women with Polycystic Ovary Syndrome and Their First Degree Relatives J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 2027 - 2031. [Abstract] [Full Text]
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K. C. Chiu, L.-M. Chuang, and C. Yoon Comparison of Measured and Estimated Indices of Insulin Sensitivity and {beta} Cell Function: Impact of Ethnicity on Insulin Sensitivity and {beta} Cell Function in Glucose-Tolerant and Normotensive Subjects J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1620 - 1625. [Abstract] [Full Text]
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S. C. Elbein, J. Sun, E. Scroggin, K. Teng, and S. J. Hasstedt Role of Common Sequence Variants in Insulin Secretion in Familial Type 2 Diabetic Kindreds: The sulfonylurea receptor, glucokinase, and hepatocyte nuclear factor 1{alpha} genes Diabetes Care, March 1, 2001; 24(3): 472 - 478. [Abstract] [Full Text]
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S. J. Hasstedt, Q.-F. Ren, K. Teng, and S. C. Elbein Effect of the Peroxisome Proliferator-Activated Receptor-{{gamma}}2 Pro12Ala Variant on Obesity, Glucose Homeostasis, and Blood Pressure in Members of Familial Type 2 Diabetic Kindreds J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 536 - 541. [Abstract] [Full Text]
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