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(Circulation. 2000;101:975.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
From the Division of Clinical Epidemiology, Department of Medicine, University of Texas Health Science Center at San Antonio.
| Abstract |
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Methods and ResultsWe examined this issue in the 7-year
follow-up of the San Antonio Heart Study, in which 195 of 1734 subjects
converted to type 2 diabetes. At baseline, converters had significantly
higher body mass index, waist circumference, triglyceride
concentration, and blood pressure and lower HDL cholesterol
than nonconverters. Atherogenic changes in converters were markedly
attenuated (and no longer significant) after adjustment for the
homeostasis model assessment of insulin resistance (HOMA IR, a
surrogate for insulin resistance); in contrast, the differences in risk
factors between converters and nonconverters increased after adjustment
for the ratio of early insulin increment to early glucose increment
(
I30-0/
G30-0) during an oral glucose
tolerance test (a surrogate for insulin secretion). We also compared
converters who had a predominant insulin resistance (high HOMA IR and
high
I30-0/
G30-0) (n=56) and converters
who had a predominant decrease in insulin secretion (low HOMA IR and
low
I30-0/
G30-0) (n=31) with
nonconverters (n=1539). Only the converters who were insulin
resistant had higher blood pressure and
triglyceride levels and lower HDL cholesterol
levels than nonconverters.
ConclusionsOur data suggest that atherogenic changes in the prediabetic state are mainly seen in insulin-resistant subjects and that strategies to prevent type 2 diabetes might focus on insulin-sensitizing interventions rather than interventions that increase insulin secretion because of potential effects on cardiovascular risk.
Key Words: insulin diabetes mellitus lipids cholesterol blood pressure
| Introduction |
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The causes of increased atherogenicity of the prediabetic state are not fully understood. Both insulin resistance (measured directly14 or through surrogates such as fasting insulin15 16 17 ) and decreased insulin secretion18 19 20 21 predict the development of type 2 diabetes. It is not known whether the increased atherogenicity of the prediabetic state is primarily due to increased insulin resistance or decreased insulin secretion, although increased resistance may be likely given the amount of information on the insulin-resistance syndrome.22 23
In this report, we examine whether insulin resistance or decreased
insulin secretion is responsible for the atherogenic prediabetic state.
In particular, we were interested in whether
cardiovascular risk factors were similar in prediabetic
subjects who had a predominant insulin-secretory defect (normal insulin
sensitivity but low insulin-secretory response) as opposed to subjects
with a predominant insulin-resistance defect (insulin resistant
but with good insulin-secretory response). This issue is important
because recently, a number of projects to prevent type 2 diabetes
have been undertaken with methods that either improve insulin
sensitivity (Diabetes Prevention Project [DPP: metformin,
intensive lifestyle24 ] and STOP-NIDDM
[acarbose]25 ) or increase insulin secretion (NANSY
[sulfonylurea {Amaryl}]; Arne Melander, Sweden, oral
communication, 1999). If atherogenic changes in the prediabetic
state are limited to subjects with insulin resistance, the use of
insulin-sensitizing agents to prevent diabetes could have a beneficial
effect on CHD. We used data from the San Antonio Heart Study, in which
we have previously shown that both high fasting insulin (a surrogate
for insulin resistance) and a decreased ratio of insulin increment
(over the first 30 minutes) to glucose increment (over the first 30
minutes) during an oral glucose tolerance test
(
I30-0/
G30-0) (a
surrogate for insulin secretion) predict the development of type 2
diabetes in Mexican Americans.20
| Methods |
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At the baseline and follow-up visits, blood specimens were obtained
after a 12- to 14-hour fast for determination of plasma glucose, serum
insulin, and serum lipids and lipoproteins. Methods for determination
of lipids and lipoproteins and glucose have been described
previously.20 We measured serum insulin with a solid-phase
radioimmunoassay (Diagnostic Products Corporation) that
shows a relatively high degree of cross-reactivity with proinsulin
(
70% to 100%).26 A 75-g oral glucose load (Orangedex;
Custom Laboratories) was administered, and blood specimens were
obtained 30 minutes, 1 hour, and 2 hours later for plasma glucose and
serum insulin concentrations. At the follow-up examination,
postglucose-load specimens were obtained only at the 2-hour time
point. Diabetes was diagnosed according to World Health Organization
(WHO) criteria.27 Subjects who did not meet WHO plasma
glucose criteria but who were undergoing treatment with oral
antidiabetic agents or insulin were considered to have diabetes. In
this report, we use the homeostasis model of insulin resistance (HOMA
IR) as a measure of insulin resistance28 29 30 and
I30-0/
G30-031
as a measure of insulin secretion (early secretory response to an oral
glucose load). The formula for the HOMA IR model28
follows:
![]() |
Anthropometric measurements (height, weight, and waist and hip circumferences) were made after participants had removed their shoes and upper garments and donned an examination gown. Body mass index (BMI) was calculated as weight (in kilograms) divided by height (in meters squared). Waist circumference was chosen as a measure of central adiposity.
The systolic (first phase) and diastolic (fifth phase) blood pressures were measured to the nearest even digit by use of a random-zero sphygmomanometer (Hawksley-Gelman). Three readings were recorded for each individual, and the average of the second and third readings was defined as the patients blood pressure.
Statistical analyses included ANCOVA performed with SAS
statistic software. Two-way ANCOVA was done initially with conversion
to diabetes and ethnicity (Mexican American versus non-Hispanic whites
as the grouping variable). The P value for these
interaction terms (ethnicity times conversion status) were all >0.100.
Because there was no evidence of different effect of conversion status
by ethnicity on variables of interest (ie,
triglycerides or blood pressure), we pooled the ethnic
groups with control for ethnicity to increase statistical power
and to simplify the analysis. One-way ANCOVA was done with
conversion to diabetes as the main effect (Tables 1
and 2
). Additional analysis was done
with 2-way ANCOVA among the converters to diabetes by dividing subjects
by their insulin-resistance or insulin-secretion status at baseline
(HOMA IR above and below median of 3.0 and insulin secretion
[
I30-0/
G30-0 in
pmol/mmol] above and below median of 155.6 pmol/L) (Table 3
).
The median was based on the overall nondiabetic population at baseline.
Finally, 1-way ANCOVAs (with pairwise contrasts) were done with
conversion to diabetes as the dependent variable to compare
subjects with predominant insulin resistance (above median for both
HOMA IR and
I30-0/
G30-0) and
subjects with a predominant insulin-secretory defect (below median for
both fasting insulin and
I30-0/
G30-0) with
subjects who did not convert to type 2 diabetes (Figure 2
).
Triglyceride, fasting insulin, HOMA IR, and
I30-0/
G30-0 were
transformed to improve the skewness and kurtosis of their distribution
for statistical testing. These variables were both back-transformed
for presentation in the tables. All probability values are
2-sided.
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| Results |
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I30-0/
G30-0 was lower
in converters to diabetes than in subjects who remained nondiabetic.
Subjects who converted to diabetes had greater obesity and an
unfavorable body fat distribution, higher blood pressure, higher
prevalence of hypertension, higher glucose levels, higher
triglyceride levels, and lower HDL
cholesterol than subjects who did not convert to diabetes.
Total and LDL cholesterol levels and smoking status were
similar in converters and nonconverters.
As shown in Table 2
(model A), after further adjustment for
fasting glucose and waist circumference, converters continued to have
higher blood pressure and higher triglyceride levels and
lower HDL cholesterol levels than subjects who did not
convert to diabetes. Table 2
shows the effects of additional
adjustment for HOMA IR (a surrogate for insulin resistance) (model B)
versus the effect of adjustment for
I30-0/
G30-0 (model
C), a surrogate for insulin secretion. Adjustment for HOMA IR
attenuated the differences between converters and nonconverters, making
them no longer statistically significant. In contrast, after adjustment
for insulin secretion
(
I30-0/
G30-0), the
differences between converters and nonconverters to type 2 diabetes
remained statistically significant.
We next categorized the subjects simultaneously by insulin
resistance (above and below the median for HOMA IR in the overall
nondiabetic population at baseline) and insulin secretion (above and
below the median for
I30-0/
G30-0). The
incidence of type 2 diabetes by insulin resistance and secretion
categories is shown in Figure 1
. As
expected, subjects with the highest rate of developing type 2 diabetes
had both insulin resistance and decreased insulin secretion (31.8% in
7 years), and the lowest rate was in subjects who were insulin
sensitive with good secretory capacity (1.0%). Subjects with insulin
resistance but good insulin secretion had a higher conversion rate than
subjects with low insulin secretion who were insulin sensitive (11.0%
versus 6.2%). These results are similar to those presented for
a smaller cohort of Mexican Americans only.20
|
We also characterized the distribution of insulin resistance and secretory effects of converters to diabetes and insulin secretion. Fifty-four percent of converters had both an insulin secretory defect and were insulin resistant compared with 1.5% of converters who were insulin sensitive with good secretion at baseline. The subjects who were predominantly insulin resistant with good insulin secretion at baseline comprised 28.7% of all converters to type 2 diabetes compared with 15.9% of subjects who had low insulin secretion but were insulin sensitive (predominantly insulin sensitive).
Table 3
shows anthropometric and
cardiovascular risk factors by insulin resistance and
secretion categories. Insulin resistance was associated with higher
BMI, greater waist circumference, and higher blood pressure and
triglyceride levels and lower HDL cholesterol
levels. Insulin secretion was not related to anthropometric or
cardiovascular risk factors. Fasting and 2-hour glucose
levels were similar in each group. Additional adjustment for BMI or
waist circumference did not appreciably change these results (data not
shown).
Figure 2
compares the
triglyceride and HDL levels and systolic blood
pressure in converters to type 2 diabetes with predominant insulin
resistance (high HOMA IR and high
I30-0/
G30-0),
converters with a predominant insulin-secretory defect (low
I30-0/
G30-0 and low
HOMA IR), and nonconverters to type 2 diabetes. Among converters to
diabetes, the only subjects with adverse cardiovascular
risk factors (high systolic blood pressure and
triglyceride levels and low HDL cholesterol
levels) were converters to diabetes with high IR and
I30-0/
G30-0
(insulin-resistant subjects).
Subjects who converted to diabetes but had predominant insulin
resistance had a BMI 3 to 4 kg/m2 higher than
subjects who did not convert to diabetes or who converted to diabetes
but had a predominant insulin-secretory defect. Adjustment for
differences in BMI somewhat attenuated the differences in lipoproteins
or blood pressure (
30%), but converters to diabetes who had
predominant insulin resistance continued to have significantly more
atherogenic risk factors than the other 2 groups
(P<0.01).
| Discussion |
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More interesting is whether the atherogenic differences in prediabetic
subjects are due to increased insulin resistance, decreased insulin
secretion, or both. To address this issue, we used 2 different
approaches: that of statistical adjustment (Tables 1
and 2
) and that of stratification (Table 3
and Figure 2
). After adjustment for HOMA IR, the differences between
converters and nonconverters were attenuated and were no longer
statistically significant. In contrast, after adjustment for
I30-0/
G30-0 (a
surrogate for decreased secretory response that has been shown to be a
significant predictor of type 2 diabetes in this
cohort20 ), the differences between converters and
nonconverters actually widened (Table 2
).
Subjects who converted to diabetes but were insulin resistant
had significantly higher triglyceride levels,
systolic blood pressure, and diastolic blood
pressure and lower HDL cholesterol levels than subjects who
converted to diabetes but who were insulin sensitive. The 2 groups of
converters to type 2 diabetes (predominantly insulin-resistant
versus insulin-sensitive converters) had similar values for both
fasting and 2-hour glucose levels, but the insulin-resistant
converters were more obese (Table 3
). After additional
adjustment for BMI (data not shown), insulin-resistant
converters to type 2 diabetes still had worse
cardiovascular risk factors than insulin-sensitive
converters. Interestingly, insulin-sensitive converters to type 2
diabetes had triglyceride and HDL cholesterol
levels and systolic blood pressure similar to those of subjects
who remained nondiabetic at baseline.
We have thus identified different subgroups of converters to type 2 diabetes with markedly different patterns of cardiovascular risk factors. The implication is that the subjects who were insulin resistant and converted to diabetes would have more cardiovascular disease than the insulin-sensitive subjects who converted to diabetes.
We should point out that the differences in lipids
(triglyceride 0.9 mmol and HDL cholesterol
0.24 mmol) and systolic blood pressure (6.5 mm Hg)
(Table 3
) are actually larger than the differences between
diabetic (n=303) and nondiabetic (n=2564) subjects in the San Antonio
Heart Study (for diabetic versus nondiabetic subjects, respectively:
triglyceride 2.3 versus 1.6 mmol/L, a 0.7 mmol/L
difference; HDL cholesterol 1.12 versus 1.24 mmol/L, a
0.12 mmol/L difference; and systolic blood pressure 124.9
versus 118.8 mm Hg, or a difference of 6.1
mm Hg).
Our results may have important implications for the prevention of diabetes. Currently, a number of clinical trials on insulin-sensitizing agents are under way (DPP [metformin, intensive lifestyle24 ] and STOPNIDDM [acarbose]25 ). Similarly, there are prevention trials involving insulin secretagogues (NANSY [sulfonylurea {Amaryl}]). If our results are correct, they suggest that the use of a sulfonylurea to prevent diabetes might increase the risk of CHD (or at least prove less beneficial) than the use of insulin-sensitizing agents. The effects of different modalities for the prevention of diabetes on CHD will be particularly informative. However, improvement in glycemic control in diabetic subjects by sulfonylurea has led to reduction in insulin resistance in diabetic subjects,32 suggesting that the differential between insulin sensitizers and insulin secretagogues with respect to cardiovascular risk factors could be overestimated in epidemiological studies such as the present report. However, whether insulin secretagogues would improve insulin sensitivity in nondiabetic subjects at high risk of diabetes (impaired glucose tolerance), which are the focus of the current report, is not known.
In this study, we have a number of limitations. First, we have not
directly measured insulin resistance or insulin sensitivity. Few
studies have compared fasting insulin versus insulin resistance as a
predictor of type 2 diabetes. Lillioja et al14 showed that
insulin resistance (as determined by hyperinsulinemic
euglycemic clamp) was a better predictor than was fasting
insulin, although both were strong predictors (hazard ratios of 30 and
15, respectively). Fasting insulin and
I30-0/
G30-0 have been
correlated with more definitive methods for assessing insulin secretion
and resistance.28 29 30 31 In the Mexico City Diabetes Study,
HOMA IR was a slightly better predictor of the incidence of type 2
diabetes than were fasting insulin levels.33 It is likely
that more precise measurements of these variables would decrease
misclassification and perhaps strengthen the present results.
In conclusion, we have shown that prediabetic subjects have an atherogenic pattern of cardiovascular risk factors, and these changes are predominantly observed in prediabetic subjects with increased HOMA IR and fasting insulin ("insulin resistance") at baseline. Insulin-sensitive converters to diabetes have a pattern of cardiovascular risk factors similar to nonconverters to diabetes. The most important possible implication of these findings is that different methods of preventing diabetes may have different effects on CHD, which is the most common cause of death in diabetic subjects.1 2 3
| Acknowledgments |
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| Footnotes |
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Received July 12, 1999; revision received September 17, 1999; accepted October 1, 1999.
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