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Risk of type 2 diabetes mellitus and coronary heart disease: a pivotal role for metabolic factors
Peter W.F. Wilson1,* and
James B. Meigs2
1 EPICORE, Suite 1 North, Emory University School of Medicine, 1256 Briarcliff Road, Atlanta, GA 30306, USA
2 General Medicine Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA 102114, USA
* Corresponding author: Tel: +1 404 727 6854; fax: +1 866 434 1997. E-mail address: peter.wf.wilson{at}emory.edu
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Abstract
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Prediction of the development of type 2 diabetes mellitus (T2DM)
and coronary heart disease has considered a large number of
factors that may have important effects on risk. Data from recent
publications of the Framingham Heart Study are reviewed from
the perspective of how metabolic factors contribute to increased
risk for T2DM, coronary heart disease, and vascular disease.
Persons with impaired fasting glucose or impaired glucose tolerance
were found to have increased risk of coronary artery calcification,
left ventricular hypertrophy among women, and augmented risk
to develop coronary artery disease events. The metabolic syndrome
risk factor burden and fasting insulin were also shown to affect
the risk of developing future T2DM. Risk estimation for the
development of T2DM showed that each of the five metabolic syndrome
traits (increased waist girth, elevated blood pressure, low
high density lipoprotein (HDL)-cholesterol, high triglycerides,
and impaired fasting glucose) were important predictors for
the development of T2DM in middle-aged men and women. Both T2DM
and coronary heart disease are consequences of persons with
elevated blood glucose levels, insulin resistance, and an increasing
burden of metabolic syndrome traits.
Key Words: Coronary artery disease • Diabetes mellitus • Insulin resistance
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Introduction
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An epidemic of type 2 diabetes mellitus (T2DM) is sweeping across
the North American continent and the prevalence is projected
to rise for several decades into the future.
1 Factors that are
associated with this rising frequency include excess adiposity
and a variety of metabolic factors. The Adult Treatment Panel
of the National Cholesterol Education Program identified five
key variables related to excess adiposity and this categorization
has provided a foundation for many research articles that have
investigated the role of adiposity, blood pressure, high density
lipoprotein (HDL)-cholesterol, triglycerides, and elevated fasting
glucose as determinants of greater risk for heart disease and
T2DM.
Framingham investigations over the past decade have included several articles concerning the role of metabolic factors on risk of developing T2DM and coronary artery disease. The current report summarizes important findings from these publications, including a very recent publication that predicts the development of diabetes in middle-aged adults and showed that the burden of metabolic risk factors increases the risk of both coronary artery disease and T2DM.
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Methods
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The data reviewed here include published findings reported for
the Framingham Heart Study participants in the Offspring cohort.
This population sample of 5135 men and women was first examined
in 1971 and has been followed since that time with regular clinical
visits and surveillance for the development of coronary heart
disease (CHD) and T2DM. At examination 5 that took place from
1991 to 1995, the participants underwent oral glucose tolerance
testing with insulin measurements, which allowed for characterization
of glycaemic status and provided especially detailed metabolic
factor data that have been used in studies related to the metabolic
syndrome, insulin resistance, occurrence of subclinical vascular
disease, and the development of clinical heart disease and new
T2DM.
2 Follow-up has included fasting glucose measurements at
the time of follow-up clinical examinations that occurred 4
and 8 years after the baseline, along with surveillance for
the occurrence of new vascular events and diabetes mellitus.
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Results and discussion
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In 1997, a formal clustering of metabolic traits was demonstrated
in the Framingham Offspring using factor analysis.
3 This article
provided evidence for a central syndrome with body mass index,
waist girth, HDL cholesterol, triglycerides, and hyperinsulinaemia
tending to cluster within individuals. Elevated blood pressure
was weakly associated with the syndrome and had a shared variance
component with body mass index. Elevated blood glucose levels
were shared largely through hyperinsulinaemia mechanisms. Cross-sectional
studies showed that greater insulin resistance was associated
with increased left ventricular mass in women and with greater
coronary artery calcification in both sexes.
4,5
Metabolic characteristics have drawn a lot of attention since the metabolic syndrome gained importance in 2001 as part of the National Cholesterol Education Program.6 The frequency of the five constituent traits (hyperglycaemia, increased waist circumference, elevated triglycerides, low HDL cholesterol, and increased blood pressure) is shown in Table 1 for participants in the Framingham Offspring Study and comparisons are made to persons in the San Antonio Heart Study. The Mexican-Americans were more likely to have the metabolic syndrome (more than three of the five traits), and increased waist circumference, higher triglycerides, and lower HDL cholesterol were especially responsible for the increased prevalence of the syndrome in this Hispanic group.7
Prospective analyses based on
7 years of follow-up after the
baseline examination that included an oral glucose tolerance
test have shown that metabolic syndrome factors (increased waist
girth, increased blood pressure, elevated blood glucose, low
HDL cholesterol, and elevated triglycerides) tend to double
the risk of CHD and lead to a sixfold increase in risk for T2DM
(
Table 2).
8 An initial analysis compared persons with zero,
one, or two metabolic traits (referent group) against persons
with three, four, or five metabolic traits (evidence of metabolic
syndrome using the National Cholesterol Education Program definition).
Further tabulations of those data showed that impaired fasting
glucose (fasting glucose 100–126 mg/dL) especially led
to an increased risk of T2DM. More detailed investigation of
the metabolic trait burden, using the absence of metabolic traits
as the reference group, demonstrated that an increasing number
of metabolic traits had very strong effects to augment risk
for both vascular disease and T2DM (
Table 3).
8 For example,
in comparison to persons without any of the metabolic syndrome
traits, those persons with three or more of the metabolic syndrome
traits experience a three- to fourfold risk of CHD and 23- to
30-fold risk of T2DM over a 7-year follow-up interval.
A recent publication that analyzed the determinants of incident
T2DM in the Framingham Offspring showed that the incidence of
new T2DM can be estimated with good discrimination.
9 A robust
prediction model with an area under the receiver operating characteristic
curve of 0.85 was shown when the metabolic syndrome traits were
included as individual variable along with age (not statistically
significant), sex (not statistically significant), and parental
history of diabetes mellitus (statistically significant), as
shown in
Table 4. It is possible to estimate the risk of
incident T2DM with this approach, and separate models are available
to use either increased waist girth or body mass index as measures
of adiposity to help predict the risk of new diabetes over a
7-year interval. An example of the application of the T2DM risk
estimation approach is shown in
Figure 1 for an adult according
to the parental history of diabetes mellitus, body mass index
level, blood pressure elevation, low HDL cholesterol, increased
triglycerides, and fasting plasma glucose 100–126 mg/dL.
The presence of multiple metabolic traits, especially elevated
fasting plasma glucose, acts synergistically to increase the
future risk of developing T2DM in this situation.
Further research that included consideration of both the metabolic
syndrome factors and evidence of insulin resistance using the
homeostatic model showed that both features were especially
predictive of the development of diabetes mellitus over a 7-year
follow-up interval.
10 The key findings are shown in
Table 5,
where persons without the metabolic syndrome or insulin resistance
served as the referent group. Higher risk for developing T2DM
was evident for both metabolic syndrome and for the presence
of insulin resistance, and the highest relative risk for T2DM
was observed in persons with both features. On the other hand,
the evidence for independent effects of both metabolic syndrome
and insulin resistance was more modest for the outcome cardiovascular
disease.
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Table 5 Relative risksa for incident type 2 diabetes mellitus and cardiovascular disease according to metabolic syndrome and insulin resistance status Framingham Offspring 8-year incidence
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A summary figure for the development of cardiovascular disease
and T2DM is shown in
Figure 2. Several features are common
to the pathogenesis of both outcomes, including high triglycerides,
elevated glucose, and low HDL cholesterol. Excess adiposity,
especially abdominal adiposity, and insulin resistance are probably
key to the development of risk factor abnormalities and adverse
clinical outcomes. Interventions that target both risk factors
and the underlying conditions that lead to the worsening of
those risk factors are thought to be effective preventive strategies
against the development of cardiovascular disease and diabetes
mellitus in adults.
Conflict of interest: none declared.
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Reference
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- Mokdad AH, Ford ES, Bowman BA, Nelson DE, Engelgau MM, Vinicor F, Marks JS. Diabetes trends in the U.S.: 1990–1998. Diabetes Care (2000) 23:1278–1283.[Abstract/Free Full Text]
- Meigs JB, Nathan DM, Wilson PW, Cupples LA, Singer DE. Metabolic risk factors worsen continuously across the spectrum of nondiabetic glucose tolerance. The Framingham Offspring Study. Ann Intern Med (1998) 128:524–533.[Abstract/Free Full Text]
- Meigs JB, D’Agostino RB, Wilson PWF, Cupples LA, Nathan DM, Singer DE. Risk variable clustering in the insulin resistance syndrome. Diabetes (1997) 46:1594–1600.[Abstract]
- Rutter MK, Parise H, Benjamin EJ, Levy D, Larson MG, Meigs JB, Nesto RW, Wilson PW, Vasan RS. Impact of glucose intolerance and insulin resistance on cardiac structure and function: sex-related differences in the Framingham Heart Study. Circulation (2003) 107:448–454.[Abstract/Free Full Text]
- Meigs JB, Larson MG, D’Agostino RB, Levy D, Clouse ME, Nathan DM, Wilson PW, O’Donnell CJ. Coronary artery calcification in type 2 diabetes and insulin resistance: The Framingham Offspring Study. Diabetes Care (2002) 25:1313–1319.[Abstract/Free Full Text]
- The Expert Panel. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA (2001) 285:2486–2497.[Free Full Text]
- Meigs JB, Wilson PW, Nathan DM, D’Agostino RB Sr, Williams K, Haffner SM. Prevalence and characteristics of the metabolic syndrome in the San Antonio Heart and Framingham Offspring Studies. Diabetes (2003) 52:2160–2167.[Abstract/Free Full Text]
- Wilson PW, D’Agostino RB, Parise H, Sullivan L, Meigs JB. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation (2005) 112:3066–3072.[Abstract/Free Full Text]
- Wilson PW, Meigs JB, Sullivan L, Fox CS, Nathan DM, D’Agostino RB Sr. Prediction of incident diabetes mellitus in middle-aged adults: The Framingham Offspring Study. Arch Intern Med (2007) 167:1068–1074.[Abstract/Free Full Text]
- Meigs JB, Rutter MK, Sullivan LM, Fox CS, D’Agostino RB Sr, Wilson PW. Impact of insulin resistance on risk of type 2 diabetes and cardiovascular disease in people with metabolic syndrome. Diabetes Care (2007) 30:1219–1225.[Abstract/Free Full Text]
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Abstract
Introduction
