Does the Metabolic Syndrome Improve Identification of Individuals at Risk of Type 2 Diabetes and/or Cardiovascular Disease?
Michael P. Stern , MD 1 ,
Ken Williams , MS 1 ,
Clicerio ...González-Villalpando , MD 2 ,
Kelly J. Hunt , PHD 1 and
Steven M. Haffner , MD 1
1 Division of Clinical Epidemiology, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas
2 Centro de Estudios en Diabetes, The American British Cowdray Hospital and Unidades de Investigación Médica en Enfermedades
Metabólicas y Epidemiología Clínica, Hospital Gabriel Mancera, Instituto Mexicano del Seguro Social, Mexico City, Mexico
Address correspondence and reprint requests to Michael P. Stern, MD, Division of Clinical Epidemiology, Department of Medicine,
University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. E-mail: stern{at}uthscsa.edu
Abstract
OBJECTIVE —The metabolic syndrome has been promoted as a method for identifying high-risk individuals for type 2 diabetes and cardiovascular
disease (CVD). We therefore sought to compare this syndrome, as defined by the National Cholesterol Education Program, to
the Diabetes Predicting Model and the Framingham Risk Score as predictors of type 2 diabetes and CVD, respectively.
RESEARCH DESIGN AND METHODS —A population-based sample of 1,709 initially nondiabetic San Antonio Heart Study (SAHS) participants were followed for 7.5
years, 195 of whom developed type 2 diabetes. Over the same time interval, 156 of 2,570 SAHS participants experienced a cardiovascular
event. A population-based sample of 1,353 initially nondiabetic Mexico City Diabetes Study (MCDS) participants were followed
for 6.5 years, 125 of whom developed type 2 diabetes. Baseline measurements included medical history, age, sex, ethnicity,
smoking status, BMI, blood pressure, fasting and 2-h plasma glucose levels, and fasting serum total and HDL cholesterol and
triglycerides.
RESULTS —The sensitivities for predicting diabetes with the metabolic syndrome were 66.2 and 62.4% in the SAHS and the MCDS, respectively,
and the false-positive rates were 27.8 and 38.7%, respectively. The sensitivity and false-positive rates for predicting CVD
with the metabolic syndrome in the SAHS were 67.3 and 34.2%, respectively. At corresponding false-positive rates, the two
predicting models had significantly higher sensitivities and, at corresponding sensitivities, significantly lower false-positive
rates than the metabolic syndrome for both end points. Combining the metabolic syndrome with either predicting model did not
improve the prediction of either end point.
CONCLUSIONS —The metabolic syndrome is inferior to established predicting models for either type 2 diabetes or CVD.
aROC, area under the received operating characteristic curve
CVD, cardiovascular disease
IGT, impaired glucose tolerance
MCDS, Mexico City Diabetes Study
NCEP ATP-III, National Cholesterol Education Program Adult Treatment Panel III
ROC, receiver operating characteristic
SAHS, San Antonio Heart Study
WHO, World Health Organization
Footnotes
Additional information for this article can be found in an online appendix at http://care.diabetesjournals.org .
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
See accompanying editorial, p. 2761.
Accepted June 28, 2004.
Received April 29, 2004.
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IMPORTANCE Latino populations have one of the highest prevalences of type 2 diabetes worldwide. OBJECTIVES To investigate the association between rare protein-coding genetic variants and prevalence ...of type 2 diabetes in a large Latino population and to explore potential molecular and physiological mechanisms for the observed relationships. DESIGN, SETTING, AND PARTICIPANTS Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 with type 2 diabetes and 1962 without diabetes) recruited from 1993 to 2013. One variant was further tested for allele frequency and association with type 2 diabetes in large multiethnic data sets of 14 276 participants and characterized in experimental assays. MAIN OUTCOME AND MEASURES Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function. RESULTS A single rare missense variant (c.1522G>A p.E508K) was associated with type 2 diabetes prevalence (odds ratio OR, 5.48; 95% CI, 2.83-10.61; P = 4.4 × 10−7) in hepatocyte nuclear factor 1-α (HNF1A), the gene responsible for maturity onset diabetes of the young type 3 (MODY3). This variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of participants with it. In multiethnic replication data sets, the p.E508K variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% CI, 1.75-9.92; P = .0013). In experimental assays, HNF-1A protein encoding the p.E508K mutant demonstrated reduced transactivation activity of its target promoter compared with a wild-type protein. In our data, carriers and noncarriers of the p.E508K mutation with type 2 diabetes had no significant differences in compared clinical characteristics, including age at onset. The mean (SD) age for carriers was 45.3 years (11.2) vs 47.5 years (11.5) for noncarriers (P = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (P = .19). CONCLUSIONS AND RELEVANCE Using whole-exome sequencing, we identified a single low-frequency variant in the MODY3-causing gene HNF1A that is associated with type 2 diabetes in Latino populations and may affect protein function. This finding may have implications for screening and therapeutic modification in this population, but additional studies are required.
•Dietary Inflammatory Index (DII) predicts low glomerular filtration rate (GFR).•Higher DII scores were linked to lower GFR, especially at lower percentiles.•Implications are provided for chronic ...kidney disease (CKD) prevention in Mexico.
We hypothesized that higher scores on the dietary inflammatory index (DII) would be associated with a lower glomerular filtration rate (GFR). This cross-sectional study included 2098 participants from Mexican Teachers Cohort Study, the Health Workers Cohort Study, and the Comitán Study belonging to the RenMex consortium. Energy-adjusted DII scores were estimated using a semi-quantitative food frequency questionnaire (FFQ). eGFR was estimated by the CKD Epidemiology Collaboration equation. Quantile regression models and ordered regression models were estimated to assess the associations of interest. Median age of study participants was 47 years, median eGFR was 102.9 mL/min/1.73m2, and the median energy-adjusted DII was 0.89 (range, -2.25, +4.86). The median eGFR was lower in participants in the highest percentile of DII compared to those in the lowest percentile (103.8 vs 101.4). We found that continuous and categorical energy-adjusted DII scores were associated with lower eGFR, especially at the lower percentiles. In adjusted ordered logistic regression, we found that the highest DII category was associated with 1.80 times the odds of belonging to the mildly decreased eGFR category or moderately decreased eGFR category compared lowest DII category (OR: 1.80, 95%CI 1.35, 2.40). A high DII score was associated with a lower eGFR among the Mexican population. Additional studies are crucial to validate these findings and explore potential strategies to reduce the consumption of pro-inflammatory foods as a preventive approach for chronic kidney disease (CKD).
Using data from the Mexican Consortium of Epidemiological Studies for the Prevention, Diagnosis, and Treatment of Chronic Kidney Disease, a non-linear association between energy-adjusted dietary inflammatory index and glomerular filtration rate was observed. Moreover, at lower percentiles of glomerular filtration rate the association with dietary inflammatory index was robust. This highlights the relation between the inflammatory capacity of the diet and the kidney health in Mexican population. Display omitted
Plasma lipid levels are a major risk factor for cardiovascular diseases. Although international efforts have identified a group of loci associated with the risk of dyslipidemia, Latin American ...populations have been underrepresented in these studies.
To know the genetic variation occurring in lipid-related loci in the Mexican population and its association with dyslipidemia.
We searched for single-nucleotide variants in 177 lipid candidate genes using previously published exome sequencing data from 2838 Mexican individuals belonging to three different cohorts. With the extracted variants, we performed a case-control study. Logistic regression and quantitative trait analyses were implemented in PLINK software. We used an LD pruning using a 50-kb sliding window size, a 5-kb window step size and a r
threshold of 0.1.
Among the 34251 biallelic variants identified in our sample population, 33% showed low frequency. For case-control study, we selected 2521 variants based on a minor allele frequency ≥1% in all datasets. We found 19 variants in 9 genes significantly associated with at least one lipid trait, with the most significant associations found in the
gene cluster on chromosome 11. Notably, all 11 variants associated with hypertriglyceridemia were within this cluster; whereas variants associated with hypercholesterolemia were located at chromosome 2 and 19, and for low high density lipoprotein cholesterol were in chromosomes 9, 11, and 19. No significant associated variants were found for low density lipoprotein. We found several novel variants associated with different lipemic traits: rs3825041 in
with hypertriglyceridemia, rs7252453 in
with decreased risk to hypercholesterolemia and rs11076176 in
with increased risk to low high density lipoprotein cholesterol.
We identified novel variants in lipid-regulation candidate genes in the Mexican population, an underrepresented population in genomic studies, demonstrating the necessity of more genomic studies on multi-ethnic populations to gain a deeper understanding of the genetic structure of the lipemic traits.
Objective. To harmonize participants’ information from five epidemiological studies. Materials and methods. The Mexican Consortium of Epidemiological Studies for the Prevention, Diagnosis, and ...Treatment of Chronic Kidney Disease (RenMex, by its Spanish acronym) was established in 2018. RenMex is a consortium of five studies: The Mexican Teachers Cohort Study; the Mexico City Diabetes Study; the Health Workers Cohort Study; the Comitán Study; and the Salt Consumption in Mexico Study, which assessed baseline serum creatinine, albumin, and C-reactive protein, all performed with standardized techniques. Results. RenMex includes 3 133 participants, with a mean age of 44.8 years, 68.8% women, 10.8% with a previous medical diagnosis of type 2 diabetes, and 24.1% living with obesity. Conclusions. In the future, RenMex will work on more detailed analyses with each cohort allowed to opt in or out for each topic according to their individual data.
To estimate the incidence of type 2 diabetes (T2D) in Mexican population.
Population based prospective study. At baseline (1990), the population at risk (1939 non-diabetic adults 35-64 years) was ...evaluated with oral glucose tolerance test. Subsequent similar evaluations were done (1994, 1998, 2008). American Diabetes Association diagnostic criteria were applied.
The period of observation was 27842 person-years, the cumulative incidence of T2D was 14.4 and 13.7 per 1000 person-years for men and women, respectively. Incidence was 15.8, 15.7 and 12.7 per 1 000 person-years for the second (1994), third (1998) and fourth (2008) follow-up phases, respectively. The mean age at diagnosis was 44 years for prevalent cases and 56 years for incident cases.
This is the first estimate of long-term incidence of T2D in Mexican population. The incidence is among the highest reported worldwide. It remained with few changes throughout the study period.
Prospective Study of C-Reactive Protein in Relation to the Development of Diabetes and Metabolic Syndrome in the Mexico City
Diabetes Study
Thang S. Han , MD, PHD 1 ,
Naveed Sattar , MD, PHD 2 ,
Ken ...Williams , MS 3 ,
Clicerio Gonzalez-Villalpando , MD 4 ,
Michael E.J. Lean , MD, FRCP 5 and
Steven M. Haffner , MD, MPH 3
1 Addenbrooke’s Hospital, Cambridge University Medical School, Cambridge, U.K
2 University Department of Pathological Biochemistry, Glasgow Royal Infirmary, Glasgow, U.K
3 Department of Medicine #7873, University of Texas Health Science Center at San Antonio, San Antonio, Texas
4 Center de Estudios in Diabetes, Mexico City, Mexico
5 Department of Human Nutrition, Glasgow Royal Infirmary, Glasgow, U.K
Abstract
OBJECTIVE —Recent evidence suggests that C-reactive protein (CRP) may predict development of diabetes in Caucasian populations. We evaluated
CRP as a possible risk factor of the development of diabetes and metabolic syndrome in a 6-year study of 515 men and 729 women
from the Mexico City Diabetes Study.
RESEARCH DESIGN AND METHODS —Baseline CRP, indexes of adiposity, and insulin resistance (homeostasis model assessment HOMA-IR) were used to predict
development of the metabolic syndrome, defined as including two or more of the following: 1 ) dyslipidemia (triglyceride ≥2.26 mmol/l or HDL cholesterol ≤0.91 mmol/l in men and ≤1.17 mmol/l in women; <35 and 40 mg/dl
for men and women); 2 ) hypertension (blood pressure >140/90 mmHg or on hypertensive medication); or 3 ) diabetes (1999 World Health Organization criteria).
RESULTS —At baseline, CRP correlated significantly ( P < 0.001) with all metabolic indexes in women, but less so in men. After 6 years, 14.2% of men and 16.0% of women developed
the metabolic syndrome. Compared with tertile 1, women with CRP in the highest tertile had an increased relative risk of developing
the metabolic syndrome by 4.0 (95% CI 2.0–7.9) and diabetes by 5.5 (2.2–13.5); these risks changed minimally after adjusting
for BMI or HOMA-IR. The area under receiver-operating characteristic (ROC) curve for the prediction of the development of
the syndrome was 0.684 for CRP, increasing to 0.706 when combined with BMI and to 0.710 for a complex model of CRP, BMI, and
HOMA-IR.
CONCLUSIONS —CRP was not a significant predictor of the development of the metabolic syndrome in men. Our data strongly support the notion
that inflammation is important in the pathogenesis of diabetes and metabolic disorders in women.
CRP, C-reactive protein
HOMA-IR, homeostasis model assessment of insulin resistance
ROC, receiver-operating characteristic
Footnotes
Address correspondence and reprint requests to Steven M. Haffner, Department of Medicine #7873, University of Texas Health
Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. E-mail: haffner{at}uthscsa.edu .
Received for publication 17 December 2001 and accepted in revised form 4 August 2002.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
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OBJECTIVE. To determine prevalence of hyperuricemia and its relation with intake of sweetened beverages (SB) and metabolic syndrome (MS) in low income urban Mexican population. MATERIALS AND METHODS. ...A cross-sectional analysis of The Mexico City Diabetes Study, a prospective population-based investigation (1 173 participants) was performed. We used logistic regression, adjusted by pertinent variables. We determined prevalence of hyperuricemia and explored associations of uric acid levels with MS and intake of SB. RESULTS. Prevalence of hyperuricemia was 26.5 and 19.8% in males and females respectively. In an adjusted multivariate model, body mass index, waist circumference, and triglyceride were higher as uric acid quartiles increased (p<0.005-0.001). The odds ratio for MS was 1.48 for 3rd uric acid quartile and 2.03 for 4th quartile. Higher consumption of SB was associated with higher uric acid levels (p<0.001). CONCLUSION. Prevalence of hyperuricemia is high. Potential association with intake of SB, resulting in metabolic alterations should be considered.
Type 2 diabetes mellitus and hypertension overlap in the population. In many subjects, development of diabetes mellitus is characterized by a relatively rapid increase in plasma glucose values. ...Whether a similar phenomenon occurs during the development of hypertension is not known. We analyzed the pattern of blood pressure (BP) changes during the development of hypertension in patients with or without diabetes mellitus using data from the MCDS (Mexico City Diabetes Study; a population-based study of diabetes mellitus in Hispanic whites) and in the FOS (Framingham Offspring Study, a community-based study in non-Hispanic whites) during a 7-year follow-up. Diabetes mellitus at baseline was a significant predictor of incident hypertension (in FOS, odds ratio, 3.14; 95% confidence interval, 2.17–4.54) independently of sex, age, body mass index, and familial diabetes mellitus. Conversely, hypertension at baseline was an independent predictor of incident diabetes mellitus (in FOS, odds ratio, 3.33; 95% CI, 2.50–4.44). In >60% of the converters, progression from normotension to hypertension was characterized by a steep increase in BP values, averaging 20 mm Hg for systolic BP within 3.5 years (in MCDS). In comparison with the nonconverters group, hypertension and diabetes mellitus converters shared a metabolic syndrome phenotype (hyperinsulinemia, higher body mass index, waist girth, BP, heart rate and pulse pressure, and dyslipidemia). Overall, results were similar in the 2 ethnic groups. We conclude that (1) development of hypertension and diabetes mellitus track each other over time, (2) transition from normotension to hypertension is characterized by a sharp increase in BP values, and (3) insulin resistance is one common feature of both prediabetes and prehypertension and an antecedent of progression to 2 respective disease states.
Using Metabolic Syndrome Traits for Efficient Detection of Impaired Glucose Tolerance
James B. Meigs , MD MPH 1 2 ,
Ken Williams , MS 3 ,
Lisa M. Sullivan , PHD 4 ,
Kelly J. Hunt , PHD 3 ,
Steven M. ...Haffner , MD 3 ,
Michael P. Stern , MD 3 ,
Clicerio González Villalpando , MD 5 ,
Jessica S. Perhanidis , MPH 1 ,
David M. Nathan , MD 2 ,
Ralph B. D’Agostino, Jr , PHD 6 ,
Ralph B. D’Agostino, Sr , PHD 4 and
Peter W.F. Wilson , MD 7
1 General Medicine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
2 Diabetes Center, Department of Medicine, Massachusetts Hospital and Harvard Medical School, Boston, Massachusetts
3 Division of Clinical Epidemiology, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas
4 Statistics and Consulting Unit of the Mathematics and Statistics Department at Boston University, Boston, Massachusetts
5 Centro de Estudios en Diabetes, The American British Coudray Hospital and Unidades de Investigación in Médica en Enfermedades
Metabolicas y Epidemiología Clínica, Hospital Gabriel Mancera, Instituto Mexicano del Seguro Social, Mexico City, México
6 Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
7 Boston University School of Medicine and Framingham Heart Study, Framingham, Massachusetts
Address correspondence and reprint requests to James B. Meigs, MD, MPH, General Internal Medicine Unit Massachusetts General
Hospital, 50 Staniford St., 9th Floor, Boston, MA 02114. E-mail: jmeigs{at}partners.org
Abstract
OBJECTIVE —Efficient detection of impaired glucose tolerance (IGT) is needed to implement type 2 diabetes prevention interventions.
RESEARCH DESIGN AND METHODS —We assessed the capacity of the metabolic syndrome (MetS) to identify IGT in a cross-sectional analysis of 3,326 Caucasian
Framingham Offspring Study (FOS), 1,168 Caucasian and 1,812 Mexican-American San Antonio Heart Study (SAHS), 1,983 Mexico
City Diabetes Study (MCDS), and 452 Caucasian, 407 Mexican-American, and 290 African-American Insulin Resistance Atherosclerosis
Study (IRAS) men and women aged 30–79 years who had a clinical examination and an oral glucose tolerance test (OGTT) during
1987–1996. Those with diabetes treatment or fasting plasma glucose ≥7.0 mmol/l were excluded (MetS was defined by Third Report
of the National Cholesterol Education Program’s Adult Treatment Panel criteria and IGT as 2-h postchallenge glucose 2hPG
≥7.8 mmol/l). We calculated positive (PPV) and negative predictive values (NPV), population attributable risk percentages
(PAR%), age- and sex-adjusted odds ratios (ORs), and areas under the receiver operating characteristic curve (AROCs) associated
with MetS traits.
RESULTS —Among FOS, SAHS, and MCDS subjects, 24–43% had MetS and 15–23% had IGT (including 2–5% with 2hPG ≥11.1 mmol/l). Among those
with MetS, OR for IGT were 3–4, PPV were 0.24–0.41, NPV were 0.84–0.91, and PAR% were 30–40%. Among subjects with MetS defined
by impaired fasting glucose (IFG) and any two other traits, OR for IGT were 9–24, PPV were 0.62–0.89, NPV were 0.78–0.87,
and PAR% were 3–12%. Among IRAS subjects, 24–34% had MetS and 37–41% had IGT. Among those with MetS, ORs for IGT were 3–6,
PPVs were 0.57–0.73, and NPVs were 0.67–0.72. In logistic regression models, IFG, large waist, and high triglycerides were
independently associated with IGT (AROC 0.71–0.83) in all study populations.
CONCLUSIONS —The MetS, especially defined by IFG, large waist, and high triglycerides, efficiently identifies subjects likely to have
IGT on OGTT and thus be eligible for diabetes prevention interventions.
AR%, attributable risk percentage
AROC, area under the receiver operating characteristic curve
FOS, Framingham Offspring Study
FPG, fasting plasma glucose
IFG, impaired fasting glucose
IGT, impaired glucose tolerance
IRAS, Insulin Resistance Atherosclerosis Study
MCDS, Mexico City Diabetes Study
MetS, metabolic syndrome
NCEP ATP III, Third Report of the National Cholesterol Education Program’s Adult Treatment Panel III
NPV, negative predictive value
PAR%, population AR%
PPV, positive predictive value
OGTT, oral glucose tolerance test
SAHS, San Antonio Heart Study
2hPG, 2-h postchallenge glucose
Footnotes
P.W.F.W. has received grant support from GlaxoSmithKline.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
Accepted March 1, 2004.
Received November 10, 2003.
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