C. Lange

Predicting Diabetes: Clinical, Biological, and Genetic Approaches Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR)

OBJECTIVE—To provide a simple clinical diabetes risk score and to identify characteristics that predict later diabetes using variables available in the clinic setting as well as biological variables and polymorphisms. RESEARCH DESIGN AND METHODS—Incident diabetes was studied in 1,863 men and 1,954 women, 30–65 years of age at baseline, with diabetes defined by treatment or by fasting plasma glucose ≥7.0 mmol/l at 3-yearly examinations over 9 years. Sex-specific logistic regression equations were used to select variables for prediction. RESULTS—A total of 140 men and 63 women developed diabetes. The predictive clinical variables were waist circumference and hypertension in both sexes, smoking in men, and diabetes in the family in women. Discrimination, as measured by the area under the receiver operating curves (AROCs), were 0.713 for men and 0.827 for women, a little higher than for the Finish Diabetes Risk (FINDRISC) score, with fewer variables in the score. Combining clinical and biological variables, the predictive equation included fasting glucose, waist circumference, smoking, and γ-glutamyltransferase for men and fasting glucose, BMI, triglycerides, and diabetes in family for women. The number of TCF7L2 and IL6 deleterious alleles was predictive in both sexes, but after including the above clinical and biological variables, this variable was only predictive in women (P < 0.03) and the AROC statistics increased only marginally. CONCLUSIONS—The best clinical predictor of diabetes is adiposity, and baseline glucose is the best biological predictor. Clinical and biological predictors differed marginally between men and women. The genetic polymorphisms added little to the prediction of diabetes.

Waist circumference and the metabolic syndrome predict the development of elevated albuminuria in non-diabetic subjects: the DESIR Study.

Objective Metabolic determinants of microalbuminuria remain poorly understood in non-diabetic individuals and particularly in women. We investigated in both sexes whether an elevated waist circumference (WC) or the presence of the metabolic syndrome (MetS) predict the development of elevated albuminuria at 6 years. Design and patients We studied 2738 subjects from the DESIR cohort without microalbuminuria or diabetes at baseline and who were followed up for 6 years. Results At 6 years, 254 individuals [9.3%; 95% confidence interval (CI) 8.2–10.4%] had developed elevated albuminuria (≥ 20 mg/l), which was significantly and positively associated with WC and blood pressure, but not with fasting glucose, lipids or body mass index in either sex. In both sexes, subjects with a high WC or with MetS at baseline were more likely to develop elevated albuminuria at 6 years compared with those with a normal WC or absence of MetS. In multivariate logistic analysis, WC as a continuous variable or a WC of 94 cm or greater for men and a WC greater than 88 cm for women were predictive of the development of elevated albuminuria, after adjusting for age, hypertension, the use of angiotensin-converting enzyme inhibitors, fibrinogen and glycaemia. MetS was a risk factor for elevated albuminuria in men (odds ratio 1.87; 95% CI 1.25–2.81), with differences according to the MetS definition. Conclusion Abdominal adiposity is related to the development of elevated albuminuria in both sexes, suggesting that the measurement of WC may improve the identification of non-diabetic individuals at risk of developing microalbuminuria and emphasizing the interest of screening for albuminuria among those with MetS.

Nine-year incident diabetes is predicted by fatty liver indices: the French D.E.S.I.R. study

BackgroundFatty liver is known to be linked with insulin resistance, alcohol intake, diabetes and obesity. Biopsy and even scan-assessed fatty liver are not always feasible in clinical practice. This report evaluates the predictive ability of two recently published markers of fatty liver: the Fatty Liver Index (FLI) and the NAFLD fatty liver score (NAFLD-FLS), for 9-year incident diabetes, in the French general-population cohort: Data from an Epidemiological Study on the Insulin Resistance syndrome (D.E.S.I.R).MethodsAt baseline, there were 1861 men and 1950 women, non-diabetic, aged 30 to 65 years. Over the follow-up, 203 incident diabetes cases (140 men, 63 women) were identified by diabetes-treatment or fasting plasma glucose ≥ 7.0 mmol/l. The FLI includes: BMI, waist circumference, triglycerides and gamma glutamyl transferase, and the NAFLD-FLS: the metabolic syndrome, diabetes, insulin, alanine aminotransferase, and asparate aminotransferase. Logistic regression was used to determine the odds ratios for incident diabetes associated with categories of the fatty liver indices.ResultsIn comparison to those with a FLI < 20, the age-adjusted odds ratio (95% confidence interval) for diabetes for a FLI ≥ 70 was 9.33 (5.05-17.25) for men and 36.72 (17.12-78.76) for women; these were attenuated to 3.43 (1.61-7.28) and 11.05 (4.09 29.81), after adjusting on baseline glucose, insulin, hypertension, alcohol intake, physical activity, smoking and family antecedents of diabetes; odds ratios increased to 4.71 (1.68-13.16) and 22.77 (6.78-76.44) in those without an excessive alcohol intake. The NAFLD-FLS also predicted incident diabetes, but with odds ratios much lower in women, similar in men.ConclusionsThese fatty liver indexes are simple clinical tools for evaluating the extent of liver fat and they are predictive of incident diabetes. Physicians should screen for diabetes in patients with fatty liver.

Hypertension and vascular dynamics in men and women with metabolic syndrome.

Metabolic syndrome (MetS), an important component of insulin resistance and cardiovascular (CV) risk, is defined by 3 or more of the following characteristics: abdominal obesity, hyperglycemia, hypertension, hypertriglyceridemia, and hypo-high-density lipoprotein cholesterolemia. Based on the previously published age- and sex-mediated DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) cohort and parallel central hemodynamic measurements, our goal was to evaluate the effects of MetS on brachial central pulse pressure (PP), PP amplification, aortic stiffness, and wave reflections. These data were then compared with those of patients with essential hypertension but without MetS for the same mean arterial pressure. Increased aortic stiffness, a major mechanical factor predicting CV risk, has been well identified as playing a role in MetS. Its age progression is proportional to the number of risk factors involved in MetS and is responsible for increased systolic blood pressure and decreased diastolic blood pressure with increasing age, the principal hallmarks of hypertension in the elderly. Beyond brachial pressure measurements, central hemodynamic parameters involve increased aortic stiffness, reduced wave reflections, and increased PP amplification, a parameter commonly associated with increased heart rate. With the exception of arterial stiffness, all these findings are opposite in direction to those observed in essential hypertension, in which MetS is absent. A divergent behavior of wave reflections and PP amplification, but not of arterial stiffness, is observed when hypertension is studied alone or when compared with MetS for the same mean arterial pressure. This pulsatile hemodynamic abnormality contributes independently to increase age- and sex-mediated CV risk, justifying new research regarding Framingham scores and drug treatment.

Blood microbiota dysbiosis is associated with the onset of cardiovascular events in a large general population: the D.E.S.I.R. study.

Aim We recently described a human blood microbiome and a connection between this microbiome and the onset of diabetes. The aim of the current study was to assess the association between blood microbiota and incident cardiovascular disease. Methods and Results D.E.S.I.R. is a longitudinal study with the primary aim of describing the natural history of the metabolic syndrome and its complications. Participants were evaluated at inclusion and at 3-, 6-, and 9-yearly follow-up visits. The 16S ribosomal DNA bacterial gene sequence, that is common to the vast majority of bacteria (Eubac) and a sequence that mostly represents Proteobacteria (Pbac), were measured in blood collected at baseline from 3936 participants. 73 incident cases of acute cardiovascular events, including 30 myocardial infarctions were recorded. Eubac was positively correlated with Pbac (r = 0.59; P<0.0001). In those destined to have cardiovascular complications, Eubac was lower (0.14±0.26 vs 0.12±0.29 ng/µl; P = 0.02) whereas a non significant increase in Pbac was observed. In multivariate Cox analysis, Eubac was inversely correlated with the onset of cardiovascular complications, (hazards ratio 0.50 95% CI 0.35–0.70) whereas Pbac (1.56, 95%CI 1.12–2.15) was directly correlated. Conclusion Pbac and Eubac were shown to be independent markers of the risk of cardiovascular disease. This finding is evidence for the new concept of the role played by blood microbiota dysbiosis on atherothrombotic disease. This concept may help to elucidate the relation between bacteria and cardiovascular disease.

Increases in Waist Circumference and Weight As Predictors of Type 2 Diabetes in Individuals With Impaired Fasting Glucose: Influence of Baseline BMI: Data from the DESIR study

OBJECTIVE To evaluate in impaired fasting glucose (IFG) the relative importance of increases in waist circumference and weight on progression to type 2 diabetes. RESEARCH DESIGN AND METHODS The 9-year incidence of diabetes was studied in 979 men and women with baseline IFG, from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort. RESULTS Increases in both waist circumference and weight were significantly associated with diabetes incidence. Standardized odds ratios (95% CI) were 1.79 (1.45–2.21) and 1.86 (1.51–2.30), respectively, after controlling for baseline risk factors. The impact of waist circumference increase was greater for BMI <25 kg/m2 (2.40 [1.63–3.52]) than for BMI ≥25 kg/m2 (1.66 [1.28–2.16]) and persisted after adjusting for concurrent changes in either insulinemia or the homeostasis model assessment of insulin resistance index. Weight change had a similar impact in both BMI groups. CONCLUSIONS In individuals with IFG, it is important to monitor and prevent increases in waist circumference, in particular for those with BMI <25 kg/m2.

Urinary albumin excretion is a risk factor for diabetes mellitus in men, independently of initial metabolic profile and development of insulin resistance. The DESIR Study.

Background Elevated urinary albumin excretion (UAE) is more frequent in patients with the metabolic syndrome or insulin resistance. Whether UAE predicts the development of diabetes mellitus, independently of the presence or the development of the metabolic syndrome, is unclear, in particular, in women. Objective We prospectively assessed the association between baseline UAE and subsequent diabetes mellitus in participants selected from the general population. Participants and methods Four thousand and seventy-four nondiabetic patients (aged 30–64 years) included in the Data from an Epidemiological Study on the Insulin Resistance syndrome Study had a baseline UAE. Among them, 3851 patients had complete data regarding diabetes mellitus. Results Diabetes mellitus occurred in 171 out of 3851 patients during the 9-year follow-up (132/2056 men and 39/1795 women). UAE was associated with diabetes mellitus in a dose-dependent manner in men [as compared to men with UAE < 9 mg/l, hazard ratios were 1.81 (P = 0.0160), 1.83 (P = 0.0134), 2.31 (P = 0.0008) and 4.43 (P = 0.0005) for men with UAE: 9–12 mg/l, 12–19 mg/l, 20–200 mg/l and >200 mg/l, respectively] but not in women; the association was more marked after exclusion of men with baseline impaired fasting glucose [hazard ratios were 3.28 (P = 0.0007), 3.08 (P = 0.0012), 3.27 (P = 0.0022), 9.23 (P < 0.0001), respectively]. The association remained significant after adjustments on BMI, sporting activity, diet, smoking, waist circumference, insulin and homeostasis model assessment of insulin resistance, lipids, C-reactive protein and family of history of diabetes mellitus. Adjustment on the first 3-year change in weight, glucose, insulin and homeostasis model assessment of insulin resistance did not modify the results. Conclusion Elevated UAE predicts the 9-year risk of diabetes mellitus in men, independent of baseline or early development of metabolic abnormalities or insulin resistance.

Predicting Diabetes: Clinical, Biological, and Genetic Approaches

OBJECTIVE—To provide a simple clinical diabetes risk score and to identify characteristics that predict later diabetes using variables available in the clinic setting as well as biological variables and polymorphisms. RESEARCH DESIGN AND METHODS—Incident diabetes was studied in 1,863 men and 1,954 women, 30–65 years of age at baseline, with diabetes defined by treatment or by fasting plasma glucose ≥7.0 mmol/l at 3-yearly examinations over 9 years. Sex-specific logistic regression equations were used to select variables for prediction. RESULTS—A total of 140 men and 63 women developed diabetes. The predictive clinical variables were waist circumference and hypertension in both sexes, smoking in men, and diabetes in the family in women. Discrimination, as measured by the area under the receiver operating curves (AROCs), were 0.713 for men and 0.827 for women, a little higher than for the Finish Diabetes Risk (FINDRISC) score, with fewer variables in the score. Combining clinical and biological variables, the predictive equation included fasting glucose, waist circumference, smoking, and γ-glutamyltransferase for men and fasting glucose, BMI, triglycerides, and diabetes in family for women. The number of TCF7L2 and IL6 deleterious alleles was predictive in both sexes, but after including the above clinical and biological variables, this variable was only predictive in women (P < 0.03) and the AROC statistics increased only marginally. CONCLUSIONS—The best clinical predictor of diabetes is adiposity, and baseline glucose is the best biological predictor. Clinical and biological predictors differed marginally between men and women. The genetic polymorphisms added little to the prediction of diabetes.

The Data from an Epidemiologic Study on the Insulin Resistance Syndrome Study: the change and the rate of change of the age-blood pressure relationship.

Objective Systolic blood pressure (SBP) and diastolic blood pressure (DBP) increase significantly until around 55 years, when SBP increases, DBP decreases. Whether the rates of change of SBP and DBP with age exhibit a similar dissociation has never been investigated. Design and participants The Data from an Epidemiologic Study on the Insulin Resistance Syndrome Study (D.E.S.I.R.), a 9-year longitudinal study included 2278 men and 2314 women, 30–65 years and SBP, DBP, and other cardiometabolic risk factors were determined every 3 years. Results Both SBP and DBP increased with age, more rapidly in women than in men. SBP and DBP were higher in the presence of risk factors (except smoking) but the increases with age were similar. For the rates of change, whereas ΔSBP increased linearly with age, ΔDBP declined as early as 45 years. This finding was not influenced by sex, menopause or other risk factors but was significantly attenuated in the presence of hypertension at baseline, whether treated or not, and mainly in men. Conclusion DBP increases with age between 30 and 60 years, ΔDBP tends to be markedly reduced as early as 45 years, in contrast with ΔSBP. Consequences for the understanding of vascular aging and antihypertensive therapy remain to be explored.

Association of vitronectin and plasminogen activator inhibitor-1 levels with the risk of metabolic syndrome and type 2 diabetes mellitus. Results from the D.E.S.I.R. prospective cohort.

It was the objective of this study to investigate the relation between vitronectin and plasminogen activator inhibitor (PAI)-1 plasma levels with nine-year incidences of the metabolic syndrome (MetS) and of type 2 diabetes mellitus (T2DM). Baseline plasma concentrations of vitronectin and PAI-1 were measured in 627 healthy participants from the prospective D.E.S.I.R. cohort who subsequently developed MetS (n = 487) and T2DM (n = 182) over a nine-year follow-up (42 presented both) and who were matched with two healthy control subjects each by use of a nested case-control design. Parameters composing the MetS explained about 20% of plasma vitronectin levels. An increase of one standard deviation of vitronectin was associated with increased risks of both the MetS (odds ratio [OR] = 1.21 [1.07 - 1.37], p = 0.003) and T2DM (OR = 1.24 [1.01 - 1.53], p = 0.045). Corresponding ORs for PAI-1 levels were 1.46 [1.27 - 1.68] (p<10(-4)) and 1.40 [1.14 - 1.72] (p = 0.0012). However, the effects of vitronectin and PAI-1 levels on outcomes were not independent. The vitronectin-MetS association was restricted to individuals with low to modest PAI-1 levels (OR = 1.33 [1.14 - 1.54], p = 0.0003) while no association was observed in individuals with high PAI-1 levels (OR = 0.87 [0.68 - 1.10], p = 0.24), the test for interaction being highly significant (p = 0.0009). In conclusion, baseline plasma vitronectin is a marker of incident MetS at nine years. Its predictive ability for MetS and T2DM should not be assessed independently of PAI-1 levels.