Simone J. S. Sep

Glucose regulation, cognition, and brain MRI in type 2 diabetes: a systematic review

Type 2 diabetes is associated with cognitive dysfunction and structural brain changes. Abnormalities in glucose regulation are involved in several complications related to type 2 diabetes, but their role in these cerebral complications is unclear. We systematically reviewed studies of the association between glucose regulation (glycaemia, hypoglycaemic events, insulin concentration, insulin resistance, and glucose-lowering treatment) and cognitive function and brain abnormalities on MRI in people with type 2 diabetes. The 86 papers included showed that glycaemia, particularly high HbA1c concentration and glucose variability, are negatively associated with cognitive function in people with type 2 diabetes without dementia. However, the strength of this association is weak, and HbA1c generally accounted for less than 10% of the variance in cognition. Importantly, few studies have measured long-term cerebral outcomes, such as dementia and structural brain changes on MRI, and the effect of glucose-lowering treatment on these outcomes. More randomised controlled trials are needed to establish the effect of glucose-lowering treatment on long-term cognitive function in people with type 2 diabetes.

Prediabetes and type 2 diabetes are associated with generalized microvascular dysfunction: the Maastricht Study

Background: Type 2 diabetes (T2DM) is associated with an increased risk of cardiovascular disease. This can be partly explained by large-artery dysfunction, which already occurs in prediabetes (“ticking clock hypothesis”). Whether a similar phenomenon also applies to microvascular dysfunction is not known. We therefore tested the hypothesis that microvascular dysfunction is already present in prediabetes and is more severe in T2DM. To do so, we investigated the associations of prediabetes, T2DM, and measures of hyperglycemia with microvascular function measured as flicker light-induced retinal arteriolar dilation and heat-induced skin hyperemia. Methods: In the Maastricht Study, a T2DM-enriched population-based cohort study (n=2213, 51% men, aged [mean±standard deviation] 59.7±8.2 years), we determined flicker light-induced retinal arteriolar %-dilation (Dynamic Vessel Analyzer), heat-induced skin %-hyperemia (laser-Doppler flowmetry), and glucose metabolism status (oral glucose tolerance test; normal glucose metabolism [n=1269], prediabetes [n=335], or T2DM [n=609]). Differences were assessed with multivariable regression analyses adjusted for age, sex, body mass index, smoking, physical activity, systolic blood pressure, lipid profile, retinopathy, estimated glomerular filtration rate, (micro)albuminuria, the use of lipid-modifying and blood pressure-lowering medication, and prior cardiovascular disease. Results: Retinal arteriolar %-dilation was (mean±standard deviation) 3.4±2.8 in normal glucose metabolism, 3.0±2.7 in prediabetes, and 2.3±2.6 in T2DM. Adjusted analyses showed a lower arteriolar %-dilation in prediabetes (B=–0.20, 95% confidence interval –0.56 to 0.15) with further deterioration in T2DM (B=–0.61 [–0.97 to –0.25]) versus normal glucose metabolism (P for trend=0.001). Skin %-hyperemia was (mean±standard deviation) 1235±810 in normal glucose metabolism, 1109±748 in prediabetes, and 937±683 in T2DM. Adjusted analyses showed a lower %-hyperemia in prediabetes (B=–46 [–163 to 72]) with further deterioration in T2DM (B=–184 [–297 to –71]) versus normal glucose metabolism (P for trend=0.001). In addition, higher glycohemoglobin A1c and fasting plasma glucose were associated with lower retinal arteriolar %-dilation and skin %-hyperemia in fully adjusted models (for glycohemoglobin A1c, standardized B=–0.10 [–0.15 to –0.05], P<0.001 and standardized B=–0.13 [–0.19 to –0.07], P<0.001, respectively; for fasting plasma glucose, standardized B=–0.09 [–0.15 to –0.04], P<0.001 and standardized B=–0.10 [–0.15 to –0.04], P=0.002, respectively). Conclusion: Prediabetes, T2DM, and measures of hyperglycemia are independently associated with impaired microvascular function in the retina and skin. These findings support the concept that microvascular dysfunction precedes and thus may contribute to T2DM-associated cardiovascular disease and other complications, which may in part have a microvascular origin such as impaired cognition and heart failure.

Index event bias-a numerical example

Studies of determinants of recurrent disease often give unexpected results. In particular, well-established risk factors may seem not to have much influence on the recurrence risk. Recently, it has been argued that such paradoxical findings may be because of the bias caused by the selection of patients based on the occurrence of an earlier episode of the disease. This bias was referred to as index event bias. Here, we give a theoretical quantitative example of index event bias, showing that, as a result of selection of patients on the basis of previous disease: (1) risk factors become inversely associated when they are not in the unselected population, and (2) the crude association between the risk factor of interest and disease becomes biased toward the null.

Associations of low grade inflammation and endothelial dysfunction with depression - The Maastricht Study

BACKGROUND The pathogenesis of depression may involve low-grade inflammation and endothelial dysfunction. We aimed to evaluate the independent associations of inflammation and endothelial dysfunction with depressive symptoms and depressive disorder, and the role of lifestyle factors in this association. METHODS In The Maastricht Study, a population-based cohort study (n=852, 55% men, m=59.8±8.5years), depressive symptoms were assessed with the Patient Health Questionnaire-9 and (major and minor) depressive disorder with the Mini-International Neuropsychiatric Interview. Plasma biomarkers of inflammation (hsCRP, SAA, sICAM-1, IL-6, IL-8, TNF-α) and endothelial dysfunction (sVCAM-1, sICAM-1, sE-selectin, vWF) were measured with sandwich immunoassays and combined into two standardized sum scores. RESULTS Biomarkers of inflammation (hsCRP, TNF-α, SAA, sICAM-1) and endothelial dysfunction (sICAM-1, sE-Selectin) were univariately associated with depressive symptoms and depressive disorder. The sum scores of inflammation and endothelial dysfunction were associated with depressive disorder after adjustment for age, sex, type 2 diabetes, kidney function and prior cardiovascular disease (OR 1.54, p=0.001 and 1.40, p=0.006). Both sum scores remained significantly associated with depressive disorder after additional adjustment for lifestyle factors smoking, alcohol consumption and body mass index. The sum score of inflammation was also independently associated with depressive symptoms, while the sum score of endothelial dysfunction was not. CONCLUSIONS Inflammation and endothelial dysfunction are both associated with depressive disorder, independent of lifestyle factors. Our results might suggest that inflammation and endothelial dysfunction are involved in depression.

Prepregnancy low-plasma volume and predisposition to preeclampsia and fetal growth restriction.

OBJECTIVE: To estimate whether recurrence risks of preeclampsia, preterm birth, and fetal growth restriction relate to prepregnancy plasma volume. METHODS: We conducted a retrospective cohort study in 580 formerly preeclamptic women and a control group. In all women we measured plasma volume (iodine125-human serum albumin indicator dilution method) in the nonpregnant state. One hundred seventy-eight normotensive (formerly preeclamptic) women had a subsequent pregnancy within the study period (1996–2008). Odds ratios (ORs) for recurrent preeclampsia, preterm birth, and small for gestational age (SGA) neonates were estimated, using multivariable logistic regression with adjustment for confounders. RESULTS: Plasma volumes were lower in women who developed recurrent preeclampsia (1,241±158 mL/m2, 17% lower compared with women in the control group) than in women without recurrent preeclampsia (1,335±167 mL/m2, 11% lower compared with women in the control group). Logistic regression analysis demonstrated that each 100-mL/m2 difference in plasma volume was associated with an OR of 0.6 (95% confidence interval [CI] 0.5–0.8) to develop recurrent preeclampsia in subsequent pregnancy. Risk of preterm delivery (before 37 weeks of gestation) depended on preeclampsia in subsequent pregnancy, the adjusted hazard ratio for preterm birth was 0.9 (95% CI 0.7–1.1) for each 100-mL/m2 change in plasma volume. Risk of delivering an SGA neonate was independent of recurrent preeclampsia. Each 100-mL/m2 change in plasma volume was associated with an adjusted OR of 0.8 (95% CI 0.5–0.9) to deliver an SGA neonate in subsequent pregnancy. CONCLUSION: The risk of recurrent preeclampsia and fetal growth restriction in subsequent pregnancy relates inversely and linearly to prepregnancy plasma volume. LEVEL OF EVIDENCE: II

Direct comparison of clinical decision limits for cardiac troponin T and I

Objective The 99th percentile upper reference limit of high-sensitivity cardiac troponin (hs-cTn) from a healthy reference population is used for diagnosing acute myocardial infarction (AMI). Accepted current thresholds of hs-cTnT (Roche) and hs-cTnI (Abbott) are 14 and 26 ng/L, respectively. Since thresholds for hs-cTnT and hs-cTnI were derived from different reference cohorts it is unclear whether they are biologically equivalent. We directly assessed sex-specific and age-specific 99th percentile upper reference limits of hs-cTnT and hs-cTnI in a single reference cohort, to investigate whether current divergent thresholds of hs-cTnT and hs-cTnI stem from intrinsic assay differences or reflect cohort variation. Methods A healthy reference population was derived from a population-based cohort (the Maastricht Study: n=3451; age: 40–75 years). Individuals with diabetes mellitus, a history of cardiovascular disease, cardiac ischaemia on ECG, N-terminal pro-brain natriuretic peptide >125 ng/L or estimated glomerular filtration rate <60 mL/min/1.73 m2 were excluded. Non-parametric analyses were performed to assess 99th percentile upper reference limits. Results 1540 individuals were included in the healthy reference population (age 57±8 years, 52.4% women). Overall 99th percentile upper reference limits of hs-cTnT and hs-cTnI were 15 and 13 ng/L, respectively. Upper reference limits were higher in men than women (hs-cTnT: 16 vs 12 ng/L), (hs-cTnI: 20 vs 11 ng/L) and increased with age. Conclusions Direct comparison reveals numerically similar thresholds for hs-cTnT and hs-cTnI assays. This finding is in line with recently reported underdiagnosis of AMI with the current decision limit of 26 ng/L for hs-cTnI, especially among women. Downwards adjustment of the hs-cTnI threshold, differentiated for sex, would equalise clinical decision limits for both assays, and may prevent further underdiagnosis of AMI.

Early-pregnancy changes in cardiac diastolic function in women with recurrent pre-eclampsia and in previously pre-eclamptic women without recurrent disease.

Please cite this paper as: Sep S, Schreurs M, Bekkers S, Kruse A, Smits L, Peeters L. Early‐pregnancy changes in cardiac diastolic function in women with recurrent pre‐eclampsia and in previously pre‐eclamptic women without recurrent disease. BJOG 2011;118:1112–1119.

Prediction Tests for Recurrent Hypertensive Disease in Pregnancy, A Systematic Review

Objective. To summarize reported evidence on the performance and clinical usefulness of prediction tests for recurrent hypertensive disease in pregnancy. Methods. A literature search was conducted in MEDLINE/PubMed and EMBASE. Test characteristics were extracted for relevant reports. Results. Thirty-three of 4,311 articles found met the inclusion criteria. Twenty-four potential predictors were identified. Pre-pregnant plasma volume, uterine-artery blood flow velocity profiles, and combined longitudinal patterns of in-pregnancy laboratory variables had reasonable predictive capacity, but also some practical shortcomings. Confidence intervals were often wide. Conclusions. Although evidence points to promising predictive accuracy of some tests, immediate applicability is hampered by statistical imprecision and clinical drawbacks.

Simple prepregnant prediction rule for recurrent early-onset hypertensive disease in pregnancy.

Objective: We aimed to develop a simple clinically useful prediction rule for early-onset recurrent preeclampsia and/or HELLP syndrome. Methods: Women with previous early-onset preeclampsia and/or HELLP, enrolled between 1996 and 2007, and a subsequent ongoing pregnancy were included. Prepregnant cardiovascular, metabolic, renal, and clotting parameters were evaluated as potential predictors for recurrent disease by logistic regression analysis. Results: Early-onset preeclampsia and/or HELLP recurred in 16 (9%) of 186 next pregnancies. The prediction model included high-density lipoprotein (mmol/L) and 24-hour urinary total protein excretion (mg/mmol creatinine). The receiver operating characteristic area was 0.77 (95% confidence interval: 0.68-0.87). Predictive sensitivity and specificity were 94% (69%-99%) and 53% (45%-60%), respectively. Nearly 50% of the women could be classified as having <1% risk of recurrent early-onset disease. Conclusions: The prediction rule identified, with clinically relevant predictive capacity, those women at very low risk for recurrent early-onset disease.

Consumption of dairy foods in relation to impaired glucose metabolism and type 2 diabetes mellitus: the Maastricht Study

Observational studies suggest an inverse association between total dairy product intake and diabetes risk. However, there is a lack of information on the relationship of specific dairy products with impaired glucose metabolism (IGM) and type 2 diabetes mellitus (T2DM). Individuals aged 40-75 years were recruited for the Maastricht Study. All the participants filled out a 253-food item FFQ, covering fifty specific dairy items that captured differences between full-fat, semi-skimmed and skimmed products, as well as fermented and non-fermented products. Glucose metabolism status was assessed by an oral glucose tolerance test, and participants were informed on their glucose metabolism status after returning the FFQ. Data of 2391 individuals were available to estimate OR (95 % CI) for IGM (n 470) and newly diagnosed (ND) T2DM (n 125), with adjustment for age, sex, BMI, physical activity, smoking status, education, energy intake and intakes of vegetables, fruits, meat and fish. For IGM, fully adjusted analyses revealed inverse associations, with OR comparing the highest with the lowest tertile of intake of 0·73 (95 % CI 0·55, 0·96) for skimmed products and 0·74 (95 % CI 0·54, 0·99) for fermented products. These dairy products were not associated with ND T2DM. In contrast, full-fat products were positively associated with ND T2DM (OR 2·01; 95 % CI 1·16, 3·47), whereas total dairy product intake was inversely associated with ND T2DM (OR 0·50; 95 % CI 0·26, 0·93). In conclusion, individuals with a high consumption of skimmed and fermented products had lower odds of having IGM, and individuals with a high consumption of total dairy products had lower odds of having ND T2DM. High intake of full-fat products was not related to IGM but was positively related to ND T2DM.