The association between birth weight and plasma fibrinogen is abolished after the elimination of genetic influences

Low birth weight is associated with an increased risk of atherothrombosis, which may be related in part to the association between low birth weight and high plasma fibrinogen. The association between birth weight and fibrinogen may be explained by intrauterine, socio-economic or genetic factors. We examined birth weight and fibrinogen in 52 dizygotic and 56 adolescent monozygotic (genetically identical) twin pairs. The dizygotic but not the monozygotic twins with the lowest birth weight from each pair had a fibrinogen level that was higher compared with their co-twins with the highest birth weight [dizygotic twins: 2.62±0.46 g

Cognitive Functioning and Hippocampal Connectivity in Patients With Longstanding Type 1 Diabetes and Apolipoprotein E ε4

OBJECTIVE: While the apolipoprotein E ε4 allele (ApoE-ε4) is related to cognitive and brain decline in the general population, its effect on the brain in type 1 diabetes mellitus (T1DM) remains unclear. Therefore, the aim was to determine the interaction between ApoE-ε4 and T1DM on cognitive performance and hippocampal structure and connectivity as the brain area most vulnerable to ApoE-ε4 effects in adult patients with T1DM. RESEARCH DESIGN AND METHODS: Blood sampling was performed in 104 patients with T1DM and 49 control subjects for ApoE genotyping, neuropsychology, and neuroimaging to determine hippocampal volume and resting-state connectivity. The interaction between T1DM status and ApoE-ε4 presence was investigated and adjusted for age and mean systolic blood pressure. RESULTS: ApoE genotyping could not be performed for three patients with T1DM. Significant interaction effects, indicating a differential effect of ApoE-ε4 between both groups, were found for overall cognitive functioning and for the subdomains of information processing speed and attention. Additionally, interaction effects were present for right hippocampal connectivity with the right posterior cingulate and supramarginal gyri. Subsequent group analysis showed that patients with T1DM with ApoE-ε4 performed worse on these cognitive domains with increased connectivity, relative to their counterparts without ApoE-ε4. In contrast, no cognitive effects, but decreased connectivity, were observed in control subjects with ApoE-ε4. In patients with T1DM, higher right hippocampus connectivity with the posterior cingulate gyrus was related to poorer overall cognitive functioning. CONCLUSIONS: The results may suggest that ApoE-ε4 presence leaves our patients with T1DM more susceptible to cognitive decrements at a younger age, possibly through vascular pathways, warranting further longitudinal studies

Accelerated executive functions decline and gray matter structural changes in middle-aged type 1 diabetes mellitus patients with proliferative retinopathy

Background The aim of the present study was to determine trajectories of cognitive and cortical changes over time in middle‐aged patients with type 1 diabetes mellitus (T1DM) and proliferative retinopathy. Methods Twenty‐five patients and 25 controls underwent neuropsychological assessment and neuroimaging twice in a mean (±SD) of 3.56 ± 0.65 and 3.94 ± 0.91 years, respectively (P = 0.098). Cognitive assessment included the domains of general cognitive ability, memory, information processing speed, executive functions, attention, and motor and psychomotor speed. Symmetrized percentage change in local cortical thickness, surface area, and volume was determined using the FreeSurfer 6 vertex‐wise general linear model method. Analyses were performed uncorrected and corrected for baseline systolic blood pressure and depressive symptoms. Results In patients versus controls, accelerated executive function decline was accompanied by, but not related to, lower left frontal and temporal surface area, left parietal and right frontal thickness, and bilateral frontal and right posterior cingulate volume (family‐wise error [FWE]‐corrected P < 0.05 for all). In patients, lower executive performance was related to loss of right precuneus surface area (PFWE = 0.005). Higher HbA1c during follow‐up was related to executive function decline (r = −0.509, P = 0.016) and loss of left hemisphere surface area (rcorrected analysis = −0.555, P = 0.007). Conclusions After 3.5 years of follow‐up, middle‐aged T1DM patients with proliferative retinopathy, mild focal changes in executive functions, and cortical structure were found, which may indicate accelerated aging

Elevated Postoperative Endogenous GLP-1 Levels Mediate Effects of Roux-en-Y Gastric Bypass on Neural Responsivity to Food Cues.

OBJECTIVE: It has been suggested that weight reduction and improvements in satiety after Roux-en-Y gastric bypass (RYGB) are partly mediated via postoperative neuroendocrine changes. Glucagon-like peptide-1 (GLP-1) is a gut hormone secreted after food ingestion and is associated with appetite and weight reduction, mediated via effects on the central nervous system (CNS). Secretion of GLP-1 is greatly enhanced after RYGB. We hypothesized that postoperative elevated GLP-1 levels contribute to the improved satiety regulation after RYGB via effects on the CNS. RESEARCH DESIGN AND METHODS: Effects of the GLP-1 receptor antagonist exendin 9-39 (Ex9-39) and placebo were assessed in 10 women before and after RYGB. We used functional MRI to investigate CNS activation in response to visual food cues (pictures) and gustatory food cues (consumption of chocolate milk), comparing results with Ex9-39 versus placebo before and after RYGB. RESULTS: After RYGB, CNS activation was reduced in the rolandic operculum and caudate nucleus in response to viewing food pictures (P = 0.03) and in the insula in response to consumption of palatable food (P = 0.003). GLP-1 levels were significantly elevated postoperatively (P < 0.001). After RYGB, GLP-1 receptor blockade resulted in a larger increase in activation in the caudate nucleus in response to food pictures (P = 0.02) and in the insula in response to palatable food consumption (P = 0.002). CONCLUSIONS: We conclude that the effects of RYGB on CNS activation in response to visual and gustatory food cues may be mediated by central effects of GLP-1. Our findings provide further insights into the mechanisms underlying the weight-lowering effects of RYGB

The presence of cerebral white matter lesions and lower skin microvascular perfusion predicts lower cognitive performance in type 1 diabetes patients with retinopathy but not in healthy controls-A longitudinal study

OBJECTIVE: Cognitive impairments in type 1 diabetes may result from hyperglycemia-associated cerebral microangiopathy. We aimed to identify cerebral microangiopathy and skin microvascular dysfunction-as a surrogate marker for generalized microvascular function-as predictors of cognitive performance over time. METHODS: In this prospective cohort study, 25 type 1 diabetes patients with proliferative retinopathy and 25 matched healthy controls underwent neurocognitive testing at baseline and after follow-up (3.8 ± 0.8 years). At baseline, 1.5-T cerebral magnetic resonance imaging was used to detect WML and cerebral microbleeds. Skin capillary perfusion was assessed by means of capillary microscopy. RESULTS: In type 1 diabetes patients, but not in healthy controls, the presence of WML (ß = -0.419; P = 0.037) as well as lower skin capillary perfusion (baseline: ß = 0.753; P < 0.001; peak hyperemia: ß = 0.743; P = 0.001; venous occlusion: ß = 0.675; P = 0.003; capillary recruitment: ß = 0.549; P = 0.022) at baseline was associated with lower cognitive performance over time, independent of age, sex, HbA1c, and severe hypoglycemia. The relationship between WML and lower cognitive performance was significantly reduced after adjusting for capillary perfusion. CONCLUSIONS: These data fit the hypothesis that cerebral microangiopathy is a manifestation of generalized microvascular dysfunction, leading to lower cognitive performance

Brain reward responses to food stimuli among female monozygotic twins discordant for BMI

Obese individuals are characterized by altered brain reward responses to food. Despite the latest discovery of obesity-associated genes, the contribution of environmental and genetic factors to brain reward responsiveness to food remains largely unclear. Sixteen female monozygotic twin pairs with a mean BMI discordance of 3.96 ± 2.1 kg/m(2) were selected from the Netherlands Twin Register to undergo functional MRI scanning while watching high- and low-calorie food and non-food pictures and during the anticipation and receipt of chocolate milk. In addition, appetite ratings, eating behavior and food intake were assessed using visual analog scales, validated questionnaires and an ad libitum lunch. In the overall group, visual and taste stimuli elicited significant activation in regions of interest (ROIs) implicated in reward, i.e. amygdala, insula, striatum and orbitofrontal cortex. However, when comparing leaner and heavier co-twins no statistically significant differences in ROI-activations were observed after family wise error correction. Heavier versus leaner co-twins reported higher feelings of hunger (P = 0.02), cravings for sweet food (P = 0.04), body dissatisfaction (P < 0.05) and a trend towards more emotional eating (P = 0.1), whereas caloric intake was not significantly different between groups (P = 0.3). Our results suggest that inherited rather than environmental factors are largely responsible for the obesity-related altered brain responsiveness to food. Future studies should elucidate the genetic variants underlying the susceptibility to reward dysfunction and obesity. CLINICAL TRIAL REGISTRATION NUMBER: NCT02025595

Intrauterine environmental and genetic influences on the association between birthweight and cardiovascular risk factors: studies in twins as a means of testing the fetal origins hypothesis

Evidence has accumulated that low birthweight is associated with several risk factors for cardiovascular disease. However, it is not known whether or not these associations are due to a programmed response to intrauterine malnutrition or genetic factors influencing both birthweight and cardiovascular risk factors. Twin studies offer a unique opportunity to distinguish between intrauterine and genetic origins of the association between birthweight and cardiovascular risk. In our twin cohort, low birthweight was associated with insulin resistance, lower HDL and shorter height within both dizygotic and monozygotic twin pairs, suggesting that these associations are, at least in part, independent of genetic factors. In contrast, low birthweight was associated with blood pressure, total and LDL cholesterol, fibrinogen and sympathetic activation within dizygotic twin pairs, but not within monozygotic twin pairs. These differences between dizygotic and monozygotic twins suggest that these associations are, at least in part, due to genetic factors. Therefore, both intrauterine environmental and genetic factors appear to play a role in the association between birthweight and cardiovascular risk factors. In the future, strategies may be developed targeted at improving or preventing impaired intrauterine growth. However, the effects of interventions that comprise changes in environment within the normal range may be limited due to the possible important role of genetic factor

Cerebral effects of glucagon‐like peptide‐1 receptor blockade before and after Roux‐en‐Y gastric bypass surgery in obese women: A proof‐of‐concept resting‐state functional MRI study

Aim: To assess the effects of Roux‐en‐Y gastric bypass surgery (RYGB)‐related changes in glucagon‐like peptide‐1 (GLP‐1) on cerebral resting‐state functioning in obese women. Materials and Methods: In nine obese females aged 40‐54 years in the fasted state, we studied the effects of RYGB and GLP‐1 on five a priori selected networks implicated in food‐ and reward‐related processes as well as environment monitoring (default mode, right frontoparietal, basal ganglia, insula/anterior cingulate and anterior cingulate/orbitofrontal networks). Results: Before surgery, GLP‐1 receptor blockade (using exendin9‐39) was associated with increased right caudate nucleus (basal ganglia network) and decreased right middle frontal (right frontoparietal network) connectivity compared with placebo. RYGB resulted in decreased right orbitofrontal (insula/anterior cingulate network) connectivity. In the default mode network, after surgery, GLP‐1 receptor blockade had a larger effect on connectivity in this region than GLP‐1 receptor blockade before RYGB (all PFWE < .05). Results remained similar after correction for changes in body weight. Default mode and right frontoparietal network connectivity changes were related to changes in body mass index and food scores after RYGB. Conclusions: These findings suggest GLP‐1 involvement in resting‐state networks related to food and reward processes and monitoring of the internal and external environment, pointing to a potential role for GLP‐1–induced changes in resting‐state connectivity in RYGB‐mediated weight loss and appetite control

Altered Eigenvector Centrality is Related to Local Resting-State Network Functional Connectivity in Patients with Longstanding Type 1 Diabetes Mellitus

Introduction: Longstanding type 1 diabetes (T1DM) is associated with microangiopathy and poorer cognition. In the brain, T1DM is related to increased functional resting-state network (RSN) connectivity in patients without, which was decreased in patients with clinically evident microangiopathy. Subcortical structure seems affected in both patient groups. How these localized alterations affect the hierarchy of the functional network in T1DM is unknown. Eigenvector centrality mapping (ECM) and degree centrality are graph theoretical methods that allow determining the relative importance (ECM) and connectedness (degree centrality) of regions within the whole-brain network hierarchy. Methods: Therefore, ECM and degree centrality of resting-state functional MRI-scans was compared between 51 patients with, 53 patients without proliferative retinopathy, and 49 controls, and associated with RSN connectivity, subcortical gray matter volume, and cognition. Results: In all patients versus controls, ECM and degree centrality were lower in the bilateral thalamus and the dorsal striatum, with lowest values in patients without proliferative retinopathy (PFWE<0.05). Increased ECM in this group versus patients with proliferative retinopathy was seen in the bilateral lateral occipital cortex, and in the right lateral cortex versus controls (PFWE<0.05). In all patients, ECM and degree centrality were related to altered visual, sensorimotor, and auditory and language RSN connectivity (PFWE0.05). Conclusion: Our findings suggest reorganization of the hierarchy of the cortical connectivity network in patients without proliferative retinopathy, which is lost with disease progression. Centrality seems sensitive to capture early T1DM-related functional connectivity alterations, but not disease progression

An IGF-I promoter polymorphism modifies the relationships between birth weight and risk factors for cardiovascular disease and diabetes at age 36

OBJECTIVE: To investigate whether IGF-I promoter polymorphism was associated with birth weight and risk factors for cardiovascular disease (CVD) and type 2 diabetes (T2DM), and whether the birth weight – risk factor relationship was the same for each genotype. DESIGN AND PARTICIPANTS: 264 subjects (mean age 36 years) had data available on birth weight, IGF-I promoter polymorphism genotype, CVD and T2DM risk factors. Student's t-test and regression analyses were applied to analyse differences in birth weight and differences in the birth weight – risk factors relationship between the genotypes. RESULTS: Male variant carriers (VCs) of the IGF-I promoter polymorphism had a 0.2 kg lower birth weight than men with the wild type allele (p = 0.009). Of the risk factors for CVD and T2DM, solely LDL concentration was associated with the genotype for the polymorphism. Most birth weight – risk factor relationships were stronger in the VC subjects; among others the birth weight – systolic blood pressure relationship: 1 kg lower birth weight was related to an 8.0 mmHg higher systolic blood pressure CONCLUSION: The polymorphism in the promoter region of the IGF-I gene is related to birth weight in men only, and to LDL concentration only. Furthermore, the genotype for this polymorphism modified the relationships between birth weight and the risk factors, especially for systolic and diastolic blood pressure