Adipokines in gestational diabetes Fasshauer, Mathias; Blüher, Matthias; Stumvoll, Michael
The lancet. Diabetes & endocrinology,
06/2014, Volume:
2, Issue:
6
Journal Article
Peer reviewed
Gestational diabetes is characterised by glucose intolerance with onset or first recognition during pregnancy. The disease shows facets of the metabolic syndrome including obesity, insulin ...resistance, and dyslipidaemia. Adipokines are a group of proteins secreted from adipocytes, which are dysregulated in obesity and contribute to metabolic and vascular complications. Recent studies have assessed the role of various adipokines including leptin, adiponectin, tumour necrosis factor α (TNFα), adipocyte fatty acid-binding protein (AFABP), retinol-binding protein 4 (RBP4), resistin, NAMPT, SERPINA12, chemerin, progranulin, FGF-21, TIMP1, LCN2, AZGP1, apelin (APLN), and omentin in gestational diabetes. This Review provides an overview of these key adipokines, their regulation in, and potential contribution to gestational diabetes. Based on the evidence so far, the adipokines adiponectin, leptin, TNFα, and AFABP seem to be the most probable candidates involved in the pathophysiology of gestational diabetes.
Exercise promotes longevity and ameliorates type 2 diabetes mellitus and insulin resistance. However, exercise also increases mitochondrial formation of presumably harmful reactive oxygen species ...(ROS). Antioxidants are widely used as supplements but whether they affect the health-promoting effects of exercise is unknown. We evaluated the effects of a combination of vitamin C (1000 mg/day) and vitamin E (400 IU/day) on insulin sensitivity as measured by glucose infusion rates (GIR) during a hyperinsulinemic, euglycemic clamp in previously untrained (n = 19) and pretrained (n = 20) healthy young men. Before and after a 4 week intervention of physical exercise, GIR was determined, and muscle biopsies for gene expression analyses as well as plasma samples were obtained to compare changes over baseline and potential influences of vitamins on exercise effects. Exercise increased parameters of insulin sensitivity (GIR and plasma adiponectin) only in the absence of antioxidants in both previously untrained (P < 0.001) and pretrained (P < 0.001) individuals. This was paralleled by increased expression of ROS-sensitive transcriptional regulators of insulin sensitivity and ROS defense capacity, peroxisomeproliferator-activated receptor gamma (PPARγ), and PPARγ coactivators PGC1α and PGC1β only in the absence of antioxidants (P< 0.001 for all). Molecular mediators of endogenous ROS defense (superoxide dismutases 1 and 2; glutathione peroxidase) were also induced by exercise, and this effect too was blocked by antioxidant supplementation. Consistent with the concept of mitohormesis, exercise-induced oxidative stress ameliorates insulin resistance and causes an adaptive response promoting endogenous antioxidant defense capacity. Supplementation with antioxidants may preclude these health-promoting effects of exercise in humans.
Lifestyle factors conferring increased diabetes risk are associated with elevated basal insulin levels (hyperinsulinaemia). The latter predicts later obesity in children and adolescents.A causal role ...of hyperinsulinaemia for adipose tissue growth is probable because pharmacological reduction of insulin secretion lowers body weight in people who are obese. Genetic inactivation of insulin gene alleles in mice also lowers their systemic insulin levels and prevents or ameliorates high-fat diet-induced obesity. Hyperinsulinaemia causes weight gain because of a physiological property of insulin. Insulin levels that are on the high side of normal, or which are slightly elevated, are sufficient to suppress lipolysis and promote lipogenesis in adipocytes. The effect of insulin on glucose transport or hepatic glucose production requires six or two times higher hormone levels, respectively.It seems justified to suggest a lifestyle that avoids high insulin levels in order to limit anabolic fat tissue activity.
Insulin-sensitive obesity Klöting, Nora; Fasshauer, Mathias; Dietrich, Arne ...
American journal of physiology: endocrinology and metabolism
299, Issue:
3
Journal Article
Peer reviewed
The association between obesity and impaired insulin sensitivity has long been recognized, although a subgroup of obese individuals seems to be protected from insulin resistance. In this study, we ...systematically studied differences in adipose tissue biology between insulin-sensitive (IS) and insulin-resistant (IR) individuals with morbid obesity. On the basis of glucose infusion rate during euglycemic hyperinsulinemic clamps, 60 individuals with a BMI of 45 +/- 1.3 kg/m(2) were divided into an IS and IR group matched for age, sex, and body fat prior to elective surgery. We measured fat distribution, circulating adipokines, and parameters of inflammation, glucose, and lipid metabolism and characterized adipose tissue morphology, function, and mRNA expression in abdominal subcutaneous (sc) and omental fat. IS compared with IR obese individuals have significantly lower visceral fat area (138 +/- 27 vs. 316 +/- 91 cm(2)), number of macrophages in omental adipose tissue (4.9 +/- 0.8 vs. 13.2 +/- 1.4%), mean omental adipocyte size (528 +/- 76 vs. 715 +/- 81 pl), circulating C-reactive protein, progranulin, chemerin, and retinol-binding protein-4 (all P values <0.05), and higher serum adiponectin (6.9 +/- 3.4 vs. 3.4 +/- 1.7 ng/ml) and omental adipocyte insulin sensitivity (all P values <0.01). The strongest predictors of insulin sensitivity by far were macrophage infiltration together with circulating adiponectin (r(2) = 0.98, P < 0.0001). In conclusion, independently of total body fat mass, increased visceral fat accumulation and adipose tissue dysfunction are associated with IR obesity. This suggests that mechanisms beyond a positive caloric balance such as inflammation and adipokine release determine the pathological metabolic consequences in patients with obesity.
Chronic systemic inflammation in obesity originates from local immune responses in visceral adipose tissue. However, assessment of a broad range of inflammation-mediating cytokines and their ...relationship to physical activity and adipometrics has scarcely been reported to date.
To characterize the profile of a broad range of pro- and anti-inflammatory cytokines and the impact of physical activity and energy expenditure in individuals with general obesity, central obesity, and non-obese subjects.
A cross-sectional study comprising 117 obese patients (body mass index (BMI) ≥ 30) and 83 non-obese community-based volunteers.
Serum levels of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ and tumor necrosis factor (TNF)-α were measured. Physical activity and energy expenditure (MET) were assessed with actigraphy. Adipometrics comprised BMI, weight, abdominal-, waist- and hip-circumference, waist to hip ratio (WHR), and waist-to-height-ratio (WHtR).
General obesity was associated with significantly elevated levels of IL-5, IL-10, IL-12, IL-13, IFN-γ and TNF-α, central obesity with significantly elevated IL-5, IL-10, IL-12, IL-13 and IFN-γ-levels. In participants with general obesity, levels of IL-4, IL-10 and IL-13 were significantly elevated in participants with low physical activity, even when controlled for BMI which was negatively associated with physical acitivity. Cytokines significantly correlated with adipometrics, particularly in obese participants.
Results confirm up-regulation of certain pro- and anti-inflammatory cytokines in obesity. In obese subjects, physical activity may lower levels and thus reduce pro-inflammatory effects of cytokines that may link obesity, insulin resistance and diabetes.
The role of mitochondrial function in the complex pathogenesis of type 2 diabetes is not yet completely understood. Therefore, the aim of this study was to investigate serum concentrations of short-, ...medium- and long-chain acylcarnitines as markers of mitochondrial function in volunteers with normal, impaired or diabetic glucose control.
Based on a 75 g oral glucose tolerance test, 1019 studied subjects were divided into a group with normal glucose tolerance (NGT; n = 636), isolated impaired fasting glycaemia (IFG; n = 184), impaired glucose tolerance (IGT; n = 87) or type 2 diabetes (T2D; n = 112). Serum concentrations of free carnitine and 24 acylcarnitines were measured by mass spectrometry.
Serum levels of acetylcarnitine (C2), propionylcarnitine (C3), octanoylcarnitine (C8), malonylcarnitine/hydroxybutyrylcarnitine (C3DC+C4OH), hexanoylcarnitine (C6), octenoylcarnitine (C8:1), decanoylcarnitine (C10), decenoylcarnitine (C10:1), dodecanoylcarnitine (C12), tetradecenoylcarnitine (C14:1), tetradecadienylcarnitine (C14:2), hydroxytetradecanoylcarnitine (C14OH), hydroxyhexadecanoylcarnitine (C16OH) and octadecenoylcarnitine (C18:1) were significantly different among the groups (all p<0.05 adjusted for age, gender and BMI). Between the prediabetic states C14:1, C14:2 and C18:1 showed significantly higher serum concentrations in persons with IGT (p<0.05). Compared to T2D the IFG and the IGT subjects showed lower serum concentrations of malonylcarnitine/hydroxybutyrylcarnitine (C3DC+C4OH) (p<0.05).
Alterations in serum concentrations of several acylcarnitines, in particular tetradecenoylcarnitine (C14:1), tetradecadienylcarnitine (C14:2), octadecenoylcarnitine (C18:1) and malonylcarnitine/hydroxybutyrylcarnitine (C3DC+C4OH) are associated not only with T2D but also with prediabetic states.
The polyphenol resveratrol has been suggested to exert beneficial effects on memory and the aging hippocampus due to calorie-restriction mimicking effects. However, the evidence based on human ...interventional studies is scarce. We therefore aimed to determine the effects of resveratrol on memory performance, and to identify potential underlying mechanisms using a broad array of blood-based biomarkers as well as hippocampus connectivity and microstructure assessed with ultra-high field magnetic resonance imaging (UHF-MRI).
In this double-blind, randomized controlled trial, 60 elderly participants (60–79 years) with a wide body-mass index (BMI) range of 21–37 kg/m2 were randomized to receive either resveratrol (200 mg/day) or placebo for 26 weeks (registered at ClinicalTrials.gov: NCT02621554). Baseline and follow-up assessments included the California Verbal Learning Task (CVLT, main outcome), the ModBent task, anthropometry, markers of glucose and lipid metabolism, inflammation and neurotrophins derived from fasting blood, multimodal neuroimaging at 3 and 7 T, and questionnaires to assess confounding factors.
Multivariate repeated-measures ANOVA did not detect significant time by group effects for CVLT performance. There was a trend for preserved pattern recognition memory after resveratrol, while performance decreased in the placebo group (n.s., p = 0.07). Further exploratory analyses showed increases in both groups over time in body fat, cholesterol, fasting glucose, interleukin 6, high sensitive C-reactive protein, tumor necrosis factor alpha and in mean diffusivity of the subiculum and presubiculum, as well as decreases in physical activity, brain-derived neurotrophic factor and insulin-like growth factor 1 at follow-up, which were partly more pronounced after resveratrol.
This interventional study failed to show significant improvements in verbal memory after 6 months of resveratrol in healthy elderly with a wide BMI range. A non-significant trend emerged for positive effects on pattern recognition memory, while possible confounding effects of unfavorable changes in lifestyle behavior, neurotrophins and inflammatory markers occurred. Our findings also indicate the feasibility to detect (un)healthy aging-related changes in measures of hippocampus microstructure after 6 months using 7T diffusion MRI. More studies incorporating a longer duration and larger sample size are needed to determine if resveratrol enhances memory performance in healthy older adults.
•In this randomized clinical trial, 6 months resveratrol supplementation showed no significant effects on verbal memory compared to placebo.•Unfavorable changes in lifestyle factors at follow-up might have introduced confounding.•Secondary analyses showed a trend towards preserved pattern recognition.•We used multimodal ultra high field MRI to detect subtle changes in microstructure of hippocampus subfields.
Objective: To explore neuroanatomical sites of eating behavior, we have developed a simple functional magnetic resonance imaging (fMRI) paradigm to image hunger vs. satiety using visual stimulation. ...Methods and Procedures: Twelve healthy, lean, nonsmoking male subjects participated in this study. Pairs of food-neutral and food-related pictures were presented in a block design, after a 14-h fast and 1 h after ad libitum ingestion of a mixed meal. Statistically, a general linear model for serially autocorrelated observations with a P level <0.001 was used. Results: During the hunger condition, significantly enhanced brain activity was found in the left striate and extrastriate cortex, the inferior parietal lobe, and the orbitofrontal cortices. Stimulation with food images was associated with increased activity in both insulae, the left striate and extrastriate cortex, and the anterior midprefrontal cortex. Nonfood images were associated with enhanced activity in the right parietal lobe and the left and right middle temporal gyrus. A significant interaction in activation pattern between the states of hunger and satiety and stimulation with food and nonfood images was found for the left anterior cingulate cortex, the superior occipital sulcus, and in the vicinity of the right amygdala. Discussion: These preliminary data from a homogenous healthy male cohort suggest that central nervous system (CNS) activation is not only altered with hunger and satiety but that food and nonfood images have also specific effects on regional brain activity if exposure takes place in different states of satiety. Wider use of our or a similar approach would help to establish a uniform paradigm to map hunger and satiety to be used for further experiments.
Functional magnetic resonance data acquired in a task-absent condition ("resting state") require new data analysis techniques that do not depend on an activation model. In this work, we introduce an ...alternative assumption- and parameter-free method based on a particular form of node centrality called eigenvector centrality. Eigenvector centrality attributes a value to each voxel in the brain such that a voxel receives a large value if it is strongly correlated with many other nodes that are themselves central within the network. Google's PageRank algorithm is a variant of eigenvector centrality. Thus far, other centrality measures - in particular "betweenness centrality" - have been applied to fMRI data using a pre-selected set of nodes consisting of several hundred elements. Eigenvector centrality is computationally much more efficient than betweenness centrality and does not require thresholding of similarity values so that it can be applied to thousands of voxels in a region of interest covering the entire cerebrum which would have been infeasible using betweenness centrality. Eigenvector centrality can be used on a variety of different similarity metrics. Here, we present applications based on linear correlations and on spectral coherences between fMRI times series. This latter approach allows us to draw conclusions of connectivity patterns in different spectral bands. We apply this method to fMRI data in task-absent conditions where subjects were in states of hunger or satiety. We show that eigenvector centrality is modulated by the state that the subjects were in. Our analyses demonstrate that eigenvector centrality is a computationally efficient tool for capturing intrinsic neural architecture on a voxel-wise level.
People with metabolically healthy obesity (MHO) may still have an increased risk for cardiovascular mortality compared to metabolically healthy lean (MHL) individuals. However, the mechanisms linking ...obesity to cardiovascular diseases are not entirely understood. We therefore tested the hypothesis that circulating cell adhesion molecules (CAMs) are higher in MHO compared to MHL individuals.
Serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), E-selectin and P-selectin were measured in age- and sex-matched groups of MHL (n = 32), MHO categorized into BMI-matched insulin sensitive (IS, n = 32) or insulin resistant (IR) obesity (n = 32) and people with metabolically unhealthy obesity (MUO, n = 32).
Indeed, individuals with MHO have significantly higher sICAM-1, E-selectin, and P-selectin serum concentrations compared to MHL people. However, these CAMs are still significantly lower in IS compared to IR MHO. There was no difference between the groups in sVCAM-1 serum concentrations. Compared to all other groups, circulating adhesion molecules were significantly higher in individuals with MUO.
These findings suggest that obesity-related increased cardiovascular risk is reflected and may be mediated by significantly higher CAMs. The mechanisms causing elevated adhesion molecules even in the absence of overt cardio-metabolic risk factors and whether circulating CAMs could predict cardiovascular events need to be explored.
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