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Therapies based on glucagon-like peptide-1 (GLP-1) long-acting analogs and insulin are often used in the treatment of metabolic diseases. Both insulin and GLP-1 receptors are expressed in metabolically relevant brain regions, suggesting a cooperative action. However, the mechanisms underlying the synergistic actions of insulin and GLP-1R agonists remain elusive. In this study, we show that insulin-induced hypoglycemia enhances GLP-1R agonists entry in hypothalamic and area, leading to enhanced whole-body fat oxidation. Mechanistically, this phenomenon relies on the release of tanycyctic vascular endothelial growth factor A, which is selectively impaired after calorie-rich diet exposure. In humans, low blood glucose also correlates with enhanced blood-to-brain passage of insulin, suggesting that blood glucose gates the passage other energy-related signals in the brain. This study implies that the preventing hyperglycemia is important to harnessing the full benefit of GLP-1R agonist entry in the brain and action onto lipid mobilization and body weight loss.

Aims/hypothesis Our aim was to investigate the relationship between average blood glucose levels and incident CHD in individuals without diabetes mellitus. Methods To investigate average blood glucose levels, we studied HbA1c as predicted by 40 variants previously shown to be associated with both type 2 diabetes and HbA1c. Linear and non-linear Mendelian randomisation analyses were performed to investigate associations with incident CHD risk in 324,830 European ancestry individuals from the UK Biobank without diabetes mellitus. Results Every one mmol/mol increase in genetically proxied HbA1c was associated with an 11% higher CHD risk (HR 1.11, 95% CI 1.05, 1.18). The dose–response curve increased at all levels of HbA1c, and there was no evidence favouring a non-linear relationship over a linear one. Conclusions/interpretations In individuals without diabetes mellitus, lowering average blood glucose levels may reduce CHD risk in a dose-dependent way. Graphical abstract

RationaleType 2 diabetes mellitus (T2D) is an established risk factor for cerebrovascular disease but the mechanisms underlying this association remain elusive. Disentangling the causal effects of T2D, hyperglycemia, and pre-diabetic phenotypes (insulin resistance, β-cell dysfunction) on major etiological stroke subtypes (ischemic stroke, intracerebral hemorrhage, ischemic stroke subtypes) could inform the development of preventive strategies.ObjectiveWe employed Mendelian randomization (MR) to explore the effects of genetic predisposition to T2D, hyperglycemia, insulin resistance, and β-cell dysfunction on risk of stroke subtypes and related cerebrovascular phenotypes.Methods and ResultsWe selected instruments for genetic predisposition to T2D, HbA1c levels, fasting glucose levels, insulin resistance, and β-cell dysfunction (proxied by pro-insulin levels) based on published genome-wide association studies (up to 898,130 individuals). Applying two-sample MR, we examined associations with ischemic stroke, intracerebral hemorrhage, and ischemic stroke subtypes (large artery, cardioembolic, small vessel stroke; up to 60,341 cases and 454,450 controls). We further explored associations with the related phenotypes of carotid atherosclerosis, imaging markers of cerebral white matter integrity, and brain atrophy. Genetic predisposition to T2D and elevated HbA1c levels in the pre-diabetic range were associated with higher risk of any ischemic stroke, large artery stroke, carotid plaque and small vessel stroke. Independently of HbA1c levels, we further found genetic predisposition to insulin resistance to be associated with large artery and small vessel stroke, whereas predisposition to β-cell dysfunction was associated with small vessel stroke. Predisposition to β-cell dysfunction was further associated with intracerebral hemorrhage, lower grey matter volume, and total brain volume.ConclusionsThis study supports causal effects of T2D and hyperglycemia on large artery and small vessel stroke. We show differential effects of genetically determined insulin resistance and β-cell dysfunction on large artery and small vessel stroke that might have implications for anti-diabetic treatments targeting these mechanisms.

The apolipoprotein E (APOE) polymorphism impacts blood lipids and biomarkers of oxidation and inflammation, contributing to an isoform-dependent disease risk. We investigated the effect of the APOE genotype on postprandial metabolism after consumption of three different isoenergetic (4200 kJ) meals in older adults with a CVD risk phenotype. In a randomized crossover study, participants with metabolic syndrome traits (APOE E3, n = 39, E4, n = 10, mean age, 70 ± 5 years, BMI 31.3 ± 3.0 kg/m2) consumed a Western-like diet high-fat (WDHF), Western-like diet high-carbohydrate (WDHC), or Mediterranean-like diet (MED) meal. Parameters of lipid and glucose metabolism, inflammatory, and oxidative parameters were analyzed in blood samples collected at fasting and 1–5 h postprandially. Data were analyzed by linear mixed models. The magnitude of the IL-6 increase after the WDHF meal was significantly higher in E4 than in E3 carriers (iAUC: E4 = 7.76 vs. E3 = 2.81 pg/mL × h). The time to detect the IL-6 increase was shorter in the E4 group. All meals produced postprandial glycemia, insulinemia, and lipidemia, without differences between the E3 and the E4 groups. IL-1β and oxidized LDL levels did not change postprandially. In conclusion, APOE E4 carriers display increased postprandial inflammation, indicated by higher postprandial IL-6 increase, when compared to non-carriers.

Background: Metabolic syndrome and impaired insulin sensitivity may occur as side effects of atypical antipsychotic drugs. However, studies of peripheral insulin resistance using the homeostatic model assessment of insulin resistance (HOMA-IR) or oral glucose tolerance tests (OGTT) suggest that abnormal glucose metabolism is already present in drug-naive first-episode schizophrenia (DNFES). We hypothesized impairments of neuronal insulin signaling in DNFES. Methods: To gain insight into neuronal insulin-signaling in vivo, we analyzed peripheral blood extracellular vesicles enriched for neuronal origin (nEVs). Phosphorylated insulin signal transduction serine-threonine kinases pS312-IRS-1, pY-IRS-1, pS473-AKT, pS9-GSK3β, pS2448-mTOR, pT389-p70S6K and respective total protein levels were determined in plasma nEVs from 48 DNFES patients and healthy matched controls after overnight fasting. Results: Upstream pS312-IRS-1 was reduced at trend level (p = 0.071; this condition may amplify IRS-1 signaling). Exploratory omnibus analysis of downstream serine-threonine kinases (AKT, GSK3β, mTOR, p70S6K) revealed lower phosphorylated/total protein ratios in DNFES vs. controls (p = 0.013), confirming decreased pathway activation. Post-hoc-tests indicated in particular a reduced phosphorylation ratio of mTOR (p = 0.027). Phosphorylation ratios of p70S6K (p = 0.029), GSK3β (p = 0.039), and at trend level AKT (p = 0.061), showed diagnosis-dependent statistical interactions with insulin blood levels. The phosphorylation ratio of AKT correlated inversely with PANSS-G and PANSS-total scores, and other ratios showed similar trends. Conclusion: These findings support the hypothesis of neuronal insulin resistance in DNFES, small sample sizes notwithstanding. The counterintuitive trend towards reduced pS312-IRS-1 in DNFES may result from adaptive feedback mechanisms. The observed changes in insulin signaling could be clinically meaningful as suggested by their association with higher PANSS scores.

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome., The genetic basis of metabolic diseases is incompletely understood. Here, by high-throughput phenotyping of 2,016 knockout mouse strains, Rozman and colleagues identify candidate metabolic genes, many of which are associated with unexplored regulatory gene networks and metabolic traits in human GWAS.

DJ-1 constitutes a ubiquitously expressed, oxidative stress-responsive protein with multiple functions. DJ-1 emerged as a candidate from our previous proteome analysis investigating alterations in the hypothalamus in three mouse strains differing in their susceptibility to diet-induced obesity (DIO). Validation studies demonstrated a high-fat diet (HFD)-induced shift in the DJ-1 isoform pattern in the hypothalamus and several other tissues of mice. Others found HFD-induced alterations in DJ-1 protein abundance in adipose tissue and pancreatic islets in wild-type rodents. Here, we investigated the gene-diet interaction by challenging Dj-1(-/-) mice with a HFD. We demonstrate that the development of diet-induced obesity (DIO) Dj-1(-/-) mice is according to wild-type mice with the exception of transient higher gains in fat mass at the expense of lean mass after 14 weeks of feeding.

Increased blood glucose level (BGL) has been reported to cause alterations of FDG uptake in the brain that mimic Alzheimer’s disease (AD), even within the "acceptable" range ≤ 160 mg/dl. The aim of this study was (i) to confirm this in a large sample of well-characterized normal control (NC) subjects, and (ii) to analyze its impact on the prediction of AD dementia (ADD) in mild cognitive impairment (MCI). The study included NCs from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) that were cognitively stable for ≥36 months after PET (n = 87, 74.2 ± 5.3 y), and ADNI MCIs with ≥36 months follow-up if not progressed to ADD earlier (n = 323, 71.1 ± 7.1 y). Seventy-three of the MCIs had progressed to ADD within 36 months. In the NCs, parenchyma-scaled FDG uptake was tested for clusters of correlation with BGL on the family-wise, error-corrected 5% level. In the MCIs, ROC analysis was used to assess the power of FDG uptake in a predefined AD-typical region for prediction of ADD. ROC analysis was repeated after correcting mean FDG uptake in the AD-typical region for BGL based on linear regression in the NCs. In the NCs, BGL (59–149 mg/dl) was negatively correlated with FDG uptake in a cluster comprising the occipital cortex and precuneus but sparing the posterior cingulate, independent of amyloid-β and ApoE4 status. In the MCIs, FDG uptake in the AD-typical region provided an area of 0.804 under the ROC curve for prediction of ADD. Correcting FDG uptake in the AD-typical region for BGL (55–189 mg/dl) did not change predictive performance (area = 0.808, p = 0.311). Increasing BGL is associated with relative reduction of FDG uptake in the posterior cortex even in the "acceptable" range ≤ 160 mg/dl. The BGL-associated pattern is similar to the typical AD pattern, but not identical. BGL-associated variability of regional FDG uptake has no relevant impact on the power of FDG PET for prediction of MCI-to-ADD progression.

We investigated the associations of fasting (FG) and 2-h postload (2HG) plasma glucose from oral glucose tolerance test (OGTT) with gray (GMV) and white (WMV) matter volume.We analyzed data from 1330 subjects without known diabetes mellitus, aged 21 to 81, from the second cohort (SHIP-Trend-0) of the population-based Study of Health in Pomerania (SHIP). Following the OGTT, individuals were classified in five groups (according to the American Diabetes Association criteria): normal glucose tolerance (NGT), isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), combined IFG and IGT (IFG + IGT) and unknown type 2 diabetes mellitus (UDM). GMV and WMV were determined by magnetic resonance imaging. FG, 2HG and OGTT groups were associated with GMV and WMV by linear regression models adjusted for confounders. FG and 2HG were inversely associated with GMV. The adjusted mean GMV, when compared with the NGT group (584 ml [95% CI: 581 to 587]), was significantly lower in the groups i-IFG (578 ml [95% CI: 573 to 582]; p = 0.035) and UDM (562 ml [95% CI: 551 to 573]; p 0.001), but not different in the i-IGT (586 ml [95% CI: 576 to 596]; p = 0.688) and IFG + IGT (579 ml [95% CI: 571 to 586]; p = 0.209) groups. There were no associations of FG, 2HG and OGTT parameters with WMV.Our findings suggest that elevated FG levels, even within the prediabetic range, might already have some harmful effects on GMV.

L-Homoarginine (hArg) is an endogenous amino acid which has emerged as a novel biomarker for stroke and cardiovascular disease. Low circulating hArg levels are associated with increased mortality and vascular events, whereas recent data have revealed positive correlations between circulating hArg and metabolic vascular risk factors like obesity or blood glucose levels. However, it is unclear whether hArg levels are causally linked to metabolic parameters. Therefore, the aim of our study was to investigate whether hArg directly influences body weight, blood glucose, glucose tolerance or insulin sensitivity. Here, we show that hArg supplementation (14 and 28 mg/mL orally per drinking water) ameliorates blood glucose levels in mice on high-fat diet (HFD) by a reduction of 7.3 ± 3.7 or 13.4 ± 3.8 %, respectively. Fasting insulin concentrations were slightly, yet significantly affected (63.8 ± 11.3 or 162.1 ± 39.5 % of control animals, respectively), whereas body weight and glucose tolerance were unaltered. The substantial augmentation of hArg plasma concentrations in supplemented animals (327.5 ± 40.4 or 627.5 ± 60.3 % of control animals, respectively) diminished profoundly after the animals became obese (129.9 ± 16.6 % in control animals after HFD vs. 140.1 ± 8.5 or 206.3 ± 13.6 %, respectively). This hArg-lowering effect may contribute to the discrepancy between the inverse correlation of plasma hArg levels with stroke and cardiovascular outcome, on the one hand, and the direct correlation with cardiovascular risk factors like obesity and blood glucose, on the other hand, that has been observed in human studies. Our results suggest that the glucose-lowering effects of hArg may reflect a compensatory mechanism of blood glucose reduction by hArg upregulation in obese individuals, without directly influencing body weight or glucose tolerance.

Eating behavior, body weight regulation, peripheral glucose metabolism, and cognitive function depend on adequate insulin action in the brain, and recent studies in humans suggested that impaired insulin action in the brain emerges upon fat intake, obesity, and genetic variants. As insulin enters into the brain in a receptor-mediated fashion, we hypothesized that whole-body insulin sensitivity might affect the transport of insulin into the brain and contribute to the aversive effect of insulin resistance in the central nervous system. In this study, we aimed to determine the ratio of insulin in the cerebrospinal fluid and serum to whole-body insulin sensitivity. Healthy human subjects participated in an oral glucose tolerance test to determine whole-body insulin sensitivity and underwent lumbar puncture. Blood and CSF concentrations of insulin were significantly correlated. The CSF/serum ratio for insulin was significantly associated with whole body insulin sensitivity with reduced insulin transported into the CSF in insulin-resistant subjects. Together, our data suggest that transport of insulin into the CSF relates to peripheral insulin sensitivity and impairs insulin action in the brain. This underlines the need for sensitizing measures in insulin-resistant subjects.

Sequences encoding DUF1220 protein domains show the most extreme human lineage-specific copy number increase of any coding region in the genome and have been linked to human brain evolution. In addition, DUF1220 copy number (dosage) has been implicated in influencing brain size within the human species, both in normal populations and in individuals associated with brain size pathologies (1q21-associated microcephaly and macrocephaly). More recently, increasing dosage of a subtype of DUF1220 has been linked with increasing severity of the primary symptoms of autism. Despite these intriguing associations, a function for these domains has not been described. As a first step in addressing this question, we have developed the first transgenic model of DUF1220 function by removing the single DUF1220 domain (the ancestral form) encoded in the mouse genome. In a hypothesis generating exercise, these mice were evaluated by 197 different phenotype measurements. While resulting DUF1220-minus (KO) mice show no obvious anatomical peculiarities, they exhibit a significantly reduced fecundity (χ 2 = 19.1, df = 2, p = 7.0 × 10−5). Further extensive phenotypic analyses suggest hyperactivity (p

The majority of amyotrophic lateral sclerosis (ALS) cases as well as many patients suffering from frontotemporal lobar dementia (FTLD) with ubiquitinated inclusion bodies show TDP-43 pathology, the protein encoded by the TAR DNA-binding protein (Tardbp) gene. We used recombinase-mediated cassette exchange to introduce an ALS patient cDNA into the mouse Tdp-43 locus. Expression levels of human A315T TDP-43 protein were 300% elevated in heterozygotes, whereas the endogenous mouse Tdp-43 was decreased to 20% of wild type levels as a result of disturbed feedback regulation. Heterozygous TDP-43(A315TKi) mutants lost 10% of their body weight and developed insoluble TDP-43 protein starting as early as 3 months after birth, a pathology that was exacerbated with age. We analyzed the splicing patterns of known Tdp-43 target genes as well as genome-wide gene expression levels in different tissues that indicated mitochondrial dysfunction. In heterozygous mutant animals, we observed a relative decrease in expression of Parkin (Park2) and the fatty acid transporter CD36 along with an increase in fatty acids, HDL cholesterol, and glucose in the blood. As seen in transmission electron microscopy, neuronal cells in motor cortices of TDP-43(A315TKi) animals had abnormal neuronal mitochondrial cristae formation. Motor neurons were reduced to 90%, but only slight motoric impairment was detected. The observed phenotype was interpreted as a predisease model, which might be valuable for the identification of further environmental or genetic triggers of neurodegeneration.

Insulin, insulin-like growth factor-1 (IGF-1), and leptin signaling have been proposed to play an important role in regulating energy homeostasis. In order to specifically address the role of neuronal IGF-1 receptor (IGF-1R) signaling for energy expenditure and metabolism we used conditional mutagenesis. Deletion of one copy of the IGF-1R specifically in post-mitotic neurons (nIGF-1R +/ − ) does not result in growth retardation or skeletal abnormalities. Interestingly, male nIGF-1R +/ − mice accumulate less fat mass during aging accompanied with decreased leptin levels compared to wild-type littermates. Furthermore, male nIGF-1R +/ − mice present with increased locomotor activity and energy expenditure. In contrast, female nIGF-1R +/ − mice remained nearly unaffected. Circadian pattern of locomotor activity and energy expenditure as well as food and water intake did not change. Consistent with increased locomotor activity, the respiratory quotient was shifted to increased fat oxidation in nIGF-1R +/ − mice. Surprisingly, serum IGF-1 and IGF-1 binding protein 3 (IGF-BP3) concentrations were decreased in nIGF-1R +/ − mice despite the presence of normal pituitaries suggesting a functional feedback mechanism via neuronal IGF-1Rs, which regulate serum IGF-1 levels. Thus, we show that neuron-specific IGF-1R deletion in male mice decreases body fat accumulation and increases energy expenditure during aging.

Background Maintenance of the botanical integrity of cereal kernels and the addition of acetic acid (as vinegar) in the product or meal has been shown to lower the postprandial blood glucose and insulin response and to increase satiety. However, the mechanism behind the benefits of acetic acid on blood glucose and satiety is not clear. We hypothesized that the gastric emptying rate could be involved. Thus, the aim of this study was to evaluate the possible influence of maintained botanical integrity of cereals and the presence of acetic acid (vinegar) on gastric emptying rate (GER), postprandial blood glucose and satiety. Methods Fifteen healthy subjects were included in a blinded crossover trial, and thirteen of the subjects completed the study. Equicarbohydrate amounts of the following wheat-based meals were studied: white wheat bread, whole-kernel wheat bread or wholemeal wheat bread served with white wine vinegar. The results were compared with a reference meal consisting of white wheat bread without vinegar. The GER was measured with standardized real-time ultrasonography using normal fasting blood glucose Results The whole-kernel wheat bread with vinegar resulted in significantly higher ( Conclusion The present study shows higher satiety after a whole-kernel wheat bread meal with vinegar. This may be explained by increased antral distension after ingestion of intact cereal kernels but, in this study, not by a lower gastric emptying rate or higher postprandial blood glucose response. Trial registration NTR1116

BACKGROUND: Dairy consumption has been postulated to reduce the risk of obesity and metabolic disturbances.\n\nOBJECTIVE: The aim of this study was to evaluate the associations of dairy consumption with body weight and other components of the metabolic syndrome.\n\nDESIGN: We used cross-sectional data for 2064 men and women aged 50-75 y who participated in the Hoorn Study. The metabolic syndrome was defined according to the National Cholesterol Education Program Expert Panel. Dairy consumption was assessed by using a semiquantitative food-frequency questionnaire.\n\nRESULTS: The median consumption of total dairy products was 4.1 servings/d. After adjustment for potential confounders (ie, dietary factors, physical activity, smoking, income, educational level, and antihypertensive medication), total dairy consumption was significantly associated with lower diastolic blood pressure (beta +/- SE: -0.31 +/- 0.12 mm Hg/serving) and higher fasting glucose concentrations (0.04 +/- 0.02 mmol/L per serving), but not with body weight or other metabolic variables (ie, lipids, postload glucose, or insulin). When different dairy products were distinguished, borderline significant (P

AimTo investigate whether reduced lung function is a risk factor for developing diabetes. MethodsNon-diabetic men (n = 382) from the population-based cohort 'Men Born in 1914' were examined with spirometry at age 55 years. The cohort was re-examined at 68 years. Diabetes and fasting plasma glucose at follow-up were studied in relation to vital capacity (VC) and forced expiratory volume (FEV1.0) at baseline. ResultsFifteen men developed diabetes during the follow-up. The percentage with diabetes in the 1st, 2nd, 3rd and top quartile of vital capacity were 7%, 5%, 2%, and 1%, respectively (P for trend = 0.01). Fasting glucose (log transformed, mmol/l) at follow-up was 1.63 ± 0.16, 1.62 ± 0.18, 1.61 ± 0.11 and 1.60 ± 0.11, respectively (P for trend = 0.11). The longitudinal associations between VC and diabetes (P = 0.001) and log glucose (P = 0.036) were significant after adjustments for several potential confounders. FEV1.0 at baseline showed similar associations with diabetes at follow-up. ConclusionsThe risk of developing diabetes is inversely associated with pulmonary function among middle-aged men.

AimsTo examine determinants for glycaemic control in primary care patients with Type 2 diabetes. MethodsIn a community-based surveillance of primary care patients with Type 2 diabetes, 190 men and 186 women were consecutively identified and examined for cardiovascular risk factors. Insulin resistance and beta-cell function were estimated using homeostasis model assessment (HOMA). Good glycaemic control was defined as HbA1c < 6.5%. ResultsFollowing adjustment for age and gender, HbA1c>= 6.5% was associated with duration of diabetes (10.6 vs. 6.4 years, P < 0.001), lower levels of serum insulin (6.3 vs. 8.0 mU/l, P = 0.012), higher serum triglyceride levels (2.0 vs. 1.7 mmol/l, P = 0.002) and impairment of beta-cell function (HOMA index 19.5 vs. 45.8, P < 0.001). The association between HbA1c levels and duration remained with adjustment for age, gender, waist-hip ratio (WHR) and serum triglycerides (odds ratio (OR) for HbA1c>= 6.5% by 5 years diabetes duration = 1.7; 95% confidence interval (CI) 1.4-2.1) but was lost following additional adjustment for beta-cell function (OR for HbA1c>= 6.5% = 1.3; 95% CI 0.96-1.7). In a separate linear regression with beta-cell function as the dependent variable there was a significant association with HbA1c after adjustments for differences in age, gender, WHR, serum triglyceride levels and diabetes duration (P < 0.001). ConclusionsIncreasing HbA1c by time was associated with declining beta-cell function.