Diurnal distribution of carbohydrates and fat affects substrate oxidation and adipokine secretion in humans.

BACKGROUND: A diet in which fat is mainly eaten in the morning and carbohydrates mainly in the evening (compared with the reverse order) was recently shown to worsen glycemic control in people with prediabetes. OBJECTIVE: We investigated the effects of these dietary patterns on energy metabolism, and on the daily profiles of circulating lipids, adipokines, and inflammatory markers. DESIGN: In a randomized controlled crossover trial, 29 nonobese men (with normal glucose tolerance, n = 18; or impaired fasting glucose/glucose tolerance, n = 11) underwent 2 isocaloric 4-wk diets: 1) carbohydrate-rich meals until 1330 and fat-rich meals between 1630 and 2200 (HC/HF); or 2) the inverse sequence of meals (HF/HC). During a 12-h clinical investigation day after each intervention period, 2 meal tolerance tests were performed, at 0900 and 1540, respectively. Substrate oxidation and concentrations of circulating lipids, adipokines, and cytokines were assessed pre- and postprandially. The postprandial inflammatory response in leukocytes was analyzed ex vivo. RESULTS: Fasting carbohydrate oxidation decreased (P = 0.004) and lipid oxidation increased (P = 0.012) after the HC/HF diet. Fasting concentrations of blood markers did not differ between diets. The diets modulated the daily profiles of carbohydrate oxidation, lipid oxidation, and β-hydroxybutyrate, although the average daily values of these parameters showed no difference between the diets, and no interaction between diet and glucose tolerance status. Diurnal patterns of triglycerides, low-density lipoprotein cholesterol, leptin, visfatin, and of LPS-induced cytokine secretion in blood leukocytes were also modulated by the diets. Average daily concentrations of leptin (P = 0.017) and visfatin (P = 0.041) were lower on the HF/HC diet than on the HC/HF diet. CONCLUSIONS: Diurnal distribution of carbohydrates and fat affects the daily profiles of substrate oxidation, circulating lipids, and cytokine secretion, and alters the average daily concentrations of adipokine secretion in nonobese nondiabetic humans. The study was registered at clinicaltrials.gov as NCT02487576

A distinct metabolic signature predicts development of fasting plasma glucose

ABSTRACT: BACKGROUND: High blood glucose and diabetes are amongst the conditions causing the greatest losses in years of healthy life worldwide. Therefore, numerous studies aim to identify reliable risk markers for development of impaired glucose metabolism and type 2 diabetes. However, the molecular basis of impaired glucose metabolism is so far insufficiently understood. The development of so called `omics' approaches in the recent years promises to identify molecular markers and to further understand the molecular basis of impaired glucose metabolism and type 2 diabetes. Although univariate statistical approaches are often applied, we demonstrate here that the application of multivariate statistical approaches is highly recommended to fully capture the complexity of data gained using high-throughput methods. METHODS: We took blood plasma samples from 172 subjects who participated in the prospective Metabolic Syndrome Berlin Potsdam follow-up study (MESY-BEPO Follow-up). We analysed these samples using Gas Chromatography coupled with Mass Spectrometry (GC-MS), and measured 286 metabolites. Furthermore, fasting glucose levels were measured using standard methods at baseline, and after an average of six years. We did correlation analysis and built linear regression models as well as Random Forest regression models to identify metabolites that predict the development of fasting glucose in our cohort. RESULTS: We found a metabolic pattern consisting of nine metabolites that predicted fasting glucose development with an accuracy of 0.47 in tenfold cross-validation using Random Forest regression. We also showed that adding established risk markers did not improve the model accuracy. However, external validation is eventually desirable. Although not all metabolites belonging to the final pattern are identified yet, the pattern directs attention to amino acid metabolism, energy metabolism and redox homeostasis. CONCLUSIONS: We demonstrate that metabolites identified using a high-throughput method (GC-MS) perform well in predicting the development of fasting plasma glucose over several years. Notably, not single, but a complex pattern of metabolites propels the prediction and therefore reflects the complexity of the underlying molecular mechanisms. This result could only be captured by application of multivariate statistical approaches. Therefore, we highly recommend the usage of statistical methods that seize the complexity of the information given by high-throughput methods

Isoforms of Retinol binding protein 4 (RBP4) are increased in chronic diseases of the kidney but not of the liver

<p>Abstract</p> <p>Background</p> <p>The levels of retinol-binding protein 4 (RBP4) – the carrier protein for Vitamin A in plasma – are tightly regulated under healthy circumstances. The kidney, the main site of RBP4 catabolism, contributes to an elevation of RBP4 levels during chronic kidney disease (CKD) whereas during chronic liver disease (CLD) RBP4 levels decrease. Little is known about RBP4 isoforms including apo-RBP4, holo-RBP4 as well as RBP4 truncated at the C-terminus (RBP4-L and RBP4-LL) except that RBP4 isoforms have been reported to be increased in hemodialysis patients. Since it is not known whether CLD influence RBP4 isoforms, we investigated RBP4 levels, apo- and holo-RBP4 as well as RBP4-L and RBP4-LL in plasma of 36 patients suffering from CKD, in 55 CLD patients and in 50 control subjects. RBP4 was determined by ELISA and apo- and holo-RBP4 by native polyacrylamide gel electrophoresis (PAGE). RBP4-L and RBP4-LL were analyzed after immunoprecipitation by mass spectrometry (MALDI-TOF-MS).</p> <p>Results</p> <p>RBP4 isoforms and levels were highly increased in CKD patients compared to controls (P < 0.05) whereas in CLD patients RBP4 isoforms were not different from controls. In addition, in hepatic dysfunction RBP4 levels were decreased whereas the amount of isoforms was not affected.</p> <p>Conclusion</p> <p>The occurrence of RBP4 isoforms is not influenced by liver function but seems to be strongly related to kidney function and may therefore be important in investigating kidney function and related disorders.</p

The effect of diurnal distribution of carbohydrates and fat on glycaemic control in humans: a randomized controlled trial.

Diurnal carbohydrate and fat distribution modulates glycaemic control in rodents. In humans, the optimal timing of both macronutrients and its effects on glycaemic control after prolonged consumption are not studied in detail. In this cross-over trial, 29 non-obese men were randomized to two four-week diets: (1) carbohydrate-rich meals until 13.30 and fat-rich meals between 16.30 and 22.00 (HC/HF) versus (2) inverse sequence of meals (HF/HC). After each trial period two meal tolerance tests were performed, at 09.00 and 15.40, respectively, according to the previous intervention. On the HF/HC diet, whole-day glucose level was increased by 7.9% (p = 0.026) in subjects with impaired fasting glucose and/or impaired glucose tolerance (IFG/IGT, n = 11), and GLP-1 by 10.2% (p = 0.041) in normal glucose-tolerant subjects (NGT, n = 18). Diet effects on fasting GLP-1 (p = 0.009) and PYY (p = 0.034) levels were observed in IFG/IGT, but not in NGT. Afternoon decline of glucose tolerance was more pronounced in IFG/IGT and associated with a stronger decrease of postprandial GLP-1 and PYY levels, but not with changes of cortisol rhythm. In conclusion, the HF/HC diet shows an unfavourable effect on glycaemic control in IFG/IGT, but not in NGT subjects. Consequently, large, carbohydrate-rich dinners should be avoided, primarily by subjects with impaired glucose metabolism

Shotgun Lipidomics Discovered Diurnal Regulation of Lipid Metabolism Linked to Insulin Sensitivity in Nondiabetic Men.

CONTEXT: Meal timing affects metabolic homeostasis and body weight, but how composition and timing of meals affect plasma lipidomics in humans is not well studied. OBJECTIVE: We used high throughput shotgun plasma lipidomics to investigate effects of timing of carbohydrate and fat intake on lipid metabolism and its relation to glycemic control. DESIGN: 29 nondiabetic men consumed (1) a high-carb test meal (MTT-HC) at 09.00 and a high-fat meal (MTT-HF) at 15.40; or (2) MTT-HF at 09.00 and MTT-HC at 15.40. Blood was sampled before and 180 minutes after completion of each MTT. Subcutaneous adipose tissue (SAT) was collected after overnight fast and both MTTs. Prior to each investigation day, participants consumed a 4-week isocaloric diet of the same composition: (1) high-carb meals until 13.30 and high-fat meals between 16.30 and 22:00 or (2) the inverse order. RESULTS: 12 hour daily lipid patterns showed a complex regulation by both the time of day (67.8%) and meal composition (55.4%). A third of lipids showed a diurnal variation in postprandial responses to the same meal with mostly higher responses in the morning than in the afternoon. Triacylglycerols containing shorter and more saturated fatty acids were enriched in the morning. SAT transcripts involved in fatty acid synthesis and desaturation showed no diurnal variation. Diurnal changes of 7 lipid classes were negatively associated with insulin sensitivity, but not with glucose and insulin response or insulin secretion. CONCLUSIONS: This study identified postprandial plasma lipid profiles as being strongly affected by meal timing and associated with insulin sensitivity

A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations

Saliva Samples as A Tool to Study the Effect of Meal Timing on Metabolic And Inflammatory Biomarkers.

: Meal timing affects metabolic regulation in humans. Most studies use blood samples for their investigations. Saliva, although easily available and non-invasive, seems to be rarely used for chrononutritional studies. In this pilot study, we tested if saliva samples could be used to study the effect of timing of carbohydrate and fat intake on metabolic rhythms. In this cross-over trial, 29 nonobese men were randomized to two isocaloric 4-week diets: (1) carbohydrate-rich meals until 13:30 and high-fat meals between 16:30 and 22:00 or (2) the inverse order of meals. Stimulated saliva samples were collected every 4 h for 24 h at the end of each intervention, and levels of hormones and inflammatory biomarkers were assessed in saliva and blood. Cortisol, melatonin, resistin, adiponectin, interleukin-6 and MCP-1 demonstrated distinct diurnal variations, mirroring daytime reports in blood and showing significant correlations with blood levels. The rhythm patterns were similar for both diets, indicating that timing of carbohydrate and fat intake has a minimal effect on metabolic and inflammatory biomarkers in saliva. Our study revealed that saliva is a promising tool for the non-invasive assessment of metabolic rhythms in chrononutritional studies, but standardisation of sample collection is needed in out-of-lab studies

Management of patients with type 2 diabetes in cardiovascular rehabilitation

The clinical benefits of rehabilitation in cardiovascular disease are well established. Among cardiovascular disease patients, however, patients with type 2 diabetes mellitus require a distinct approach. Specific challenges to clinicians and healthcare professionals in patients with type 2 diabetes include the prevalence of peripheral and autonomic neuropathy, retinopathy, nephropathy, but also the intake of glucose-lowering medication. In addition, the psychosocial wellbeing, driving ability and/or occupational status can be affected by type 2 diabetes. As a result, the target parameters of cardiovascular rehabilitation and the characteristics of the cardiovascular rehabilitation programme in patients with type 2 diabetes often require significant reconsideration and a multidisciplinary approach. This review explains how to deal with diabetes-associated comorbidities in the intake screening of patients with type 2 diabetes entering a cardiovascular rehabilitation programme. Furthermore, we discuss diabetes-specific target parameters and characteristics of cardiovascular rehabilitation programmes for patients with type 2 diabetes in a multidisciplinary context, including the implementation of guideline-directed medical therapy.status: publishe