Marjukka Kolehmainen

IMPACT OF DIETARY POLYPHENOLS ON CARBOHYDRATE METABOLISM

Polyphenols, including flavonoids, phenolic acids, proanthocyanidins and resveratrol, are a large and heterogeneous group of phytochemicals in plant-based foods, such as tea, coffee, wine, cocoa, cereal grains, soy, fruits and berries. Growing evidence indicates that various dietary polyphenols may influence carbohydrate metabolism at many levels. In animal models and a limited number of human studies carried out so far, polyphenols and foods or beverages rich in polyphenols have attenuated postprandial glycemic responses and fasting hyperglycemia, and improved acute insulin secretion and insulin sensitivity. The possible mechanisms include inhibition of carbohydrate digestion and glucose absorption in the intestine, stimulation of insulin secretion from the pancreatic β–cells, modulation of glucose release from the liver, activation of insulin receptors and glucose uptake in the insulin-sensitive tissues, and modulation of intracellular signalling pathways and gene expression. The positive effects of polyphenols on glucose homeostasis observed in a large number of in vitro and animal models are supported by epidemiological evidence on polyphenol-rich diets. To confirm the implications of polyphenol consumption for prevention of insulin resistance, metabolic syndrome and eventually type 2 diabetes, human trials with well-defined diets, controlled study designs and clinically relevant end-points together with holistic approaches e.g., systems biology profiling technologies are needed.

Effects of an isocaloric healthy Nordic diet on insulin sensitivity, lipid profile and inflammation markers in metabolic syndrome – a randomized study (SYSDIET)

Different healthy food patterns may modify cardiometabolic risk. We investigated the effects of an isocaloric healthy Nordic diet on insulin sensitivity, lipid profile, blood pressure and inflammatory markers in people with metabolic syndrome.

The Common Variant in the FTO Gene Did Not Modify the Effect of Lifestyle Changes on Body Weight: The Finnish Diabetes Prevention Study

The common single‐nucleotide polymorphism in the FTO (fat mass and obesity associated) gene is consistently associated with an increased risk of obesity. However, the knowledge of a potential modifying effect of the FTO gene on changes in body weight achieved by lifestyle intervention is limited. We examined whether the FTO gene variant (rs9939609, T/A) is associated with body weight and BMI and long‐term weight changes in the Finnish Diabetes Prevention Study (DPS). Altogether, 522 (aged 40–65 years; BMI ≥25 kg/m2) subjects with impaired glucose tolerance (IGT) were randomized to control and lifestyle intervention groups. SNP rs9939609 was genotyped from 502 subjects. At baseline, those with the AA genotype had higher BMI than subjects with other genotypes (P = 0.006). The association was observed in women (P = 0.016) but not in men. During the 4‐year follow‐up, the subjects with the AA genotype had consistently the highest BMI (P = 0.009) in the entire study population. The magnitude of weight reduction was greater in the intervention group, but the risk allele did not modify weight change in either of the groups. Our results confirm the association between the common FTO variant and BMI in a cross‐sectional setting and during the long‐term lifestyle intervention. We did not observe association between FTO variant and the magnitude of weight reduction achieved by long‐term lifestyle intervention. Based on the results from the DPS, it is unlikely that the common variant of the FTO gene affects the success of lifestyle modification on weight loss.

Link between plasma ceramides, inflammation and insulin resistance: association with serum IL-6 concentration in patients with coronary heart disease

Aims/hypothesisCeramides and IL-6 have a role in immune–inflammatory responses and cardiovascular diseases, and are suggested to be involved in insulin and glucose metabolism. We sought to assess the associations of circulating levels of IL-6, TNF-α and high-sensitivity C reactive protein (hsCRP), which are inflammatory markers related to insulin resistance (IR), with the plasma lipid metabolites ceramides and diacylglycerols (DAG) in patients with CHD.MethodsCross-sectional analyses were carried out on data from 33 patients with CHD. Serum levels of the inflammatory markers and plasma lipid metabolites (lipidomics approach performed by ultra-performance liquid chromatography coupled to electrospray ionisation MS) were measured at the same time point as insulin resistance (IR) (HOMA-IR index).ResultsSerum circulating levels of IL-6 were strongly correlated with plasma ceramide concentrations (r = 0.59, p < 0.001). Adjustments for serum TNF-α or hsCRP levels, smoking, BMI, age, sex or HOMA-IR did not change the results (p < 0.001). After adjustments for the effect of serum inflammatory markers (TNF-α or hsCRP), HOMA-IR and BMI the correlation between plasma DAG and serum IL-6 (r = 0.33) was also significant (p < 0.03). In a linear regression model, circulating levels of both ceramides and TNF-α had a significant independent influence on circulating levels of IL-6, altogether accounting for 41% of its variation (p < 0.001).Conclusions/interpretationOur results strongly suggest that the link between ceramides, IR and inflammation is related to the inflammatory marker IL-6. Ceramides may contribute to the induction of inflammation involved in IR states that frequently coexist with CHD.Trial registration:ClinicalTrials.gov NCT00720655Funding:The study was supported by the Finnish Cultural Foundation, the North-Savo Regional Fund of the Finnish Cultural Foundation, the Yrjö Jahnsson Foundation, the Sigrid Juselius Foundation, the Juho Vainio Foundation, the Kuopio University Hospital (grant 510RA07), the Academy of Finland (Projects 117844 and 118590) and by the Nordic Centre of Excellence on ‘Systems biology in controlled dietary interventions and cohort studies’ (SYSDIET), Project 070014.

Association of ADIPOQ gene variants with body weight, type 2 diabetes and serum adiponectin concentrations: the Finnish Diabetes Prevention Study

BackgroundAdiponectin, secreted mainly by mature adipocytes, is a protein with insulin-sensitising and anti-atherogenic effects. Human adiponectin is encoded by the ADIPOQ gene on the chromosomal locus 3q27. Variations in ADIPOQ are associated with obesity, type 2 diabetes (T2DM) and related phenotypes in several populations. Our aim was to study the association of the ADIPOQ variations with body weight, serum adiponectin concentrations and conversion to T2DM in overweight subjects with impaired glucose tolerance. Moreover, we investigated whether ADIPOQ gene variants modify the effect of lifestyle changes on these traits.MethodsParticipants in the Finnish Diabetes Prevention Study were randomly assigned to a lifestyle intervention group or a control group. Those whose DNA was available (n = 507) were genotyped for ten ADIPOQ single nucleotide polymorphisms (SNPs). Associations between SNPs and baseline body weight and serum adiponectin concentrations were analysed using the univariate analysis of variance. The 4-year longitudinal weight data were analysed using linear mixed models analysis and the change in serum adiponectin from baseline to year four was analysed using Kruskal-Wallis test. In addition, the association of SNPs with the risk of developing T2DM during the follow-up of 0-11 (mean 6.34) years was analysed by Cox regression analysis.Resultsrs266729, rs16861205, rs1501299, rs3821799 and rs6773957 associated significantly (p < 0.05) with body weight at baseline and in the longitudinal analyses. The rs266729 C allele and the rare minor alleles of rs2241766 and rs2082940 were associated with an increased adjusted hazard ratio of developing T2DM. The differences in baseline serum adiponectin concentrations were seen according to rs16861210, rs17366568, rs2241766, rs6773957 and rs2082940 and differences in the change of serum adiponectin levels from baseline to the four year examination were seen according to rs16861205, especially in subjects who were able to lose weight during the first year of intervention.ConclusionsThese results from the Finnish Diabetes Prevention Study support the concept that genetic variation in ADIPOQ locus contributes to variation in body size and serum adiponectin concentrations and may also modify the risk of developing T2DM.Trial registration numberClinicalTrials.gov NCT00518167

Triacylglycerol fatty acid composition in diet-induced weight loss in subjects with abnormal glucose metabolism--the GENOBIN study.

Background The effect of weight loss on different plasma lipid subclasses at the molecular level is unknown. The aim of this study was to examine whether a diet-induced weight reduction result in changes in the extended plasma lipid profiles (lipidome) in subjects with features of metabolic syndrome in a 33-week intervention. Methodology/Principal Findings Plasma samples of 9 subjects in the weight reduction group and 10 subjects in the control group were analyzed using mass spectrometry based lipidomic and fatty acid analyses. Body weight decreased in the weight reduction group by 7.8±2.9% (p<0.01). Most of the serum triacylglycerols and phosphatidylcholines were reduced. The decrease in triacylglycerols affected predominantly the saturated short chain fatty acids. This decrease of saturated short chain fatty acid containing triacylglycerols correlated with the increase of insulin sensitivity. However, levels of several longer chain fatty acids, including arachidonic and docosahexanoic acid, were not affected by weight loss. Levels of other lipids known to be associated with obesity such as sphingolipids and lysophosphatidylcholines were not altered by weight reduction. Conclusions/Significance Diet-induced weight loss caused significant changes in global lipid profiles in subjects with abnormal glucose metabolism. The observed changes may affect insulin sensitivity and glucose metabolism in these subjects. Trial Registration ClinicalTrials.gov NCT00621205

Weight reduction modulates expression of genes involved in extracellular matrix and cell death: the GENOBIN study

Objective:Lifestyle and genetic factors interact in the development of obesity and the metabolic syndrome. The molecular mechanisms underlying the beneficial dietary modifications are, however, unclear. We aimed to examine the effect of the long-term moderate weight reduction on gene expression in adipose tissue (AT) and to identify genes and gene clusters responsive to treatment and thereby likely contributing to the development of the metabolic syndrome.Design:Randomized controlled and individualized weight reduction intervention.Subjects:Forty-six subjects with impaired fasting glycemia or impaired glucose tolerance and features of metabolic syndrome, aged 60±7 years were randomized either to a weight reduction (WR) (n=28) or a control (n=18) group lasting for 33 weeks.Measurements:Oral and intravenous glucose tolerance tests and subcutaneous AT biopsies were performed before and after the intervention. Gene expression of AT was studied using microarray technology in subgroups of WR (with weight reduction ⩾5%, n=9) and control group (n=10). The results were confirmed using quantitative PCR.Results:In the WR group, glucose metabolism improved. Moreover, an inverse correlation between the change in S I and the change in body weight was found (r=−0.44, P=0.026). Downregulation of gene expression (P<0.01) involving gene ontology groups of extracellular matrix and cell death was seen. Such changes did not occur in the control group. The tenomodulin-gene was one of the most downregulated genes (−39±16%, P<0.0001). Moreover, its expression correlated with insulin sensitivity (r=−0.34, P=0.005) before the intervention and with body adiposity both before (r=0.42, P=0.007) and after (r=0.30, P=0.056) the intervention.Conclusion:Genes regulating the extracellular matrix and cell death showed a strong downregulation after long-term weight reduction. This likely reflects a new stable state at the molecular level in AT. Further studies are warranted to elucidate the mechanisms of these genetic factors.

Effect of weight loss on cytokine messenger RNA expression in peripheral blood mononuclear cells of obese subjects with the metabolic syndrome

Inflammation is associated with obesity, the metabolic syndrome, and diabetes. No data are available on the effect of weight reduction on the gene expression of cytokines in immune cells in obesity and the metabolic syndrome. We assessed how long-term weight loss affects expression of cytokines in peripheral blood mononuclear cells (PBMCs) in individuals with impaired glucose metabolism and the metabolic syndrome. Data from 34 subjects randomized to either a weight reduction or a control group for a 33-week period were analyzed. The messenger RNA (mRNA) expression of interleukins (ILs) in PBMCs was measured using real-time polymerase chain reaction. Measures of insulin and glucose metabolism (intravenous and oral glucose tolerance tests), body composition, and circulating adipokines and inflammatory markers were also assessed. Weight reduction resulted in a decrease in the mRNA expression of IL-1beta (IL1B), IL-1 receptor antagonist, and tumor necrosis factor alpha (P < .001) and an increase in expression of IL-6 (IL6) and IL-8 (P < .01). The increase in IL6 expression was associated with a decrease in fasting glycemia (r = -0.53, P < .01). Interestingly, the decrease in IL1B expression was correlated with an increase in insulin sensitivity index (r = -0.68, P < .01). In general, a decrease in circulating levels of adipokines and inflammatory markers was also observed after weight loss. Weight loss altered gene expression of cytokines related to inflammation and the immune response in PBMCs. Changes in IL6 mRNA expression were associated with changes in fasting glycemia. The decrease in IL-1 receptor antagonist expression after weight loss and the strong correlation between the decrease in IL1B expression and the increase in insulin sensitivity suggest a contribution of these genes to insulin-resistant states found in obesity and the metabolic syndrome.

Bilberries reduce low-grade inflammation in individuals with features of metabolic syndrome

SCOPE Low-grade inflammation is a hallmark of cardiometabolic risk. Bilberries (Vaccinium myrtillus) are rich in polyphenols with potential anti-inflammatory properties. We studied the impact of bilberries on inflammation and gene expression profile in peripheral blood mononuclear cells in subjects with metabolic syndrome. METHODS AND RESULTS In randomized, controlled dietary intervention, the participants consumed either a diet rich in bilberries (n = 15) or a control diet (n = 12). The bilberry group consumed daily an equivalent dose of 400 g fresh bilberries, while the control group maintained their habitual diet. No differences were found between the groups in body weight, glucose, or lipid metabolism, but bilberry supplementation tended to decrease serum high-sensitivity C-reactive protein, IL-6, IL-12, and LPS concentrations. An inflammation score was significantly different between the groups (p = 0.024). In transcriptomics analyses (three participants with improved oral glucose tolerance test in the bilberry group), Toll-like receptor signaling, cytoplasmic ribosomal proteins, and B-cell receptor signaling pathways were differently regulated. QPCR analyses (n = 13 and 11 in the bilberry and control groups, respectively) showed decreased expression of MMD and CCR2 transcripts associated with monocyte and macrophage function associated genes. CONCLUSION Regular bilberry consumption may reduce low-grade inflammation indicating decreased cardiometabolic risk in the long term.

Whole Grain Products, Fish and Bilberries Alter Glucose and Lipid Metabolism in a Randomized, Controlled Trial: The Sysdimet Study

Background Due to the growing prevalence of type 2 diabetes, new dietary solutions are needed to help improve glucose and lipid metabolism in persons at high risk of developing the disease. Herein we investigated the effects of low-insulin-response grain products, fatty fish, and berries on glucose metabolism and plasma lipidomic profiles in persons with impaired glucose metabolism. Methodology/Principal Findings Altogether 106 men and women with impaired glucose metabolism and with at least two other features of the metabolic syndrome were included in a 12-week parallel dietary intervention. The participants were randomized into three diet intervention groups: (1) whole grain and low postprandial insulin response grain products, fatty fish three times a week, and bilberries three portions per day (HealthyDiet group), (2) Whole grain enriched diet (WGED) group, which includes principally the same grain products as group (1), but with no change in fish or berry consumption, and (3) refined wheat breads (Control). Oral glucose tolerance, plasma fatty acids and lipidomic profiles were measured before and after the intervention. Self-reported compliance with the diets was good and the body weight remained constant. Within the HealthyDiet group two hour glucose concentration and area-under-the-curve for glucose decreased and plasma proportion of (n-3) long-chain PUFAs increased (False Discovery Rate p-values <0.05). Increases in eicosapentaenoic acid and docosahexaenoic acid associated curvilinearly with the improved insulin secretion and glucose disposal. Among the 364 characterized lipids, 25 changed significantly in the HealthyDiet group, including multiple triglycerides incorporating the long chain (n-3) PUFA. Conclusions/Significance The results suggest that the diet rich in whole grain and low insulin response grain products, bilberries, and fatty fish improve glucose metabolism and alter the lipidomic profile. Therefore, such a diet may have a beneficial effect in the efforts to prevent type 2 diabetes in high risk persons. Trial Registration ClinicalTrials.gov NCT00573781