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Ghrelin in Diabetes and Metabolic Syndrome
Leena Pulkkinen,Olavi Ukkola,Marjukka Kolehmainen,Matti Uusitupa
International Journal of Peptides , 2010, DOI: 10.1155/2010/248948
Abstract: Metabolic syndrome is a cluster of related risk factors for cardiovascular disease, type 2 diabetes and liver disease. Obesity, which has become a global public health problem, is one of the major risk factors for development of metabolic syndrome and type 2 diabetes. Obesity is a complex disease, caused by the interplay between environmental and genetic factors. Ghrelin is one of the circulating peptides, which stimulates appetite and regulates energy balance, and thus is one of the candidate genes for obesity and T2DM. During the last years both basic research and genetic association studies have revealed association between the ghrelin gene and obesity, metabolic syndrome or type 2 diabetes 1. Introduction A great deal of evidence suggests that ghrelin is involved in the development of metabolic syndrome and type 2 diabetes (T2DM). Ghrelin plays also an important role in cardiovascular system. We have examined ghrelin and its genetic variation with respect to the occurrence of the components of metabolic syndrome and the risk of T2DM. In this paper we give an overview of what is known about the role of ghrelin in obesity, insulin resistance, T2DM, and cardiovascular disease, and how ghrelin is involved in the regulation of glucose, insulin, adipose tissue, and cardiovascular metabolism. We also discuss the putative role of genetic variation in the ghrelin and ghrelin receptor genes in metabolic syndrome and T2DM. 2. Ghrelin Concentrations in Obesity, Insulin Resistance, and Type 2 Diabetes Mellitus The recent literature suggests that in addition to food intake and energy balance, ghrelin also controls glucose metabolism [1]. Furthermore, current evidence suggests that ghrelin could contribute to the metabolic syndrome [1]. It has been shown that ghrelin concentrations are reduced in different pathophysiological conditions including obesity, type 2 diabetes, and other conditions with metabolic disturbances [2, 3]. Ghrelin is a target for posttranslational modifications, which results in two different forms of circulating ghrelin: unacylated ghrelin (UAG) and acylated ghrelin (AG), in which Ser 3 is octanoylated [4]. A relative excess of AG compared to UAG has been reported in insulin resistance and related conditions [3] raising the possibility that UAG/AG ratio could play a role in development of metabolic syndrome. Plasma ghrelin concentration has been shown to be lower in obese Caucasians when compared with lean Caucasians [2, 3, 5, 6], and in some studies higher AG concentrations have been reported in obese but otherwise healthy subjects compared
Psychobehavioural Factors Are More Strongly Associated with Successful Weight Management Than Predetermined Satiety Effect or Other Characteristics of Diet
Leila Karhunen,Marika Lyly,Anja Lapvetel inen,Marjukka Kolehmainen,David E. Laaksonen,Liisa L hteenm ki,Kaisa Poutanen
Journal of Obesity , 2012, DOI: 10.1155/2012/274068
Abstract: This study aimed to investigate factors associated with weight management, especially whether satiety value of food as a part of a weight-maintenance diet would affect self-regulation of food intake and weight management. Altogether 82 obese subjects completed the study consisting of weight-loss and weight-maintenance (WM) periods. During the WM, subjects were randomized into higher- and lower-satiety food groups. No differences were observed in the changes in body weight, energy intake, or eating behaviour between the groups, even despite the different macronutrient compositions of the diets. However, when regarding all study subjects, success in WM was most strongly associated with a greater increase in the flexible control of eating and experience of greater easiness of WM and control of food intake and a greater decrease in uncontrollable eating and psychological distress. Psychobehavioural factors seem to be more strongly associated with successful weight management than the predetermined satiety effect or other characteristics of the diet.
Impact of Dietary Polyphenols on Carbohydrate Metabolism
Kati Hanhineva,Riitta T?rr?nen,Isabel Bondia-Pons,Jenna Pekkinen,Marjukka Kolehmainen,Hannu Mykk?nen,Kaisa Poutanen
International Journal of Molecular Sciences , 2010, DOI: 10.3390/ijms11041365
Abstract: 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 b-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.
Psychobehavioural Factors Are More Strongly Associated with Successful Weight Management Than Predetermined Satiety Effect or Other Characteristics of Diet
Leila Karhunen,Marika Lyly,Anja Lapvetel?inen,Marjukka Kolehmainen,David E. Laaksonen,Liisa L?hteenm?ki,Kaisa Poutanen
Journal of Obesity , 2012, DOI: 10.1155/2012/274068
Abstract: This study aimed to investigate factors associated with weight management, especially whether satiety value of food as a part of a weight-maintenance diet would affect self-regulation of food intake and weight management. Altogether 82 obese subjects completed the study consisting of weight-loss and weight-maintenance (WM) periods. During the WM, subjects were randomized into higher- and lower-satiety food groups. No differences were observed in the changes in body weight, energy intake, or eating behaviour between the groups, even despite the different macronutrient compositions of the diets. However, when regarding all study subjects, success in WM was most strongly associated with a greater increase in the flexible control of eating and experience of greater easiness of WM and control of food intake and a greater decrease in uncontrollable eating and psychological distress. Psychobehavioural factors seem to be more strongly associated with successful weight management than the predetermined satiety effect or other characteristics of the diet. 1. Introduction Success in weight management is challenging. Even after successful weight loss, weight regain is very common [1, 2]. Therefore it is important to identify factors that are associated with and could enhance the self-regulation of food intake and other behaviours related to weight management. Because obesity is always a result of an imbalance between the energy intake and energy expenditure, decreased energy intake is generally required for successful weight loss. Regulation of energy balance is very complex, however, with multiple mechanisms maintaining homeostasis and resisting changes in the energy balance [3]. Therefore, during negative energy balance, that is, when energy intake is lower than energy requirements, orexigenic pathways in the organism are activated [4], a usual consequence of which is a regain of reduced body weight. Successful long-term management of weight thus requires safe and effective means to counteract these compensatory regulatory mechanisms to reduce appetite and enhance satiety. Various foods, even regardless of their energy content, may differ in their capacity to regulate satiety [5]. This can be accounted for multiple characteristics of food, such as energy density, macro- and micronutrient composition, palatability, food form, and structure [6–10]. Among different food characteristics, especially dietary fibre and protein have recently raised much interest as potential factors capable of increasing the satiating value of food [11, 12]. Indeed, higher protein intake
Whole Grain Products, Fish and Bilberries Alter Glucose and Lipid Metabolism in a Randomized, Controlled Trial: The Sysdimet Study
Maria Lankinen, Ursula Schwab, Marjukka Kolehmainen, Jussi Paananen, Kaisa Poutanen, Hannu Mykk?nen, Tuulikki Sepp?nen-Laakso, Helena Gylling, Matti Uusitupa, Matej Ore?i?
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0022646
Abstract: 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
Association of ADIPOR2 gene variants with cardiovascular disease and type 2 diabetes risk in individuals with impaired glucose tolerance: the Finnish Diabetes Prevention Study
Niina Siitonen, Leena Pulkkinen, Jaana Lindstr?m, Marjukka Kolehmainen, Ursula Schwab, Johan G Eriksson, Pirjo Ilanne-Parikka, Sirkka Kein?nen-Kiukaanniemi, Jaakko Tuomilehto, Matti Uusitupa
Cardiovascular Diabetology , 2011, DOI: 10.1186/1475-2840-10-83
Abstract: CVD morbidity and mortality data were collected during a median follow-up of 10.2 years (range 1-13 years) and conversion from IGT to T2DM was assessed during a median follow-up of 7 years (range 1-11 years). Altogether eight SNPs in the ADIPOR2 locus were genotyped in 484 participants of the DPS. Moreover, the same SNPs were genotyped and the mRNA expression levels of ADIPOR2 were determined in peripheral blood mononuclear cells and subcutaneous adipose tissue samples derived from 56 individuals participating in the Genobin study.In the DPS population, four SNPs (rs10848554, rs11061937, rs1058322, rs16928751) were associated with CVD risk, and two remained significant (p = 0.014 for rs11061937 and p = 0.020 for rs1058322) when all four were included in the same multi-SNP model. Furthermore, the individuals homozygous for the rare minor alleles of rs11061946 and rs11061973 had increased risk of converting from IGT to T2DM. Allele-specific differences in the mRNA expression levels for the rs1058322 variant were seen in peripheral blood mononuclear cells derived from participants of the Genobin study.Our results suggest that SNPs in the ADIPOR2 may modify the risk of CVD in individuals with IGT, possibly through alterations in the mRNA expression levels. In addition an independent genetic signal in ADIPOR2 locus may have an impact on the risk of developing T2DM in individuals with IGT.ClinicalTrials.gov NCT00518167Adipose tissue (AT) secretes a number of bioactive molecules, called adipokines, which participate in regulation of various metabolic processes [1]. Excess adiposity, particularly central type of adiposity, is associated with chronic low grade inflammation and dysregulated production of adipokines with adverse metabolic consequences, such as insulin resistance, hypertension, dyslipidemia, and increased risk of cardiovascular disease (CVD) [1].Adiponectin is an adipokine with insulin-sensitising, anti-inflammatory and anti-atherogenic properties [2-7]. Circul
Association of ADIPOQ gene variants with body weight, type 2 diabetes and serum adiponectin concentrations: the Finnish Diabetes Prevention Study
Niina Siitonen, Leena Pulkkinen, Jaana Lindstr?m, Marjukka Kolehmainen, Johan G Eriksson, Mika Venoj?rvi, Pirjo Ilanne-Parikka, Sirkka Kein?nen-Kiukaanniemi, Jaakko Tuomilehto, Matti Uusitupa
BMC Medical Genetics , 2011, DOI: 10.1186/1471-2350-12-5
Abstract: Participants 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.rs266729, 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.These 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.ClinicalTrials.gov NCT00518167Type 2 diabetes (T2DM) and obesity are increasing worldwide. Although this is mainly due to environmental factors, such as changes in diet and lifestyle, much evidence for genetic predisposition to these complex traits exist [1].Adiponectin is an adipokine, and its plasma levels are decreased in obesity [2], T2DM [3], ins
Postprandial differences in the plasma metabolome of healthy Finnish subjects after intake of a sourdough fermented endosperm rye bread versus white wheat bread
Isabel Bondia-Pons, Emilia Nordlund, Ismo Mattila, Kati Katina, Anna-Marja Aura, Marjukka Kolehmainen, Matej Ore?i?, Hannu Mykk?nen, Kaisa Poutanen
Nutrition Journal , 2011, DOI: 10.1186/1475-2891-10-116
Abstract: A sourdough fermented endosperm rye bread (RB) and a standard white wheat bread (WB) as a reference were served in random order to 16 healthy subjects. Test bread portions contained 50 g available carbohydrate. In vitro hydrolysis of starch and protein were performed for both test breads. Blood samples for measuring glucose and insulin concentrations were drawn over 4 h and gastric emptying rate (GER) was measured. Changes in the plasma metabolome were investigated by applying a comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry metabolomics platform (GC×GC-TOF-MS).Plasma insulin response to RB was lower than to WB at 30 min (P = 0.004), 45 min (P = 0.002) and 60 min (P < 0.001) after bread intake, and plasma glucose response was significantly higher at time point 90 min after RB than WB intake (P = 0.045). The starch hydrolysis rate was higher for RB than WB, contrary to the in vitro protein digestibility. There were no differences in GER between breads. From 255 metabolites identified by the metabolomics platform, 26 showed significant postprandial relative changes after 30 minutes of bread intake (p and q values < 0.05). Among them, there were changes in essential amino acids (phenylalanine, methionine, tyrosine and glutamic acid), metabolites involved in the tricarboxylic acid cycle (alpha-ketoglutaric, pyruvic acid and citric acid) and several organic acids. Interestingly, the levels of two compounds involved in the tryptophan metabolism (picolinic acid, ribitol) significantly changed depending on the different bread intake.A single meal of a low fibre sourdough rye bread producing low postprandial insulin response brings in several changes in plasma amino acids and their metabolites and some of these might have properties beneficial for health.Cereal foods are an important component of the daily diet throughout Western countries, and a major source of dietary carbohydrates. In a time of dramatically increasing prevalen
Meal Frequencies Modify the Effect of Common Genetic Variants on Body Mass Index in Adolescents of the Northern Finland Birth Cohort 1986
Anne J??skel?inen, Ursula Schwab, Marjukka Kolehmainen, Marika Kaakinen, Markku J. Savolainen, Philippe Froguel, Stéphane Cauchi, Marjo-Riitta J?rvelin, Jaana Laitinen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0073802
Abstract: Recent studies suggest that meal frequencies influence the risk of obesity in children and adolescents. It has also been shown that multiple genetic loci predispose to obesity already in youth. However, it is unknown whether meal frequencies could modulate the association between single nucleotide polymorphisms (SNPs) and the risk of obesity. We examined the effect of two meal patterns on weekdays –5 meals including breakfast (regular) and ≤4 meals with or without breakfast (meal skipping) – on the genetic susceptibility to increased body mass index (BMI) in Finnish adolescents. Eight variants representing 8 early-life obesity-susceptibility loci, including FTO and MC4R, were genotyped in 2215 boys and 2449 girls aged 16 years from the population-based Northern Finland Birth Cohort 1986. A genetic risk score (GRS) was calculated for each individual by summing the number of BMI-increasing alleles across the 8 loci. Weight and height were measured and dietary data were collected using self-administered questionnaires. Among meal skippers, the difference in BMI between high-GRS and low-GRS (<8 and ≥8 BMI-increasing alleles) groups was 0.90 (95% CI 0.63,1.17) kg/m2, whereas in regular eaters, this difference was 0.32 (95% CI 0.06,0.57) kg/m2 (pinteraction = 0.003). The effect of each MC4R rs17782313 risk allele on BMI in meal skippers (0.47 [95% CI 0.22,0.73] kg/m2) was nearly three-fold compared with regular eaters (0.18 [95% CI -0.06,0.41] kg/m2) (pinteraction = 0.016). Further, the per-allele effect of the FTO rs1421085 was 0.24 (95% CI 0.05,0.42) kg/m2 in regular eaters and 0.46 (95% CI 0.27,0.66) kg/m2 in meal skippers but the interaction between FTO genotype and meal frequencies on BMI was significant only in boys (pinteraction = 0.015). In summary, the regular five-meal pattern attenuated the increasing effect of common SNPs on BMI in adolescents. Considering the epidemic of obesity in youth, the promotion of regular eating may have substantial public health implications.
Triacylglycerol Fatty Acid Composition in Diet-Induced Weight Loss in Subjects with Abnormal Glucose Metabolism – the GENOBIN Study
Ursula Schwab, Tuulikki Sepp?nen-Laakso, Laxman Yetukuri, Jyrki ?gren, Marjukka Kolehmainen, David E. Laaksonen, Anna-Liisa Ruskeep??, Helena Gylling, Matti Uusitupa, Matej Ore?i?, for the GENOBIN Study Group
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002630
Abstract: 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
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