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Phloroglucinol (PHG), an analgesic and spasmolytic drug, shows promise in preventing high-fat-diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and insulin resistance. In Wistar rats, 10 weeks of PHG treatment did not prevent HFD-induced weight gain but significantly mitigated fasting hyperglycemia, impaired insulin responses, and liver steatosis. This protective effect was not linked to hepatic lipogenesis or AMP-activated protein kinase (AMPK) activation. Instead, PHG improved mitochondrial function by reducing oxidative stress, enhancing ATP production, and increasing anti-oxidant enzyme activity. PHG also relaxed gastric smooth muscles via potassium channel activation and nitric oxide (NO) signaling, potentially delaying gastric emptying. A pilot intervention in pre-diabetic men confirmed PHG's efficacy in improving postprandial glycemic control and altering lipid metabolism. These findings suggest PHG as a potential therapeutic for NAFLD and insulin resistance, acting through mechanisms involving mitochondrial protection, anti-oxidant activity, and gastric motility modulation. Further clinical evaluation is warranted to explore PHG's full therapeutic potential.

Context: The brain-derived neurotrophic factor (BDNF) concentrations may differ between BDNF gene genotype carriers. These changes occur in individuals with metabolic and mental disorders., Objective: The aim of this study was to assess the associations of glucose homeostasis parameters and the frequency of food consumption with BDNF protein concentrations based on the BDNF single-nucleotide polymorphisms (SNPs)., Methods: Among the 439 participants, some common rs10835211 BDNF gene variants were analyzed. We evaluated BDNF concentration, fasting glucose and insulin concentrations and during oral glucose tolerance tests. Anthropometric measurements, body composition, and body fat distribution were assessed, and 3-day food intake diary and food frequency questionnaire were completed., Results: We noticed significant differences in concentration of BDNF between AA and AG genotype rs10835211 carriers (p=0.018). The group of AA genotype holders were older, and positive correlation was found between age and BDNF in the whole study population (p=0.012) and in the GG genotype carriers (p=0.023). Moreover, BDNF protein correlated with fasting insulin (p=0.015), HOMA-IR (p=0.031), HOMA-B (p=0.010) , and the VAT/SAT ratio (p=0.026) in the GG genotype individuals. Presence of the GG genotype was negatively correlated with nut and seed (p=0.047), lean pork consumption (p=0.015) and the BDNF protein. Moreover, we observed correlations between the frequency of chicken (p=0.028), pasta (p=0.033) and sweet food intake (p=0.040) and BDNF concentration in the general population. Among carriers of the AA genotype, we observed a positive correlation between the consumption of rice (p=0.048) and sweet food (p=0.028) and the BDNF protein level., Conclusion: Peripheral BDNF may be associated with visceral fat content and insulin concentrations in the GG genotype carriers and may depend on variable food intake, which warrants further investigation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Multiple sclerosis is a disabling inflammatory disorder of the central nervous system characterized by demyelination and neurodegeneration. Given that multiple sclerosis remains an incurable disease, the management of MS predominantly focuses on reducing relapses and decelerating the progression of both physical and cognitive decline. The continuous autoimmune process modulated by cytokines seems to be a vital contributing factor to the development and relapse of multiple sclerosis. This review sought to summarize the role of selected interleukins in the pathogenesis and advancement of MS. Patients with MS in the active disease phase seem to exhibit an increased serum level of IL-2, IL-4, IL-6, IL-13, IL-17, IL-21, IL-22 and IL-33 compared to healthy controls and patients in remission, while IL-10 appears to have a beneficial impact in preventing the progression of the disease. Despite being usually associated with proinflammatory activity, several studies have additionally recognized a neuroprotective role of IL-13, IL-22 and IL-33. Moreover, selected gene polymorphisms of IL-2R, IL-4, IL-6, IL-13 and IL-22 were identified as a possible risk factor related to MS development. Treatment strategies of multiple sclerosis that either target or utilize these cytokines seem rather promising, but more comprehensive research is necessary to gain a clearer understanding of how these cytokines precisely affect MS development and progression.

Some of the multiple autoimmune diseases have been already associated with IL-13 single-nucleotide polymorphisms (SNPs). However, there are only few studies regarding multiple sclerosis (MS) risk and IL-13 rs20541 (R130Q) polymorphism, and their results are conflicting. Therefore, the aim of our study was to investigate the frequency of the IL-13 gene rs20541 (R130Q) polymorphism in MS participants and its association with MS clinical subsets in the Polish population. We conducted a case‒control study including 94 relapsing remitting MS patients and 160 healthy volunteers. We genotyped the rs20541 polymorphism in the IL-13 gene and analysed the genotype frequency, age of MS onset and clinical condition (EDSS values) of the MS participants. Fisher's exact test was used for statistical analysis, and the log-linear model was applied to test for associations. Allele A, as well as the AA and AG genotypes, was observed to be significantly more common in the MS subjects. The OR (odds ratio) for the A compared to the G allele was 1.71 (1.14-2.56), whereas OR 2.33 (0.86-6.26) and OR 1.92 (1.11-3.30) were obtained for the AA and AG genotypes, respectively. We did not identify any significant associations of the studied IL-13 SNP with the investigated clinical parameters of the MS participants. Our results suggest that the rs20541 polymorphism in the IL-13 gene may play an important role in MS predisposition but not in investigated clinical parameters in MS subjects of the Polish population., (© 2023. The Author(s).)

Some common single-nucleotide polymorphisms of the brain-derived neurotrophic factor (BDNF) gene have been associated not only with the neurodegenerative diseases but also with some eating disorders. The aim of this study was to assess the possible differences in the obesity-related and glucose metabolism parameters between some BDNF genotypes', that may depend on the daily energy and macronutrients intake. In 484 adult participants we performed the anthropometric measurements, body composition analysis, and body fat distribution. The daily dietary intake was assessed using the 3-day food intake diaries. Blood glucose and insulin concentrations were measured at fasting and during oral glucose tolerance tests. Moreover, the visceral adipose tissue/subcutaneous adipose tissue (VAT/SAT) ratio and homeostatic model assessment of insulin resistance were calculated. We noted that participants carrying the GG genotype had lower skeletal muscle mass and fat free mass (FFM) when carbohydrate intake was > 48%, whereas they presented higher fat-free mass (FFM), and surprisingly higher total cholesterol and LDL-C concentrations when daily fiber intake was > 18 g. Moreover, in these subjects we noted higher waist circumference, BMI, and fasting glucose and insulin concentrations, when > 18% of total daily energy intake was delivered from proteins, and higher VAT content and HDL-C concentrations when > 30% of energy intake was derived from dietary fat. Our results suggest that glucose homeostasis and obesity-related parameters in carriers of some common variants of BDNF gene, especially in the GG (rs10835211) genotype carriers, may differ dependently on daily energy, dietary macronutrients and fiber intake., (© 2023. The Author(s).)

The relationship of high-carbohydrate (HC) meal intake to metabolic syndrome is still not fully explained. Metabolomics has the potential to indicate metabolic pathways altered by HC meals, which may improve our knowledge regarding the mechanisms by which HC meals may contribute to metabolic syndrome development. The fasting and postprandial metabolic response to HC or normo-carbohydrate (NC) meals with/without cinnamon + capsicum intake was evaluated using untargeted metabolomics and compared between normal-weight (NW) and overweight/obese (OW/OB) healthy men. Healthy male participants (age-matched) were divided into two groups (12 subjects per group). One was composed of men with normal weight (NW) and the other of men with overweight/obesity (OW/OB). On separate visits (with 2-3 week intervals), the participants received standardized HC or NC meals (89% or 45% carbohydrates, respectively). Fasting (0 min) and postprandial (30, 60, 120, 180 min) blood were collected for untargeted plasma metabolomics. Based on each metabolic feature's intensity change in time, the area under the curve (AUC) was calculated. Obtained AUCs were analyzed using multivariate statistics. Several metabolic pathways were found dysregulated after an HC meal in people from the OW/OB group but not the NW group. The consumption of HC meals by people with overweight/obesity led to a substantial increase in AUC, mainly for metabolites belonging to phospholipids and fatty acid amides. The opposite was observed for selected sphingolipids. The intake of cinnamon and capsicum normalized the concentration of selected altered metabolites induced by the intake of HC meals. A HC meal may induce an unfavourable postprandial metabolic response in individuals with overweight/obesity, and such persons should avoid HC meals.

Background: The unique ability of brown adipocytes to increase metabolic rate suggests that they could be targeted as an obesity treatment., Objective: The objective of the study was to search for new dietary factors that may enhance brown adipose tissue (BAT) activity., Methods: The study group comprised 28 healthy non-smoking males, aged 21-42 years old. All volunteers underwent a physical examination and a 75 g oral glucose tolerance test (75g-OGTT). Serum atrial and brain natriuretic peptide (ANP, BNP), PRD1-BF1-RIZ1 homologous domain containing 16 (PRDM16) and eukaryotic translation initiation factor 4E (eIF4E) measurements were taken, and 3-day food intake diaries were completed. Body composition measurements were assessed using dual-energy X-ray absorptiometry (DXA) scanning and bioimpedance methods. An fluorodeoxyglucose-18 (FDG-18) uptake in BAT was assessed by positron emission tomography/magnetic resonance (PET/MR) in all participants after 2 h cold exposure. The results were adjusted for age, daily energy intake, and DXA lean mass., Results: Subjects with detectable BAT (BAT (+) ) were characterized by a higher percentage of energy obtained from dietary protein and fat and higher muscle mass ( p = 0.01, p = 0.02 and p = 0.04, respectively). In the BAT (+) group, animal protein intake was positively associated ( p = 0.04), whereas the plant protein intake negatively correlated with BAT activity ( p = 0.03). Additionally, the presence of BAT was inversely associated with BNP concentration in the 2 h of cold exposure ( p = 0.002)., Conclusion: The outcomes of our study suggest that different macronutrient consumption may be a new way to modulate BAT activity leading to weight reduction.

Excessive adipose tissue in the body may lead to adverse health effects, carbohydrate and lipid metabolism disorders, and cardiovascular diseases. The aim of this study was to analyze the effect of a standardized high-fat meal (HF) on changes in energy expenditure and changes in the oxidation of energy substrates as well as the concentration of glucose, insulin, triglycerides and homocysteine in blood serum in relation to a standardized high-carbohydrate (non-fat, HC) meal in men with different nutritional status. In this study, 26 men (aged 19-60) without carbohydrate disorders (study group G S = 13 overweight/obese; control group G C = 13 normal body weight) were examined. It was observed that following a high-fat or high-carbohydrate meal, men with excessive body weight metabolized the main nutrients differently than men with normal body weight, and postprandial insulin secretion was also different (even without any significant differences in glucose concentrations). Overweight/obesity, which is in itself a risk factor for cardiovascular disease, contributes to an increase in the concentration of other risk factors, such as the concentration of homocysteine and triglycerides, which is referred to as cardiometabolic risk. Consumption of a high-fat meal increased the number of potential risk factors for cardiovascular disease (homocysteine and triglycerides) compared to a high-carbohydrate meal.

An investigation of new ways to activate brown adipose tissue (BAT) is highly valuable, as it is a possible tool for obesity prevention and treatment. The aim of our study was to evaluate the relationships between dietary intake and BAT activity. The study group comprised 28 healthy non-smoking males aged 21-42 years. All volunteers underwent a physical examination and 75-g OGTT and completed 3-day food intake diaries to evaluate macronutrients and fatty acid intake. Body composition measurements were assessed using DXA scanning. An FDG-18 PET/MR was performed to visualize BAT activity. Brown adipose tissue was detected in 18 subjects (67% normal-weight individuals and 33% overweight/obese). The presence of BAT corresponded with a lower visceral adipose tissue (VAT) content (p = 0.04, after adjustment for age, daily kcal intake, and DXA Lean mass). We noted significantly lower omega-6 fatty acids (p = 0.03) and MUFA (p = 0.02) intake in subjects with detected BAT activity after adjustment for age, daily average kcal intake, and DXA Lean mass, whereas omega-3 fatty acids intake was comparable between the two groups. BAT presence was positively associated with the concentration of serum IL-6 (p = 0.01) during cold exposure. Our results show that BAT activity may be related to daily omega-6 fatty acids intake., (© 2022. The Author(s).)

Genetic and environmental factors play a key role in the development of obesity. The aim of this study was to explore the potential effect of fat mass and obesity-associated ( FTO ) rs3751812, rs8050136, rs9939609, rs6499640, rs8044769, and rs7190492 genotypes and dietary fiber intake on the obesity-related parameters and lipid profile in the Polish population. We selected 819 Polish Caucasian adult subjects (52.5% female and 47.5% male) for a final gene-diet interaction analysis, with mean BMI 28.5 (±6.6) kg/m 2 . We performed measurements of anthropometric parameters, total body fat content and distribution, and blood glucose, insulin, and lipid concentrations. Daily fiber intake was analyzed based on 3-day food-intake diaries, and daily physical activity was evaluated based on the International Physical Activity Questionnaire-Long Form. Our study shows that carriers of the GG genotype (rs3751812), CC genotype (rs8050136), and GG genotype (rs6499640) presented lower hip circumference if daily fiber intake was above 18 g per day. Additionally, GG genotype (rs3751812) and CC genotype (rs8050136) carriers showed surprisingly higher total cholesterol and LDL-cholesterol levels when they were stratified to the group with higher than median fiber intake. The results of this study highlight that high-fiber diets may positively affect anthropometric parameters but may also worsen lipid profile dependent on the FTO genotype.

The melanocortin-4 receptor (MC4R) gene harbours one of the strongest susceptibility loci for obesity and obesity-related metabolic consequences. We analysed whether dietary factors may attenuate the associations between MC4R genotypes and obesity and metabolic parameters. In 819 participants genotyped for common MC4R polymorphisms (rs17782313, rs12970134, rs633265, and rs135034), the anthropometric measurements, body fat content and distribution (visceral and subcutaneous adipose tissue, VAT and SAT, respectively), and blood glucose, insulin, total-, LDL-, HDL-cholesterol, triglycerides concentrations, and daily macronutrient intake were assessed. ANOVA or Kruskal-Wallis tests were used, and multivariate linear regression models were developed. We observed that the CC genotype carriers (rs17782313) presented higher VAT, VAT/SAT ratio, fasting blood glucose and triglyceride concentrations when they were stratified to the upper quantiles of protein intake. An increase in energy derived from proteins was associated with higher BMI (Est. 5.74, R 2 = 0.12), body fat content (Est. 8.44, R 2 = 0.82), VAT (Est. 32.59, R 2 = 0.06), and VAT/SAT ratio (Est. 0.96, R 2 = 0.05). The AA genotype carriers (rs12970134) presented higher BMI, body fat, SAT and VAT, fasting blood glucose, triglycerides and total cholesterol concentrations. An increase in energy derived from proteins by AA carriers was associated with higher VAT (Est.19.95, R 2 = 0.06) and VAT/SAT ratio (Est. 0.64, R 2 = 0.05). Our findings suggest that associations of the common MC4R SNPs with obesity and its metabolic complications may be dependent on the daily dietary intake, which may open new areas for developing personalised diets for preventing and treating obesity and obesity-related comorbidities.

Risk factors for type 2 diabetes mellitus (T2DM) consist of a combination of an unhealthy, imbalanced diet and genetic factors that may interact with each other. Single nucleotide polymorphism (SNP) in the prospero homeobox 1 ( PROX1 ) gene is a strong genetic susceptibility factor for this metabolic disorder and impaired β-cell function. As the role of this gene in T2DM development remains unclear, novel approaches are needed to advance the understanding of the mechanisms of T2DM development. Therefore, in this study, for the first time, postprandial changes in plasma metabolites were analysed by GC-MS in nondiabetic men with different PROX1 genotypes up to 5 years prior to prediabetes appearance. Eighteen contestants (12 with high risk (HR) and 6 with low risk (LR) genotype) participated in high-carbohydrate (HC) and normo-carbohydrate (NC) meal-challenge tests. Our study concluded that both meal-challenge tests provoked changes in 15 plasma metabolites (amino acids, carbohydrates, fatty acids and others) in HR, but not LR genotype carriers. Postprandial changes in the levels of some of the detected metabolites may be a source of potential specific early disturbances possibly associated with the future development of T2DM. Thus, accurate determination of these metabolites can be important for the early diagnosis of this metabolic disease.

Transcription factor-7-like 2 (TCF7L2) is one of the most important susceptibility genes for type 2 diabetes mellitus (T2DM). The aim of our cross-sectional population-based study was to analyze whether daily macronutrient intake may influence the effects of the TCF7L2 rs7901695 genotype on glucose homeostasis and obesity-related parameters. We recruited 810 participants (47.5% men and 52.5% women), 18-79 years old (mean age, 42.1 (±14.5) years), who were genotyped for the common TCF7L2 rs7901695 single-nucleotide polymorphism (SNP), and anthropometric measurements, body composition, body fat distribution (visceral (VAT) and subcutaneous adipose tissue (SAT) content), blood glucose and insulin concentrations after fasting and during OGTTs, and HbA1c were assessed. The VAT/SAT ratio, HOMA-IR (homeostatic model assessment of insulin resistance), HOMA-B (homeostatic model assessment of β-cell function), and CIR30 (corrected insulin response) were calculated. The daily macronutrient intake was evaluated based on 3-day food-intake diaries. Daily physical activity was evaluated based on a validated questionnaire. We performed ANOVA or Kruskal-Wallis tests, and multivariate linear regression models were created to evaluate the effects of dietary macronutrient intake on glucose homeostasis and obesity-related parameters in carriers of the investigated genotypes. This study was registered at ClinicalTrials.gov as NCT03792685. The TT-genotype carriers stratified to the upper protein intake quantiles presented higher HbA1c levels than the CT- and CC-genotype participants in the same quantiles ( p = 0.038 and p = 0.022, respectively). Moreover, we observed higher HOMA-IR ( p = 0.014), as well as significantly higher blood glucose and insulin concentrations, during the OGTTs for those in the upper quantiles, when compared to subjects from the lower quantiles of protein intake, while the CC-genotype carriers presented significantly lower HbA1c ( p = 0.033) and significantly higher CIR30 ( p = 0.03). The linear regression models revealed that an increase in energy derived from proteins in TT carriers was associated with higher HbA1c levels (β = 0.37 (95% CI: 0.01-0.74, p = 0.05)), although, in general, carrying the TT genotype, but without considering protein intake, showed an opposite tendency-to lower HbA1c levels (β = -0.22 (95% CI: 0.47 to -0.01, p = 0.05). Among the subjects stratified to the lower quantile of carbohydrate intake, the TT-genotype individuals presented higher HbA1c ( p = 0.041), and the CC-genotype subjects presented higher VAT ( p = 0.033), lower SAT ( p = 0.033), and higher VAT/SAT ratios ( p = 0.034). In both the CC- and TT-genotype carriers, we noted higher VAT ( p = 0.012 and p = 0.0006, respectively), lower SAT ( p = 0.012 and p = 0.0006, respectively) and higher VAT/SAT ratios ( p = 0.016 and p = 0.00062, respectively) when dietary fat provided more than 30% of total daily energy intake, without any differences in total body fat content. Our findings suggest that associations of the common TCF7L2 SNP with glucose homeostasis and obesity-related parameters may be dependent on daily macronutrient intake, which warrants further investigations in a larger population, as well as interventional studies.

Fc receptors have been shown to play a role in several autoimmune diseases. We aimed to test, for the first time, whether some of the single nucleotide variants in the FCRL5 gene were associated with multiple sclerosis (MS) susceptibility and clinical manifestations in the Polish population. The case-control study included 94 individuals with MS and 160 healthy subjects. We genotyped two single nucleotide variants of the FCRL5 gene: rs2012199 and rs6679793. The age of onset, disease duration, and clinical condition of the MS subjects were analyzed. For statistical analysis, we used the chi-squared test confirmed with Fisher's exact test. We observed the significant differences in the distribution of investigated FCRL5 genotypes between MS subjects and healthy controls. The CC and CT genotypes, as well as the C allele of rs2012199, were significantly more common in the MS subjects, as were genotypes AA and AG, and allele A of rs6679793. We noted that decreased MS susceptibility was associated with the T allele rs2012199 (OR = 0.37, p = 0.0002) and G allele rs6679793 (OR = 0.6, p = 0.02). Our results support the role of the FCRL5 locus in MS predisposition and extend the evidence of its influence on autoimmunity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chorazy, Wawrusiewicz-Kurylonek, Adamska-Patruno, Czarnowska, Zajkowska, Kapica-Topczewska, Posmyk, Kretowski, Kochanowicz and Kułakowska.)

Purpose: Multiple sclerosis (MS) is an autoimmune disease, and genetic factors play an important role in its pathogenesis and progression. The aim of our study was to evaluate the frequencies of alleles and genetic variants of the T-cell homeostasis-related genes, in subjects with MS, as well as to investigate the association with MS clinical manifestations and disability., Methods: 94 subjects with MS and 160 healthy individuals have been genotyped for seven common single-nucleotide variants in IL-2RA, CTLA4, CD40, and PADI4 genes. The ages of onset, duration of the disease, and clinical condition of the MS subjects were analysed. We used the Chi 2 test confirmed with Fisher's exact test for statistical analysis., Results: The frequency of allele T and CT/TT genotypes (rs7093069) in the IL2RA gene, as well as the T allele and CT/TT genotypes in rs12722598, were significantly higher in the control group. The significant differences between studied groups we also found for the G allele and GG/GA genotypes of rs3087243 in CTLA4 gene, which were more common among the control group. The heterozygous genotype TC (rs1883832) of CD40 gene was more common in the control subjects, and the frequency of the alleles and genotypes in the rs1748033 of the PADI4 gene did not differ between the studied groups. Between the studied genotypes, we did not observe any significant differences in the age of onset and duration of disease, including sex stratification., Conclusion: Our results highlight the protective role of some of the T-cell homeostasis-related genetic variants in MS development, but not in its clinical manifestation., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020 Monika Chorąży et al.)

Numerous studies have identified the various fat mass and obesity-associated ( FTO ) genetic variants associated with obesity and its metabolic consequences; however, the impact of dietary factors on these associations remains unclear. The aim of this study was to evaluate the association between FTO single nucleotide polymorphisms (SNPs), daily macronutrient intake, and obesity and its metabolic consequences. From 1549 Caucasian subjects of Polish origin, genotyped for the FTO SNPs (rs3751812, rs8044769, rs8050136, and rs9939609), 819 subjects were selected for gene-diet interaction analysis. Anthropometric measurements were performed and total body fat content and distribution, blood glucose and insulin concentration during oral glucose tolerance test (OGTT), and lipid profile were determined. Macronutrient intake was analyzed based on three-day food records, and daily physical activity levels were evaluated using the International Physical Activity Questionnaire Long Form (IPAQ-LF). Our study shows that carriers of the GG genotype of rs3751812 presented lower body weight, body mass index (BMI), total body fat content, and hip and waist circumference and presented lower obesity-related markers if more than 48% of daily energy intake was derived from carbohydrates and lower subcutaneous and visceral fat content when energy intake derived from dietary fat did not exceed 30%. Similar results were observed for rs8050136 CC genotype carriers. We did not notice any significant differences in obesity markers between genotypes of rs8044769, but we did observe a significant impact of diet-gene associations. Body weight and BMI were significantly higher in TT and CT genotype carriers if daily energy intake derived from carbohydrates was less than 48%. Moreover, in TT genotype carriers, we observed higher blood glucose concentration while fasting and during the OGTT test if more than 18% of total energy intake was derived from proteins. In conclusion, our results indicate that daily macronutrient intake may modulate the impact of FTO genetic SNPs on obesity and obesity-related metabolic consequences.

Women with polycystic ovary syndrome (PCOS) are at an increased risk of developing insulin resistance and abdominal obesity in the state of an improper diet balance. Leptin is a peptide considered to be a satiety hormone that plays an important role in the long-term energy balance, whereas ghrelin is a hormone that controls short-term appetite regulation and is considered a hunger hormone. The aim of the present study was to assess the relationship between serum leptin and ghrelin concentrations and the dietary macronutrient content in PCOS women. We examined 73 subjects: 39 women diagnosed with PCOS by the Rotterdam criteria and 34 healthy controls, matched by the body mass index. The subjects completed a consecutive three-day dietary diary to identify the macronutrient and micronutrient intake. Serum concentrations of leptin and total ghrelin were measured and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. The studied groups did not differ significantly in terms of the intake of macronutrients (proteins, fats, and carbohydrates) and serum concentrations of ghrelin and leptin (all p > 0.05). In the PCOS group, the serum leptin concentration positively correlated with the intake of total fat (r = 0.36, p = 0.02), total cholesterol (r = -0.36, p = 0.02), saturated fatty acids (r = 0.43, p < 0.01), and monounsaturated fatty acids (MUFA) (r = 0.37, p = 0.02), whereas the serum ghrelin concentration correlated in an inverse manner with the intake of total fat (r = -0.37, p = 0.02), MUFA (r = -0.37, p = 0.02), polyunsaturated fatty acids (r = -0.34, p = 0.03), and long chain polyunsaturated fatty acids (r = -0.38, p = 0.02). In this group, we also found a negative association of HOMA-IR with serum ghrelin levels (r = -0.4, p = 0.03) and a positive relationship with the serum leptin concentration (r = 0.5, p < 0.01) and relationships between HOMA-IR and total dietary fat (r = 0.38, p = 0.03) and MUFA (r = 0.35, p = 0.04) intake. In PCOS women, dietary components such as the total fat and type of dietary fat and HOMA-IR are positively connected to serum leptin concentrations and negatively connected to serum ghrelin concentrations, which may influence the energy balance.

Berries are considered "promising functional fruits" due to their distinct and ubiquitous therapeutic contents of anthocyanins, proanthocyanidins, phenolic acids, flavonoids, flavanols, alkaloids, polysaccharides, hydroxycinnamic, ellagic acid derivatives, and organic acids. These polyphenols are part of berries and the human diet, and evidence suggests that their intake is associated with a reduced risk or the reversal of metabolic pathophysiologies related to diabetes, obesity, oxidative stress, inflammation, and hypertension. This work reviewed and summarized both clinical and non-clinical findings that the consumption of berries, berry extracts, purified compounds, juices, jams, jellies, and other berry byproducts aided in the prevention and or otherwise management of type 2 diabetes mellitus (T2DM) and related complications. The integration of berries and berries-derived byproducts into high-carbohydrate (HCD) and high-fat (HFD) diets, also reversed/reduced the HCD/HFD-induced alterations in glucose metabolism-related pathways, and markers of oxidative stress, inflammation, and lipid oxidation in healthy/obese/diabetic subjects. The berry polyphenols also modulate the intestinal microflora ecology by opposing the diabetic and obesity rendered symbolic reduction of Bacteroidetes/Firmicutes ratio, intestinal mucosal barrier dysfunction-restoring bacteria, short-chain fatty acids, and organic acid producing microflora. All studies proposed a number of potential mechanisms of action of respective berry bioactive compounds, although further mechanistic and molecular studies are warranted. The metabolic profiling of each berry is also included to provide up-to-date information regarding the potential anti-oxidative/antidiabetic constituents of each berry.

Due to a global increase in the prevalence of type 2 diabetes mellitus (T2DM), there is an urgent need for early identification of prediabetes, as these people have the highest risk of developing diabetes. Circulating miRNAs have shown potential as progression biomarkers in other diseases. This study aimed to conduct a baseline comparison of serum-circulating miRNAs in prediabetic individuals, with the distinction between those who later progressed to T2DM and those who did not. The expression levels of 798 miRNAs using NanoString technology were examined. Spearman correlation, receiver operating characteristic (ROC) curve analysis, and logistic regression modeling were performed. Gene ontology (GO) and canonical pathway analysis were used to explore the biological functions of the miRNA target genes. The study revealed that three miRNAs were upregulated in the serum samples of patients who later progressed to T2DM. Pathway analysis showed that the miRNA target genes were mainly significantly enriched in neuronal NO synthase (nNOS) signaling in neurons, amyloid processing, and hepatic cholestasis. ROC analysis demonstrated that miR-491-5p, miR-1307-3p, and miR-298 can be introduced as a diagnostic tool for the prediction of T2DM (area under the curve (AUC) = 94.0%, 88.0%, and 84.0%, respectively). Validation by real-time quantitative polymerase chain reaction (qRT-PCR) confirmed our findings. The results suggest that circulating miRNAs can potentially be used as predictive biomarkers of T2DM in prediabetic patients.

Multiple mechanisms have been suggested to confer to the pathophysiology of metabolic syndrome (MetS), however despite great interest from the scientific community, the exact contribution of each of MetS risk factors still remains unclear. The present study aimed to investigate molecular signatures in peripheral blood of individuals affected by MetS and different degrees of obesity. Metabolic health of 1204 individuals from 1000PLUS cohort was assessed, and 32 subjects were recruited to four study groups: MetS lean, MetS obese, "healthy obese", and healthy lean. Whole-blood transcriptome next generation sequencing with functional data analysis were carried out. MetS obese and MetS lean study participants showed the upregulation of genes involved in inflammation and coagulation processes: granulocyte adhesion and diapedesis ( p < 0.0001, p = 0.0063), prothrombin activation pathway ( p = 0.0032, p = 0.0091), coagulation system ( p = 0.0010, p = 0.0155). The results for "healthy obese" indicate enrichment in molecules associated with protein synthesis ( p < 0.0001), mitochondrial dysfunction ( p < 0.0001), and oxidative phosphorylation ( p < 0.0001). Our results suggest that MetS is related to the state of inflammation and vascular system changes independent of excess body weight. Furthermore, "healthy obese", despite not fulfilling the criteria for MetS diagnosis, seems to display an intermediate state with a lower degree of metabolic abnormalities, before they proceed to a full blown MetS.

The world's population is progressively becoming older, and age‑related conditions are a major public health concern. A worrying phenomenon worldwide is the increasing obesity among aging societies, which occurs in parallel with a higher prevalence of sarcopenia in older populations. As a result of the combination of these 2 states, new medical conditions, such as sarcopenic obesity, have recently become a public health concern. Data from the literature indicate a higher risk of metabolic syndrome, type 2 diabetes (T2D), and atherosclerosis among patients with sarcopenic obesity than the risk associated with simple obesity or sarcopenia alone. The mechanisms underlying sarcopenic obesity are multifactorial. There is an interplay between low‑grade inflammation, insulin resistance, hormonal changes, a sedentary lifestyle, eating habits, and aging. The aim of this review is to summarize the available data regarding the definition, epidemiology, and pathways that lead to sarcopenic obesity, as well as treatment strategies.

Purpose: The interactions between lifestyle and genetic factors play an important role in obesity development. Mutations in melanocortin-4-receptor (MC4R) gene are one of the most common cause of monogenic obesity, however, the functional effects of polymorphic variants near MC4R gene in general populations remain uncertain. The aim of our study was to analyze whether the common single nucleotide polymorphisms (SNPs) of MC4R gene influence the food preferences, physical activity, body fat content and distribution, as well as fasting and postprandial energy expenditure and substrates utilization., Methods: We genotyped previously identified MC4R SNPs: rs17782313, rs633265, rs1350341, rs12970134 in 927 subjects, who underwent anthropometric, total body fat content, visceral (VAT) and subcutaneous adipose tissue (SAT) measurements, and daily physical activity and dietary intake analysis. In randomly selected 47 subjects the energy expenditure, carbohydrate and lipid utilizations were evaluated in fasting state and after high-carbohydrate and control meals intake., Results: We found the significant associations between studied SNPs of MC4R gene and VAT and VAT/SAT ratio. Moreover, the GG genotype carriers of rs1350341, who had the lowest VAT accumulation (p = 0.012), presented higher relative increase in postprandial carbohydrate utilization (p = 0.013, p = 0.024)., Conclusions: We have observed that common SNPs of the MC4R gene influence the body fat content and distribution, as well as relative increase in postprandial carbohydrate utilization. We believe that our study may help to understand better the impact of MC4R gene on obesity development, and to help to provide personalized prevention/treatment strategies to fight against obesity and its metabolic consequences.

Introduction: Environmental and genetic factors play an important role in the development of type 2 diabetes (T2D). One of the most important lifestyle factors is a low level of physical activity (PA), but no studies have explicitly compared the amount of variation in diabetes prevalence explained by variation in PA compared with the amount explained by genetic variation., Objectives: We examined associations between PA and patients stratified by the levels of genetic susceptibility to T2D and the prevalence of the disease., Patients and Methods: We assessed the level of PA and family history (FH) of T2D in first‑degree relatives as well as calculated the genetic risk score (GRS). We examined associations of PA, GRS, and FH with the prevalence of T2D among 1195 individuals enrolled in the 1000 Polish Longitudinal University Study (1000‑PLUS) by stratifying the sample according to GRS, FH, and PA., Results: We found that FH, in contrast to GRS, was positively associated with a higher prevalence of T2D (23.4% in patients with positive FH [FH+], 11.6% in those with negative [FH-]; P <0.001), with the association being stronger in men than in women. The prevalence of T2D was slightly lower among physically active individuals in the FH- group (10.6% in high PA vs 14.7% in low PA) as well as in the FH+ group (19.2% in high PA vs 34.0% in low PA), but the differences were not significant. Similar results were found for high and low GRSs., Conclusions: We confirmed that PA is significantly associated with glucose homeostasis parameters and T2D prevalence, and that this association may be stronger in individuals who are more genetically predisposed to diabetes.

Lipid oxidation is one of the most important processes occurring in living cells and has been investigated through stable end-products. Currently, new insights into many physiological and pathophysiological processes provide a measurement of the first products of oxidation, e.g., oxidized glycerophosphatidylcholines (oxGPCs). Here, we evaluate the capacity of untargeted global metabolomics to measure oxGPCs in serum samples. This evaluation covered analytical reproducibility and data quality as well as the ability to capture metabolic alterations in diverse conditions. The analytical evaluation was performed based on the quality control samples, while the comparative analysis was based on the model of the development of type 2 diabetes mellitus (T2DM). The novelty of this approach arises not only from the measurement of oxGPCs instead of lipid peroxide-derived aldehydes but also from the stratification of the patients according to body mass index (BMI). Such a scenario was dictated by the fact that, despite the well-known relationship between obesity and T2DM development, there are lean individuals suffering from T2DM as well as obese people with normal glucose homeostasis. Our results provided evidence to support the ability of nontargeted metabolomics to measure oxGPCs. Comparative analysis of measured oxGPCs revealed differences in the level of oxGPCs either between different stages of disease development (insulin resistance, prediabetes) or BMI groups (normal weight, overweight, obese). The obtained results provided new insights into the metabolic processes leading to the development of T2DM and opened new paths in the investigation of the impact of body mass in T2DM progress., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The transcription factor 7-like 2 (TCF7L2) gene confers one of the strongest genetic predispositions to type 2 diabetes, but diabetes development can be modified by diet., Objective: The aim of our study was to evaluate postprandial metabolic alterations in healthy men with a high genetic risk of diabetes, after two meals with varying macronutrient content., Methods: The study was conducted in 21 homozygous nondiabetic men carrying the high-risk (HR, n = 8, age: 31.2 ± 6.3 y, body mass index (BMI, kg/m2) 28.5 ± 8.1) or low-risk (LR, n = 13, age: 35.2 ± 10.3 y, BMI: 28.1 ± 6.4) genotypes at the rs7901695 locus. During two meal challenge test visits subjects received standardized isocaloric (450 kcal) liquid meals: high-carbohydrate (HC, carbohydrates: 89% of energy) and normo-carbohydrate (NC, carbohydrates: 45% of energy). Fasting (0 min) and postprandial (30, 60, 120, 180 min) plasma samples were analyzed for metabolite profiles through untargeted metabolomics. Metabolic fingerprinting was performed on an ultra-high-performance liquid chromatography (UHPLC) system connected to an iFunnel quadrupole-time-of-flight (Q-TOF) mass spectrometer., Results: In HR-genotype men, after the intake of an HC-meal, we noted a significantly lower area under the curves (AUCs) of postprandial plasma concentrations of most of the phospholipids (-37% to -53%, variable importance in the projection (VIP) = 1.2-1.5), lysophospholipids (-29% to -86%, VIP = 1.1-2.6), sphingolipids (-32% to -47%, VIP = 1.1-1.3), as well as arachidonic (-36%, VIP = 1.4) and oleic (-63%, VIP = 1.3) acids, their metabolites: keto- and hydoxy-fatty acids (-38% to -78%, VIP = 1.3-2.5), leukotrienes (-65% to -83%, VIP = 1.4-2.2), uric acid (-59%, VIP = 1.5), and pyroglutamic acid (-65%, VIP = 1.8). The AUCs of postprandial sphingosine concentrations were higher (125-832%, VIP = 1.9-3.2) after the NC-meal, AUCs of acylcarnitines were lower (-21% to -61%, VIP = 1.1-2.4), and AUCs of fatty acid amides were higher (51-508%, VIP = 1.7-3.1) after the intake of both meals., Conclusions: In nondiabetic men carrying the TCF7L2 HR genotype, subtle but detectable modifications in intermediate lipid metabolism are induced by an HC-meal. This trial was registered at www.clinicaltrials.gov as NCT03792685., (Copyright © American Society for Nutrition 2019.)

The prospero homeobox 1 (PROX1) gene may show pleiotropic effects on metabolism. We evaluated postprandial metabolic alterations dependently on the rs340874 genotypes, and 28 non-diabetic men were divided into two groups: high-risk (HR)-genotype (CC-genotype carriers, n = 12, 35.3 ± 9.5 years old) and low-risk (LR)-genotype (allele T carriers, n = 16, 36.3 ± 7.0 years old). Subjects participated in two meal-challenge-tests with high-carbohydrate (HC, carbohydrates 89%) and normo-carbohydrate (NC, carbohydrates 45%) meal intake. Fasting and 30, 60, 120, and 180 min after meal intake plasma samples were fingerprinted by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). In HR-genotype men, the area under the curve (AUC) of acetylcarnitine levels was higher after the HC-meal [+92%, variable importance in the projection (VIP) = 2.88] and the NC-meal (+55%, VIP = 2.00) intake. After the NC-meal, the HR-risk genotype carriers presented lower AUCs of oxidized fatty acids (-81-66%, VIP = 1.43-3.16) and higher linoleic acid (+80%, VIP = 2.29), while after the HC-meal, they presented lower AUCs of ornithine (-45%, VIP = 1.83), sphingosine (-48%, VIP = 2.78), linoleamide (-45%, VIP = 1.51), and several lysophospholipids (-40-56%, VIP = 1.72-2.16). Moreover, lower AUC (-59%, VIP = 2.43) of taurocholate after the HC-meal and higher (+70%, VIP = 1.42) glycodeoxycholate levels after the NC-meal were observed. Our results revealed differences in postprandial metabolites from inflammatory and oxidative stress pathways, bile acids signaling, and lipid metabolism in PROX1 HR-genotype men. Further investigations of diet-genes interactions by which PROX1 may promote T2DM development are needed.

The major risk factors of T2DM (type 2 diabetes mellitus) development are still under investigation. We evaluate the possible risk factors associated with type 2 diabetes (T2DM) in adult subjects during a five-year prospective cohort study. We recruited 1160 subjects who underwent oral glucose tolerance test, anthropometric measurements, and body composition and body fat distribution analysis at a baseline visit and again at follow-up after approximately five years. The conclusions of this study are based on observation of 219 subjects who attended both the first and follow-up visits. The fasting serum insulin was measured, and HOMA-IR (homeostatic model assessment of insulin resistance) was calculated. During the follow-up period, T2DM was diagnosed in 7.4% of participants, impaired fasting glucose in 37.7%, and impaired glucose tolerance in 9.3%. Logistic regression models, adjusted for age, were constructed. The changes in glucose concentration, visceral fat tissue content, insulin resistance, and %loss of muscle mass were chosen as the potential predictors for T2DM development. A set of independent variables was extracted. The constructed feature set comprised change in HOMA-IR (OR (odds ratio) = 1.01, p < 0.01) and change in %loss of muscle mass (OR = 0.84, p < 0.03). With an aim to validate the prediction capability using the selected attributes, a support vector machine classifier and leave-one-out cross-validation procedure was applied, yielding 92.78% classification accuracy. Our results show the correlation between the %loss of muscle mass and T2DM development in adults, independent of changes in insulin resistance.

The energy balance regulation may differ in lean and obese people. The purposes of our study were to evaluate the hormonal response to meals with varying macronutrient content, and the differences depending on body weight., Methods: The crossover study included 46 men, 21⁻58 years old, normal-weight and overweight/obese. Every subject participated in two meal-challenge-tests with high-carbohydrate (HC), and normo-carbohydrate (NC) or high-fat (HF) meals. Fasting and postprandial blood was collected for a further 240 min, to determine adiponectin, leptin and total ghrelin concentrations., Results: In normal-weight individuals after HC-meal we observed at 60min higher adiponectin concentrations (12,554 ± 1531 vs. 8691 ± 1070 ng/mL, p = 0.01) and significantly ( p < 0.05) lower total ghrelin concentrations during the first 120 min, than after HF-meal intake. Fasting and postprandial leptin levels were significantly ( p < 0.05) higher in overweigh/obese men. Leptin concentrations in normal-weight men were higher (2.72 ± 0.8 vs. 1.56 ± 0.4 ng/mL, p = 0.01) 180 min after HC-meal than after NC-meal intake., Conclusions: Our results suggest that in normal-body weight men we can expect more beneficial leptin, adiponectin, and total ghrelin response after HC-meal intake, whereas, in overweight/obese men, the HC-meal intake may exacerbate the feeling of hunger, and satiety may be induced more by meals with lower carbohydrate content.

Background: Hormones, which influence satiety and hunger, play a significant role in body energy balance regulation. Ghrelin is a peptide that plays an important role in short-term appetite regulation, whereas leptin is a factor that controls long-term energy balance and is considered as a satiety hormone. The aim of this study was to evaluate the leptin/ghrelin ratio in a fasting state and after the intake of meals with varying macronutrient contents and to assess the possible differences between normal body weight and overweight/obese men., Methods: We examined 46 healthy adult men (23 with normal body weight and 23 overweight/obese) aged 21-58, who were divided into two groups. In the crossover study, participants received isocaloric (450 kcal) meals with different macronutrient contents: men from the first group received high-carbohydrate (HC) and normo-carbohydrate (NC) meals, and in the second group, participants received high-carbohydrate and high-fat (HF) meals. The ratio of leptin/ghrelin levels was calculated from leptin and total ghrelin serum concentrations in a fasting state and 30, 60, 120, 180 and 240 min after meal intake. One-way ANOVA and Wilcoxon signed-rank tests were carried out. The normality of the variable distribution was checked with the Shapiro-Wilk test, the homogeneity of variances was verified with the Levene test, and the false discovery rate p-value adjustment method was used., Results: The leptin/ghrelin ratio was significantly higher in overweight/obese men than individuals with normal body weight in a fasting state, as well as postprandially. We observed trends towards a higher leptin/ghrelin ratio values from the 60 min after HC-meal intake compared to the NC- and HF-meals in normal body weight participants, while in overweight/obese men, we did not note any significant differences dependent on the meal type., Conclusions: We have observed a significantly different postprandial leptin/ghrelin ratio in normal body weight and overweight/obese men, and our results suggest that in men with normal body weight, a greater feeling of satiety may occur after high-carbohydrate meal intake, which was not noted in the overweight/obese individuals.

Different kinds of gastrointestinal tract modulations known as "bariatric surgery" are actually the most effective treatment for obesity and associated co-morbidities, such as type 2 diabetes (T2DM). The potential causes of those effects have yet to be explained. In our study, we focused on molecular changes evoked by laparoscopic sleeve gastrectomy leading to T2DM remission. Two complementary metabolomics techniques, namely, liquid chromatography coupled with mass spectrometry (LC-MS) and gas chromatography mass spectrometry (GC-MS), were used to study those effects in a group of 20 obese patients with T2DM selected from a cohort of 372 obese individuals who underwent bariatric surgery and did not receive anti-diabetic treatment afterward. Modified levels of carnitines, lipids, amino acids (including BCAA) and α- and β-hydroxybutyric acids were detected. Presented alterations suggest a major role of mitochondria activity in T2DM remission process. Moreover, some of the observed metabolites suggest that changes in gut microbiota composition may also correlate with the tempo of diabetes recovery. Additional analyses confirmed a relationship between biochemical and clinical parameters and the aforementioned metabolites, thereby, highlighting a role of mitochondria and microbes. Our data suggests that there is a previously undescribed relationship between mitochondria and gut microbiota, which changes after the bariatric surgery. More investigations are needed to confirm and explore the observed findings.

This study investigated the efficacy of a plant-derived dietary supplement with respect to decreasing postprandial glucose and insulin peaks after the intake of real-world meals. Two randomized, double-blind, placebo-controlled, cross-over experiments were conducted on healthy subjects who received a supplement containing extracts of white mulberry, white bean, and green coffee or one containing the three extracts with added fibre before consuming high-GI/GL (glycaemic index/glycaemic load) meals. In study one, 32 subjects received an investigational product/placebo before a standardized meal at two visits. In study two, 150 subjects received an investigational product/placebo before five different standardized meals. Postprandial glucose and insulin concentrations were lower 20⁻35 min after meal intake among subjects taking the investigational product, and fewer episodes of postprandial reactive hypoglycaemia were noted. For example, after consuming breakfast cereal with milk, lower glucose peaks were observed for the investigational product (vs. placebo) after 20 min (100.2 ± 1.97 vs. 112.5 ± 3.12 mg/dL, respectively; p < 0.01); lower insulin peaks were noted at the same time point (45.9 ± 4.02 IU/mL vs. 68.2 ± 5.53 IU/mL, respectively, p < 0.01). The combined formulation decreases the adverse consequences of high-GI/GL meal consumption. It can be an effective dietary supplement for the management of metabolic syndrome and type 2 diabetes mellitus.

Obesity is a result of positive energy balance. The aim of this study was to measure (in crossover trials) the energy expenditure and oxidation of glucose and lipids, both at the fasting state and after an intake of meals with a varying macronutrient content, in normal-weight and overweight/obese people. In the study, 46 healthy adult males (23 with normal body weight and 23 overweight/obese), aged 21⁻58, were examined. During two consecutive visits, subjects received isocaloric standardized meals (450 kcal) with different content of basic nutrients. Resting metabolic rate and carbohydrate and fat utilization were evaluated during the fasting state and postprandially, using an indirect calorimetry method. Energy expenditure was higher in people with normal body weight and slightly higher after the high-carbohydrate meal. In overweight/obese people, increased expenditure was noted after normo-carbohydrate meal intake. The high-fat meal induced lower postprandial thermal response compared to a high-carbohydrate meal, both in people with normal body weight and in overweight/obese men. Glucose utilization was higher after the high-carbohydrate meal, and it was higher in the normal body weight group than in overweight/obese people. In addition, overweight/obese people showed a lower level of fatty acid oxidation under fasting conditions which, together with limited ability to oxidize energy substrates, depending on their availability, indicates that these people are characterized by lower metabolic flexibility.