CC Genotype at TCF7L2 Diabetes Risk Locus rs7903146 Directs a Coordinated Fatty Acid Response to a Mediterranean Diet Intervention: A Randomized Controlled Trial

The effect of the paraoxonase 1 (PON1) T(−107)C polymorphism on serum PON1 activity in women is dependent on fatty acid intake

BackgroundThe TCF7L2 gene is a significant genetic factor contributing to the risk of metabolic and cardiovascular diseases (CVD). We previously found that subjects with the TT genotype of TCF7L2 rs7903146 variant, who consume a low-fat diet (LF) had a higher incidence of stroke than subjects with the CC genotype. Yet this association was abolished in subjects with the TT genotype who consumed a Mediterranean-type diet (MetD). However, the mechanism by which MetD diet modulates the association between TCF7L2 and CVD risk is unclear. This study aims to validate these findings under real-world conditions and clinical practice to elucidate the biological mechanisms involved in this correlation.MethodsThirty-five participants with BMI ranging from 27 to 34 kg/m2 were recruited based on rs7903146 genotype. Of those consented to participate, 21 had the CC and 14 had the TT genotype. Participants were randomly assigned to two dietary intervention groups, ensuring an equal distribution of CC and TT carriers. Each participant followed one of two diets (LF or MetD) for one week, followed by a 10-day washout period before switching to the other diet for one week. Blood samples were collected before and after each diet for metabolomic analysis using nuclear magnetic resonance (NMR) spectroscopy. The differential effect of the diets on triglyceride-rich lipoproteins was determined based on TCF7L2 genotype.ResultsThe MetD significantly reduced triglyceride-rich lipoprotein concentrations compared to the LF diet. After consuming the LF diet, TT carriers exhibited more small VLDL particles, potentially contributing to CVD risk compared to CC carriers. However, this difference in risk was not observed with the MetD. Furthermore, the order in which the two diets were crossed affected the triglyceride-rich lipoprotein profile, with LF-MetD regimen showing a stronger effect on triglyceride-rich lipoproteins (TRL) levels than the MetD-LF regimen.ConclusionsOur findings suggest that rs7903146 TT carriers benefit more from a MetD than a LF diet in terms of their triglyceride-rich lipoprotein profile, which may reduce their risk of CVD. These results support the notion that genotype is a factor in determining the extent to which the MetD affects cardiovascular health.

The response to metformin, the most commonly used drug for the treatment of type 2 diabetes (T2D), is highly variable. The common variant rs7903146 C>T within the transcription factor 7-like 2 gene (TCF7L2) is the strongest genetic risk factor associated with T2D to date. In this study, we explored the effects of the TCF7L2 rs7903146 genotype on metformin response in T2D. The study included 86 newly diagnosed patients with T2D, incident users of metformin. Levels of fasting glucose, insulin, HbA1c, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and anthropometric parameters were measured prior to metformin therapy, and 6 and 12 months after the treatment. Genotyping of the TCF7L2 rs7903146 was performed by the Sequenom MassARRAY® iPLEX® platform. At baseline, the diabetes risk allele (T) showed an association with lower triglyceride levels (p = 0.037). After 12 months of metformin treatment, the T allele was associated with 25.9% lower fasting insulin levels (95% CI 10.9-38.3%, p = 0.002) and 29.1% lower HOMA-IR index (95% CI 10.1-44.1%, p = 0.005), after adjustment for baseline values. Moreover, the T allele was associated with 6.7% lower fasting glucose levels (95% CI 1.1-12.0%, p = 0.021), adjusted for baseline glucose and baseline HOMA-%B levels, after 6 months of metformin treatment. This effect was more pronounced in the TT carriers who had 16.8% lower fasting glucose levels (95% CI 7.0-25.6%, p = 0.002) compared to the patients with CC genotype. Our results suggest that the TCF7L2 rs7903146 variant affects markers of insulin resistance and glycemic response to metformin in newly diagnosed patients with T2D within the first year of metformin treatment.

The Mediterranean diet (MD), despite the fact that it is acknowledged as one of the healthiest diets in the world, is paradoxically becoming less the diet of choice in most Mediterranean countries. This process of erosion of the MD is alarming as it has undesirable impacts not only on health, but also on social, cultural, economic and environmental domains in the Mediterranean area. The Med Diet 4.0 has been developed as a multidimensional framework to revitalize the MD. It characterizes the MD as a sustainable diet model, through four interdependent sustainable benefits, with country-specific variations: (i) well-documented nutrition and health advantages, preventing chronic and degenerative diseases and reducing public health costs; (ii) low environmental impacts and richness in biodiversity, reducing pressure on natural resources and climate change; (iii) positive local economic returns, reducing rural poverty; and (iv) high social and cultural food values, increasing appreciation, mutual respect and social inclusion. All these elements interact and feed into each other synergistically, contributing to holistic well-being of individuals and communities. The Med Diet 4.0 has the broader scope to catalyze a renewed multi-stakeholder interest in the MD as a sustainable driver connecting food consumption to production towards more Mediterranean sustainable food systems. It will allow a new awareness among Mediterranean people of the multiple sustainable values and benefits of the MD, thereby facilitating its revitalization. The Med Diet 4.0 reshapes a contemporary knowledge of the MD and its appreciation in terms of a more holistic vision of sustainability linked to nutritional well-being and food security. The complexity of interdependent challenges, within the radical transformation of the contemporary Mediterranean and global scenario, requires new forms of transdisciplinary and intercultural dialogues, strategies and research, at different levels, for the revitalization of the MD. Within such complexity, the Med Diet 4.0 provides a synthesis to better understand and enhance the MD as a sustainable diet model in the context of the improvement of the sustainability of Mediterranean food systems, reconnecting diets, food consumption, food production, food security and sustainability in the Mediterranean region. It provides useful insights to tackle the challenging policy issue of balancing human and planetary health, within an interconnected, globalized food system.

Aim. To study the associations of angiotensinogen (AGT) (s4762(С521Т), rs699(Т704C)) and angiotensin II receptor type I (AGTR1) (rs5186(A1166C)) genetic polymorphisms with serum levels of insulin, glucagon, C-peptide, leptin, as well as with dyslipidemia and glycemic levels in Dagestan residents with combination of type 2 diabetes (T2D) and hypertension (HTN), as well as with isolated T2D/HTN.Material and methods. We examined 16 patients with isolated T2D, 59 patients with T2D+HTN and 51 patients with isolated HTN from Dagestan. Genetic polymorphisms of the AGT and AGTR1 genes were studied. The levels of insulin, glucagon, C-peptide, and leptin were studied by enzyme-linked immunosorbent assay (ELISA), while lipid and carbohydrate metabolism — by biochemical methods.Results. In patients with T2D, the association of CC genotype of AGT gene rs4762(С521Т) polymorphism with a leptin decrease was determined, while its CT genotype was associated with an increase in serum level of triglycerides. The TC genotype of AGT gene rs699(Т704C) polymorphism was associated with an increase in leptin, triglyceride and glucose levels. The AA genotype of AGTR1 gene rs5186(A1166C) polymorphism was associated with an increase in insulin and glucose levels, as well as a decrease in leptin level. In patients with a combination of T2D and HTN, CC and CT genotypes of AGT gene rs4762(С521Т) polymorphism was associated with a decrease in glucagon level. The TT genotype of AGT gene rs699(Т704C) polymorphism was associated with an increase in insulin, triglyceride, glucose and body mass index (BMI) levels. In isolated HTN, the CC and CT genotypes of AGT gene rs4762(С521Т) polymorphism were associated ith a decrease in glucagon level. The TT genotype of AGT gene rs699(Т704C) polymorphism was associated with increased levels of insulin, low density lipoproteins, and BMI.Conclusion. Associations of AGT (s4762(С521Т), rs699(Т704C)) and AGTR1 (rs5186(A1166C)) genetic polymorphisms with carbohydrate and lipid metabolism changes are an important pathogenetic link of T2D and HTN, which allows developing an individual prognosis of these diseases in Dagestan residents.

Dietary approaches to stop hypertension, mediterranean dietary pattern, and diabetic nephropathy in women with type 2 diabetes: A case-control study

Mediterranean Diet (Med Diet) is one of the healthiest dietary patterns. We aimed to verify the effects of weaning (i.e., the introduction of solid foods in infants previously fed only with milk) using adult foods typical of Med Diet on children eating habits, and on the microbiota composition. A randomized controlled clinical trial on 394 healthy infants randomized in a 1:1 ratio in a Med Diet group weaned with fresh; seasonal and tasty foods of Med Diet and control group predominantly weaned with industrial baby foods. The primary end point was the percentage of children showing a good adherence to Med Diet at 36 months. Secondary end points were mother’s changes in adherence to Med Diet and differences in children gut microbiota. At 36 months, children showing a good adherence to Med Diet were 59.3% in the Med Diet group and 34.3% in the control group (p < 0.001). An increase in adherence to the Med Diet was observed in the mothers of the Med Diet group children (p < 0.001). At 4 years of age children in the Med Diet group had a higher gut microbial diversity and a higher abundance of beneficial taxa. A Mediterranean weaning with adult food may become a strategy for early nutritional education, to develop a healthy microbiota, to prevent inflammatory chronic diseases and to ameliorate eating habits in children and their families.

Few prospective studies in Spain and US have linked a Mediterranean (Med) dietary pattern with reduced MetS risk. We evaluated the prospective association of Med diet pattern, based on various diet scores, with 6‐y incident risk of MetS in 3,232 middleaged adults, free from diabetes and CVD at baseline, who participated in the French SU.VI.MAX study. Three different Med diet scores were computed from repeated (&gt;=3) 24‐hr records over two years: the original Med diet score (MDS) and its recent revisions namely rev‐MDS (incorporating cereal/grain quality and sugared‐beverage consumption) and Med‐style diet pattern score (MSDPS) relating adherence to Med diet pyramid. MetS was defined by the 2009 Joint Interim Societies definition. In logistic regression models adjusted for confounders including traditional CVD risk factors, a lower risk of MetS was observed with increasing rev‐MDS score and MDS (P for trend: 0.001 and 0.03, respectively) but not with MSDPS. Relative risk (95% CI) for MetS risk comparing the 3rd to the 1st tertile were 0.47 (0.32–0.69) and 0.50 (0.32–0.77) for rev‐MDS score and MDS, respectively. These findings highlight the importance of following Med diet in MetS prevention.

The Mediterranean Diet (Med Diet) has long been shown to be associated with lower cardiovascular mortality in epidemiological studies. However, the direct effect of the dietary pattern on cardiovascular risk factors is less clear. Furthermore, the effect of Med Diet interventions in non-Mediterranean populations on cardiovascular and metabolic risk is variable. A Cochrane Review in 2019 concluded there was low to moderate evidence of a modest benefit but noted that there were still ongoing trials. Since 2019, there have been a number of published trials that have not shown a benefit of the Med Diet over other interventions or usual care. It is possible that dietary factors such as quality or quantity of carbohydrate and energy restriction are more important factors, along with the degree of weight loss, than the Med Diet itself. There are also many other factors that influence the uptake and effectiveness of the Med Diet in populations that have a different traditional or habitual diet. This review paper examines a selection of 20 Med Diet intervention trials specifically looking at clinical outcomes of glucose metabolism: fasting plasma glucose, HbA1c, development of type 2 diabetes or need for hypoglycaemic medications, with or without other cardiometabolic risk factors. These trials are a mix of randomised controlled trials, crossover studies and cohort studies of greater than 8 weeks duration with more than 25 participants. There is heterogeneity in study designs and outcomes, making comparison difficult, but there is no clear benefit of the Med Diet presented.

Background: Common variants of the transcription factor-7-like-2 gene (TCF7L2) have been implicated in the progression of prediabetes to T2D. We explored the effect of the rs7903146 variant on the incretin effect in youths with dysglycemia. Methods: 5 carriers with the risk-genotype of TCF7L2 (TT at the rs7903146, 14.4±2.3y, BMI 34.7±6.4kg/m2) and 5 with the wild type genotype CC (16.2±1.9y, BMI 36.8±6.0kg/m2) underwent a 3-hour OGTT followed, a week later, by an isoglycemic intravenous glucose infusion (IVGTT), designed to match the plasma glucose concentrations during the OGTT. The incretin effect was measured as 100*(SROGTT-SRIVGTT)/SROGTT where SR was the secretion rate of c-peptide. Results: As shown in the Figure, the plasma glucose profile in the OGTT and IVGTT were well matched in both groups. The increase in SR during the OGTT compared to IVGTT was significantly lower in the carriers of the TT compared to CC genotype (ΔiAUCc-peptide 1281±688.6 vs. 5632±1604 pmol/L*min, p &amp;lt; 0.025). Thus, relative to the control group, carriers of the TT-risk genotype had a significant reduction of the incretin effect (TT 0% [-11.74, 16.84], CC: +35% [12.05, 55.71]; p &amp;lt;0.018). Conclusion: The TCF7L2 variant rs7903146 impairs the incretin effect in obese youths carrying the risk-genotype (TT), suggesting a causative mechanism for the association of this variant with progression to T2D. Disclosure A. Galderisi: None. B. Pierpont: None. D. D'Alessio: Consultant; Self; Intarcia Therapeutics, Inc., Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk A/S. N. Santoro: None. S. Caprio: None.

Maternal and Offspring Fatty Acid Desaturase Variants, Prenatal DHA Supplementation, and Dietary n–6:n–3 Fatty Acid Ratio in Relation to Cardiometabolic Health in Mexican Children

Does Intermittent Energy Restriction Plus Mediterranean Diet Reduce Visceral Adipose Tissue and Minimize Adaptive Responses of Energy Restriction? A Randomized Pilot Study (P21-016-19)

Melanocortin-4 receptor (MC4R) has roles in regulating food intake and energy balance. A number of studies have reported that variant rs17782313 is significantly associated with obesity in many populations. However, their contribution to obesity in the Vietnamese population is not fully described. The purpose of the present study was to evaluate the association of rs17782313 with anthropometric indices and obesity in the Vietnamese children population. A case-control study was conducted on 559 children aged 6-11 years (278 obese cases and 281 normal controls). The nutrition status of the children was classified using both criteria of International Obesity Task Force 2000 and World Health Organization 2007. The results showed that in normal group, the data of z score of weight for age was highest in CC genotype group and was lowest in TT genotype group (0.11 and -0.38 respectively, P=0.023). In obese group, the waist hip ratio was lowest in TT genotype group and the highest one was in CC genotype group (0.93 and 0.97 respectively, P=0.031). Our findings indicate that the variant rs17782313 near MC4R is likely to have an impact on the changing of weight and central obesity in the Vietnamese children.

Association between Mediterranean and Nordic diet scores and changes in weight and waist circumference: influence of FTO and TCF7L2 loci

Apolipoprotein A2 -265T>C polymorphism interacts with dietary fatty acids intake to modulate inflammation in type2diabetes mellitus patients.