Hepatic glucokinase regulatory protein and carbohydrate response element binding protein attenuation reduce de novo lipogenesis but do not mitigate intrahepatic triglyceride accumulation in Aldob deficiency.

OBJECTIVE: Stable isotope studies have shown that hepatic de novo lipogenesis (DNL) plays an important role in the pathogenesis of intrahepatic lipid (IHL) deposition. Furthermore, previous research has demonstrated that fructose 1-phosphate (F1P) not only serves as a substrate for DNL, but also acts as a signalling metabolite that stimulates DNL from glucose. The aim of this study was to elucidate the mediators of F1P-stimulated DNL, with special focus on two key regulators of intrahepatic glucose metabolism, i.e., glucokinase regulatory protein (GKRP) and carbohydrate response element binding protein (ChREBP). METHODS: Aldolase B deficient mice (Aldob-/-), characterized by hepatocellular F1P accumulation, enhanced DNL, and hepatic steatosis, were either crossed with GKRP deficient mice (Gckr-/-) or treated with short hairpin RNAs directed against hepatic ChREBP. RESULTS: Aldob-/- mice showed higher rates of de novo palmitate synthesis from glucose when compared to wildtype mice (p < 0.001). Gckr knockout reduced de novo palmitate synthesis in Aldob-/- mice (p = 0.017), without affecting the hepatic mRNA expression of enzymes involved in DNL. In contrast, hepatic ChREBP knockdown normalized the hepatic mRNA expression levels of enzymes involved in DNL and reduced fractional DNL in Aldob-/- mice (p < 0.05). Of interest, despite downregulation of DNL in response to Gckr and ChREBP attenuation, no reduction in intrahepatic triglyceride levels was observed. CONCLUSIONS: Both GKRP and ChREBP mediate F1P-stimulated DNL in aldolase B deficient mice. Further studies are needed to unravel the role of GKRP and hepatic ChREBP in regulating IHL accumulation in aldolase B deficiency.

Brain function in classic galactosemia, a galactosemia network (GalNet) members review.

Classic galactosemia (CG, OMIM #230400, ORPHA: 79,239) is a hereditary disorder of galactose metabolism that, despite treatment with galactose restriction, affects brain function in 85% of the patients. Problems with cognitive function, neuropsychological/social emotional difficulties, neurological symptoms, and abnormalities in neuroimaging and electrophysiological assessments are frequently reported in this group of patients, with an enormous individual variability. In this review, we describe the role of impaired galactose metabolism on brain dysfunction based on state of the art knowledge. Several proposed disease mechanisms are discussed, as well as the time of damage and potential treatment options. Furthermore, we combine data from longitudinal, cross-sectional and retrospective studies with the observations of specialist teams treating this disease to depict the brain disease course over time. Based on current data and insights, the majority of patients do not exhibit cognitive decline. A subset of patients, often with early onset cerebral and cerebellar volume loss, can nevertheless experience neurological worsening. While a large number of patients with CG suffer from anxiety and depression, the increased complaints about memory loss, anxiety and depression at an older age are likely multifactorial in origin.

Fructose intake from sugar-sweetened beverages is associated with a greater risk of hyperandrogenism in women: UK Biobank cohort study.

OBJECTIVE: To assess the association between fructose consumption and serum sex hormone-binding globulin (SHBG), (free) testosterone, and risk of hyperandrogenism in a population-based cohort. DESIGN: An observational and genetic association study in participants of the UK Biobank (n = 136 384 and n = 383 392, respectively). METHODS: We assessed the relationship of (1) the intake of different sources of fructose (ie, total, fruit, fruit juice, and sugar-sweetened beverages [SSBs]) and (2) rs2304681 (a missense variant in the gene encoding ketohexokinase, used as an instrument of impaired fructose metabolism), with SHBG, total and free testosterone levels, and risk of hyperandrogenism (free androgen index >4.5). RESULTS: The intake of total fructose and fructose from fruit was associated with higher serum SHBG and lower free testosterone in men and women and lower risk of hyperandrogenism in women. In contrast, fructose intake from SSB (≥10 g/day) was associated with lower SHBG in men and women and with higher free testosterone levels and risk of hyperandrogenism in women (odds ratio [OR]: 1.018; 95% confidence interval [CI]: 1.010; 1.026). Carriers of the rs2304681 A allele were characterized by higher circulating SHBG (both men and women), lower serum free testosterone (women), and a lower risk of biochemical hyperandrogenism (OR: 0.997, 95% CI: 0.955; 0.999; women) and acne vulgaris (OR: 0.975, 95% CI: 0.952; 0.999; men and women combined). CONCLUSIONS: The consumption of ≥10 g/day fructose from SSB, corresponding to ≥200 mL serving, is associated with a 2% higher risk of hyperandrogenism in women. These observational data are supported by our genetic data.

Relationship between educational attainment and non-alcoholic fatty liver disease: A two-sample Mendelian randomization study.

BACKGROUND: Observational studies have identified an inverse association between education and non-alcoholic fatty liver disease (NAFLD). However, it is not possible to establish causality for this relationship. AIMS: To gain more insight into the causal nature of the relationship between education and NAFLD. METHODS: We performed two-sample Mendelian randomization (MR) analyses using summary-level, large-scale datasets to study the association of genetically predicted educational attainment (n = 1271 genetic instruments, obtained from 1,131,881 participants) with risk of NAFLD (i.e., liver fat [n = 32,858 participants] and electronic health record (EHR)-based NAFLD [n = 778,614 participants]). In sensitivity analyses, educational attainment was replaced by three education-related traits (i.e., genetically predicted cognition, math ability and highest math). RESULTS: Inverse-variance weighted method showed a statistically significant association between genetically predicted educational attainment and liver fat (beta: -0.251, 95%CI: -0.305; -0.198) and EHR-based NAFLD (OR: 0.609, 95%CI: 0.547; 0.677). MR-Egger regression did not show statistically significant intercepts. Similar findings were obtained when other MR tests were used or when educational attainment was replaced by education-related traits. CONCLUSIONS: This study suggests a causal, protective effect of higher education on NAFLD risk. Societal interventions targeted at people with low education are needed to alleviate the burden of NAFLD.

Development of tools to facilitate the diagnosis of hereditary fructose intolerance.

Although hereditary fructose intolerance (HFI) is an inborn error of fructose metabolism that classically presents at infancy, the diagnosis is often missed or delayed. In this study, we aimed to develop tools to facilitate the diagnosis of HFI. The intake of fructose-containing food products, that is, fruit, fruit juice and sugar-sweetened beverages, was assessed by a 3-day food diary in adult HFI patients (n = 15) and age, sex, and BMI-matched controls (n = 15). Furthermore, glycosylation of transferrin was examined using high-resolution mass spectrometry and abnormally glycosylated transferrin was expressed as ratio of normal glycosylated transferrin. We found that the sensitivity and specificity of the 3-day food diary for the intake of at least one fructose-containing food product were both 100%. Both mono-glyco:diglyco transferrin and a-glyco+mono-glyco:di-glyco transferrin were greater in HFI patients and had a high-discriminatory power (area under the receiver operating characteristic curve: 0.97 and 0.94, respectively). In this well-characterized cohort of adult HFI patients, the 3-day food questionnaire and the glycosylation pattern of transferrin are valuable tools to facilitate the recognition and diagnosis of HFI in adult patients.

Quality of life of adult patients with hereditary fructose intolerance.

BACKGROUND: Although patients with hereditary fructose intolerance (HFI) generally have a good prognosis on a fructose-restricted diet, relatively little is known about their quality of life. The aim of this study was to investigate the quality of life in adult patients with HFI in comparison to patients with dietary-treated, classical phenylketonuria (PKU). METHODS: Patients with HFI and patients with classical PKU were recruited from the adult metabolic centers in The Netherlands and Belgium and via social media. Patients were asked to fill out the 36-item Short Form Health survey (SF-36) and a modified PKU Quality Of Life (PKU-QoL) questionnaire. RESULTS: Patients with HFI (n = 19) did not report any restrictions in their health-related quality of life, except for vitality and general mental health, which were scored more unfavorable compared to patients with PKU (n = 19) (p < 0.05, adjusted for level of education and country of origin). The results from the modified PKU-QoL demonstrated a statistically significantly greater impact of the disease in the social domain in HFI. A substantial proportion of both HFI and PKU patients (21%) reported a great to severe emotional impact of their disease. Finally, patients with HFI experienced statistically significantly less food temptations, less guilt if dietary restrictions not followed, and less overall difficulty following dietary restrictions. CONCLUSIONS: Although patients with HFI showed to have a generally good quality of life, they scored lower on vitality and general mental health, and reported a greater social impact of the disease. These aspects deserve further study and clinical attention.

Traditional lifestyle factors partly mediate the association of socioeconomic position with intrahepatic lipid content: The Maastricht study.

Background & Aims: Recent studies have unveiled an association between socioeconomic position (SEP) and intrahepatic lipid (IHL) content. The aim of this study was to examine to what extent traditional lifestyle factors mediate the relationship between SEP and IHL content, independent of aetiology, and non-alcoholic fatty liver disease (NAFLD). Methods: We used cross-sectional data derived from The Maastricht Study (N = 4,001; mean age: 60 years, 49% women, 32% low education level, 21% diabetes, 21% NAFLD). Education, income, and occupation were used as indicators of SEP. Physical activity (accelerometer), intake of total energy, alcohol, saturated fat, protein, vitamin E, dietary fibre, and fructose from sugar-sweetened beverages (SSBs) and fruit juice (food frequency questionnaires) were potential mediators. IHL content was quantified by magnetic resonance imaging. Age, sex, and type 2 diabetes were covariates. Multiple parallel mediation analyses (bootstraps = 10,000) were performed. Results: Individuals with a low education level had a 1.056-fold higher IHL content (95% CI: 1.03-1.08) and a 44% greater NAFLD risk (OR:1.44; 95% CI:1.18-1.77) compared with those with higher education levels. Approximately 8.9% of educational disparity in risk of IHL content was attributable to moderate-to-vigorous physical activity; 6.3% to fructose intake from SSBs; 5.5% to dietary fibre; and -23% to alcohol. Approximately 8.7% of educational disparity in risk of NAFLD was attributable to moderate-to-vigorous physical activity; and 7.7% to fructose intake from SSBs. However, the indirect effect of these mediators was small (0.998 for IHL content and 1.045 for NAFLD) in comparison to the total effect. Similar results were found when income and occupation were used as SEP indicators. Conclusions: Societal measures may alleviate the burden of NAFLD and further studies that identify mediators other than traditional lifestyle factors are warranted to define the relationship underlying SEP and IHL content. Impact and implications: Individuals with a low or medium level of education, income, or occupational status had more fat accumulation in their livers than individuals with a higher education, income, or occupational status. This difference may be attributed to the influence of unhealthy lifestyle factors, such as reduced physical activity and a higher intake of sugar-sweetened beverages among individuals with lower socioeconomic position. Nevertheless, other yet unknown factors may also play a role.

Cardiovascular Implications of Metabolic Dysfunction-Associated Fatty Liver Disease.

Both nonalcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD) have been associated with incident cardiovascular disease (CVD), independent of confounders. Causality has recently been inferred by Mendelian randomization studies. Although these findings have contributed to current guidelines that recommend screening for and treatment of cardiovascular risk factors, it not yet clear how to position NAFLD/MAFLD in cardiovascular risk estimation scores and, consequently, which treatment targets should be used. This review aims to provide practical tools as well as suggestions for further research in order to effectively prevent CVD events in patients with NAFLD/MAFLD.

Genetic Susceptibility to Nonalcoholic Fatty Liver Disease and Risk for Pancreatic Cancer: Mendelian Randomization.

BACKGROUND: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer. METHODS: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes. RESULTS: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88-1.22; MR-Egger OR, 0.89; 95% CI, 0.65-1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90-1.27; MR-Egger OR, 0.93; 95% CI, 0.67-1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample. CONCLUSIONS: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk. IMPACT: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.

Effects of fructose added to an oral glucose tolerance test on plasma glucose excursions in healthy adults.

Background and objective: Previous experimental studies have shown that fructose interacts with glucose metabolism by increasing hepatic glucose uptake. However, human studies investigating the effects of small ('catalytic') amounts of fructose, added to an oral glucose load, on plasma glucose levels remain inconclusive. The aim of this study, therefore, was to repeat and extend these previous studies by examining the plasma glucose response during a 75 g oral glucose tolerance test (OGTT) with the addition of different doses of fructose. Methods: Healthy adults (n = 13) received an OGTT without addition of fructose and OGTTs with addition of different doses of fructose (1, 2, 5, 7.5 and 15 g) in a random order, on six separate occasions. Plasma glucose levels were measured every 15 min for 120 min during the study. Findings: The plasma glucose incremental area under the curve (iAUC) of the OGTT without addition of fructose was not significantly different from any OGTT with fructose (p ≥ 0.2 for all fructose doses). Similar results were observed when these data were clustered with data from a similar, previous study (pooled mean difference: 10.6; 95%CI: 45.0; 23.8 for plasma glucose iAUC of the OGTT without addition of fructose versus an OGTT with 5 g fructose; fixed-effect meta-analysis, n = 38). Of interest, serum fructose increased from 4.8 µmol/L (interquartile range: 4.1-5.9) at baseline to 5.3 µmol/L (interquartile range: 4.8-7.5) at T = 60 min during an OGTT without addition of fructose (p = 0.002). Conclusion: Low doses of fructose added to an OGTT do not affect plasma glucose levels in healthy adults. The role of endogenous fructose production, as a potential explanation of these null-findings, deserves further investigation.

Preferred Conversation Topics with Respect to Treatment Decisions Among Individuals with Type 2 Diabetes.

Purpose: Greater knowledge of individuals' needs and preferences can enhance shared decision-making, which is associated with improved quality of decisions and increased satisfaction. This study aimed to identify and prioritize the attributes (ie conversation topics) that individuals with type 2 diabetes find it most important to discuss with their healthcare provider regarding treatment decisions. Patients and Methods: First, small group interviews were organized with adults with type 2 diabetes (N=8) treated in primary care to identify the attributes that they find important to discuss regarding treatment decisions. A five-step nominal group technique was applied during the interviews. An object best-worst scaling (BWS) survey was subsequently distributed to individuals with self-reported diabetes participating in the Dutch Health Care Consumer Panel of the Netherlands Institute for Health Services Research (N=600) to determine the relative importance score (RIS) of the identified attributes. A higher RIS indicates a higher level of perceived importance. Subgroup and latent class analyses were performed to explore whether individuals' demographic and disease characteristics influenced their attribute preferences. Results: A total of 21 attributes were identified during three small group interviews with individuals with type 2 diabetes. Respondents in the BWS survey (N=285) viewed "quality of life" (RIS=11.97), "clinical outcomes" (RIS=10.40), "long-term diabetes complications" (RIS=9.83) and "short-term adverse medication" (RIS=7.72) as the most important in the decision-making process for the treatment of type 2 diabetes. Some differences in attribute preferences were identified according to demographic and disease characteristics. Conclusion: In general, individuals with type 2 diabetes not only want to discuss the biological effects of treatments, but also the impact of treatment on their quality of life. Healthcare providers should be aware that attributes are viewed differently by different individuals. This emphasizes the need for tailor-made healthcare decisions, which means eliciting and responding to individual preferences in the decision-making process.

Relationship between NAFLD and coronary artery disease: A Mendelian randomization study.

BACKGROUND AND AIMS: There is an ongoing debate on whether NAFLD is an active contributor or an innocent bystander in the pathogenesis of coronary artery disease (CAD). The aim of the present study was to assess the causal relationship between NAFLD and CAD. APPROACH AND RESULTS: We performed two-sample Mendelian randomization (MR) analyses using summary-level data to assess the association between genetically predicted NAFLD (i.e., chronically elevated serum alanine aminotransferase levels [cALT], imaging-based and biopsy-confirmed NAFLD) and risk of CAD. Analyses were repeated after exclusion of NAFLD susceptibility genes that are associated with impaired VLDL secretion.Inverse-variance weighted MR analyses showed a statistically significant association between genetically predicted cALT and risk of CAD (OR: 1.116, 95% CI: 1.039, 1.199), but not for the other NAFLD-related traits (OR: 1.046, 95% CI: 0.764, 1.433 and OR: 1.014, 95% CI: 0.968, 1.062 for imaging-based and biopsy-confirmed NAFLD, respectively). MR-Egger regression revealed a statistically significant intercept, indicative of directional pleiotropy, for all traits. Repeat analyses after exclusion of genes associated with impaired VLDL secretion showed consistent associations between genetically predicted NAFLD and CAD for all traits (i.e., cALT [OR: 1.203, 95% CI: 1.113, 1.300]), imaging-based (OR: 2.149, 95% CI: 1.276, 3.620) and biopsy-confirmed NAFLD (OR: 1.113, 95% CI: 1.041, 1.189), which persisted when more stringent biopsy-confirmed NAFLD criteria were used (OR: 1.154, 95% CI: 1.043, 1.278) or when more stringent MR methods were applied. MR-Egger regression did not show a statistically significant intercept. CONCLUSION: The two-sample MR analyses showed a robust association between genetically predicted NAFLD and CAD after exclusion of genetic variants that are implicated in impaired VLDL secretion.

Serum sex hormone-binding globulin is a mediator of the association between intrahepatic lipid content and type 2 diabetes: the Maastricht Study.

AIMS/HYPOTHESIS: Serum sex hormone-binding globulin (SHBG) has been proposed to act as a hepatokine that contributes to the extrahepatic complications observed in non-alcoholic fatty liver disease (NAFLD). However, it remains uncertain whether serum SHBG mediates the association between intrahepatic lipids (IHL) and type 2 diabetes. Therefore, we studied whether, and to what extent, serum SHBG mediates the association between IHL content and type 2 diabetes. METHODS: We used cross-sectional data from the Maastricht Study (n=1554), a population-based cohort study with oversampling of individuals with type 2 diabetes. Type 2 diabetes status was assessed by oral glucose tolerance test, and IHL content was measured using 3T Dixon MRI. Mediation analyses were performed to assess the role of serum SHBG in mediating the association between IHL content and type 2 diabetes. RESULTS: IHL content was significantly associated with type 2 diabetes in women and men (OR 1.08 [95% CI 1.04, 1.14] and OR 1.12 [95% CI 1.08, 1.17], respectively). Serum SHBG significantly mediated the association between IHL content and type 2 diabetes. The contribution of serum SHBG was higher in women (OR 1.04 [95% CI 1.02, 1.07]; proportion mediated 50.9% [95% CI 26.7, 81.3]) than in men (OR 1.02 [95% CI 1.01, 1.03]; proportion mediated 17.2% [95% CI 9.6, 27.6]). Repeat analyses with proxies of type 2 diabetes and adjustment for covariates did not substantially affect the results. CONCLUSIONS/INTERPRETATION: In this large-scale population-based cohort study, serum SHBG was found to be a mediator of the association between IHL content and type 2 diabetes. These findings extend our understanding of the potential mechanisms by which NAFLD is a risk factor for type 2 diabetes, and further elaborate on the role of SHBG as a hepatokine.

Associations between plasma sulfur amino acids and specific fat depots in two independent cohorts: CODAM and The Maastricht Study.

PURPOSE: Sulfur amino acids (SAAs) have been associated with obesity and obesity-related metabolic diseases. We investigated whether plasma SAAs (methionine, total cysteine (tCys), total homocysteine, cystathionine and total glutathione) are related to specific fat depots. METHODS: We examined cross-sectional subsets from the CODAM cohort (n = 470, 61.3% men, median [IQR]: 67 [61, 71] years) and The Maastricht Study (DMS; n = 371, 53.4% men, 63 [55, 68] years), enriched with (pre)diabetic individuals. SAAs were measured in fasting EDTA plasma with LC-MS/MS. Outcomes comprised BMI, skinfolds, waist circumference (WC), dual-energy X-ray absorptiometry (DXA, DMS), body composition, abdominal subcutaneous and visceral adipose tissues (CODAM: ultrasound, DMS: MRI) and liver fat (estimated, in CODAM, or MRI-derived, in DMS, liver fat percentage and fatty liver disease). Associations were examined with linear or logistic regressions adjusted for relevant confounders with z-standardized primary exposures and outcomes. RESULTS: Methionine was associated with all measures of liver fat, e.g., fatty liver disease [CODAM: OR = 1.49 (95% CI 1.19, 1.88); DMS: OR = 1.51 (1.09, 2.14)], but not with other fat depots. tCys was associated with overall obesity, e.g., BMI [CODAM: ß = 0.19 (0.09, 0.28); DMS: ß = 0.24 (0.14, 0.34)]; peripheral adiposity, e.g., biceps and triceps skinfolds [CODAM: ß = 0.15 (0.08, 0.23); DMS: ß = 0.20 (0.12, 0.29)]; and central adiposity, e.g., WC [CODAM: ß = 0.16 (0.08, 0.25); DMS: ß = 0.17 (0.08, 0.27)]. Associations of tCys with VAT and liver fat were inconsistent. Other SAAs were not associated with body fat. CONCLUSION: Plasma concentrations of methionine and tCys showed distinct associations with different fat depots, with similar strengths in the two cohorts.

(Pre)diabetes, glycemia, and daily glucose variability are associated with retinal nerve fiber layer thickness in The Maastricht Study.

Retinopathy and neuropathy in type 2 diabetes are preceded by retinal nerve fibre layer (RNFL) thinning, an index of neurodegeneration. We investigated whether glucose metabolism status (GMS), measures of glycaemia, and daily glucose variability (GV) are associated with RNFL thickness over the entire range of glucose tolerance. We used cross-sectional data from The Maastricht Study (up to 5455 participants, 48.9% men, mean age 59.5 years and 22.7% with type 2 diabetes) to investigate the associations of GMS, measures of glycaemia (fasting plasma glucose [FPG], 2-h post-load glucose [2-h PG], HbA1c, advanced glycation endproducts [AGEs] assessed as skin autofluorescence [SAF]) and indices of daily GV (incremental glucose peak [IGP] and continuous glucose monitoring [CGM]-assessed standard deviation [SD]) with mean RNFL thickness. We used linear regression analyses and, for GMS, P for trend analyses. We adjusted associations for demographic, cardiovascular risk and lifestyle factors, and, only for measures of GV, for indices of mean glycaemia. After full adjustment, type 2 diabetes and prediabetes (versus normal glucose metabolism) were associated with lower RNFL thickness (standardized beta [95% CI], respectively - 0.16 [- 0.25; - 0.08]; - 0.05 [- 0.13; 0.03]; Ptrend = 0.001). Greater FPG, 2-h PG, HbA1c, SAF, IGP, but not CGM-assessed SD, were also associated with lower RNFL thickness (per SD, respectively - 0.05 [- 0.08; - 0.01]; - 0.06 [- 0.09; - 0.02]; - 0.05 [- 0.08; - 0.02]; - 0.04 [- 0.07; - 0.01]; - 0.06 [- 0.12; - 0.01]; and - 0.07 [- 0.21; 0.07]). In this population-based study, a more adverse GMS and, over the entire range of glucose tolerance, greater glycaemia and daily GV were associated with lower RNFL thickness. Hence, early identification of individuals with hyperglycaemia, early glucose-lowering treatment, and early monitoring of daily GV may contribute to the prevention of RNFL thinning, an index of neurodegeneration and precursor of retinopathy and neuropathy.

Effects of fructose restriction on blood pressure: Secondary analysis of a double-blind randomized controlled trial.

BACKGROUND: Despite convincing animal data, there is an ongoing debate on whether and how fructose affects blood pressure in humans. The aim of this study was to investigate the effects of fructose restriction on blood pressure, and the role of endothelial function herein. METHODS: forty-four overweight individuals were asked to follow a fructose-restricted diet (<7.5 g/meal and <10 g/day) for 6 weeks. They were randomly assigned to double-blind supplementation with glucose (=intervention group) or fructose (=control group) powder three times daily. Office blood pressure was measured with an automated device, and endothelial function was assessed by reactive hyperemia peripheral arterial tonometry, skin laser doppler flowmetry, and serum sE-selectin. RESULTS: Thirty-seven participants completed the study. Systolic blood pressure decreased significantly in the intervention group (change from baseline: -3.3 mmHg; 95%CI:-8.8,- 0.3), but this change was not statistically different from the control group. In contrast, diastolic blood pressure decreased significantly in the intervention group in comparison to controls (difference: -4.0 mmHg; 95%CI:-9.5,-0.5). Furthermore, the change in fructose intake was associated with the change in diastolic blood pressure (beta: 0.085 mmHg; 95% CI: 0.032;0.138). The endothelial markers were not affected by the intervention. Finally, the effects of the intervention on diastolic blood pressure appeared to be higher in individuals consuming high amounts of salt at baseline (difference: -9.0 mmHg; 95%CI:-14.5,-2.5). CONCLUSIONS: Six-week fructose restriction per se results in a dose-dependent decrease in diastolic blood pressure. Further studies are warranted to elucidate the effects of fructose restriction on salt-sensitive hypertension in humans. TRIAL REGISTRATION: www. CLINICALTRIALS: gov; NCT03067428.

Association between de novo lipogenesis susceptibility genes and coronary artery disease.

BACKGROUND AND AIMS: Coronary artery disease (CAD) is the principal cause of death in individuals with non-alcoholic fatty liver disease (NAFLD). The aim of this study was to use genetic epidemiology to study the association between de novo lipogenesis (DNL), one of the major pathways leading to NAFLD, and CAD risk. METHODS AND RESULTS: DNL susceptibility genes were used as instruments and selected using three approaches: 1) genes that are associated with both high serum triglycerides and low sex hormone-binding globulin, both downstream consequences of DNL (unbiased approach), 2) genes that have a known role in DNL (biased approach), and 3) genes that have been associated with serum fatty acids, used as a proxy of DNL. Gene-CAD effect estimates were retrieved from the meta-analysis of CARDIoGRAM and the UK Biobank (∼76014 cases and ∼264785 controls). Effect estimates were clustered using a fixed-effects meta-analysis. Twenty-two DNL susceptibility genes were identified by the unbiased approach, nine genes by the biased approach and seven genes were associated with plasma fatty acids. Clustering of genes selected in the unbiased and biased approach showed a statistically significant association with CAD (OR:1.016, 95%CI:1.012; 1.020 and OR:1.013, 95%CI:1.007; 1.020, respectively), while clustering of fatty acid genes did not (OR:1.004, 95%CI:0.996-1.011). Subsequent exclusion of potential influential outliers did reveal a statistically significant association (OR:1.009, 95%CI:1.000; 1.018). CONCLUSIONS: DNL susceptibility genes are associated with an increased risk of CAD. These findings suggest that DNL may be involved in the pathogenesis of CAD and favor further development of strategies that target NAFLD through DNL.

Fructose 1-phosphate, an evolutionary signaling molecule of abundancy.

Evidence is accumulating that specifically fructose exerts adverse cardiometabolic effects in humans. Recent experimental studies have shown that fructose not only serves as a substrate for, among others, intrahepatic lipid formation, but also has a signaling function. It is postulated that fructose 1-phosphate (F1-P) has evolved as a signaling molecule of abundancy that stimulates nutrient absorption, lipid storage, and reproduction. Such a role would provide an explanation for why fructose contributes to the pathogenesis of evolutionary mismatch diseases, including nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, polycystic ovary syndrome (PCOS), and colorectal cancer, in the current era of nutritional abundance. It is anticipated that reducing F1-P, by either pharmacological inhibition of ketohexokinase (KHK) or societal measures, will mitigate the risk of these diseases.