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Anna Tichler,1,2 Dorijn FL Hertroijs,1,2 Dirk Ruwaard,1,2 Martijn CGJ Brouwers,2,3 Mickaël Hiligsmann,1,2 Judith D de Jong,1,2,4 Arianne MJ Elissen1,2 1Department of Health Services Research, Faculty of Health, Medicine and Life Sciences (FHML), Maastricht University, Maastricht, the Netherlands; 2Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, the Netherlands; 3Department of Internal Medicine, Division of Endocrinology and Metabolic Disease, Maastricht University Medical Center+, Maastricht, the Netherlands; 4The Netherlands Institute for Health Services Research (NIVEL), Utrecht, the NetherlandsCorrespondence: Anna Tichler, Department of Health Services Research, Faculty of Health, Medicine and Life Sciences (FHML), Maastricht University, P.O. Box 616, Maastricht, 6200 MD, the Netherlands, Tel +31433882193, Email a.tichler@maastrichtuniversity.nlPurpose: 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.Keywords: shared decision-making, person-centered care, patient preferences, diabetes type 2

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

The aim of this study was to investigate the associations between sex hormone binding globulin (SHBG), visceral fat (VAT), liver fat content, and risk of type 2 diabetes. In the Netherlands Epidemiology of Obesity study 5690 women (53%) and men without pre-existing diabetes were included and followed for incident type 2 diabetes. SHBG concentrations were measured in all, VAT with MRI, and liver fat content with proton-MR spectroscopy in n=1822. We examined associations between SHBG and liver fat with linear regression and bidirectional Mendelian randomization analyses, and between SHBG and type 2 diabetes with Cox regression adjusted for confounding, and additionally for VAT and liver fat to examine mediation. The mean(SD) age was 56(6) years, BMI 30(4) kg/m2, median(IQR) SHBG was 47 (34,65) nmol/L in women and 34 (26,43) nmol/L in men, median(IQR) liver fat was 3.4(1.6,8.2)% in women and 6.0 (2.9,13.5)% in men. Compared with the highest SHBG quartile, liver fat was 2.9-fold (95%CI: 2.4,3.4) increased in women and 1.6-fold (95%CI: 1.3,1.8) in men, and the hazard ratio (95%CI) of type 2 diabetes was 4.9 (2.4,9.9) in women and 1.8 (1.1,2.9) in men. Genetically predicted SHBG was associated with liver fat content (women: SD (95%CI) -0.45(-0.55,-0.35), men: ln(95%CI) -0.25 (-0.34,-0.16)). VAT and liver fat together mediated 43% (women) and 60% (men) of the SHBG-type 2 diabetes association. To conclude, in a middle-aged population with overweight, the association between low SHBG and increased risk of type 2 diabetes was for a large part mediated by increased VAT and liver fat., (© 2024 by the American Diabetes Association.)

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., Competing Interests: Conflict of interest The authors declare there are no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Panis, Vos, Barić, Bosch, Brouwers, Burlina, Cassiman, Coman, Couce, Das, Demirbas, Empain, Gautschi, Grafakou, Grunewald, Kingma, Knerr, Leão-Teles, Möslinger, Murphy, Õunap, Pané, Paci, Parini, Rivera, Scholl-Bürgi, Schwartz, Sdogou, Shakerdi, Skouma, Stepien, Treacy, Waisbren, Berry and Rubio-Gozalbo.)

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., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

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., Competing Interests: Declaration of Competing Interest MCGJB received consultancy fees from Arrowhead and Editas Medicine., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., (©2023 American Association for Cancer Research.)

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., Competing Interests: Bianca Panis, Lise E.F. Janssen, Dirk J. Lefeber, Nynke Simons and M. Estela Rubio‐Gozalbo declare that they have no conflict of interest. Martijn C.G.J. Brouwers received consultancy fees from Arrowhead and Editas Medicine., (© 2023 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

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., Competing Interests: All authors declare no conflicts of interest related to this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

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: β = 0.19 (0.09, 0.28); DMS: β = 0.24 (0.14, 0.34)]; peripheral adiposity, e.g., biceps and triceps skinfolds [CODAM: β = 0.15 (0.08, 0.23); DMS: β = 0.20 (0.12, 0.29)]; and central adiposity, e.g., WC [CODAM: β = 0.16 (0.08, 0.25); DMS: β = 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., (© 2022. The Author(s).)

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., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., (© 2022. The Author(s).)

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., Competing Interests: Declaration of competing interest The authors declare that there is no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

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]; P trend  = 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., (© 2022. The Author(s).)

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., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Tyrosinemia type 1 (TT1) and phenylketonuria (PKU) are both inborn errors of phenylalanine-tyrosine metabolism. Neurocognitive and behavioral outcomes have always featured in PKU research but received less attention in TT1 research. This study aimed to investigate and compare neurocognitive, behavioral, and social outcomes of treated TT1 and PKU patients. We included 33 TT1 patients (mean age 11.24 years; 16 male), 31 PKU patients (mean age 10.84; 14 male), and 58 age- and gender-matched healthy controls (mean age 10.82 years; 29 male). IQ (Wechsler-subtests), executive functioning (the Behavioral Rating Inventory of Executive Functioning), mental health (the Achenbach-scales), and social functioning (the Social Skills Rating System) were assessed. Results of TT1 patients, PKU patients, and healthy controls were compared using Kruskal-Wallis tests with post-hoc Mann-Whitney U tests. TT1 patients showed a lower IQ and poorer executive functioning, mental health, and social functioning compared to healthy controls and PKU patients. PKU patients did not differ from healthy controls regarding these outcome measures. Relatively poor outcomes for TT1 patients were particularly evident for verbal IQ, BRIEF dimensions "working memory", "plan and organize" and "monitor", ASEBA dimensions "social problems" and "attention problems", and for the SSRS "assertiveness" scale (all p values <0.001). To conclude, TT1 patients showed cognitive impairments on all domains studied, and appeared to be significantly more affected than PKU patients. More attention should be paid to investigating and monitoring neurocognitive outcome in TT1 and research should focus on explaining the underlying pathophysiological mechanism., (© 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Purpose of Review: The rise in fructose consumption in parallel with the current epidemic of obesity and related cardiometabolic disease requires a better understanding of the pathophysiological pathways that are involved., Recent Findings: Animal studies have shown that fructose has various effects on the intestines that subsequently affect intrahepatic lipid accumulation and inflammation. Fructose adversely affects the gut microbiome - as a producer of endotoxins and intermediates of de novo lipogenesis - and intestinal barrier function. Furthermore, intestinal fructose metabolism shields fructose away from the liver. Finally, fructose 1-phosphate (F1-P) serves as a signal molecule that promotes intestinal cell survival and, consequently, intestinal absorption capacity. Intervention and epidemiological studies have convincingly shown that fructose, particularly derived from sugar-sweetened beverages, stimulates de novo lipogenesis and intrahepatic lipid accumulation in humans. Of interest, individuals with aldolase B deficiency, who accumulate F1-P, are characterized by a greater intrahepatic lipid content. First phase II clinical trials have recently shown that reduction of F1-P, by inhibition of ketohexokinase, reduces intrahepatic lipid content., Summary: Experimental evidence supports current measures to reduce fructose intake, for example by the implementation of a tax on sugar-sweetened beverages, and pharmacological inhibition of fructose metabolism to reduce the global burden of cardiometabolic disease., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Evidence is accumulating that liver sinusoidal endothelial cells are involved in the pathogenesis of non-alcoholic fatty liver disease. Previous studies have suggested that the endothelial biomarker soluble E-selectin (sE-selectin) is to an important extent liver-derived., Aims: To study the relationship of intrahepatic lipid (IHL) content with sE-selectin at the population level., Methods: This study was conducted in participants of The Maastricht Study (n = 1,634), a population-based cohort study enriched with patients with type 2 diabetes. We assessed the cross-sectional association between IHL content, quantified by MRI, and sE-selectin via multivariable regression with adjustment for age, sex, type 2 diabetes, educational level, BMI, Dutch Healthy Diet index, physical activity, and the Matsuda index., Results: Standardized IHL content was associated with (log) sE-selectin (age-, sex- and type 2 diabetes-adjusted regression coefficient [B]: 0.048 [95%CI:0.038;0.058], p<0.001), even after full adjustment (B: 0.030 [0.019;0.042], p<0.001). Such an association was not observed for soluble vascular cell adhesion molecule 1 (sVCAM-1) levels., Conclusion: IHL content is an independent determinant of sE-selectin at the population level. These findings support further studies to unravel the involvement of liver sinusoidal endothelial cells in the different stages of non-alcoholic fatty liver disease and the specific role of E-selectin herein., Competing Interests: Conflict of interest The authors declare that they have no competing interests., (Copyright © 2022. Published by Elsevier Ltd.)

Aims: Sodium-glucose co-transporter-2 (SGLT-2) inhibitor-induced weight loss might play a role in the debated elevated fracture risk with these agents. The aim of the current study was to investigate the association between SGLT-2 inhibitor use, changes in body mass index (BMI) and fracture risk., Methods: A retrospective cohort study was conducted using data from the UK Clinical Practice Research Datalink (CPRD) GOLD (2013-2018). The study population (N = 34,960) consisted of adults with diabetes initiating a sulphonylurea or SGLT-2 inhibitor. Cox proportional hazards models estimated hazard ratios (HRs) for major osteoporotic fracture with SGLT-2 inhibitor use versus sulphonylurea use, stratified by change in BMI, average daily dose and cumulative dose. Analyses were adjusted for age, sex, lifestyle variables, comorbidities, and concomitant drug use., Results: SGLT-2 inhibitor use was not associated with an increased fracture risk compared to sulphonylurea use (adjusted HR 1.19; 95% confidence interval (CI): 0.80-1.79). This finding remained consistent after stratification by BMI change. However, the highest cumulative dose category was associated with an increased fracture risk (adjusted HR: 2.10, 95 %CI: 1.11-3.99)., Conclusion: SGLT-2 inhibitor use was not associated with increased osteoporotic fracture risk, irrespective of change in BMI. However, a high cumulative dose could be an important risk factor., Competing Interests: Declaration of Competing Interest RE reports grants from Amgen, grants and personal fees from IDS, grants from Alexion, grants for Roche, personal fees from GSK Nutrition, personal fees from Mereo, personal fees from Sandoz, grants and personal fees from Nittobo, personal fees from Samsung, personal fees from Haoma Medica, personal fees from Elsevier, personal fees from CL Bio, personal fees from UCSF. Other authors declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: De novo lipogenesis has been inversely associated with serum sex hormone-binding globulin (SHBG) levels. However, the directionality of this association has remained uncertain. We, therefore, studied individuals with glycogen storage disease type 1a (GSD1a), who are characterized by a genetic defect in glucose-6-phosphatase resulting in increased rates of de novo lipogenesis, to assess the downstream effect on serum SHBG levels., Methods: A case-control study comparing serum SHBG levels in patients with GSD1a (n = 10) and controls matched for age, sex, and BMI (n = 10). Intrahepatic lipid content and saturated fatty acid fraction were quantified by proton magnetic resonance spectroscopy., Results: Serum SHBG levels were statistically significantly lower in patients with GSD1a compared to the controls (p = 0.041), while intrahepatic lipid content and intrahepatic saturated fatty acid fraction-a marker of de novo lipogenesis-were significantly higher in patients with GSD1a (p = 0.001 and p = 0.019, respectively). In addition, there was a statistically significant, inverse association of intrahepatic lipid content and saturated fatty acid fraction with serum SHBG levels in patients and controls combined (β: - 0.28, 95% CI: - 0.47;- 0.09 and β: - 0.02, 95% CI: - 0.04;- 0.01, respectively)., Conclusion: Patients with GSD1a, who are characterized by genetically determined higher rates of de novo lipogenesis, have lower serum SHBG levels than controls., (© 2022. The Author(s).)

Background & Aims: Glycogen storage disease type Ia (GSDIa) is an inborn error of carbohydrate metabolism caused by pathogenic variants in the glucose-6-phosphatase catalytic subunit 1 ( G6PC1 ) gene and is associated with hepatocellular adenoma (HCA) formation. Data on risk factors for HCA occurrence in GSDIa are scarce. We investigated HCA development in relation to sex, G6PC1 genotype, and serum triglyceride concentration (TG)., Methods: An observational study of patients with genetically confirmed GSDIa ≥12 years was performed. Patients were categorised for sex; presence of 2, 1, or 0 predicted severe G6PC1 variant (PSV); and median TG during childhood (<12 years; stratified for above/below 5.65 mmol/L, i.e. 500 mg/dl)., Results: Fifty-three patients (23 females) were included, of which 26 patients developed HCA at a median (IQR) age of 21 (17-25) years. At the age of 25 years, 48% of females and 30% of males had developed HCA (log-rank p  = 0.045). Two-thirds of patients with GSDIa carried 2 PSVs, 20% carried 1, and 13% carried none. Neither the number of PSVs nor any specific G6PC1 variants were associated with HCA occurrence. Childhood TG was 3.4 (3.0-4.2) mmol/L in males vs . 5.6 (4.0-7.9) mmol/L in females ( p  = 0.026). Childhood TG >5.65 mmol/L was associated with HCA development at younger age, compared with patients with childhood TG <5.65 mmol/L (18 vs . 33 years; log-rank p  = 0.001). Cox regression analysis including TG, sex, and TG-sex interaction correction revealed childhood TG >5.65 mmol/L as an independent risk factor for HCA development (hazard ratio [HR] 6.0; 95% CI 1.2-29.8; p  = 0.028)., Conclusions: In patients with GSDIa, high childhood TG was associated with an increased risk of HCA, and earlier onset of HCA development, independent of sex-associated hypertriglyceridaemia, and G6PC1 genotype., Lay Summary: Glycogen storage disease type Ia (GSDIa) is a rare, inherited metabolic disease that can be complicated by liver tumours (hepatocellular adenomas), which in turn may cause bleeding or progress to liver cancer. Risk factors associated with hepatocellular adenoma formation in patients with GSDIa are largely unknown. In our study, we found that high serum triglyceride concentrations during childhood, but not specific genetic variants, were associated with increased risk of hepatocellular adenoma diagnosis later in life., Competing Interests: There are no conflicts of interest to be reported. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

Objective: Epidemiological evidence regarding the relationship between fructose intake and intrahepatic lipid (IHL) content is inconclusive. We, therefore, assessed the relationship between different sources of fructose and IHL at the population level., Research Design and Methods: We used cross-sectional data from The Maastricht Study, a population-based cohort study (n = 3,981; mean ± SD age: 60 ± 9 years; 50% women). We assessed the relationship between fructose intake (assessed with a food-frequency questionnaire)-total and derived from fruit, fruit juice, and sugar-sweetened beverages (SSB)-and IHL (quantified with 3T Dixon MRI) with adjustment for age, sex, type 2 diabetes, education, smoking status, physical activity, and intakes of total energy, alcohol, saturated fat, protein, vitamin E, and dietary fiber., Results: Energy-adjusted total fructose intake and energy-adjusted fructose from fruit were not associated with IHL in the fully adjusted models (P = 0.647 and P = 0.767). In contrast, energy-adjusted intake of fructose from fruit juice and SSB was associated with higher IHL in the fully adjusted models (P = 0.019 and P = 0.009). Individuals in the highest tertile of energy-adjusted intake of fructose from fruit juice and SSB had a 1.04-fold (95% CI 0.99; 1.11) and 1.09-fold (95% CI 1.03; 1.16) higher IHL, respectively, in comparison with the lowest tertile in the fully adjusted models. Finally, the association for fructose from fruit juice was stronger in individuals with type 2 diabetes (P for interaction = 0.071)., Conclusions: Fructose from fruit juice and SSB is independently associated with higher IHL. These cross-sectional findings contribute to current knowledge in support of measures to reduce the intake of fructose-containing beverages as a means to prevent nonalcoholic fatty liver disease at the population level., (© 2022 by the American Diabetes Association.)

Objective: Polycystic ovary syndrome (PCOS) has been associated with an increased risk of coronary artery disease (CAD). However, it remains uncertain whether this increased risk is the result of PCOS per se or, alternatively, is explained by obesity, a common feature of PCOS. The aim of this study was to assess the causal association between PCOS and CAD and the role of obesity herein., Design and Methods: We conducted two-sample Mendelian randomisation analyses in large-scale, female-specific datasets to study the association between genetically predicted (1) risk of PCOS and risk of CAD, (2) body mass index (BMI) and risk of PCOS and (3) BMI and risk of CAD. Primary analyses were conducted with the inverse-variance weighted (IVW) method. Simple median, penalized weighted median and contamination mixture analyses were performed to assess the robustness of the outcomes., Results: IVW analyses did not show a statistically significant association between PCOS and CAD (odds ratio [OR]: 0.99, 95% confidence interval [CI]: 0.89, 1.11). In contrast, genetically predicted BMI was statistically significantly associated with an increased odds of PCOS (OR: 3.21, 95% CI: 2.26, 4.56) and CAD (OR: 1.38, 95% CI: 1.14, 1.67). Similar results were obtained when secondary analyses were performed., Conclusion: These sex-specific analyses show that the genetically predicted risk of PCOS is not associated with the risk of CAD. Instead, the genetically predicted risk of obesity (and its downstream metabolic effects) is the common denominator of both PCOS and CAD risk., (© 2021 The Authors. Clinical Endocrinology Published by John Wiley & Sons Ltd.)

Background and Aims: Thiazolidinediones (TZDs) and glucagon-like peptide-1 (GLP-1) receptor agonists are potential pharmacological treatment options for patients at risk of NAFLD. Therefore, we examined the association between the risk of NAFLD and the use of TZDs and GLP-1 receptor agonists compared with the use of sulfonylureas (SUs) and insulins. Additionally, we calculated the incidence of HCC in users of TZDs and GLP-1 receptor agonists., Approach and Results: We conducted a population-based cohort study using primary care data from the Clinical Practice Research Datalink database (2007-2018). All patients aged ≥18 with a prescription of an oral glucose-lowering agent or GLP-1 receptor agonist were included. The first prescription defined the start of follow-up. The primary outcome was a new diagnosis of NAFLD. Cox proportional hazards regression was used to estimate HRs and 95% CIs of the primary outcome. Incidence rates of HCC were determined per 1,000 person-years for all exposures. The study identified 207,367 adults with a prescription for a glucose-lowering agent. The risk of NAFLD was lower in patients prescribed a TZD than in those prescribed an SU (adjusted HR [aHR], 0.32; 95% CI, 0.20-0.51). No difference in risk of NAFLD was observed comparing GLP-1 receptor agonist use with insulin use (aHR, 1.22; 95% CI, 0.91-1.63)., Conclusions: Results of our study endorse the use of TZDs for selected patients at risk of NAFLD but do not support previous findings regarding the beneficial effect of GLP-1 receptor agonists. The low number of events in several subgroups may affect the generalizability of the current findings., (© 2021 The Authors. HEPATOLOGY published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)