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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.

BACKGROUND & AIMS: There is an ongoing debate on whether non-alcoholic fatty liver disease (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 & 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 (IVW) MR analyses showed a statistically significant association between genetically predicted cALT and risk of CAD (odds ratio [OR]:1.116, 95% confidence interval [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.

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, with a population-based cohort (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.

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.

Background: Glucose variability (GV) measured by continuous glucose monitoring (CGM) has become an accepted marker of glycemic control. Nevertheless, several methodological aspects of GV assessment require further study. We, therefore, investigated the minimum number of days needed to reliably measure GV, assessed GV reference values, and studied the correlation of GV with established glycemic indices (i.e., HbA(1c), seven-point oral glucose tolerance test [OGTT]-derived indices). Methods: We used cross-sectional data from The Maastricht Study, an observational population-based cohort enriched with type 2 diabetes. Participants with more than 48 h of CGM (iPro2; Medtronic) were included for analysis (n = 851; age: 60 +/- 9years; 49% women; 23% type 2 diabetes). We used mean sensor glucose (MSG), standard deviation (SD), and coefficient of variation (CV) as CGM-derived indices (the latter two for GV quantification). We calculated reliability using the Spearman-Brown prophecy formula, established reference values by calculating 2.5th-97.5th percentiles, and studied correlations using Spearman's rho. Results: Sufficient reliability (R > 0.80) was achieved with two (MSG and SD), or three monitoring days (CV). The reference ranges, assessed in individuals with normal glucose metabolism (n = 470), were 90.5-120.6 mg/dL (MSG), 7.9-24.8 mg/dL (SD), and 7.74%-22.45% (CV). For MSG, the strongest correlation was found with fasting plasma glucose (rho = 0.65 [0.61; 0.69]); for SD, with the 1-h OGTT value (rho = 0.61 [0.56; 0.65]); and for CV, with both the incremental glucose peak (IGP) during the OGTT (rho = 0.50 [0.45; 0.55]) and the 1-h OGTT value (rho = 0.50 [0.45; 0.55]). Conclusions: The reliability findings and reference values are relevant for studies that aim to investigate CGM-measured GV. One-hour OGTT and IGP values can be used as GV indices when CGM is unavailable.

Context: Hepatokines have emerged as potential mediators of obesity-associated comorbidities, such as type 2 diabetes, cardiovascular disease, fractures, and central hypogonadism.Objective: To assess whether weight loss-induced changes in hepatokines are mediated by intrahepatic triglyceride (IHTG) content.Design: Cross-sectional study and randomized controlled trial.Setting: General community.Participants: Metabolically healthy, lean men (waistIntervention: Men with abdominal obesity were randomized to 8-week dietary weight loss or no weight loss.Main Outcome Measures: IHTG and serum hepatokines, that is, serum IGF1, IGF binding protein 1 (IGFBP1), SHBG, fibroblast growth factor 21 (FGF21), fetuin A, and plasma fetuin B.Results: All hepatokines, except for fetuin B, were significantly different between lean men and men with obesity. After the weight-loss intervention (-10.3 kg; 95% CI, -11.4 to-9.2), serum IGF1, IGFBP1, SHBG, and fetuin A approached the values observed in lean men. Cross-sectional associations were observed between IHTG and IGF1 (beta = -0.51; 95% CI, -0.82 to -0.20), IGFBP1 (beta = -4.2; 95% CI, -7.7 to -0.7), and FGF21 (beta = 2.1; 95% CI, 1.3 to 2.9) in lean men and men with abdominal obesity combined. Weight loss resulted in a reduction of IHTG (treatment effect, -2.2%; 95% CI, -3.4% to -1.2%) that was associated with a change in IGF1 (beta = -0.9; 95% CI, -1.3 to -0.4), IGFBP1 (beta = -0.17; 95% CI, -0.31 to -0.03), and SHBG levels (beta = -0.18; 95% CI, -0.29 to -0.07). Mediation analyses showed that only the weight loss-induced change in serum IGF1 was mediated by IHTG (mediated effect, 32.7%; 95% CI, 4.6% to 79.2%).Conclusions: Dietary weight loss has differential effects on hepatokines. This study shows that the change in serum IGF1 levels after dietary weight loss is mediated by the change in IHTG content.

Context: There is an ongoing debate about whether and how fructose is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A recent experimental study showed an increased intrahepatic triglyceride (IHTG) content in mice deficient for aldolase B (aldo B-/-), the enzyme that converts fructose-1-phosphate to triose phosphates.Objective: To translate these experimental findings to the human situation.Design: Case-control study.Setting: Outpatient clinic for inborn errors of metabolism.Patients or Other Participants: Patients with hereditary fructose intolerance, a rare inborn error of metabolism caused by a defect in aldolase B (n = 15), and healthy persons matched for age, sex, and body mass index (BMI) (n =15).Main Outcome Measure: IHTG content, assessed by proton magnetic resonance spectroscopy.Results: IHTG content was higher in aldo B-/- patients than controls (2.5% vs 0.6%; P = 0.001) on a background of lean body mass (median BMI, 20.4 and 21.8 kg/m(2), respectively). Glucose excursions during an oral glucose load were higher in aldo B-/- patients (P = 0.043). Hypoglycosylated transferrin, a surrogate marker for hepatic fructose-1-phosphate concentrations, was more abundant in aldo B-/- patients than in controls (P <0.001). Finally, plasma beta-hydroxybutyrate, a biomarker of hepatic beta-oxidation, was lower in aldo B-/- patients than controls (P = 0.009).Conclusions: This study extends previous experimental findings by demonstrating that aldolase B deficiency also results in IHTG accumulation in humans. It suggests that the accumulation of fructose-1-phosphate and impairment of beta-oxidation are involved in the pathogenesis.