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.

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.

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.

Fructose Intake From Fruit Juice and Sugar-Sweetened Beverages Is Associated With Higher Intrahepatic Lipid Content: The Maastricht Study.

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.

Development and validation of a UPLC-MS/MS method to quantify fructose in serum and urine.

BACKGROUND: The study of the involvement of fructose in the pathogenesis of cardiometabolic disease requires accurate and precise measurements of serum and urinary fructose. The aim of the present study was to develop and validate such a method by Ultra Performance Liquid Chromatography-tandem Mass Spectrometry (UPLC-MS/MS). METHODS: Fructose was quantified using hydrophilic interaction UPLC-MS/MS with a labelled internal standard. Serum fructose levels were determined in healthy individuals (n = 3) after a 15-gram oral fructose load. Twenty-four hours urinary fructose levels were determined in individuals consuming low (median: 1.4 g/day, interquartile range [IQR]: 0.9-2.0; n = 10), normal (31 g/day, 23-49; n = 15) and high (70 g/day, 55-84; n = 16) amounts of fructose. RESULTS: The calibration curves showed perfect linearity in water, artificial, serum, and urine matrices (r2 > 0.99). Intra- and inter-day assay variation of serum and urinary fructose ranged from 0.3 to 5.1% with an accuracy of ~98%. Fasting serum fructose levels (5.7 ± 0.6 µmol/L) increased 60 min after a 15-gram oral fructose load (to 150.3 ± 41.7 µmol/L) and returned to normal after 180 min (8.4 ± 0.6 µmol/L). Twenty-four hours urinary fructose levels were significantly lower in low fructose consumers when compared to normal and high fructose consumers (median: 36.1 µmol/24 h, IQR: 26.4-64.2; 142.3 µmol/24 h, 98.8-203.0; and 238.9 µmol/24 h, 127.1-366.1; p = 0.004 and p < 0.001, respectively). CONCLUSION: Fructose concentrations can be measured accurately and precisely with this newly-developed UPLC-MS/MS method. Its robustness makes it suitable for assessing the value of fructose in clinical studies.

Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease.

Hereditary fructose intolerance (HFI) is a rare inborn disease characterized by a deficiency in aldolase B, which catalyzes the cleavage of fructose 1,6-bisphosphate and fructose 1-phosphate (Fru 1P) to triose molecules. In patients with HFI, ingestion of fructose results in accumulation of Fru 1P and depletion of ATP, which are believed to cause symptoms, such as nausea, vomiting, hypoglycemia, and liver and kidney failure. These sequelae can be prevented by a fructose-restricted diet. Recent studies in aldolase B-deficient mice and HFI patients have provided more insight into the pathogenesis of HFI, in particular the liver phenotype. Both aldolase B-deficient mice (fed a very low fructose diet) and HFI patients (treated with a fructose-restricted diet) displayed greater intrahepatic fat content when compared to controls. The liver phenotype in aldolase B-deficient mice was prevented by reduction in intrahepatic Fru 1P concentrations by crossing these mice with mice deficient for ketohexokinase, the enzyme that catalyzes the synthesis of Fru 1P. These new findings not only provide a potential novel treatment for HFI, but lend insight into the pathogenesis of fructose-induced non-alcoholic fatty liver disease (NAFLD), which has raised to epidemic proportions in Western society. This narrative review summarizes the most recent advances in the pathogenesis of HFI and discusses the implications for the understanding and treatment of fructose-induced NAFLD.

Total Fermented Dairy Food Intake Is Inversely Associated with Cardiovascular Disease Risk in Women.

BACKGROUND: The relation between fermented dairy consumption and type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) in an Australian population remains to be established. OBJECTIVES: The aim of this study was to investigate the association between fermented dairy consumption and T2DM and CVD risk. METHODS: The Australian Longitudinal Study on Women's Health included Australian women (aged 45-50 y) at baseline in 2001, who were followed up through 5 surveys until 2016. Dietary intake was assessed through the use of a validated 101-item FFQ at baseline. Main study outcomes were self-reported physician-diagnosed T2DM and CVD. Logistic regression models adjusted for sociodemographic and lifestyle factors were used to estimate the association between dairy intake and T2DM and CVD risk. RESULTS: Of 7633 women free of diabetes at baseline, 701 (9.2%) developed T2DM during a maximum 15-y follow-up period. Women in the highest tertile of yogurt intake had lower adjusted odds of T2DM than those in the lowest tertile (OR: 0.81; 95% CI: 0.67, 0.99; P = 0.041). This relation became nonsignificant after adjustment for dietary variables and total energy intake (OR: 0.88; 95% CI: 0.71, 1.08; P = 0.21). Of 7679 women free of CVD at baseline, 835 (10.9%) cases of CVD were reported during follow-up. High intake of yogurt and total fermented dairy was associated with lower CVD risk (OR: 0.84; 95% CI: 0.70, 1.00; P = 0.05, 0.80; 0.67, 0.96; 0.017, respectively) than observed in the lowest tertile of dairy product intake. Additional adjustment attenuated the relation (OR: 0.87; 95% CI: 0.72, 1.04; P = 0.13, 0.83; 0.69, 1.00; 0.048, for yogurt and total fermented dairy, respectively). No associations were found with other dairy groups. CONCLUSION: The findings from this population-based study of Australian women suggest an inverse association between total fermented dairy intake and CVD risk, which may partly be accounted for by other dietary components.