Metabolic effects of a prolonged, very-high-dose dietary fructose challenge in healthy subjects

Abstract

Background Increased fructose intake has been associated with metabolic consequences such as impaired hepatic lipid metabolism and development of nonalcoholic fatty liver disease (NAFLD). Objectives The aim of this study was to investigate the role of fructose in glucose and lipid metabolism in the liver, heart, skeletal muscle, and adipose tissue. Methods Ten healthy subjects (age: 28 ± 19 y; BMI: 22.2 ± 0.7 kg/m2) underwent comprehensive metabolic phenotyping prior to and 8 wk following a high-fructose diet (150 g daily). Eleven patients with NAFLD (age: 39.4 ± 3.95 y; BMI: 28.4 ± 1.25) were characterized as “positive controls.” Insulin sensitivity was analyzed by a 2-step hyperinsulinemic euglycemic clamp, and postprandial interorgan crosstalk of lipid and glucose metabolism was evaluated, by determining postprandial hepatic and intra-myocellular lipid and glycogen accumulation, employing magnetic resonance spectroscopy (MRS) at 7 T. Myocardial lipid content and myocardial function were assessed by 1H MRS imaging and MRI at 3 T. Results High fructose intake resulted in lower intake of other dietary sugars and did not increase total daily energy intake. Ectopic lipid deposition and postprandial glycogen storage in the liver and skeletal muscle were not altered. Postprandial changes in hepatic lipids were measured [Δhepatocellular lipid (HCL)_healthy_baseline: −15.9 ± 10.7 compared with ± ΔHCL_healthy_follow-up: −6.9 ± 4.6; P = 0.17] and hepatic glycogen (Δglycogen_baseline: 64.4 ± 14.1 compared with Δglycogen_follow-up: 51.1 ± 9.8; P = 0.42). Myocardial function and myocardial mass remained stable. As expected, impaired hepatic glycogen storage and increased ectopic lipid storage in the liver and skeletal muscle were observed in insulin-resistant patients with NAFLD. Conclusions Ingestion of a high dose of fructose for 8 wk was not associated with relevant metabolic consequences in the presence of a stable energy intake, slightly lower body weight, and potentially incomplete absorption of the orally administered fructose load. This indicated that young, metabolically healthy subjects can at least temporarily compensate for increased fructose intake. This trial was registered at www.clinicaltrials.gov as NCT02075164.

Overview of Non-Alcoholic Fatty Liver Disease (NAFLD) and the Role of Sugary Food Consumption and Other Dietary Components in Its Development

“…A systematic review and meta-analysis of six observational studies and 21 intervention studies concluded that there was insufficiently robust evidence available to demonstrate that high intake of fructose, HFCS, or sucrose is associated with a higher incidence of NAFLD and suggested that the relationship between fructose intake and NAFLD could be confounded by excessive energy intake [ 88 ]. In accordance with this, a recent short-term interventional study found that a high-fructose diet (150 g a day for 8 weeks) in an isocaloric context does not have negative health impacts on weight, liver health, cholesterol, insulin sensitivity, or glucose/blood sugar tolerance in healthy individuals [ 89 ]. In this trial with healthy individuals, no change in intramuscular or intrahepatic fat was observed, but there were higher levels of serum triglycerides and DNL.…”

“…High consumption of simple, high-glycaemic-index carbohydrates is associated with NAFLD [ 70 ]. Therefore, lower consumption of sugars should be advised, especially in high-calorie diets, although the pernicious effect of carbohydrates is more controversial in isocaloric or hypocaloric diets [ 89 , 90 ]. Fructose, as a paradigmatic example of this type of carbohydrate, deserves special attention.…”

“…However, these studies have some limitations [ 88 , 89 , 91 ]. The follow-up period in these trials is short (mostly 4 weeks or less), whereas we know from animal models that fatty liver develops after at least 8–24 weeks on a high-fructose diet [ 92 ].…”

Metabolic effects of the dietary monosaccharides fructose, fructose–glucose, or glucose in mice fed a starch‐containing moderate high–fat diet

“…The absence of a difference between glucose and fructose, but higher hepatic TG levels in the hypercaloric condition compared with the isocaloric condition confirm the notion that it is particularly the energy intake, rather than specific effects of fructose compared with glucose that results in the adverse metabolic effects. Indeed, a recent human study showed also overall lack of effects by high fructose intake (Smajis et al, 2019).…”

Multiple Parallel Hits Hypothesis in Nonalcoholic Fatty Liver Disease: Revisited After a Decade

“…( 79 ) A recent study in 10 healthy subjects, however, with excess isocaloric fructose consumption for 8 weeks showed no detrimental metabolic effects including the liver. ( 80 ) This raises some doubts as to whether fructose indeed damages the human liver to promote NAFLD. Wheat amylase trypsin inhibitors, a common dietary wheat component, activates intestinal macrophages ( 81 ) and has also been linked to experimental NAFLD as its consumption aggravates liver and AT inflammation.…”