During the baseline phase of the study, subjects resided in the UCD Clinical and Translational Science Center’s Clinical Research Center (CCRC) for 2 weeks and consumed an energy-balanced, high–complex carbohydrate (55%) diet (Supplemental Table 1; supplemental material available online with this article; doi:10.1172/JCI37385DS1). Procedures conducted during the baseline CCRC visit included a 24-hour serial blood collection, a 26-hour stable isotope infusion for determination of fractional DNL, fasting and postprandial postheparin blood sampling, an oral glucose tolerance test (OGTT) and disposal test, a gluteal adipose biopsy, and a CT scan of the abdomen. Subjects then began an 8-week outpatient intervention and consumed either fructose- (n = 17) or glucose-sweetened (n = 15) beverages at 25% of energy requirements with self-selected ad libitum diets. The subjects returned to the CCRC after 2 outpatient weeks for 2 days and then again for the final 2 weeks of the intervention for inpatient metabolic studies, during which the glucose- or fructose-sweetened beverages were consumed as part of an energy-balanced diet. Blood was collected over four 24-hour periods, during baseline and after 2, 8, and 10 weeks of intervention. The study design is outlined in Table .
Twelve-week inpatient/outpatient, procedure, and diet schedule
Baseline characteristics and parameters.
There were no significant differences between the 2 experimental groups in baseline anthropomorphic characteristics or in any of the measured metabolic parameters (Table ).
Baseline anthropomorphic and metabolic parameters
Outpatient food intake, BW and composition, adipose tissue gene expression, and blood pressure.
During 24-hour food-intake recall interviews conducted on 6 outpatient days, both groups of subjects reported consuming significantly more energy than their calculated energy requirements. There were no significant differences between men and women or between subjects consuming glucose and subjects consuming fructose in fat, sugar, or alcohol intake as a percentage of energy intake or in the amount of energy consumed as a percentage of calculated energy requirements (Supplemental Table 2).
The changes in anthropomorphic outcomes are summarized in Table , and detailed analyses are presented in Supplemental Table 3. Despite comparable weight gain, there were differential effects of glucose and fructose on regional adipose deposition and gene expression. BW was stable during the 2-week inpatient periods at both the beginning and end of the study. However, during the 8-week outpatient intervention period, when the subjects consumed 25% of daily energy requirement as glucose- or fructose-sweetened beverages along with ad libitum self-selected diets, both groups of subjects exhibited significant increases of BW (Figure A), fat mass, and waist circumference. Total and visceral adipose tissue (VAT) volumes were not significantly changed in subjects consuming glucose; however, subcutaneous adipose tissue (SAT) volume was significantly increased. In contrast, both total abdominal fat and VAT volume were significantly increased in subjects consuming fructose (Figure B).
Baseline values and percentage changes in body composition and blood pressure after consumption of glucose- or fructose-sweetened beverages for 10 weeks
Changes of BW and abdominal fat.
SAT from the gluteal region was biopsied at 0 weeks and 10 weeks and analyzed for the expression of lipogenic and other genes (Supplemental Table 4). The percentage changes of gene expression at 10 weeks compared with baseline (0 weeks) were greater in subjects consuming glucose than in those consuming fructose for stearoyl-CoA desaturase, fatty acid desaturase 1, and fatty acid desaturase 2.
All subjects had normal blood pressure measurements at baseline, and blood pressure values did not change during the consumption of either fructose or glucose over the course of the 10-week intervention period (Table ; Supplemental Table 5).
Lipid and lipoprotein concentrations, fractional hepatic DNL, and lipoprotein lipase activity.
Plasma concentrations of lipid and lipoprotein parameters measured at 0 weeks, 2 weeks, 8 weeks, and 10 weeks with detailed analyses are presented in Supplemental Table 6.
In general, plasma lipid and lipoprotein concentrations increased markedly during fructose consumption and were unchanged during glucose consumption (Table ). In exception, fasting TG concentrations increased in subjects consuming glucose but were unchanged in subjects consuming fructose (2, 8, and 10 weeks vs. 0 weeks: +1.0% ± 5.5%, +1.0% ± 5.0% and +3.9% ± 5.5%; P = 0.92). There was marked variability in the fasting TG responses to fructose consumption both within groups and within the individual subject. The mean SD of the percentage changes at 2 weeks, 8 weeks, and 10 weeks compared with 0 weeks in each subject was 13.4% ± 1.5%. In contrast to fasting TG, indices of postprandial TG — 23-hour AUC, TG exposure, postprandial TG peak — did not increase in subjects consuming glucose but were markedly increased in subjects consuming fructose (Figure , A and B). Fasting (Figure , A and B) and postprandial apoB, the apoB/apoA1 ratio, and total and LDL cholesterol were also unchanged during consumption of glucose and increased during consumption of fructose. In both groups of subjects, plasma HDL concentrations were unchanged at 10 weeks but increased at the 2- and 8-week time points.
Baseline levels and percentage changes in lipid, lipoprotein, DNL, and LPL activity after consumption of glucose- or fructose-sweetened beverages for 10 weeks
In subjects consuming glucose, fasting small dense LDL (sdLDL) concentrations (Figure , C and D) initially decreased at 2 weeks and were not different from baseline at 10 weeks. In contrast, fasting sdLDL concentrations increased progressively in subjects consuming fructose. sdLDL was the lipid parameter most affected by preexisting metabolic syndrome risk factors (MSRF), with increases during fructose consumption more than 2-fold greater in subjects with 3 MSRF than in subjects with 0 to 2 MSRF (Supplemental Table 7). Fasting oxidized LDL concentrations did not change in subjects consuming glucose but increased in subjects consuming fructose.
Fasting plasma remnant-like particle lipoprotein–TG (RLP-TG) and RLP-cholesterol (RLP-C) concentrations were unaffected by consumption of glucose or fructose (data not shown). In subjects consuming glucose, postprandial concentrations of RLP-TG (Figure , E and F) were unchanged; however RLP-C concentrations were increased at 8 weeks. During consumption of fructose, postprandial concentrations of both RLP-TG and RLP-C were increased. FFA exposure over 24 hours was increased in subjects consuming glucose but unchanged in subjects consuming fructose.
Increased DNL contributed to the increases of postprandial TG during fructose consumption. Fractional hepatic DNL was unchanged during glucose consumption, both in the fasting (8.8% ± 1.8% vs. 9.5% ± 1.8%; P = 0.47) and postprandial states (13.4% ± 2.8% vs. 14.2% ± 1.7%; P = 0.31). Fasting DNL was unaffected during fructose consumption (9.9% ± 1.3% vs. 8.3% ± 0.9%; P = 0.25), but postprandial DNL was significantly increased (11.4% ± 1.3% vs. 16.9% ± 1.4%; P = 0.021) (Table ). The 16-hour AUC for fractional DNL was not increased compared with baseline in subjects consuming glucose (54% ± 17% vs. 60% ± 8% × 16 h; P = 0.69) but was significantly increased in subjects consuming fructose (21% ± 9% vs. 104% ± 19% × 16 h; P = 0.0043). The increase of the 16-hour AUC for fractional DNL during fructose consumption was significantly larger than that during glucose consumption (83% ± 22% vs. 7% ± 14% × 16 h; P = 0.016) (Figure ).
Reduced TG clearance may also contribute to increases of postprandial TG in subjects consuming fructose. Postprandial postheparin lipoprotein lipase (LPL) activity tended to increase after 10 weeks of glucose consumption and to decrease after 10 weeks of fructose consumption, and the overall difference between the sugars was significant (P = 0.041). Fasting postheparin LPL activity was not significantly affected by consumption of either glucose or fructose (Table ).
Plasma glucose, plasma insulin, and insulin sensitivity.
Indices of insulin sensitivity/glucose tolerance at the measured time points with effects of sugar analyses are presented in Supplemental Table 8. In general, insulin sensitivity and glucose tolerance were not affected by the consumption of glucose but were decreased during the consumption of fructose (Table ). Fasting glucose concentrations decreased in subjects consuming glucose but increased in subjects consuming fructose. Fasting insulin concentrations were unchanged during glucose consumption but were increased during consumption of fructose beverages. Glucose excursions, as assessed by the 3-hour AUC, increased in both groups of subjects during the OGTT (Figure , A and B). Insulin excursions were unchanged in subjects consuming glucose but increased in subjects consuming fructose (Figure , C and D). The insulin sensitivity index, assessed by the deuterated glucose disposal (5
), was unchanged in subjects consuming glucose but decreased by 17% in subjects consuming fructose (Figure E). The magnitude of the changes of indices of insulin sensitivity during fructose consumption were not significantly affected by the number of MSRF (Supplemental Table 9).
Baseline levels and percentage changes in fasting glucose and insulin and indices of insulin sensitivity after consumption of glucose- or fructose-sweetened beverages for 10 weeks
Effect of sexual phenotype.
The total and percentage increases of fat mass (men: +4.4% ± 0.8%; women: +1.5% ± 0.7%; P = 0.020) and intraabdominal fat volume (men: +18.1% ± 5.1%; women: –0.6% ± 4.4%; P = 0.049) were greater in men than in women. Men consuming fructose also had larger increases of intraabdominal fat compared with women consuming fructose (P = 0.033; Supplemental Table 3). Fructose consumption resulted in larger increases of 24-hour TG exposure, postprandial TG peak, and postprandial RLP-C in men compared with women (Supplemental Table 10). There were no significant differences in the effects of fructose on indices of glucose tolerance/insulin sensitivity between men and women (Supplemental Table 11). However, overall the changes in insulin sensitivity were different between men and women (P = 0.033; Supplemental Table 9), with women exhibiting significantly greater decreases of insulin sensitivity in response to sugar consumption than men. The insulin sensitivity index decreased by 10.2% ± 12.1% in women consuming glucose but increased by 12.5% ± 12.6% in men consuming glucose. The insulin sensitivity index decreased by 23.6% ± 4.4% in women consuming fructose and by 11.7% ± 5.6% in men consuming fructose.
Effects of energy intake during the previous day.
Subjects consumed significantly more energy ad libitum on the days prior to the 2-week and 8-week 24-hour serial blood collections than during the energy-balanced feeding that preceded the 0-week and 10-week 24-hour serial blood collections (Supplemental Table 12). The previous day’s energy intakes were included in the mixed procedures (PROC MIXED) repeated measures (RM) ANOVA model as a time-level covariable; therefore, the contribution and significance of the effect of the previous day’s energy intake on the variation of the outcome response can be ascertained by the F statistic and P value of the covariable (Supplemental Table 13). Within subjects consuming fructose, postprandial apoB was the outcome most significantly affected by energy intake during the previous day; TG exposure, fasting apoB, and postprandial RLP-C were significantly affected as well.