Intervention outcomes 1. Tolerability/side effects

There were no subject drop outs, and all six study assessments were attended by all. There were no procedure or investigation related incidents. One subject reported headaches during the first period. These were ascribed to his

self-enforced concurrent caffeine restriction and resolved when he increased his caffeine intake back to his baseline level (glucose group). All other reported symptoms were gastrointestinal in origin. Such symptoms were more common with fructose than glucose, as shown on table 5, p=0.08. Most symptoms were mild and only two subjects were sufficiently troubled to contact the lead investigator in between study visits to discuss them. One was regarding constipation during the first period, which may well be attributed to the change in food intake during this period. The other subject was in the fructose group and was significantly troubled by bowel frequency. This was partially alleviated by modifying the monosaccharide consumption pattern though tended to persist throughout both two week periods.

Fructose (n=15)

Glucose (n=17)

Frequency 6 1

Constipation 0 1

Wind / gurgling 3 2

Bloating / pain 2 2

Nausea 1 0

Any GI symptom 8 4

Table 5. Gastrointestinal side effects reported during the study.

3.8.2. Changes in weight and metabolism between the two baseline assessments

The absolute change at the second baseline assessment as compared to the first of all principal variables measured for chapters 3, 4, and 5 is presented in table 6. There were no significant differences, or trends, in terms of weight, ectopic lipids, serum triglycerides, insulin resistance, renal and liver function, and whole body oxidative metabolism. Indeed no subject had a second baseline weight that differed by more than 3.5% from their first baseline weight, and 27 out of the 32 had a repeat weight within 2% of the first.

Amongst all the subjects there was a significant change in only one factor, NEFA, and near significance for uric acid (p=0.052). Between the groups there was a trend for a difference in uric acid only.

All Fructose Glucose Significance between groups (p)

Weight (kg) 0.33±1.37 0.59±1.7 0.09±1.0 0.32

Resting energy expenditure (kcal/day)

-39.6±114.1 -72.0±130.8 -11.0±91.7 0.13

Respiratory quotient (RQ) 0.05±0.038 0.0003±0.31 0.010±0.04 0.50 Lipid oxidation (mg/kg/min) -0.16±0.31 -0.20±0.35 -0.13±0.29 0.54 Carbohydrate oxidation

(mg/kg/min)

0.48±0.51 0.44±0.54 0.51±0.50 0.78

Hepatic triglyceride (%) 0.15±2.09 0.25±1.88 0.07±2.30 0.81 Intra-myocellular lipid (%) 0.01±2.26 0.23±1.96 -0.18±2.55 0.62 Extra-myocellular lipid (%) -0.54±3.13 0.42±3.37 -1.39±2.72 0.10 Triglycerides (mmol/L) -0.14±0.56 -0.18±0.63 -0.10±0.50 0.68

HOMA-IR 0.32±1.22 0.25±1.52 0.38±0.91 0.76

Glucose disposal (mg/kg/min) -0.14±1.11 -0.23±0.86 -0.05±1.40 0.80 Noradrenaline (nmol/L) -0.07±0.62 -0.01±0.69 -0.13±0.57 0.60 Adrenaline (nmol/L) -0.04±0.17 -0.04±0.19 -0.04±0.17 0.97 Non-esterified free fatty acids

(mmol/L)

-59±161* -34±149 -80±171 0.44

Creatinine ( mol/L) -1.8±5.6 -0.9±6.8 -2.5±4.5 0.43 Uric acid ( mol/L) -20.6±57.6 0.2±64.2 -38.9±45.4 0.054 Alkaline phosphatase (IU/L) -1.6±6.2 -1.1±7.4 -2.1±5.0 0.66 Alanine transaminase (U/L) -1.7±9.0 -4.3±9.3 0.7±8.3 0.12 Aspartate transaminase (U/L) -1.4±5.2 -2.2±5.6 -0.8±4.9 0.45 Gamma glutamyl

transpeptidase (U/L)

-1.9±6.5 -2.2±4.2 -1.7±8.2 0.82

Table 6. The absolute change within the entire cohort and each group at the second baseline assessment compared to the first baseline assessment, mean ± SD. (*=p<0.05)

3.8.3. Weight changes during the study

The changes in weight reflected the differing energy statuses of the two periods, with weight maintenance during the first period and gain during the second, see table 7 and figure 1. During the first period 26 volunteers maintained their weight within 1kg of their baseline weight. Four volunteers lost more than 1kg and 2 gained more than 1kg. In order to maintain stable weights, the food

plans were increased after the week 1 visit by 200kcal/day in two volunteers and reduced by 200kcal/day in two volunteers.

During the second period both groups gained significant amounts of weight at both weeks one and two. By week two weight increased by +1.03±1.37 kg in the fructose group (p=0.01) and by +0.57±1.00 kg in the glucose group (p=0.03). There was no significant difference between the groups in terms of the amounts of change.

Table 7. The subjects’ weight (kg) during the study, mean ± SD. (*=p<0.05,

**=p<0.01 compared to baseline value in that group.)

week 1 week 2 week 1 week 2

Figure 1. The change in weight from baseline during the two study periods, mean ±SEM. (*=p<0.05 from baseline in that group)

3.8.4. Satiety outcomes a. First period

The self completed visual analogue scale responses during the first period for subject’s satiety, energy and food enjoyment are presented in table 8. The baseline responses were essentially identical between the groups except that the glucose group reported less food satisfaction. It is however the change in response as opposed to the absolute value that is of greater interest. Overall the subjects reported increased fullness and reduced hunger during this first period despite weight maintenance. The degree of change was small and matched between the groups.

Table 8. Visual analogue scale responses during the first period to the statement: ‘Over the last week I have...’ (A score of 0 = never, whereas a score of 100 = all of the time), mean ± SD. (*=p<0.05, **=p<0.01 compared to baseline value in that group. † = p<0.05 difference between the groups at baseline.)

b. Second period

Baseline responses in the second period were not matched. The fructose group reported significantly greater food enjoyment and satisfaction, and a lower hunger and sense of lacking energy, see table 9. The reasons for this are unclear, though again what is more important is the change in values during the period

itself. Despite weight changes there were minimal changes in responses, and these were even more blunted than during the first period. During both periods there were no significant associations between change in weight and changes in visual analogue scale responses.

Of note, hunger levels reduced in the glucose group during the second period (p=0.042), whereas there was no change in the fructose group. The interpretation of this isolated finding is uncertain as there were no changes in satisfaction, fullness or energy in this group.

Over the last week I have…

All subjects

Fructose Glucose Difference between

Table 9. Visual analogue scale responses during the second period to the statement: ‘Over the last week I have...’. (A score of 0 = never, whereas a score of 100 =all of the time) , mean ± SD. (*=p<0.05 compared to baseline value in that group. † = p<0.05 difference between the groups at baseline.)

3.8.5. Renal outcomes

The fasted serum creatinine data at each main visit are presented in table 10. There were no significant changes during the study or differences between the groups.