This small meta-analysis of six controlled feeding trials in 118 subjects over a median follow-up of 6 weeks showed that ‘catalytic’ doses (22·5–36 g/d) of fructose in isoenergetic exchange for other carbohydrates may improve glycaemic control without adversely affecting other cardiometabolic risk factors. The reduction in HbA1c of 0·4 % was clinically significant, lying at the lower limit of efficacy expected for oral hypoglycaemic agents(
. These results support an earlier meta-analysis by Livesey & Taylor(
, which did not show a dose threshold for HbA1c reductions across a wider dose range of fructose.
A benefit of ‘catalytic’ doses of fructose has implications for the benefit of low-GI fruit. In a secondary analysis of a randomised controlled trial investigating the effect of a 6-month low-GI diet compared with a high-cereal fibre diet in 152 participants with type 2 diabetes(
, we showed that low-GI fruit intake was the strongest independent predictor of HbA1c. The HbA1c decrease of 0·5 % (highest v.
lowest quartile of low-GI fruit intake) was similar to that seen in the present analysis, despite none of the trials in the meta-analysis using fruit. Although it is unclear whether this reduction in HbA1c was attributable to a ‘catalytic’ effect of fructose, its ability to lower the GI of the diet, or both, the low-GI fruit increase (2·2 servings/d) was equivalent to a ‘catalytic’ increase in fructose, which expressed as the most commonly consumed low-GI fruit in the study, apples, represents approximately 24 g/d of fructose.
A dose threshold for harm, however, remains an important consideration for fructose(
. The ‘catalytic’ mechanism through which fructose is thought to operate, up-regulation of glucokinase, may under certain circumstances contribute to increased de novo
lipogenesis with downstream metabolic sequelae(
. Despite showing an improvement in HbA1c, the meta-analysis by Livesey & Taylor(
showed a consistent TAG-raising effect of fructose at doses >100 g/d (>95th percentile total US fructose intake(
). In another meta-analysis of controlled feeding trials, we also showed that fructose in excess of the Canadian Diabetes Association threshold of >60 g/d(
increased TAG in type 2 diabetes(
. Body-weight-raising effects have otherwise been restricted to more extreme doses in hyperenergetic feeding trials (+18 to 50 % energy)(
, making it difficult to disentangle the relative contributions of excess fructose and energy. Sugar-sweetened beverage intakes as low as one or two servings/d, nevertheless, have been associated with overweight/obesity, the metabolic syndrome and diabetes in meta-analyses of prospective cohort studies(
. The present findings confirm that fructose at intakes below these thresholds does not appear to have adverse effects on related cardiometabolic risk factors: fasting insulin, body weight, TAG or uric acid.
Limitations of the present analysis need to be considered. First, only two to six trials were included in the meta-analyses for each endpoint. It meant that effects were sensitive to the removal of individual trials, there may have been too little power to detect some differences and publication bias was difficult to assess reliably. Second, the trials were of short duration with only three of the six trials ≥ 8 weeks. It is possible that shorter trials may have underestimated the true effect on HbA1c, given the evidence of a t1/2
for HbA1c reductions of 35·2 d(
. Subgroup analyses, however, did not show effect modification by follow-up. Third, inter-study heterogeneity complicated the analyses of fasting glucose and insulin. Although the removal of Rizkalla et al.
explained the heterogeneity for fasting insulin, sensitivity and subgroup analyses did not explain the heterogeneity for fasting glucose. Random-effects models, however, were used to address residual heterogeneity in all analyses. Finally, although there was a preference for change-from-baseline differences, end differences were used almost exclusively owing to the data reported. There was, however, no evidence of baseline differences between the trials (data not shown).
In conclusion, this small meta-analysis of controlled feeding trials supports earlier 13
C NMR spectroscopy investigations(
and acute feeding studies(
showing that ‘catalytic’ doses ( ≤ 36 g/d) of fructose may improve glycaemic control. This benefit is seen without the adverse cardiometabolic effects reported when fructose is fed at high doses or as excess energy. The strength of these conclusions is limited by the small number of trials and their relatively short duration, especially in relation to HbA1c measurements. That such a small number of eligible trials were identified despite our broad inclusion criteria reinforces that there is a lack of adequate data. To clarify the effect of ‘catalytic’ doses of fructose and low-GI fruit as sources of ‘catalytic’ doses of fructose on glycaemic control, larger and longer-term ( ≥ 6 months) feeding trials are required.