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A systematic review and meta-analysis of controlled feeding trials

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The American Diabetes Association guidelines, however, acknowledge that fructose produces a lower glycemic response in people with diabetes when it replaces sucrose and starch in the diet 7. This discrepancy is likely due in part to the use of glycated albumin exclusively in the type 1 diabetes studies 15 , Food and Drug Administration for the development of new drugs for diabetes 29 and lies at the lower limit of efficacy expected for oral hypoglycemic agents Table 1 Characteristics of experimental trials included in the meta-analysis. Heterogeneity was assessed by the Cochran Q statistic and quantified by the I 2 statistic. It is important to note, however, that their analysis, in contrast to the current meta-analysis, did not focus exclusively on diabetes.

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Effect of Fructose on Glycemic Control in Diabetes

Sensitivity analyses were performed to determine if any single study exerted an undue influence on the overall result. To address this point, we systematically removed each individual study from the meta-analysis and recalculated the pooled effect size from the remaining studies. Meta-regression was performed to assess the significance of subgroup effects with Stata software version Publication bias was investigated by inspection of funnel plots and quantitatively assessed with Begg and Egger tests.

A total of 4, eligible reports were identified with the search; of these, 4, were determined to be irrelevant on review of the titles and abstracts.

The remaining 54 reports were retrieved and reviewed in full, and a further 38 were excluded. A total of 16 reports 18 trials were selected for pooled analyses Fig.

The characteristics of the 18 included trials are shown in Table 1. Flowchart of literature search for the effect of fructose on glycemic end points fasting glucose, fasting insulin, and glycated blood proteins [HbA 1c and glycated albumin]. Characteristics of experimental trials included in the meta-analysis. Patients had a median age of Their median baseline HbA 1c values were 8.

The median follow-up was 8 weeks IQR 4— No eligible study measured fructosamine. No hypercaloric feeding trials met the inclusion criteria. Figure 2 A shows the effect of isocaloric fructose exchange for other carbohydrates on glycated blood proteins. Systematic removal of individual studies did not alter the results.

Meta-regression revealed no statistically significant subgroup effects Supplementary Fig. Forest plot of controlled feeding trials investigating the effect of isocaloric exchange of fructose for other carbohydrate on A glycated blood proteins HbA 1c and glycated albumin , B fasting glucose, and C fasting insulin.

P values are for generic inverse variance random effects models. There were no studies investigating type 1 or undifferentiated diabetes for fasting insulin. A high-quality color representation of this figure is available in the online issue. Their median baseline fasting glucose values were 9. The median follow-up was 4 weeks IQR 2— A significant fasting glucose lowering effect was seen in the overall analysis after the systematic removal of either Bantle et al.

There was no change in the interstudy heterogeneity during sensitivity analyses. The median follow-up was 4 weeks IQR 3—10 weeks. No hypercaloric feeding trial met the inclusion criteria.

Sensitivity analyses did not alter the effect estimate or degree of heterogeneity for fasting insulin, and meta-regression revealed no statistically significant subgroup effects Supplementary Fig.

None of the subjects were treated with insulin. In the current aggregate analyses of 18 controlled feeding trials with subjects with type 1 and 2 diabetes, isocaloric fructose exchange for other carbohydrate decreased glycated blood proteins aggregated glycated albumin and HbA 1c but not fasting glucose or insulin.

Food and Drug Administration for the development of new drugs for diabetes 29 and lies at the lower limit of efficacy expected for oral hypoglycemic agents The lack of change in fasting glucose and insulin suggests that fructose consumption does not promote hepatic and systemic insulin resistance.

Future meta-analyses of direct measures of insulin sensitivity would be of value. Our observed reduction in glycated blood proteins was consistent with the findings of an earlier meta-analysis by Livesey and Taylor 31 , who found an improvement in HbA 1c It is important to note, however, that their analysis, in contrast to the current meta-analysis, did not focus exclusively on diabetes.

Unlike Livesey and Taylor 31 , we found the reduction in glycated blood proteins to be significant only in people with type 1 diabetes in stratified analyses. This discrepancy is likely due in part to the use of glycated albumin exclusively in the type 1 diabetes studies 15 , The null finding in individuals with type 2 diabetes might be explained by the choice of glycated protein, because those trials used both HbA 1c 9 — 13 , 21 — 23 and glycated albumin 15 , An improvement in glycemic control in individuals with type 2 diabetes is supported by an improvement in fasting glucose after removal of either Bantle et al.

It is noteworthy that the small, unusually precise study of Turner et al. Subgroup analyses revealed no significant effect modification for glycated blood proteins, fasting glucose, or insulin. Although Livesey and Taylor 31 in their earlier meta-analysis found that the improvement in HbA 1c was dependent on the degree of dysglycemia, fructose dose, and follow-up, we did not find that these conditions altered any of the outcomes, nor in a separate analysis did we see any effect of fructose dose, follow-up, or comparator on triglycerides in type 2 diabetes with the same subgroup criteria There was, however, evidence of significant interstudy heterogeneity across most subgroup categories.

These may be related to real biological differences between study populations or to methodological differences between trials that were not assessed in our a priori subgroup analyses.

A number of potential mechanisms have been proposed to explain the improvements in glycemia seen with the consumption of fructose. One possibility is that the addition of fructose to the diet may help control postprandial glycemic excursions. The resulting fructoseP is able to displace fructoseP from its binding site on the glucokinase regulatory protein, allowing increased translocation of glucokinase from the nucleus to the cytosol, where it is active.

Both these mechanisms may be operating. Although it appears that isocaloric fructose feeding benefits glycemia, a dose threshold for harm must also be considered because fructose, more than other sources of carbohydrate, may increase serum triglycerides. We therefore must consider the possible adverse effects of substituting fructose for other carbohydrates at high doses.

There are currently no meta-analyses investigating the effect of fructose on LDL. A number of limitations complicate the interpretation of these aggregate analyses. Second, several studies included participants who were receiving insulin or oral hypoglycemic agents, treatments that in themselves would be expected to influence glycemia. Third, given the small number of trials included in each stratum, meta-regression may have been underpowered to detect true differences.

Fourth, a significant amount of unexplainable heterogeneity was detected in both primary and subgroup analyses, although our random-effects model did account for this heterogeneity. These deficiencies were especially of concern in the context of the small sample sizes, with most of the trials having 15 or fewer participants.

Finally, because only published trials were included, publication bias remains a possibility for all outcomes, although we noted statistical evidence of publication bias only for fasting glucose. The harm-reduction approach to fructose taken by diabetes associations 2 , 7 , 8 , which is based on possible adverse serum lipid effects, may need to be reconciled with a possible glycemic benefit.

These conclusions, however, are limited by the short follow-up, small sample size, and poor quality of most trials included in our meta-analysis, as well as the large degree of unexplained significant heterogeneity. Larger, longer, and higher-quality trials of controlled fructose feeding that also weigh any possible glycemic benefit against adverse metabolic effects are required for definitive confirmation of these findings.

None of the sponsors had a role in any aspect of the current study, including design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

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Skip to main content. Diabetes Care Jul; 35 7: Data extraction Reports that met the inclusion criteria were each independently reviewed and extracted by at least two investigators with a standardized form. RESULTS Search results A total of 4, eligible reports were identified with the search; of these, 4, were determined to be irrelevant on review of the titles and abstracts.

Figure 1 Flowchart of literature search for the effect of fructose on glycemic end points fasting glucose, fasting insulin, and glycated blood proteins [HbA 1c and glycated albumin].

View inline View popup Download powerpoint. Table 1 Characteristics of experimental trials included in the meta-analysis. Download figure Open in new tab Download powerpoint. Figure 2 Forest plot of controlled feeding trials investigating the effect of isocaloric exchange of fructose for other carbohydrate on A glycated blood proteins HbA 1c and glycated albumin , B fasting glucose, and C fasting insulin.

Publication bias Supplementary Figs. Footnotes Clinical trial reg. The World Health Report Life in the 21st Century: A Vision for All. Geneva, World Health Organization, Canadian Diabetes Association clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes ; Height, predictors of C-peptide and cancer risk in men. Int J Epidemiol ; National estimates of dietary fructose intake increased from to in the United States. J Nutr ; Intakes and food sources of fructose in the United States.

Am J Clin Nutr ; 58 Suppl: Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr ; Nutrition recommendations and interventions for diabetes: Diabetes Care ; 31 Suppl. S61 — S78 pmid: Evidence-based nutritional approaches to the treatment and prevention of diabetes mellitus. Nutr Metab Cardiovasc Dis ; Metabolic effects of dietary sucrose and fructose in type II diabetic subjects. It requires all packaged foods to bear nutrition labeling and all health claims for foods to be consistent with terms defined by the Secretary of HHS.

As a concession to food manufacturers, the FDA authorizes some health claims for foods. This is pretty much the nutrition label as we know it today. Food labels are to list the most important nutrients in an easy-to-follow format. Criteria are simple—low in saturated fat and cholesterol, for healthy people over age 2. And a certification payment to AHA by the food manufacturer.

After repeated debilitation and stakeholder pressures, the law finally went into effect only 7 years later, on March 16, , and even then with many loopholes. Announcement made that FDA will require food labels to include trans-fat content. Labeling went into effect in The FDA announced plans to permit the manufacturers of food products sold in the United States to make health claims that are supported by less than conclusive evidence.

Opponents criticize it as opening the door to ill-founded claims. Advocates believe it will make more information available to the public. The following year Kraft launches a similar initiative, called Sensible Solutions. Hannaford Supermarkets launches Guiding Stars, intended to help customers choose healthy foods.

Foods are ranked 0 to 3 stars, with three stars awarded to most nutritious foods. Front-of-package information includes daily percentage values for 6 nutrients. NuVal announced—the nutritional value NuVal system scores food on a scale of 1 to The higher the NuVal Score, the higher the nutrition of a food product.