Effects of the Non-Nutritive Sweeteners on Glucose Metabolism and Appetite Regulating Hormones: Systematic Review of Observational Prospective Studies and Clinical Trials

<div><p>Background</p><p>The effects of non-nutritive sweeteners (NNS) on glucose metabolism and appetite regulating hormones are not clear. There is an ongoing debate concerning NNS use and deleterious changes in metabolism.</p><p>Objectives</p><p>The aim of this review is to analyze the scientific available evidence regarding the effects of NNS on glucose metabolism and appetite regulating hormones.</p><p>Data Sources and Study Eligibility Criteria</p><p>We identified human observational studies evaluating the relation between NNS consumption and obesity, diabetes, and metabolic syndrome, in addition to clinical trials evaluating the effects of NNS in glucose metabolism and appetite regulating hormones.</p><p>Results</p><p>Fourteen observational studies evaluating the association between NNS consumption and the development of metabolic diseases and twenty-eight clinical trials studying the effects of NNS on metabolism were included. Finally, two meta-analyses evaluating the association between the consumption of NNS-containing beverages and the development of type 2 diabetes were identified.</p><p>Conclusions</p><p>Some observational studies suggest an association between NNS consumption and development of metabolic diseases; however, adiposity is a confounder frequently found in observational studies. The effects of the NNS on glucose metabolism are not clear. The results of the identified clinical trials are contradictory and are not comparable because of the major existing differences between them. Studies evaluating specific NNS, with an adequate sample size, including a homogeneous study group, identifying significant comorbidities, with an appropriate control group, with an appropriate exposure time, and considering adjustment for confounder variables such as adiposity are needed.</p></div

Clinical trials evaluating the effect of non-nutritive sweeteners consumption on glucose metabolism and appetite regulating hormones.

<p>Clinical trials evaluating the effect of non-nutritive sweeteners consumption on glucose metabolism and appetite regulating hormones.</p

Crude and adjusted associations between the consumption of artificially sweetened beverages and the development of metabolic diseases in observational prospective studies.

<p>Crude and adjusted associations between the consumption of artificially sweetened beverages and the development of metabolic diseases in observational prospective studies.</p

Summary of the studied variables, non-nutritive sweetener used, study methodology and findings of the clinical trials evaluated in Table 3.

<p>Summary of the studied variables, non-nutritive sweetener used, study methodology and findings of the clinical trials evaluated in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0161264#pone.0161264.t003" target="_blank">Table 3</a>.</p

Flow diagram of the systematic search.

<p>Flow diagram of the systematic search.</p

Flow chart of the study protocol.

<p>Flow chart of the study protocol.</p

Clinical and biochemical parameters of the sample studied before and after two weeks of supervised physical activity (n = 60).

<p>Data are expressed as mean±SD or as median (interquartil range). NS = not significant. SBP = systolic blood pressure; DBP = diastolic blood pressure; BMI = body mass index; WHR = waist-hip-ratio; ALT = alanine aminotransfarase; AST = aspartate aminotransferase; LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol; GGT = gamma-glutamyltransferase.</p>*<p>Daily physical activity measured with questionnaire.</p

Correlations of the DELTA log FGF21 (final-basal) with the delta and mean values of related parameters associated with physical activity, lipolysis and adrenergic response (n = 60).

<p>FGF21 was log-transformed before analysis. All the correlations were adjusted for BMI. FGF21 = Fibroblast Growth Factor 21 (ng/l); RHR = Rest heart rate; MHR = Maximum heart rate; METs = Metabolic equivalents; FFA = Free fatty acids;</p>*<p>p<0.05;</p>**<p>p<0.01.</p

Comparisons of biochemical parameters before and after supervised physical activity (n = 60).

<p>Data are expressed as mean±SD or as median (interquartil range). FGF21 was log-transformed before analysis. NS = not significant. BMI = body mass index; WC = waist circumference; FFAs = free fatty acids.</p>*<p>Bonferroni adjustment for multiple comparisons. Parameters of the repeated measures model of: Glucose: Hotteling's trace = 0.33; F = 3.29; p = 0.034; Insulin: Hotteling's trace = 1.80; F = 18.01; p<0.0001; FGF21: Hotteling's trace = 2.62; F = 22.76; p<0.0001; FFAs: Hotteling's trace = 1.58; F = 13.2; p<0.0001; Leptin: Hotteling's trace = 0.96; F = 10.93; p<0.0001; Epinephrine: Hotteling's trace = 2.29; F = 19.13; p<0.0001; Adiponectin: Hotteling's trace = 0.17; F = 1.98; p = 0.135.</p

Correlation of the log delta FGF21 (final-basal) levels with METs (A), delta epinephrine (B), and delta free fatty acids (C) in 60 women after two weeks of supervised physical activity.

<p>Correlation of the log delta FGF21 (final-basal) levels with METs (A), delta epinephrine (B), and delta free fatty acids (C) in 60 women after two weeks of supervised physical activity.</p