Fructose stimulates GLP-1 but not GIP secretion in mice, rats, and humans

Abstract

Nutrients often stimulate gut hormone secretion, but the effects of fructose are incompletely understood. We studied the effects of fructose on a number of gut hormones with particular focus on glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). In healthy humans, fructose intake caused a rise in blood glucose and plasma insulin and GLP-1, albeit to a lower degree than isocaloric glucose. Cholecystokinin secretion was stimulated similarly by both carbohydrates, but neither peptide YY3-36 nor glucagon secretion was affected by either treatment. Remarkably, while glucose potently stimulated GIP release, fructose was without effect. Similar patterns were found in the mouse and rat, with both fructose and glucose stimulating GLP-1 secretion, whereas only glucose caused GIP secretion. In GLUTag cells, a murine cell line used as model for L cells, fructose was metabolized and stimulated GLP-1 secretion dose-dependently (EC50 = 0.155 mM) by ATP-sensitive potassium channel closure and cell depolarization. Because fructose elicits GLP-1 secretion without simultaneous release of glucagonotropic GIP, the pathways underlying fructose-stimulated GLP-1 release might be useful targets for type 2 diabetes mellitus and obesity drug development.

Keywords: enteroendocrine axis; gastric inhibitory peptide; glucagon-like peptide-1.

Fig. 1.

Blood glucose and plasma insulin and glucagon responses to oral glucose and fructose challenge in healthy humans. Mean values + 1 SE are shown in response to oral glucose (black) and fructose (gray) stimulation. Total area under the curve (AUC) values are shown for comparison between treatments. A: blood glucose (mM); B: blood glucose AUC values (min × mM); C: plasma insulin (pM); D: plasma insulin AUC values (min × pM); E: plasma glucagon (pM); F: plasma glucagon AUC values (min × pM). *Within-group significance compared with baseline (mean value for −15 and 0 min control samples). #Level of between-group significance. Within-group significance was tested by one-way ANOVA for repeated measurements followed by Bonferroni post hoc test. Between-group significance was tested by two-tailed paired t-test on AUC values. *^/#P < 0.05, **^/##P < 0.01, ***P < 0.001, and ****P < 0.0001, n = 9.

Fig. 2.

Enteroendocrine hormone responses to oral glucose and fructose challenge in healthy humans. Mean values + 1 SE are shown in response to oral (75 g in 300 ml water) glucose (black) and fructose (gray) intake. Total AUC values are shown for comparison between treatments. A: plasma total glucagon-like peptide-1 (GLP-1_total, pM); B: plasma GLP-1_total AUC values (min × pM); C: plasma total glucose-dependent insulinotropic polypeptide (GIP_total, pM); D: total plasma GIP_total AUC values (min × pM); E: plasma peptide YY (PYY)_3–36 values (pM); F: Plasma PYY_3–36 AUC values (min × pM); G: plasma cholecystokinin (CCK) values (pM); H: plasma CCK AUC values (min × pM); I: plasma neutotensin (NTS)_1–13 values (pM); J: plasma NTS_1–13 AUC values (min × pM). *Within-group significance compared with base level (mean value for −15 and 0 min control samples). ^#Between-group significance. Significance was tested by one-way ANOVA for repeated measurements followed by Bonferroni post hoc test or paired t-test. ^#/*P < 0.05, **P < 0.01, ***P < 0.001, and ^####/****P < 0.0001, n = 9.

Fig. 3.

Blood glucose and plasma GLP-1 and GIP responses to oral glucose and fructose stimulation in the rat. Mean values + 1 SE are shown in response to oral glucose (gray), fructose (blue), and saline (black) intake. A: blood glucose levels; B: blood glucose AUC levels (min × mM); C: plasma GIP_total levels (pg/ml); D: plasma GIP_total AUC values (min × pg/ml); E: plasma GLP-1_active concentrations (pM); F: plasma GLP-1_active AUC values (min × pM). Between-group significance was tested by two-tailed paired t-test on AUC values. *Within-group significance. ^#Between group significance. **P < 0.01, ^###/***P < 0.001, *P < 0.05, and ****P < 0.0001 relative to base level, n = 7 for glucose and n = 6 for fructose and saline.

Fig. 4.

Blood glucose and plasma GLP-1 and GIP responses to oral glucose and fructose stimulation in the mouse. Values are shown as means ± 1 SE at 0 min (white bars, base level) and 6 min (gray bars, response). A: blood glucose concentrations (mM); B: plasma GLP-1_total levels (pg/ml); C: plasma GIP_total concentrations (pg/ml). Data were analyzed by one-way ANOVA followed by Bonferroni post hoc test or Student's t-test. *Within-group significance. ^#Between-group significance. ****^/####P < 0.0001, ***P < 0.001, **P < 0.01, and *P < 0.05, n = 31/group in A and B and 24–29/group in C.

Fig. 5.

Fructose is metabolized by the GLUTag cell and stimulates GLP-1 secretion dose dependently by ATP-sensitive potassium (K_ATP) channel closure. Data are presented as mean values ± 1 SE with sample size indicated over the respective bars. Responses are shown relative to base level (B) secretion measured in parallel on the same day. A: representative trace of changes in intracellular NAD(P)H levels [fluorescence intensity (340/10 nM)] in response to 10 mM fructose/glucose. Each trace represents one cell. B: collected changes in NAD(P)H levels in response to 10 mM fructose and glucose. C: changes in NAD(P)H levels in response to depicted concentrations series of fructose (F) and mannitol (M) (osmolarity control). D: relative GLP-1_active levels in response to concentrations of fructose or as indicated. EC₅₀ = 0.155 mM. E: relative GLP-1_active secretion levels in response to mannitol (100 mM), fructose (10 mM), fructose (10 mM) + gliclazide (10 μM) (F + GLI), fructose (10 mM) + diazoxide (340 μm) (F + D), and diazoxide (340 μM) (D). F: relative GLP-1_active levels in response to 10 μM tolbutamide (TBM) and gliclazide (GLI). Statistical significance was tested by Student's t-test (B) or one-way ANOVA analysis followed by Bonferroni post hoc test (C–F). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 relative to base level.