Gut carbohydrate inhibits GIP secretion via a microbiota/SCFA/FFAR3 pathway

in Journal of Endocrinology
Correspondence should be addressed to T Miki: tmiki@faculty.chiba-u.jp
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Mechanisms of carbohydrate-induced secretion of the two incretins namely glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are considered to be mostly similar. However, we found that mice exhibit opposite secretory responses in response to co-administration of maltose plus an α-glucosidase inhibitor miglitol (maltose/miglitol), stimulatory for GLP-1, as reported previously, but inhibitory for GIP. Gut microbiota was shown to be involved in maltose/miglitol-induced GIP suppression, as the suppression was attenuated in antibiotics (Abs)-treated mice and abolished in germ-free mice. In addition, maltose/miglitol administration increased plasma levels of short-chain fatty acids (SCFAs), carbohydrate-derived metabolites, in the portal vein. GIP suppression by maltose/miglitol was not observed in mice lacking a SCFA receptor Ffar3, but it was normally seen in Ffar2-deficient mice. Similar to maltose/miglitol administration, co-administration of glucose plus a sodium glucose transporter inhibitor phloridzin (glucose/phloridzin) induced GIP suppression, which was again cancelled by Abs treatment. In conclusion, oral administration of carbohydrates with α-glucosidase inhibitors suppresses GIP secretion through a microbiota/SCFA/FFAR3 pathway.

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  • Supplementary Figure 1. Effect of administration of vehicle, maltose or miglitol on blood glucose and plasma incretin and SCFA levels. We administered WT mice with vehicle (distilled water) (n =14), 2 g/kg maltose (n =7), or 10 mg/kg miglitol (n =8) orally, and blood glucose (A) and plasma GLP-1 (B) and GIP (C) were measured. Plasma SCFAs (D-I) were also measured (n =6~7 for each group). (A-I) Data are means ± SEM. *P < 0.05, ***P < 0.001 by one-way ANOVA with Tukey’s post hoc analysis.
  • Supplementary Figure 2. Effects of the direct glucose infusion into the mid small intestine on blood glucose and plasma GLP-1 and GIP levels. We administered WT mice with vehicle (distilled water) (n =7) or 2 g/kg glucose (n =8) into the mid small intestine. Blood glucose (A), plasma GLP-1 (B), and plasma GIP (C) were measured. (A-C) Data are means ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 by unpaired-Student t-test.
  • Supplementary Figure 3. Intestinal transit of the mice administered orally with various test solutions. After overnight fasting, we administered WT mice orally (10 μl/g body weight) (0 min) with (1) vehicle (distilled water, n =10), (2) 2 g/kg maltose (n =9), (3) 2 g/kg maltose plus 10 mg/kg miglitol (n =12), or (4) 2 g/kg glucose plus 500 mg/kg phloridzin (n =6). Thirty min after loading of the test solutions, 5% (wt/vol) Evans blue (WAKO) (5 μl/g body weight) was further administered orally (30 min). Ten min after Evans blue loading, the mice were euthanized (40 min) and total length of small intestine was dissected. Then, the length from the pylorus to the most distal point of migration of Evans blue (X) and from the pylorus to the terminal ileum (Y) was measured. Intestinal transit was expressed as percentage of X to Y. As a positive control, exogenous human GLP1 was used. For this aim, vehicle (distilled water, 10 μl/g body weight) was administered to WT mice (0 min), then 100 μg/mouse human GLP-1 (Peptide Institute, Osaka, Japan) (in 0.1 ml) was subcutaneously administered to at 20 min after vehicle administration (20 min). Ten min after GLP-1 injection, Evans blue was administered orally (30 min) and 10 min later the mice were euthanized (40 min). The mice were then subjected to measuring intestinal transit. Blood glucose levels were measured in the tail vein. (A, B) Data are means ± SEM. ***P < 0.001 by one-way ANOVA with Tukey’s post hoc analysis.
  • Supplementary Figure 4. Morphological changes of the cecum and the gallbladder of Abs-treated mice. (A) General appearance of the intestine of Abs-treated (left) and Abs-untreated (right) mice. (B) The gallbladder of Abs-treated (left) and Abs-untreated (right) mice. (C) The weight of gallbladder in Abs-treated mice (n =5) and Abs-untreated (n = 14) mice. *P < 0.05, by unpaired-Student t-test.

 

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    Meal tolerance test (MTT). (A) Changes in blood glucose levels during MTT (Ensure Liquid, 10 μL/g) with or without co-administration of miglitol (10 mg/kg) (n = 8 for each group). (B, C and D) Blood glucose (B), plasma GLP-1 (C) and plasma GIP (D) in the portal vein at 30 min after oral administration of either vehicle, liquid formula or liquid formula plus miglitol (n = 7–9). *P < 0.05, **P < 0.01, ***P < 0.001 between the animal groups by unpaired-Student t-test (A) or one-way ANOVA with Tukey’s post hoc analysis (B, C and D). (A, B, C and D) Data are means ± s.e.m.

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    Incretin secretory response to a variable dose of glucose. (A, B, C, D and E) Blood glucose (A), plasma GLP-1 (B) and plasma GIP (C) in the portal vein at 5 min after oral administration of a variable dose of glucose to WT (filled columns) and Kir6.2/ (open columns) mice are shown (n = 10–15). *P < 0.05, **,††P < 0.01, and ***,†††P < 0.001 vs vehicle administration by one-way ANOVA with Tukey’s post hoc analysis. (A, B and C) Data are means ± s.e.m. (D and E) Scatter plots between blood glucose and plasma GLP-1 (D) or GIP (E) of WT (filled circles) and Kir6.2/ (open circles) mice.

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    Effect of α-GIs on maltose-induced incretin secretion in WT mice. (A, B and C) Blood glucose (A), plasma GLP-1 (B) and plasma GIP (C) in the portal vein at 30 min after oral administration of vehicle, maltose/miglitol or maltose/acarbose (n = 24–28). **P < 0.01, ***P < 0.001 by one-way ANOVA with Tukey’s post hoc analysis. (A, B and C) Data are means ± s.e.m.

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    Effect of gut dysbiosis on carbohydrate-induced incretin secretion. (A, B, C, D, E and F) Blood glucose (A and D), plasma GLP-1 (B and E) and plasma GIP (C and F) in the portal vein at 30 min after oral administration of vehicle or maltose/miglitol (n = 18–34) in the WT mice with (Abs (+)) or without (Abs (−)) Abs treatment (A, B and C) and GF mice (D, E and F). NS, not significant, *P < 0.05, **P < 0.01, and ***P < 0.001 by two-way ANOVA plus Tukey’s post hoc analysis (A, B and C) or by unpaired-Student t-test (D, E and F). (A, B, C, D, E and F) Data are means ± s.e.m.

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    Plasma SCFA and GIP concentrations in the portal vein after maltose/miglitol administration. (A, B, C, D, E and F) Plasma SCFAs (acetate (A), propionate (B), n-butyrate (C), n-valerate (D), iso-butyrate (E) and iso-valerate (F)) in the portal vein at 30 min after oral administration of vehicle (n = 16) (open columns) or maltose/miglitol (n = 16) (filled columns) to WT mice with (Abs (+)) or without (Abs (−)) Abs treatment. (G, H, I, J, K and L) Blood glucose (G and J), plasma GLP-1 (H and K) and plasma GIP (I and L) in the portal vein at 30 min after oral administration of vehicle or maltose/miglitol to Ffar2/ mice (n = 15–16) (G, H and I) or Ffar3/ mice (n = 12–21) (J, K and L). NS, not significant, *P < 0.05, **P < 0.01, and ***P < 0.001 by two-way ANOVA plus Tukey’s post hoc analysis (A, B, C, D, E, F, G, H, I, J, K and L). (A, B, C, D, E, F, G, H, I, J, K and L) Data are means ± s.e.m.

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    Effect of blockade of glucose absorption on GIP secretion. (A, B and C) Blood glucose (A), plasma GLP-1 (B) and plasma GIP (C) in the portal vein at 30 min after oral administration of vehicle (open columns) or glucose/phloridzin (filled columns) to WT mice with (Abs (+)) or without (Abs (−)) Abs treatment (n = 8–15). (D, E, F, G, H and I) Plasma SCFAs (acetate (D), propionate (E), n-butyrate (F), n-valerate (G), iso-butyrate (H) and iso-valerate (I)) in the portal vein at 30 min after oral administration of vehicle or glucose/phloridzin (n = 8–10) to WT mice with (Abs (+)) or without (Abs (−)) Abs-treatment. NS, not significant, *P < 0.05, **P < 0.01, and ***P < 0.001 by two-way ANOVA plus Tukey’s post hoc analysis (A, B, C, D, E, F, G, H and I). (A, B, C, D, E, F, G, H and I) Data are means ± s.e.m.

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    A mechanism of GIP suppression by intra-intestinal carbohydrate retention (model). See text in detail. ΔΨ, membrane depolarization.

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