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Mechanisms of the incretin effect in subjects with normal glucose tolerance and patients with type 2 diabetes.

Mari A, Bagger JI, Ferrannini E, Holst JJ, Knop FK, Vilsbøll T - PLoS ONE (2013)

Bottom Line: The incretin effect on potentiation also increased (0.97 ± 0.06, 1.45 ± 0.20, 1.24 ± 0.16, P<0.0001).In the whole group, the incretin effect was inversely associated with total secretion during IIGI, although systematically lower in T2D.In conclusion, 1) In NGT, glucose sensitivity and potentiation mediate the dose-dependent incretin effect increase; 2) In T2D, the incretin effect is blunted vs NGT, but rate sensitivity is enhanced at all loads; 3) Relatively lower incretin effect in NGT is associated with higher secretion during IIGI, suggesting that the reduced incretin effect does not result from ß-cell dysfunction.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedical Engineering, National Research Council, Padova, Italy.

ABSTRACT
The incretin effect on insulin secretion was investigated in 8 subjects with type 2 diabetes (T2D) and 8 with normal glucose tolerance (NGT), using 25, 75, and 125 g oral glucose tolerance tests (OGTT) and isoglycemic intravenous glucose infusions (IIGI). The ß-cell response was evaluated using a model embedding a dose-response (slope=glucose sensitivity), an early response (rate sensitivity), and potentiation (time-related secretion increase). The incretin effect, as OGTT/IIGI ratio, was calculated for each parameter. In NGT, the incretin effect on total secretion increased with dose (1.3 ± 0.1, 1.7 ± 0.2, 2.2 ± 0.2 fold of IIGI, P<0.0001), mediated by a dose-dependent increase of the incretin effect on glucose sensitivity (1.9 ± 0.4, 2.4 ± 0.4, 3.1 ± 0.4, P=0.005), and a dose-independent enhancement of the incretin effect on rate sensitivity (894 [1145], 454 [516], 783 [1259] pmol m(-2) L mmol(-1) above IIGI; median [interquartile range], P<0.0001). The incretin effect on potentiation also increased (0.97 ± 0.06, 1.45 ± 0.20, 1.24 ± 0.16, P<0.0001). In T2D, the incretin effect on total secretion (1.0 ± 0.1, 1.1 ± 0.1, 1.3 ± 0.1, P=0.004) and glucose sensitivity (1.2 ± 0.2, 1.3 ± 0.2, 2.0 ± 0.2, P=0.005) were impaired vs NGT; however, the incretin effect on rate sensitivity increased already at 25 g (269 [169], 284 [301], 193 [465] pmol m(-2) L mmol(-1) above IIGI; negligible IIGI rate sensitivity in T2D prevented the calculation of the fold increment). OGTT did not stimulate potentiation above IIGI (0.94 ± 0.04, 0.89 ± 0.06, 1.06 ± 0.09; P<0.01 vs NGT). In the whole group, the incretin effect was inversely associated with total secretion during IIGI, although systematically lower in T2D. In conclusion, 1) In NGT, glucose sensitivity and potentiation mediate the dose-dependent incretin effect increase; 2) In T2D, the incretin effect is blunted vs NGT, but rate sensitivity is enhanced at all loads; 3) Relatively lower incretin effect in NGT is associated with higher secretion during IIGI, suggesting that the reduced incretin effect does not result from ß-cell dysfunction.

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Average relationship between incretin effect and incretin hormones.Relationship between the incretin effect on total insulin secretion and the corresponding mean OGTT plasma GLP-1 and GIP in NGT and T2D participants. Plots are mean±SE.
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pone-0073154-g006: Average relationship between incretin effect and incretin hormones.Relationship between the incretin effect on total insulin secretion and the corresponding mean OGTT plasma GLP-1 and GIP in NGT and T2D participants. Plots are mean±SE.

Mentions: As previously reported [5], GLP-1 increased with the glucose dose during the OGTT but not during the IIGI (P<0.003 for the test × dose interaction) (Table 2). The responses were widely variable (especially for GIP), and differences in mean hormones between patients with NGT and T2D were not significant statistically. When the GLP-1 and GIP responses during the OGTT were regressed against the incretin effect on total insulin secretion (Figure 6), the relationship was significantly flatter in patients with T2D than subjects with NGT for both incretin hormones, as expected. Likewise, when the incretin effect on total insulin secretion was plotted against the OGTT/IIGI ratio of mean hormone concentrations, the individual dose trajectories for the patients with T2D ran consistently below those of the NGT individuals (Figure 7). Although the study didn’t allow rigorous assessment of the sensitivity to incretin hormones, an estimate could be obtained from the slope of the individual trajectories. The estimate of the sensitivity to GLP-1 in NGT was ∼3.5 fold that in patients with T2D; the estimate for GIP was ∼5 fold (NGT/T2D ratio of the median of the slopes; P = 0.02 for GLP-1 and P<0.05 for GIP).


Mechanisms of the incretin effect in subjects with normal glucose tolerance and patients with type 2 diabetes.

Mari A, Bagger JI, Ferrannini E, Holst JJ, Knop FK, Vilsbøll T - PLoS ONE (2013)

Average relationship between incretin effect and incretin hormones.Relationship between the incretin effect on total insulin secretion and the corresponding mean OGTT plasma GLP-1 and GIP in NGT and T2D participants. Plots are mean±SE.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3760909&req=5

pone-0073154-g006: Average relationship between incretin effect and incretin hormones.Relationship between the incretin effect on total insulin secretion and the corresponding mean OGTT plasma GLP-1 and GIP in NGT and T2D participants. Plots are mean±SE.
Mentions: As previously reported [5], GLP-1 increased with the glucose dose during the OGTT but not during the IIGI (P<0.003 for the test × dose interaction) (Table 2). The responses were widely variable (especially for GIP), and differences in mean hormones between patients with NGT and T2D were not significant statistically. When the GLP-1 and GIP responses during the OGTT were regressed against the incretin effect on total insulin secretion (Figure 6), the relationship was significantly flatter in patients with T2D than subjects with NGT for both incretin hormones, as expected. Likewise, when the incretin effect on total insulin secretion was plotted against the OGTT/IIGI ratio of mean hormone concentrations, the individual dose trajectories for the patients with T2D ran consistently below those of the NGT individuals (Figure 7). Although the study didn’t allow rigorous assessment of the sensitivity to incretin hormones, an estimate could be obtained from the slope of the individual trajectories. The estimate of the sensitivity to GLP-1 in NGT was ∼3.5 fold that in patients with T2D; the estimate for GIP was ∼5 fold (NGT/T2D ratio of the median of the slopes; P = 0.02 for GLP-1 and P<0.05 for GIP).

Bottom Line: The incretin effect on potentiation also increased (0.97 ± 0.06, 1.45 ± 0.20, 1.24 ± 0.16, P<0.0001).In the whole group, the incretin effect was inversely associated with total secretion during IIGI, although systematically lower in T2D.In conclusion, 1) In NGT, glucose sensitivity and potentiation mediate the dose-dependent incretin effect increase; 2) In T2D, the incretin effect is blunted vs NGT, but rate sensitivity is enhanced at all loads; 3) Relatively lower incretin effect in NGT is associated with higher secretion during IIGI, suggesting that the reduced incretin effect does not result from ß-cell dysfunction.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedical Engineering, National Research Council, Padova, Italy.

ABSTRACT
The incretin effect on insulin secretion was investigated in 8 subjects with type 2 diabetes (T2D) and 8 with normal glucose tolerance (NGT), using 25, 75, and 125 g oral glucose tolerance tests (OGTT) and isoglycemic intravenous glucose infusions (IIGI). The ß-cell response was evaluated using a model embedding a dose-response (slope=glucose sensitivity), an early response (rate sensitivity), and potentiation (time-related secretion increase). The incretin effect, as OGTT/IIGI ratio, was calculated for each parameter. In NGT, the incretin effect on total secretion increased with dose (1.3 ± 0.1, 1.7 ± 0.2, 2.2 ± 0.2 fold of IIGI, P<0.0001), mediated by a dose-dependent increase of the incretin effect on glucose sensitivity (1.9 ± 0.4, 2.4 ± 0.4, 3.1 ± 0.4, P=0.005), and a dose-independent enhancement of the incretin effect on rate sensitivity (894 [1145], 454 [516], 783 [1259] pmol m(-2) L mmol(-1) above IIGI; median [interquartile range], P<0.0001). The incretin effect on potentiation also increased (0.97 ± 0.06, 1.45 ± 0.20, 1.24 ± 0.16, P<0.0001). In T2D, the incretin effect on total secretion (1.0 ± 0.1, 1.1 ± 0.1, 1.3 ± 0.1, P=0.004) and glucose sensitivity (1.2 ± 0.2, 1.3 ± 0.2, 2.0 ± 0.2, P=0.005) were impaired vs NGT; however, the incretin effect on rate sensitivity increased already at 25 g (269 [169], 284 [301], 193 [465] pmol m(-2) L mmol(-1) above IIGI; negligible IIGI rate sensitivity in T2D prevented the calculation of the fold increment). OGTT did not stimulate potentiation above IIGI (0.94 ± 0.04, 0.89 ± 0.06, 1.06 ± 0.09; P<0.01 vs NGT). In the whole group, the incretin effect was inversely associated with total secretion during IIGI, although systematically lower in T2D. In conclusion, 1) In NGT, glucose sensitivity and potentiation mediate the dose-dependent incretin effect increase; 2) In T2D, the incretin effect is blunted vs NGT, but rate sensitivity is enhanced at all loads; 3) Relatively lower incretin effect in NGT is associated with higher secretion during IIGI, suggesting that the reduced incretin effect does not result from ß-cell dysfunction.

Show MeSH
Related in: MedlinePlus