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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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Incretin effect on potentiation.Time-course of the incretin effect on OGTT/IIGI ratio of the potentiation factor with increasing glucose loads in NGT and T2D participants. The potentiation factor is normalized to the baseline value before calculating the ratio. Plots are mean±SE.
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pone-0073154-g004: Incretin effect on potentiation.Time-course of the incretin effect on OGTT/IIGI ratio of the potentiation factor with increasing glucose loads in NGT and T2D participants. The potentiation factor is normalized to the baseline value before calculating the ratio. Plots are mean±SE.

Mentions: In subjects with NGT, the incretin effect on total insulin secretion showed a remarkably wide range (0.87–3.3, all doses), increased progressively with the glucose load (Figure 3), and was significantly greater than 1 with all doses (P<0.0001 for the dose effect). Modulation of the incretin effect was mediated by a dose-dependent increase in glucose sensitivity (P<0.0001) (Figure 3), and a dose-independent enhancement of rate sensitivity P<0.0001, P = 0.07 for dose-dependence by Friedman test) (Table 1). The incretin effect on potentiation also increased dose-dependently (P<0.0001) (Figure 4).


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)

Incretin effect on potentiation.Time-course of the incretin effect on OGTT/IIGI ratio of the potentiation factor with increasing glucose loads in NGT and T2D participants. The potentiation factor is normalized to the baseline value before calculating the ratio. Plots are mean±SE.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0073154-g004: Incretin effect on potentiation.Time-course of the incretin effect on OGTT/IIGI ratio of the potentiation factor with increasing glucose loads in NGT and T2D participants. The potentiation factor is normalized to the baseline value before calculating the ratio. Plots are mean±SE.
Mentions: In subjects with NGT, the incretin effect on total insulin secretion showed a remarkably wide range (0.87–3.3, all doses), increased progressively with the glucose load (Figure 3), and was significantly greater than 1 with all doses (P<0.0001 for the dose effect). Modulation of the incretin effect was mediated by a dose-dependent increase in glucose sensitivity (P<0.0001) (Figure 3), and a dose-independent enhancement of rate sensitivity P<0.0001, P = 0.07 for dose-dependence by Friedman test) (Table 1). The incretin effect on potentiation also increased dose-dependently (P<0.0001) (Figure 4).

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