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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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Incremental insulin secretion response to intravenous and oral glucose.Individual trajectories for the relationship between the dose-dependent increment above basal in total insulin secretion during the OGTT and the IIGI in NGT and T2D participants. The dotted lines are the identity line.
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pone-0073154-g005: Incremental insulin secretion response to intravenous and oral glucose.Individual trajectories for the relationship between the dose-dependent increment above basal in total insulin secretion during the OGTT and the IIGI in NGT and T2D participants. The dotted lines are the identity line.

Mentions: To further illustrate the mechanisms of the incretin effect, the increment above basal of insulin secretion during the OGTT was plotted against the corresponding increments during IIGI, at all doses (Figure 5). The individual relationships were remarkably linear in most cases, with some notable deviations in two T2D subjects. The slope of these lines was estimated by linear regression and denoted as incretin effect slope. In the two T2D subjects with a nonlinear pattern, this estimate does represent an average slope but is potentially less reliable. We have thus evaluated if the results were affect by the exclusion of these subjects. The incretin effect slope represents a dose-independent measure of the individual incretin effect: the steeper the line the greater the enhancement of oral vs IIGI glucose-induced increase in insulin secretion. Along the identity lines (dotted lines in Figure 5), the increments of insulin secretion during the i.v. and oral tests are the same, i.e., there is no incretin effect. The incretin effect slope, in contrast to the classical total incretin effect, is not intrinsically dependent on total insulin secretion and related parameters. The incretin effect slope was significantly impaired in patients with T2D (1.8 [0.8] vs 3.3 [1.2], P = 0.001; the significance was maintained after exclusion of the T2D subjects with potentially unreliable incretin effect slope).


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)

Incremental insulin secretion response to intravenous and oral glucose.Individual trajectories for the relationship between the dose-dependent increment above basal in total insulin secretion during the OGTT and the IIGI in NGT and T2D participants. The dotted lines are the identity line.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0073154-g005: Incremental insulin secretion response to intravenous and oral glucose.Individual trajectories for the relationship between the dose-dependent increment above basal in total insulin secretion during the OGTT and the IIGI in NGT and T2D participants. The dotted lines are the identity line.
Mentions: To further illustrate the mechanisms of the incretin effect, the increment above basal of insulin secretion during the OGTT was plotted against the corresponding increments during IIGI, at all doses (Figure 5). The individual relationships were remarkably linear in most cases, with some notable deviations in two T2D subjects. The slope of these lines was estimated by linear regression and denoted as incretin effect slope. In the two T2D subjects with a nonlinear pattern, this estimate does represent an average slope but is potentially less reliable. We have thus evaluated if the results were affect by the exclusion of these subjects. The incretin effect slope represents a dose-independent measure of the individual incretin effect: the steeper the line the greater the enhancement of oral vs IIGI glucose-induced increase in insulin secretion. Along the identity lines (dotted lines in Figure 5), the increments of insulin secretion during the i.v. and oral tests are the same, i.e., there is no incretin effect. The incretin effect slope, in contrast to the classical total incretin effect, is not intrinsically dependent on total insulin secretion and related parameters. The incretin effect slope was significantly impaired in patients with T2D (1.8 [0.8] vs 3.3 [1.2], P = 0.001; the significance was maintained after exclusion of the T2D subjects with potentially unreliable incretin effect slope).

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