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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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Beta-cell dose-response.Insulin secretion dose-response obtained from the IIGI at the three glucose doses in subjects with NGT subjects (top) and patients with T2D (bottom). Plots are mean±SE; glucose spans reflect the average observed levels.
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pone-0073154-g001: Beta-cell dose-response.Insulin secretion dose-response obtained from the IIGI at the three glucose doses in subjects with NGT subjects (top) and patients with T2D (bottom). Plots are mean±SE; glucose spans reflect the average observed levels.

Mentions: During IIGI in NGT subjects, the insulin secretion dose-response was shifted upwards at the two higher glucose doses, but with similar slopes (Figure 1). Thus, at a glucose level of 5.3 mmol/L, insulin secretion rate from the dose-response was 88 [33], 104 [70] and 126 [41] pmol.min−1.m−2 in the IIGI tests matching the 25, 75 and 125 g glucose dose, respectively (P<0.01). Rate sensitivity was low and dose-independent (P = 0.32) (Table 1). The mean potentiation ratio, on the other hand, increased with the glucose dose (P<0.0001 for the dose effect), and was positively related to insulin secretion at 5.3 mmol/L glucose (ρ = 0.63, P = 0.001, all doses pooled) and to mean glucose levels (ρ = 0.81, P<0.0001, all doses pooled; Figure 2). Thus, with i.v. glucose progressive stimulation by increasing glucose loads resulted in an insulin response characterized by stimulation of potentiation and an upward shift of the ß-cell dose-response, but comparable glucose sensitivity and early response.


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)

Beta-cell dose-response.Insulin secretion dose-response obtained from the IIGI at the three glucose doses in subjects with NGT subjects (top) and patients with T2D (bottom). Plots are mean±SE; glucose spans reflect the average observed levels.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0073154-g001: Beta-cell dose-response.Insulin secretion dose-response obtained from the IIGI at the three glucose doses in subjects with NGT subjects (top) and patients with T2D (bottom). Plots are mean±SE; glucose spans reflect the average observed levels.
Mentions: During IIGI in NGT subjects, the insulin secretion dose-response was shifted upwards at the two higher glucose doses, but with similar slopes (Figure 1). Thus, at a glucose level of 5.3 mmol/L, insulin secretion rate from the dose-response was 88 [33], 104 [70] and 126 [41] pmol.min−1.m−2 in the IIGI tests matching the 25, 75 and 125 g glucose dose, respectively (P<0.01). Rate sensitivity was low and dose-independent (P = 0.32) (Table 1). The mean potentiation ratio, on the other hand, increased with the glucose dose (P<0.0001 for the dose effect), and was positively related to insulin secretion at 5.3 mmol/L glucose (ρ = 0.63, P = 0.001, all doses pooled) and to mean glucose levels (ρ = 0.81, P<0.0001, all doses pooled; Figure 2). Thus, with i.v. glucose progressive stimulation by increasing glucose loads resulted in an insulin response characterized by stimulation of potentiation and an upward shift of the ß-cell dose-response, but comparable glucose sensitivity and early response.

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