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.
Highlights
In subjects with normal glucose tolerance (NGT), the insulin response to the ingestion of a glucose load or a meal is influenced by the concomitant release of incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), which potentiate glucose-induced insulin secretion
The incretin effect has been evaluated by comparing the insulin secretory response to an oral glucose tolerance test (OGTT) with that elicited by an isoglycemic intravenous (i.v.) glucose infusion (IIGI) [4]
Total insulin secretion increased with the glucose dose in both NGT and type 2 diabetes (T2D) (P,0.0001); the increase was larger on the OGTT than the IIGI only in NGT (P = 0.004 for the interaction test 6 group)
Summary
In subjects with normal glucose tolerance (NGT), the insulin response to the ingestion of a glucose load or a meal is influenced by the concomitant release of incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), which potentiate glucose-induced insulin secretion. The incretin effect has been evaluated by comparing the insulin secretory response to an oral glucose tolerance test (OGTT) with that elicited by an isoglycemic intravenous (i.v.) glucose infusion (IIGI) (i.e., at matched plasma glucose levels) [4] Using this approach, it has been shown that in NGT subjects the incretin effect increases with the glucose load [4], and that this increase is diminished in T2D [5]. To quantify the incretin effect, these studies typically use the ratio of total insulin secretion during the OGTT to that obtained during the IIGI This simple and robust index, does not provide detailed insight into the mechanisms by which the incretin response affects the dynamic relationship between insulin secretion and glucose concentrations. A marked increase of the early insulin secretion response has been observed with oral compared to i.v. glucose [2,6]
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