DPP-4 inhibition increases GIP and decreases GLP-1 incretin effects during intravenous glucose tolerance test in Wistar rats

Feb 2, 2011Biological chemistry

Blocking DPP-4 raises GIP but lowers GLP-1 hormone responses during glucose test in rats

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Abstract

Systemic DPP-4 inhibition significantly altered the insulin response to GIP and GLP-1 in Wistar rats.

DPP-4 inhibition increased the insulin response to GIP, measured as I-AUC, from 115±34 to 153±39 ng·min/ml.
The insulinogenic index for GIP also improved from 0.74±0.24 to 0.99±0.26 ng/mmol with DPP-4 inhibition.
GIP demonstrated improved glucose efflux with DPP-4 inhibition, increasing from 19.8±3.1 to 20.5±5.0 min⁻¹.
In contrast, the insulin response to GLP-1 decreased with DPP-4 inhibition, with I-AUC dropping from 124±18 to 106±38 ng·min/ml.
The insulinogenic index for GLP-1 declined from 0.70±0.18 to 0.50±0.19 ng/mmol when DPP-4 was inhibited.
GLP-1's glucose efflux decreased from 14.9±3.1 to 11.1±3.7 min⁻¹ under DPP-4 inhibition.

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GIP metabolite [GIP (3-42)] and GLP-1 metabolite [GLP-1 (9-36) amide] have been reported to differ with regard to biological actions. Systemic DPP-4 inhibition can therefore reveal different actions of GIP and GLP-1. In catheter wearing Wistar rats, insulinotropic effects of equipotent doses of GIP (2.0 nmol/kg) and GLP-1 (7-36) amide (4.0 nmol/kg) and vehicle were tested in the absence/presence of DPP-4 inhibition. Blood glucose and insulin were frequently sampled. DPP-4 inhibitor was given at -20 min, the incretin at -5 min and the intravenous glucose tolerance test (0.4 g glucose/kg) commenced at 0 min. G-AUC and I-AUC, insulinogenic index and glucose efflux, were calculated from glucose and insulin curves. Systemic DPP-4 inhibition potentiated the acute GIP incretin effects: I-AUC (115±34 vs. 153±39 ng·min/ml), increased the insulinogenic index (0.74±0.24 vs. 0.99±0.26 ng/mmol), and improved glucose efflux (19.8±3.1 vs. 20.5±5.0 min⁻¹). The GLP-1 incretin effects were diminished: I-AUC (124±18 vs. 106±38 ng·min/ml), the insulinogenic index was decreased (0.70±0.18 vs. 0.50±0.19 ng/mmol), and glucose efflux declined (14.9±3.1 vs. 11.1±3.7 min⁻¹). GLP-1 and GIP differ remarkably in their glucoregulatory actions in healthy rats when DPP-4 is inhibited. These previously unrecognized actions of DPP-4 inhibitors could have implications for future use in humans.

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DPP-4 inhibition increases GIP and decreases GLP-1 incretin effects during intravenous glucose tolerance test in Wistar rats

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