Aims: In our preceding study DPP-4 inhibition diminished GLP-1 incretin effects. This finding sheds new light on biological role of GLP-1 metabolite (GLP-1m). In the present study we investigated the involvement of GLP-1m in the effects exerted by GLP-1 incretin and the time duration through which GLP-1m effects are maintained.
Materials and methods: (A) Chronically catheterized Wistar rats were injected with vehicle (V; 0.1% bovine serum albumin in saline), 4.0 nmol/kg GLP-1m (Probiodrug AG, Halle/Saale, Germany), 4.0 nmol/kg GLP-1a (GLP-1 (7–36) amide; Neo MPS, Strasbourg, France) or GLP-1m and GLP-1a each at a dose of 4.0 nmol/kg. The incretin(s) were administered 5min before IVGTT (0.4g glucose/kg). Blood samples for glucose (G) and insulin (I) analysis were drawn at -5, 0, 1, 2, 3, 5, 7, 10, 15, 25, 40, 60min. G- and I- AUC0–25min, insulinogenic Index iI (ratio of I- and G-AUC) and glucose efflux KG (Conard, 1959) were calculated from the G- and I-curves.
(B): GLP-1m was administered at 4.0 nmol/kg in random order 20, 10, 5 and 2.5min before IVGTT and was compared with V given 5min before IVGTT. Blood samples were drawn up to 20min.
Results: In (A), 5min after incretin injection, glucose tolerance was not affected (G-AUC0–25min: V 182±19 (mean±SD), GLP-1m 185±17, GLP-1a 179±23, GLP-1m+a 187±25 mmol·min/L). GLP-1m tended to lower glucose efflux (KG: V 15.6±4.3, GLP-1m 11.5±3.4, GLP-1a 15.2±4.7, GLP-1m+a: 14.2±2.0%) and induced an insulin response (I-AUC0–25min: V 58±26, GLP-1m 76±35, GLP-1a 152±80, GLP-1m+a 137±61ng·min/mL; iI: V 0.33±0.18, GLP-1m 0.40±0.19, GLP-1a 0.87±0.46, GLP-1m+a: 0.77±0.42µg/mmol). – When GLP-1m was injected in (B) at defined times before IVGTT, it improved glucose tolerance (G-AUC0–20min; V: 176±12, -2.5: 170±22, -5: 177±17, -10: 166±12, -20min: 165±9 mmol·min/L), increased glucose efflux (KG; V: 12.6±2.1, -2.5: 15.4±3.8, -5: 13.6±2.9, -10: 16.9±1.2*, -20: 14.1±2.6%) and enhanced insulin response as revealed by alterations of I-AUC0–20min (V: 59±11, -2.5: 66±19, -5: 61±14, -10: 66±11, -20: 70±16ng·min/mL)) and iI (V: 0.32±0.07, -2.5: 0.42±0.16, -5: 0.36±0.11, -10: 0.39±0.07, -20: 0.42±0.09µg/mmol).
Conclusions: GLP-1m stimulates the insulin response in (A) significantly during an IVGTT compared to a V control. In (B) GLP-1m exerts both short and long lasting effects resulting in an improved (enhanced) insulin response after glucose stimulation. The anti-hyperglycaemic actions were more pronounced 10 or 20min after injection of GLP-1m. Nevertheless, the efficacy of GLP-1m on glucose and insulin metabolism is limited and therefore this metabolite seems to have minor importance in mediating effects of incretins.
We thank Probiodrug AG, Halle/Saale, for donation of GLP-1m compound.
