Glucagon‐like peptide‐1 and glucose‐dependent insulinotropic peptide: effects alone and in combination on insulin secretion and glucose disappearance in mice

Glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic peptide (GIP) stimulate insulin secretion. They are both released after meal ingestion, and therefore they might cooperate in their actions. However, whether there is a cooperative action of the two incretins is not known. This study therefore investigated the effects on insulin secretion and glucose disappearance of GLP‐1 and GIP when given together with intravenous glucose both alone and in combination in mice. Four different doses were used (0.003, 0.03, 0.3 and 3.0 nmol/kg), which ranged from subthreshold to maximal doses to stimulate first‐phase insulin secretion as evident from initial dose–response studies. It was found that at 0.03 nmol/kg and higher doses, glucose‐stimulated insulin secretion was augmented by both incretins. When they were given in combination, no further increase was observed, indicating no synergistic effect. Also, glucose disappearance rate was increased by 0.03 and 3.0 nmol/kg of the two incretins, both when they were given alone and in combination with, again, no synergy. Finally, glucose effectiveness (an index of noninsulin‐mediated processes) was enhanced by the two incretins, in particular GIP. We also found that insulin‐dependent and insulin‐independent mechanisms contributed 38% and 62%, respectively, to glucose tolerance after glucose alone; with GIP, the contribution by noninsulin‐dependent processes was remarkably dominant and with GLP‐1, insulin‐dependent processes were prevailing. In conclusion, GIP and GLP‐1 stimulate insulin secretion and glucose effectiveness in mice with no synergistic action, but with a dissociated contributory effector on glucose disposal: with GLP‐1 being more active on insulin‐dependent processes and GIP more active on noninsulin‐dependent processes.