Glucose-Dependent Insulinotropic Polypeptide Is a Pancreatic Polypeptide Secretagogue in Humans

Background: Glucose-dependent insulinotropic polypeptide (GIP) has been suggested to stimulate the secretion of pancreatic polypeptide (PP), an islet hormone thought to regulate gut motility, appetite, and glycemia. Objective: To determine whether human GIP(1-42) (hGIP) stimulates PP secretion. Method: As glycemia modulates the secretion of PP, we measured plasma PP concentrations from 2 studies in healthy men (n = 10) and in patients with type 2 diabetes (T2D) (n = 12), where hGIP(1-42) had been administered intravenously during fasting glycemia, hyperglycemia (12 mmol/L), and insulin-induced hypoglycemia (targets: 2.5 mmol/L [healthy]; 3.5 mmol/L [T2D]). Porcine GIP(1-42) (pGIP) was also infused intra-arterially in isolated porcine pancreata (n = 4). Results: Mean fasting plasma glucose concentrations were approximately 5 mmol/L (healthy) and approximately 8 mmol/L (T2D). At fasting glycemia, PP concentrations were higher during intravenous hGIP(1-42) infusion compared with saline in healthy men (mean [standard error of the mean, SEM], net incremental areas under the curves (iAUCs)([0-30min]), 403 [116] vs -6 [57] pmol/L x min; P = 0.004) and in patients with T2D (905 [177] vs -96 [86] pmol/L x min; P = 0.009). During hyperglycemic clamping, mean [SEM] PP concentrations were significantly higher during hGIP(1-42) infusion compared with saline in patients with T2D (771 [160] vs -183 [117] pmol/L x min; P = 0.001), but not in healthy individuals (-8 [86] vs -57 [53] pmol/L x min; P = 0.69). When plasma glucose levels were declining in response to exogenous insulin, mean [SEM] PP concentrations were higher during hGIP(1-42) infusion compared with saline in healthy individuals (294 [88] vs -82 [53] pmol/L x min; P = 0.0025), but not significantly higher in patients with T2D (586 [314] vs -120 [53]; P = 0.070). At target hypoglycemia, PP levels surged in both groups during both hGIP(1-42) and saline infusions. In isolated pancreata, pGIP(1-42) increased mean [SEM] PP output in the pancreatic venous effluent (baseline vs infusion, 24[5] vs 79 [16] pmol/min x min; P = 0.044). Conclusion: GIP(1-42) increases plasma PP secretion in healthy individuals, patients with T2D, and isolated porcine pancreata. Hyperglycemia blunts the stimulatory effect of hGIP(1-42) in healthy individuals, but not in patients with T2D.