Peripherally delivered hepatopreferential insulin analog insulin‐406 mimics the hypoglycaemia‐sparing effect of portal vein human insulin infusion in dogs

Aims We previously quantified the hypoglycaemia-sparing effect of portal vs peripheral human insulin delivery. The current investigation aimed to determine whether a bioequivalent peripheral vein infusion of a hepatopreferential insulin analog, insulin-406, could similarly protect against hypoglycaemia. Materials and methods Dogs received human insulin infusions into either the hepatic portal vein (PoHI, n = 7) or a peripheral vein (PeHI, n = 7) for 180 minutes at four-fold the basal secretion rate (6.6 pmol/kg/min) in a previous study. Insulin-406 (Pe406, n = 7) was peripherally infused at 6.0 pmol/kg/min, a rate determined to decrease plasma glucose by the same amount as with PoHI infusion during the first 60 minutes. Glucagon was fixed at basal concentrations, mimicking the diminished alpha-cell response seen in type 1 diabetes. Results Glucose dropped quickly with PeHI infusion, reaching 41 +/- 3 mg/dL at 60 minutes, but more slowly with PoHI and Pe406 infusion (67 +/- 2 and 72 +/- 4 mg/dL, respectively; P < 0.01 vs PeHI for both). The hypoglycaemic nadir (c. 40 mg/dL) occurred at 60 minutes with PeHI infusion vs 120 minutes with PoHI and Pe406 infusion. Delta AUC(epinephrine) during the 180-minute insulin infusion period was two-fold higher with PeHI infusion compared with PoHI and Pe406 infusion. Glucose production (mg/kg/min) was least suppressed with PeHI infusion (Delta = 0.79 +/- 0.33) and equally suppressed with PoHI and Pe406 infusion (Delta = 1.16 +/- 0.21 and 1.18 +/- 0.17, respectively; P = NS). Peak glucose utilization (mg/kg/min) was highest with PeHI infusion (4.94 +/- 0.17) and less with PoHI and Pe406 infusion (3.58 +/- 0.58 and 3.26 +/- 0.08, respectively; P < 0.05 vs Pe for both). Conclusions Peripheral infusion of hepatopreferential insulin can achieve a metabolic profile that closely mimics portal insulin delivery, which reduces the risk of hypoglycaemia compared with peripheral insulin infusion.