Nano-Amounts of Glucagon Premixed With Fast-Acting Insulin Lispro: Effect on Insulin Absorption in Pigs.

Background: Glucagon leads to substantial but short-lived subcutaneous vasodilation. Using micro-amounts of glucagon at the insulin injection site increases insulin absorption.

Objective: We hypothesized that a premixed solution of insulin and nanogram doses of glucagon would improve the pharmacokinetic and pharmacodynamic properties of subcutaneously injected insulin.

Methods: In this series of proof-of-concept experiments, 17 anesthetized pigs were included. Nine pigs were included in the control groups; they received a subcutaneous injection of 10 U of insulin lispro (Lyumjev or Humalog). Eight pigs were included in the glucagon groups; they received 10 U of a premixed insulin (Lyumjev or Humalog)/glucagon solution (5 ng glucagon/unit of insulin). Arterial blood was frequently sampled for 210 minutes to assess insulin and glucose concentrations. The impact on glucose metabolism was evaluated through euglycemic clamp investigation.

Results: When premixed insulin Lyumjev/glucagon was injected, insulin T decreased from 33 to 20 minutes (SE = 6.6, = 0.08), and C was 2-fold higher than that in the control group (100 mU/L vs 46 mU/L, SE = 4.8, = 0.007). When premixed insulin Humalog/glucagon was injected, T and C did not change significantly ( = 0.53 and = 0.83, respectively). Insulin AUC for the first 15 minutes increased two-fold when insulin Lyumjev/glucagon was injected (946 mU×min/L vs 337 mU×min/L, SE = 196, = 0.02). A similar trend was observed when Humalog/glucagon was injected (306 mU×min/L vs 65 mU×min/L, SE = 125), although this difference did not reach statistical significance ( = 0.102) compared with the control groups.

Conclusions: This series of proof-of-concept experiments in anesthetized pigs indicate that premixing nanogram doses of glucagon in fast-acting insulin lispro formulations may speed up the absorption of subcutaneously injected insulin.