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

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

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

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.

When premixed insulin Lyumjev^Ⓡ/glucagon was injected, insulin T_max decreased from 33 to 20 minutes (SE = 6.6, P = 0.08), and C_max was 2-fold higher than that in the control group (100 mU/L vs 46 mU/L, SE = 4.8, P = 0.007). When premixed insulin Humalog^Ⓡ/glucagon was injected, T_max and C_max did not change significantly (P = 0.53 and P = 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, P = 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 (P = 0.102) compared with the control groups.

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.