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

Abstract

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_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.

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.

Keywords: Animal experiments; Glucagon; Insulin; Insulin infusion systems.

Fig. 1

Mean (± range) serum insulin lispro concentration–time change from baseline for Lyumjev^Ⓡ (black dashed line) and Humalog^Ⓡ (brown dashed line) and premixed Lyumjev^Ⓡ/glucagon (black line) and Humalog^Ⓡ/glucagon (brown line). (A) 0 to 210 minutes after injection of Lyumjev^Ⓡ; (B) 0 to 210 minutes after injection of Humalog^Ⓡ; (C) 0 to 60 minutes after injection of Lyumjev^Ⓡ; (D) 0 to 60 minutes after injection of Humalog^Ⓡ.

Fig. 2

Glucose infusion rate change from baseline (± range) after insulin (dashed line) and premixed insulin/glucagon injection (solid line); (A) 0 to 210 minutes after injection of Lyumjev^Ⓡ; (B) 0 to 210 minutes after injection of Humalog^Ⓡ.