Novel PEGylated Basal Insulin LY2605541 Has a Preferential Hepatic Effect on Glucose Metabolism

Abstract

The impact of the novel basal insulin LY2605541 (LY) on hepatic and nonhepatic glucose uptake (non-HGU) was evaluated. Conscious dogs underwent euglycemic clamps with tracer and hepatic balance measurements. Clamp period infusions were peripheral venous regular insulin (0.1 nmol ⋅ kg−1 ⋅ h−1 [control], n = 6) or LY (bolus [nmol/kg], continuous [nmol ⋅ kg−1 ⋅ h−1]: 0.5, 0.5 [n = 6]; 0.375, 0.375 [n = 5]; 0.25, 0.25 [n = 4]), somatostatin, and glucose, as well as intraportal glucagon (basal). During the clamp, the dogs switched from net hepatic glucose output to uptake (rates reached 2.1 ± 1.2, 0.9 ± 2.1, 8.6 ± 2.3, and 6.0 ± 1.1 µmol ⋅ kg−1 ⋅ min−1 within 5 h in control, LY0.25, LY0.375, and LY0.5, respectively). Non-HGU in LY increased less than in control; the ratio of change from basal in non-HGU to change in net hepatic glucose balance, calculated when glucose infusion rates (GIRs) were ~20 µmol ⋅ kg-1 ⋅ min−1 in all groups, was higher in control (1.17 ± 0.38) versus LY0.25 (0.39 ± 0.33), LY0.375 (−0.01 ± 0.13), and LY0.5 (−0.09 ± 0.07). Likewise, the change from baseline in glucose Rd-to-Ra ratio was greatest in control (1.4 ± 0.3 vs. 0.6 ± 0.4, 0.5 ± 0.2, and 0.6 ± 0.2 in LY0.25, LY0.375, and LY0.5, respectively). In contrast to exogenously administered human insulin, LY demonstrated preferential hepatic effects, similar to endogenously secreted insulin. Therefore, the analog might reduce complications associated with current insulin therapy.

LY2605541—A Preferential Hepato-Specific Insulin Analogue

“…During peripheral intravenous infusion of LY2605541, a switch from hepatic glucose output to uptake was reported, and nonhepatic glucose uptake increased less than in control experiments with human insulin, indicating that LY2605541 possesses preferential hepatic effects, thereby mimicking endogenously secreted insulin (3).…”

Basal Insulin Peglispro Demonstrates Preferential Hepatic Versus Peripheral Action Relative to Insulin Glargine in Healthy Subjects

“…Basal insulin peglispro (BIL; LY2605541), a novel, polyethylene glycolylated insulin analog currently in phase III, has a hepatopreferential action and decreased peripheral action in an insulinopenic dog model (16). The half-life of BIL is ;2 to 3 days (17) and therefore requires ;7 to 10 days to reach steady state when administered subcutaneously.…”

Tissue barriers and novel approaches to achieve hepatoselectivity of subcutaneously-injected insulin therapeutics

“…In euglycemic clamp studies on conscious dogs, the change from baseline in glucose Rd-to-Ra ratio was 0.5-0.6 in the Peglispro infusion group compared with 1.4 § 0.3 in the INS group. 20 It is believed that the large hydrodynamic radius of Peglispro impedes its transport across peripheral blood capillaries to the interstitial fluid of skeletal muscles and adipose, which leaves more Peglispro available for filtration through hepatic sinusoids 19 In addition, the reduced binding affinity of Peglispro to IR (less than 6% of INS lispro) possibly decreases peripheral IRmediated clearance and contributes to a longer residence time in liver microcirculation. 21 However, hepatopreference of Peglispro was prominent only below a certain dose.…”

“…When the amount of infused Peglispro increased, PGD also increased indicating decreased hepatoselectivity. 20 In active liver-targeting, one approach is to preferentially target IR isoform B (IR-B), which is the dominant isoform expressed on human liver compared to the other isoform of IR, IR-A. The INS analog INS-B [A8H, B25N, B27E, desB30 human insulin] 22 displays a 2 to 4-fold higher binding affinity toward IR-B than IR-A.…”