OBJECTIVEWe evaluated the endogenous glucose production (EGP) and glucose disposal rate (GDR) over a range of doses of basal insulin peglispro (BIL) and insulin glargine in healthy subjects.
RESEARCH DESIGN AND METHODSThis was a single-center, randomized, open-label, four-period, incomplete-block, crossover study conducted in eight healthy male subjects. Subjects had 8-h euglycemic clamps performed with primed, continuous infusions of BIL (5.1 to 74.1 mU/min) in three dosing periods and insulin glargine (20 or 30 mU/m 2 /min) in a fourth period, targeted to achieve 50-100% suppression of EGP. D-[3-3 H] glucose was infused to assess rates of glucose appearance and disappearance.
RESULTSMean BIL and insulin glargine concentrations (targeted to reflect the differences in intrinsic affinities of the two basal insulins) ranged from 824 to 11,400 and 212 to 290 pmol/L, respectively, and increased accordingly with increases in dose. Suppression of EGP and stimulation of GDR were observed with increasing concentrations of both insulins. At insulin concentrations where EGP was significantly suppressed, insulin glargine resulted in increased GDR. In contrast, at comparable suppression of EGP, BIL had minimal effect on GDR at lower doses and had substantially less effect on GDR than insulin glargine at higher doses.
CONCLUSIONSThe novel basal insulin analog BIL has relative hepatopreferential action and decreased peripheral action, compared with insulin glargine, in healthy subjects.In vivo, insulin is secreted from pancreatic b-cells and enters the circulation via the portal vein, where on first pass the liver extracts ;40-80% (1-7). As a result, systemic circulating insulin levels are reduced compared with those in the portal vein, and subsequent insulin action in the peripheral target tissues is also reduced compared with the liver. Consequently, the relative ratio of hepatic action to peripheral action ranges between 2:1 and 4:1 (1,2,4,8-10). In contrast, when exogenous insulin is administered peripherally, insulin is distributed equally across the liver and peripheral tissues (11,12) and thus does not mimic normal physiology.