Basal Insulin Peglispro Demonstrates Preferential Hepatic Versus Peripheral Action Relative to Insulin Glargine in Healthy Subjects Diabetes Care 2014;37:2609–2615 | DOI: 10.2337/dc14-0210 OBJECTIVE We 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 METHODS This was a single-center, randomized, open-label, four-period, incomplete-block, crossover study conducted in eight healthy male subjects. Subjects had 8-h eugly- cemic 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. RESULTS Mean 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. Sup- pression of EGP and stimulation of GDR were observed with increasing concen- trations 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 sub- stantially less effect on GDR than insulin glargine at higher doses. CONCLUSIONS The novel basal insulin analog BIL has relative hepatopreferential action and de- creased 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 pe- ripheral action ranges between 2:1 and 4:1 (1,2,4,8–10). In contrast, when exoge- nous insulin is administered peripherally, insulin is distributed equally across the liver and peripheral tissues (11,12) and thus does not mimic normal physiology. 1 Center for Metabolic Research, VA San Diego Healthcare System, San Diego, CA 2 University of California, San Diego, La Jolla, CA 3 Eli Lilly and Company, Indianapolis, IN 4 Eli Lilly and Company, Singapore, Singapore Corresponding author: Helle Linnebjerg, linnebjerg_helle@lilly.com. Received 22 January 2014 and accepted 19 May 2014. Clinical trial reg. no. NCT01654380, clinicaltrials .gov. This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/ suppl/doi:10.2337/dc14-0210/-/DC1. V.P.S. is currently affiliated with the Office of Clinical Pharmacology, Center for Drug Evalua- tion and Research, U.S. Food and Drug Adminis- tration, Silver Spring, MD. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. Robert R. Henry, 1,2 Sunder Mudaliar, 1,2 Theodore P. Ciaraldi, 1,2 Debra A. Armstrong, 1 Paivi Burke, 1 Jeremy Pettus, 2 Parag Garhyan, 3 Siak Leng Choi, 4 Scott J. Jacober, 3 Mary Pat Knadler, 3 Eric Chen Quin Lam, 4 Melvin J. Prince, 3 Namrata Bose, 2 Niels Porksen, 3 Vikram P. Sinha, 3 and Helle Linnebjerg 3 Diabetes Care Volume 37, September 2014 2609 PATHOPHYSIOLOGY/COMPLICATIONS Downloaded from http://diabetesjournals.org/care/article-pdf/37/9/2609/486435/2609.pdf by guest on 20 September 2022