title: Reduced peripheral activity leading to hepato-preferential action of basal insulin peglispro compared with insulin glargine in patients with type 1 diabetes.
abstract: Basal insulin peglispro (BIL), a novel PEGylated basal insulin with a large hydrodynamic size, has a delayed absorption and reduced clearance that prolongs the duration of action. The current study compared the effects of BIL and insulin glargine (GL) on endogenous glucose production (EGP), glucose disposal rate (GDR) and lipolysis in patients with type 1 diabetes.
  
  
  
  This was a randomized, open-label, four-period, crossover study. Patients received intravenous infusions of BIL and GL, each at two dose levels selected for partial and maximal suppression of EGP, during an 8 to 10 h euglycemic clamp procedure with d-[3-3H] glucose.
  
  
  
  Following correction for equivalent human insulin concentrations (EHIC), low-dose GL infusion resulted in similar EGP at the end of the clamp compared to low-dose BIL infusion (GL/BIL ratio of 1.03) but a higher GDR (GL/BIL ratio of 2.42), indicating similar hepatic activity but attenuated peripheral activity of BIL. Consistent with this, the EHIC-corrected GDR/EGP at the end of the clamp was 1.72-fold greater for GL than BIL following low-dose administration. At the lower dose of BIL and GL (concentrations in the therapeutic range), BIL produced less suppression of lipolysis compared with GL as indicated by free fatty acid and glycerol levels at the end of the clamp.
  
  
  
  Compared with GL, BIL restored the hepato-peripheral insulin action gradient seen in normal physiology via its peripherally restricted action on target tissues related to carbohydrate and lipid metabolism.
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.|Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mudaliar
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.|Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, CA, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Henry
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.|Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, CA, USA.
authors.forename: T P
authors.initials: TP
authors.lastname: Ciaraldi
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Armstrong
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Burke
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, CA, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Pettus
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: P
authors.initials: P
authors.lastname: Garhyan
authors.affiliation: Eli Lilly and Company, Singapore, Singapore.
authors.forename: S L
authors.initials: SL
authors.lastname: Choi
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Knadler
authors.affiliation: Eli Lilly and Company, Singapore, Singapore.
authors.forename: E C Q
authors.initials: EC
authors.lastname: Lam
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Prince
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Bose
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: N K
authors.initials: NK
authors.lastname: Porksen
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: V P
authors.initials: VP
authors.lastname: Sinha
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: H
authors.initials: H
authors.lastname: Linnebjerg
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA. jacober_scott_j@lilly.com.
authors.forename: S J
authors.initials: SJ
authors.lastname: Jacober
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D015309:Glucose Clamp Technique; D005990:Glycerol / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007262:Infusions, Intravenous; D000069036:Insulin Glargine / Q000494:pharmacology* / Q000627:therapeutic use; D061268:Insulin Lispro / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008066:Lipolysis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D014316:Tritium; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D061268:Insulin Lispro; C000621851:basal insulin peglispro; D014316:Tritium; D000069036:Insulin Glargine; D011092:Polyethylene Glycols; D005990:Glycerol
keywords: basal insulin; clinical trial; drug development; pharmacodynamics; phase III study