title: Changes in glucose and fat metabolism in response to the administration of a hepato-preferential insulin analog.
abstract: Endogenous insulin secretion exposes the liver to three times higher insulin concentrations than the rest of the body. Because subcutaneous insulin delivery eliminates this gradient and is associated with metabolic abnormalities, functionally restoring the physiologic gradient may provide therapeutic benefits. The effects of recombinant human insulin (HI) delivered intraportally or peripherally were compared with an acylated insulin model compound (insulin-327) in dogs. During somatostatin and basal portal vein glucagon infusion, insulin was infused portally (PoHI; 1.8 pmol/kg/min; n = 7) or peripherally (PeHI; 1.8 pmol/kg/min; n = 8) and insulin-327 (Pe327; 7.2 pmol/kg/min; n = 5) was infused peripherally. Euglycemia was maintained by glucose infusion. While the effects on liver glucose metabolism were greatest in the PoHI and Pe327 groups, nonhepatic glucose uptake increased most in the PeHI group. Suppression of lipolysis was greater during PeHI than PoHI and was delayed in Pe327 infusion. Thus small increments in portal vein insulin have major consequences on the liver, with little effect on nonhepatic glucose metabolism, whereas insulin delivered peripherally cannot act on the liver without also affecting nonhepatic tissues. Pe327 functionally restored the physiologic portal-arterial gradient and thereby produced hepato-preferential effects.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN dale.edgerton@vanderbilt.edu.
authors.forename: Dale S
authors.initials: DS
authors.lastname: Edgerton
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Moore
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Winnick
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Melanie
authors.initials: M
authors.lastname: Scott
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Ben
authors.initials: B
authors.lastname: Farmer
authors.affiliation: Novo Nordisk, Copenhagen, Denmark.
authors.forename: Helle
authors.initials: H
authors.lastname: Naver
authors.affiliation: Novo Nordisk, Copenhagen, Denmark.
authors.forename: Claus B
authors.initials: CB
authors.lastname: Jeppesen
authors.affiliation: Novo Nordisk, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Madsen
authors.affiliation: Novo Nordisk, Copenhagen, Denmark.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Kjeldsen
authors.affiliation: Novo Nordisk, Copenhagen, Denmark.
authors.forename: Erica
authors.initials: E
authors.lastname: Nishimura
authors.affiliation: Novo Nordisk, Copenhagen, Denmark.
authors.forename: Christian L
authors.initials: CL
authors.lastname: Brand
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Cherrington
mesh_terms: D000818:Animals; D001786:Blood Glucose; D004285:Dogs; D005260:Female; D005934:Glucagon / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects*; D008066:Lipolysis / Q000187:drug effects; D008297:Male
chemical_list: D001786:Blood Glucose; D007328:Insulin; D005934:Glucagon; D005947:Glucose