title: Portal or subcutaneous insulin infusion: efficacy and impact on liver inflammation.
abstract: Intraperitoneal insulin allows physiological portal insulin administration and first-pass hepatic insulin extraction, but the impact on liver metabolism and inflammation is unknown. Our objective was to compare the impact, on metabolic control and liver function, of the same dose of insulin administered either intraperitoneally or subcutaneously during continuous infusion in diabetic rats. Wistar rats were randomly divided into 4 groups: control (C), untreated diabetic (streptozotocin, 100 mg/kg) and diabetic rats treated by continual subcutaneous Insuplant® infusion (CSII) and continual intraperitoneal Insuplant(®) infusion (CPII) of 2 UI/200 g/day (via an osmotic mini-pump for 1-4 weeks). Insulin signalling pathways were analysed through hepatic expression of growth hormone receptor and phosphorylated insulin receptor substrate 1. Metabolic control was determined by measurement of body weight, blood glucose and fructosamine. Liver function was assessed by measuring insulin-like growth factor-1 (IGF-1), with global inflammation assessed by levels of alpha-2-macroglobulin (α2M) and lipid peroxidation in plasma. Liver inflammation was evaluated by quantification of hepatic macrophage infiltration and reactive oxygen species production. CPII induced a better improvement in metabolic control and liver function than CSII, producing a significant decrease in blood glucose and fructosamine, coupled with increased IGF-1 and hepatic glycogen storage. Moreover, liver oxidative stress and liver inflammation were reduced. Such observations indicate that the same insulin level in CPII improves glucose control and hepatic glucose metabolism and function, attenuating the hepatic inflammatory response to diabetes. These data demonstrate the importance of focusing on therapeutics to allow first-pass hepatic insulin extraction or prevent diabetic complications.
authors.affiliation: DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Bld René Leriche, Strasbourg, 67200, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Dal
authors.affiliation: Structure d'Endocrinologie, Diabète -Nutrition et Addictologie, Pôle NUDE, Hôpitaux Universitaires de Strasbourg (HUS), Strasbourg, 67000, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jeandidier
authors.affiliation: DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Bld René Leriche, Strasbourg, 67200, France.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Schaschkow
authors.affiliation: Structure d'Endocrinologie, Diabète -Nutrition et Addictologie, Pôle NUDE, Hôpitaux Universitaires de Strasbourg (HUS), Strasbourg, 67000, France.
authors.forename: Anne-Hélène
authors.initials: AH
authors.lastname: Spizzo
authors.affiliation: DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Bld René Leriche, Strasbourg, 67200, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Seyfritz
authors.affiliation: DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Bld René Leriche, Strasbourg, 67200, France.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Sookhareea
authors.affiliation: DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Bld René Leriche, Strasbourg, 67200, France.
authors.forename: William
authors.initials: W
authors.lastname: Bietiger
authors.affiliation: DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Bld René Leriche, Strasbourg, 67200, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Péronet
authors.affiliation: Structure d'Endocrinologie, Diabète -Nutrition et Addictologie, Pôle NUDE, Hôpitaux Universitaires de Strasbourg (HUS), Strasbourg, 67000, France.
authors.forename: François
authors.initials: F
authors.lastname: Moreau
authors.affiliation: Structure d'Endocrinologie, Diabète -Nutrition et Addictologie, Pôle NUDE, Hôpitaux Universitaires de Strasbourg (HUS), Strasbourg, 67000, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Pinget
authors.affiliation: DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Bld René Leriche, Strasbourg, 67200, France.
authors.forename: Elisa
authors.initials: E
authors.lastname: Maillard
authors.affiliation: DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Bld René Leriche, Strasbourg, 67200, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Sigrist
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D019270:Fructosamine / Q000097:blood; D006505:Hepatitis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007262:Infusions, Intravenous; D055104:Infusions, Subcutaneous; D007328:Insulin / Q000008:administration & dosage*; D007332:Insulin Infusion Systems; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D011169:Portal Vein; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D017382:Reactive Oxygen Species; D000511:alpha-Macroglobulins; C548904:insulin-like growth factor-1, rat; D019270:Fructosamine; D007334:Insulin-Like Growth Factor I
keywords: diabetes; glycogen; insulin therapy; liver function