title: Metabolic effects of insulin in a human model of ketoacidosis combining exposure to lipopolysaccharide and insulin deficiency: a randomised, controlled, crossover study in individuals with type 1 diabetes.
abstract: Diabetic ketoacidosis (DKA) is often caused by concomitant systemic inflammation and lack of insulin. Here we used an experimental human model to test whether and how metabolic responses to insulin are impaired in the early phases of DKA with a specific focus on skeletal muscle metabolism.
  
  
  
  Nine individuals with type 1 diabetes from a previously published cohort were investigated twice at Aarhus University Hospital using a 120 min infusion of insulin (3.0/1.5 mU kg-1min-1) after an overnight fast under: (1) euglycaemic conditions (CTR) or (2) hyperglycaemic ketotic conditions (KET) induced by an i.v. bolus of lipopolysaccharide and 85% reduction in insulin dosage. The primary outcome was insulin resistance in skeletal muscle. Participants were randomly assigned to one of the two arms at the time of screening using www.randomizer.org . The study was not blinded.
  
  
  
  All nine volunteers completed the 2 days and are included in the analysis. Circulating concentrations of glucose and 3-hydroxybutyrate increased during KET (mean ± SEM 17.7 ± 0.6 mmol/l and 1.6 ± 0.2 mmol/l, respectively), then decreased after insulin treatment (6.6 ± 0.7 mmol/l and 0.1 ± 0.07 mmol/l, respectively). Prior to insulin infusion (KET vs CTR) isotopically determined endogenous glucose production rates were 17 ± 1.7 μmol kg-1min-1vs 8 ± 1.3 μmol kg-1min-1(p = 0.003), whole body phenylalanine fluxes were 2.9 ± 0.5 μmol kg-1min-1vs 3.1 ± 0.4 μmol kg-1min-1(p = 0.77) and urea excretion rates were 16.9 ± 2.4 g/day vs 7.3 ± 1.7 g/day (p = 0.01). Insulin failed to stimulate forearm glucose uptake and glucose oxidation in KET compared with CTR (p < 0.05). Glycogen synthase phosphorylation was impaired in skeletal muscle.
  
  
  
  In KET, hyperglycaemia is primarily driven by increased endogenous glucose production. Insulin stimulation during early phases of DKA is associated with reduced glucose disposal in skeletal muscle, impaired glycogen synthase function and lower glucose oxidation. This underscores the presence of muscle insulin resistance in the pathogenesis of DKA. Trial registration www.clinicaltrials.gov (ID number: NCT02157155). Funding This work was funded by the Danish Council for Strategic Research (grant no. 0603-00479B).
authors.affiliation: Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark.|Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Mads V
authors.initials: MV
authors.lastname: Svart
authors.affiliation: Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark.|Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Nikolaj
authors.initials: N
authors.lastname: Rittig
authors.affiliation: Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Ulla
authors.initials: U
authors.lastname: Kampmann
authors.affiliation: Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark.|Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Voss
authors.affiliation: Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark.|Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Møller
authors.affiliation: Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark. niels.jessen@biomed.au.dk.|Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 4, DK-8000, Aarhus C, Denmark. niels.jessen@biomed.au.dk.
authors.forename: Niels
authors.initials: N
authors.lastname: Jessen
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000097:blood; D000328:Adult; D001706:Biopsy; D001786:Blood Glucose / Q000032:analysis; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D016883:Diabetic Ketoacidosis / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D006006:Glycogen Synthase / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007328:Insulin / Q000172:deficiency* / Q000627:therapeutic use; D007333:Insulin Resistance; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010649:Phenylalanine / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D007328:Insulin; D008070:Lipopolysaccharides; D010649:Phenylalanine; D006006:Glycogen Synthase; D010100:Oxygen; D020155:3-Hydroxybutyric Acid
keywords: Clinical diabetes; Endogenous glucose production; Glucose transport; Hyperglycaemia; Insulin action; Insulin resistance; Insulin sensitivity; Skeletal muscle