title: Combined Insulin Deficiency and Endotoxin Exposure Stimulate Lipid Mobilization and Alter Adipose Tissue Signaling in an Experimental Model of Ketoacidosis in Subjects With Type 1 Diabetes: A Randomized Controlled Crossover Trial.
abstract: Most often, diabetic ketoacidosis (DKA) in adults results from insufficient insulin administration and acute infection. DKA is assumed to release proinflammatory cytokines and stress hormones that stimulate lipolysis and ketogenesis. We tested whether this perception of DKA can be reproduced in an experimental human model by using combined insulin deficiency and acute inflammation and tested which intracellular mediators of lipolysis are affected in adipose tissue. Nine subjects with type 1 diabetes were studied twice: 1) insulin-controlled euglycemia and 2) insulin deprivation and endotoxin administration (KET). During KET, serum tumor necrosis factor-α, cortisol, glucagon, and growth hormone levels increased, and free fatty acids and 3-hydroxybutyrate concentrations and the rate of lipolysis rose markedly. Serum bicarbonate and pH decreased. Adipose tissue mRNA contents of comparative gene identification-58 (CGI-58) increased and G0/G1 switch 2 gene (G0S2) mRNA decreased robustly. Neither protein levels of adipose triglyceride lipase (ATGL) nor phosphorylations of hormone-sensitive lipase were altered. The clinical picture of incipient DKA in adults can be reproduced by combined insulin deficiency and endotoxin-induced acute inflammation. The precipitating steps involve the release of proinflammatory cytokines and stress hormones, increased lipolysis, and decreased G0S2 and increased CGI-58 mRNA contents in adipose tissue, compatible with latent ATGL stimulation.
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark mvsv@clin.au.dk.
authors.forename: Mads
authors.initials: M
authors.lastname: Svart
authors.affiliation: Department of Internal Medicine, Silkeborg Regional Hospital, Silkeborg, Denmark.
authors.forename: Ulla
authors.initials: U
authors.lastname: Kampmann
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Voss
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Steen B
authors.initials: SB
authors.lastname: Pedersen
authors.affiliation: Section for Forensic Chemistry, Department of Forensic Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Mogens
authors.initials: M
authors.lastname: Johannsen
authors.affiliation: Department of Endocrinology and Internal Medicine, 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 Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Per L
authors.initials: PL
authors.lastname: Poulsen
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Nielsen
authors.affiliation: Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Jessen
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Møller
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D000328:Adult; D001706:Biopsy; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016883:Diabetic Ketoacidosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004731:Endotoxins / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007328:Insulin / Q000008:administration & dosage / Q000627:therapeutic use; D049528:Insulin, Long-Acting / Q000008:administration & dosage / Q000627:therapeutic use; D061266:Insulin, Short-Acting / Q000008:administration & dosage / Q000627:therapeutic use; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D018448:Models, Immunological; D015434:Panniculitis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D050507:Subcutaneous Fat, Abdominal / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D018797:Cell Cycle Proteins; D004731:Endotoxins; C508073:G0S2 protein, human; D007004:Hypoglycemic Agents; D007328:Insulin; D049528:Insulin, Long-Acting; D061266:Insulin, Short-Acting; C484564:insulin, long-acting, human; C044101:endotoxin, Escherichia coli; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C439972:ABHD5 protein, human