title: Insulin Detemir Is Transported From Blood to Cerebrospinal Fluid and Has Prolonged Central Anorectic Action Relative to NPH Insulin.
abstract: Insulin detemir (DET) reduces glycemia comparably to other long-acting insulin formulations but causes less weight gain. Insulin signaling in the brain is catabolic, reducing food intake. We hypothesized that DET reduces weight gain, relative to other insulins, owing to increased transport into the central nervous system and/or increased catabolic action within the brain. Transport of DET and NPH insulin into the cerebrospinal fluid (CSF) was compared over several hours and after the administration of different doses peripherally in rats. DET and NPH had comparable saturable, receptor-mediated transport into the CSF. CSF insulin remained elevated significantly longer after intraperitoneal DET than after NPH. When administered acutely into the 3rd cerebral ventricle, both DET and NPH insulin reduced food intake and body weight at 24 h, and both food intake and body weight remained lower after DET than after NPH after 48 h. In direct comparison with another long-acting insulin, insulin glargine (GLAR), DET led to more prolonged increases in CSF insulin despite a shorter plasma half-life in both rats and mice. Additionally, peripheral DET administration reduced weight gain and increased CSF insulin compared with saline or GLAR in mice. Overall, these data support the hypothesis that DET has distinct effects on energy balance through enhanced and prolonged centrally mediated reduction of food intake.
authors: Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH School of Psychology, UNSW Australia, Sydney, NSW, Australia.
authors: Denovan P
authors: DP
authors: Begg
authors: Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH.
authors: Aaron A
authors: AA
authors: May
authors: Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH Joslin Diabetes Center, Harvard Medical School, Boston, MA.
authors: Joram D
authors: JD
authors: Mul
authors: Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH.
authors: Min
authors: M
authors: Liu
authors: Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH Department of Medicine, Duke University, Durham, NC.
authors: David A
authors: DA
authors: D'Alessio
authors: Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH Department of Surgery, University of Michigan, Ann Arbor, MI.
authors: Randy J
authors: RJ
authors: Seeley
authors: Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH steve.woods@uc.edu.
authors: Stephen C
authors: SC
authors: Woods
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D001692:Biological Transport; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D004435:Eating / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000097:blood / Q000134:cerebrospinal fluid; D000069057:Insulin Detemir; D007336:Insulin, Isophane / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D049528:Insulin, Long-Acting / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001067:Appetite Depressants; D007004:Hypoglycemic Agents; D007328:Insulin; D049528:Insulin, Long-Acting; D000069057:Insulin Detemir; D007336:Insulin, Isophane