title: Leptin deficiency causes insulin resistance induced by uncontrolled diabetes.
abstract: OBJECTIVE
  Depletion of body fat stores during uncontrolled, insulin-deficient diabetes (uDM) results in markedly reduced plasma leptin levels. This study investigated the role of leptin deficiency in the genesis of severe insulin resistance and related metabolic and neuroendocrine derangements induced by uDM.
  
  
  METHODS
  Adult male Wistar rats remained nondiabetic or were injected with the beta-cell toxin, streptozotocin (STZ) to induce uDM and subsequently underwent subcutaneous implantation of an osmotic minipump containing either vehicle or leptin at a dose (150 microg/kg/day) designed to replace leptin at nondiabetic plasma levels. To control for leptin effects on food intake, another group of STZ-injected animals were pair fed to the intake of those receiving leptin. Food intake, body weight, and blood glucose levels were measured daily, with body composition and indirect calorimetry performed on day 11, and an insulin tolerance test to measure insulin sensitivity performed on day 16. Plasma hormone and substrate levels, hepatic gluconeogenic gene expression, and measures of tissue insulin signal transduction were also measured.
  
  
  RESULTS
  Physiologic leptin replacement prevented insulin resistance in uDM via a mechanism unrelated to changes in food intake or body weight. This effect was associated with reduced total body fat and hepatic triglyceride content, preservation of lean mass, and improved insulin signal transduction via the insulin receptor substrate-phosphatidylinositol-3-hydroxy kinase pathway in the liver, but not in skeletal muscle or adipose tissue. Although physiologic leptin replacement lowered blood glucose levels only slightly, it fully normalized elevated plasma glucagon and corticosterone levels and reversed the increased hepatic expression of gluconeogenic enzymes characteristic of rats with uDM.
  
  
  CONCLUSIONS
  We conclude that leptin deficiency plays a key role in the pathogenesis of severe insulin resistance and related endocrine disorders in uDM. Treatment of diabetes in humans may benefit from correction of leptin deficiency as well as insulin deficiency.
authors.affiliation: Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: German
authors.forename: Brent E
authors.initials: BE
authors.lastname: Wisse
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Thaler
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Oh-I
authors.forename: David A
authors.initials: DA
authors.lastname: Sarruf
authors.forename: Kayoko
authors.initials: K
authors.lastname: Ogimoto
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Kaiyala
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Fischer
authors.forename: Miles E
authors.initials: ME
authors.lastname: Matsen
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Taborsky
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Morton
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D004435:Eating / Q000187:drug effects / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D020738:Leptin / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001786:Blood Glucose; D007328:Insulin; D020738:Leptin