title: Leptin induces fasting hypoglycaemia in a mouse model of diabetes through the depletion of glycerol.
abstract: OBJECTIVE
  Leptin has profound glucose-lowering effects in rodent models of type 1 diabetes, and is currently being tested clinically to treat this disease. In addition to reversing hyperglycaemia, leptin therapy corrects multiple lipid, energy and neuroendocrine imbalances in rodent models of type 1 diabetes, yet the precise mechanism has not been fully defined. Thus, we performed metabolic analyses to delineate the downstream metabolic pathway mediating leptin-induced glucose lowering in diabetic mice.
  
  
  METHODS
  Mice were injected with streptozotocin (STZ) to induce insulin-deficient diabetes, and were subsequently treated with 20 μg/day recombinant murine leptin or vehicle for 5 to 14 days. Energy-yielding substrates were measured in the liver and plasma, and endogenous glucose production was assessed by tolerance to extended fasting.
  
  
  RESULTS
  STZ-leptin-treated mice developed severe hypoketotic hypoglycaemia during prolonged fasting, indicative of suppressed endogenous ketone and glucose production. STZ-leptin mice displayed normal gluconeogenic and glycogenolytic capacity, but had depleted circulating glycerol and NEFA. The depletion of glycerol and NEFA correlated tightly with the kinetics of glucose lowering in response to chronic leptin administration, and was not mimicked by single leptin injection. Administration of glycerol acutely reversed fasting-induced hypoglycaemia in leptin-treated mice.
  
  
  CONCLUSIONS
  The findings of this study suggest that the diminution of circulating glycerol reduces endogenous glucose production, contributing to severe fasting-induced hypoglycaemia in leptin-treated rodent models of type 1 diabetes, and support that depletion of glycerol contributes to the glucose-lowering action of leptin.
authors.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, Canada, V6T 1Z3.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Denroche
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Kwon
authors.forename: Whitney L
authors.initials: WL
authors.lastname: Quong
authors.forename: Ursula H
authors.initials: UH
authors.lastname: Neumann
authors.forename: Jerzy E
authors.initials: JE
authors.lastname: Kulpa
authors.forename: Subashini
authors.initials: S
authors.lastname: Karunakaran
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Clee
authors.forename: Roger W
authors.initials: RW
authors.lastname: Brownsey
authors.forename: Scott D
authors.initials: SD
authors.lastname: Covey
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition / Q000187:drug effects / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D005990:Glycerol / Q000097:blood* / Q000494:pharmacology; D007003:Hypoglycemia / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000494:pharmacology / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice
chemical_list: D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D005990:Glycerol