title: Insulin Knockout Mice Have Extended Survival but Volatile Blood Glucose Levels on Leptin Therapy.
abstract: Leptin can reverse hyperglycemia in rodent models of type 1 diabetes. However, these models have used chemical or immune mediated β-cell destruction where insulin depletion is incomplete. Thus it is unknown which actions of leptin are entirely insulin independent, versus those which require insulin. To directly assess this we maximized blockage of insulin action using an insulin receptor antagonist in combination with streptozotocin-diabetic mice; leptin treatment was still able to reduce blood glucose. Next, we leptin-treated adult insulin knockout (InsKO) mice. Remarkably, leptin-treated InsKO mice were viable for up to 3 weeks without insulin therapy. Leptin treatment reduced plasma corticosterone, glucagon, β-hydroxybutyrate, triglycerides, cholesterol, fatty acids and glycerol. However, leptin-treated InsKO mice exhibited overt fed hyperglycemia and severe fasting hypoglycemia. Therefore, leptin can normalize many metabolic parameters in the complete absence of insulin, but blood glucose levels are volatile and the length of survival finite.
authors.affiliation: Departments of Cellular and Physiological Sciences (U.H.N., H.C.D., M.M., T.J.K.), Biochemistry and Molecular Biology (S.D.C.), and Surgery (T.J.K.), Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Ursula H
authors.initials: UH
authors.lastname: Neumann
authors.affiliation: Departments of Cellular and Physiological Sciences (U.H.N., H.C.D., M.M., T.J.K.), Biochemistry and Molecular Biology (S.D.C.), and Surgery (T.J.K.), Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Denroche
authors.affiliation: Departments of Cellular and Physiological Sciences (U.H.N., H.C.D., M.M., T.J.K.), Biochemistry and Molecular Biology (S.D.C.), and Surgery (T.J.K.), Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Majid
authors.initials: M
authors.lastname: Mojibian
authors.affiliation: Departments of Cellular and Physiological Sciences (U.H.N., H.C.D., M.M., T.J.K.), Biochemistry and Molecular Biology (S.D.C.), and Surgery (T.J.K.), Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Covey
authors.affiliation: Departments of Cellular and Physiological Sciences (U.H.N., H.C.D., M.M., T.J.K.), Biochemistry and Molecular Biology (S.D.C.), and Surgery (T.J.K.), Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D003345:Corticosterone / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D005227:Fatty Acids / Q000097:blood; D005934:Glucagon / Q000097:blood / Q000187:drug effects; D005990:Glycerol / Q000097:blood; D006943:Hyperglycemia; D007003:Hypoglycemia; D007328:Insulin / Q000235:genetics*; D020738:Leptin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000494:pharmacology*; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors*; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; C514817:Ins1 protein, mouse; C561967:Ins2 protein, mouse; D007328:Insulin; D020738:Leptin; D010455:Peptides; C532752:S961 peptide; D014280:Triglycerides; D005934:Glucagon; D002784:Cholesterol; D011972:Receptor, Insulin; D005990:Glycerol; D020155:3-Hydroxybutyric Acid; D003345:Corticosterone