title: Mechanism for leptin's acute insulin-independent effect to reverse diabetic ketoacidosis.
abstract: The mechanism by which leptin reverses diabetic ketoacidosis (DKA) is unknown. We examined the acute insulin-independent effects of leptin replacement therapy in a streptozotocin-induced rat model of DKA. Leptin infusion reduced rates of lipolysis, hepatic glucose production (HGP), and hepatic ketogenesis by 50% within 6 hours and were independent of any changes in plasma glucagon concentrations; these effects were abrogated by coinfusion of corticosterone. Treating leptin- and corticosterone-infused rats with an adipose triglyceride lipase inhibitor blocked corticosterone-induced increases in plasma glucose concentrations and rates of HGP and ketogenesis. Similarly, adrenalectomized type 1 diabetic (T1D) rats exhibited decreased rates of lipolysis, HGP, and ketogenesis; these effects were reversed by corticosterone infusion. Leptin-induced decreases in lipolysis, HGP, and ketogenesis in DKA were also nullified by relatively small increases (15 to 70 pM) in plasma insulin concentrations. In contrast, the chronic glucose-lowering effect of leptin in a STZ-induced mouse model of poorly controlled T1D was associated with decreased food intake, reduced plasma glucagon and corticosterone concentrations, and decreased ectopic lipid (triacylglycerol/diacylglycerol) content in liver and muscle. Collectively, these studies demonstrate marked differences in the acute insulin-independent effects by which leptin reverses fasting hyperglycemia and ketoacidosis in a rodent model of DKA versus the chronic pleotropic effects by which leptin reverses hyperglycemia in a non-DKA rodent model of T1D.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Perry
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
authors.forename: Abudukadier
authors.initials: A
authors.lastname: Abulizi
authors.forename: Lynn
authors.initials: L
authors.lastname: Kennedy
authors.forename: Gary W
authors.initials: GW
authors.lastname: Cline
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016883:Diabetic Ketoacidosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004075:Diglycerides / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000378:metabolism
chemical_list: D004075:Diglycerides; D007328:Insulin; D020738:Leptin; D014280:Triglycerides