Mechanism for leptin’s acute insulin-independent effect to reverse diabetic ketoacidosis
Rachel J. Perry, … , Gary W. Cline, Gerald I. Shulman
Rachel J. Perry, … , Gary W. Cline, Gerald I. Shulman
Published February 1, 2017; First published January 23, 2017
Citation Information: J Clin Invest. 2017;127(2):657-669. https://doi.org/10.1172/JCI88477.
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Concise Communication Endocrinology Metabolism

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

Rachel J. Perry, Liang Peng, Abudukadier Abulizi, Lynn Kennedy, Gary W. Cline, Gerald I. Shulman

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Figure 1

Leptin suppression of hypercorticosteronemia is required to mediate its glucose-lowering effects by suppressing lipolysis in DKA.

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Leptin suppression of hypercorticosteronemia is required to mediate its ...
(A) Plasma glucose during a 6-hour acute infusion of saline (control), leptin, or leptin and corticosterone with or without pretreatment with atglistatin. (A and H) *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 vs. controls; §§§P < 0.001, §§§§P < 0.0001 vs. leptin-treated rats; and ##P < 0.01, ###P < 0.001, ####P < 0.0001 vs. leptin plus corticosterone–treated rats. (B) Fasting plasma insulin. (C–E) Plasma leptin, corticosterone, and ACTH concentrations at 0 and 6 hours of the infusion. **P < 0.01, ***P < 0.001, ****P < 0.0001 between the groups indicated; §§P < 0.01, §§§§P < 0.0001 vs. the same group at time zero. (F and G) Fasting plasma glucagon and IGF-1 concentrations. (H) HGP after 6 hours. In all panels, data were compared by 1-way ANOVA with Bonferroni’s multiple comparisons test, with data presented as the mean ± SEM of n = 7 (control), n = 7 (leptin), n = 10 (leptin plus corticosterone), and n = 6 (leptin plus corticosterone plus atglistatin) rats.