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. 2017 Feb 1;127(2):657-669.
doi: 10.1172/JCI88477. Epub 2017 Jan 23.

Mechanism for leptin's acute insulin-independent effect to reverse diabetic ketoacidosis

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

Mechanism for leptin's acute insulin-independent effect to reverse diabetic ketoacidosis

Rachel J Perry et al. J Clin Invest. .

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.

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Conflict of interest statement

The authors have declared that no conflict of interest exists.

Figures

Figure 1
Figure 1. Leptin suppression of hypercorticosteronemia is required to mediate its glucose-lowering effects by suppressing lipolysis in DKA.
(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.
Figure 2
Figure 2. Suppression of lipolysis reverses hyperglycemia and ketoacidosis in T1D rats.
(A) Plasma NEFA during a 6-hour acute infusion of saline (control), leptin, or leptin and corticosterone with or without pretreatment with atglistatin. (B and C) Plasma βOHB concentrations and anion gap after 6 hours of infusion. (D–F) Whole-body palmitate, glycerol, and βOHB turnover at the end of the 6-hour infusion. (G and H) Liver acetyl and malonyl CoA content. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 vs. controls; §§P < 0.01, §§§P < 0.001, §§§§P < 0.0001 vs. leptin-treated rats; #P < 0.05, ##P < 0.01, ###P < 0.001, and ####P < 0.0001 vs. leptin plus corticosterone–treated rats 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.
Figure 3
Figure 3. Suppression of hepatic acetyl CoA accounts for leptin’s ability to reverse DKA.
(A and B) Plasma acetate and liver acetyl CoA. (C and D) Plasma insulin and leptin. (E and F) Plasma glucose concentrations and HGP. (G and H) Plasma βOHB concentrations and whole-body βOHB turnover. In all panels, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 vs. leptin-treated rats; §§§P < 0.001, §§§§P < 0.0001 vs. leptin plus acetate–treated rats. Data are the mean ± SEM of n = 6 (leptin), n = 7 (leptin plus acetate), and n = 7 (leptin → leptin plus acetate) per group, with data compared by ANOVA with Bonferroni’s multiple comparisons test. Arrow denotes rats that were treated with leptin alone for 4 hours, then infused with leptin plus acetate for the final 2 hours.
Figure 4
Figure 4. Hypercorticosteronemia drives DKA through increased lipolysis.
(A–C) Plasma glucose, NEFA, and βOHB concentrations in adrenalectomized T1D rats. In all panels, unless indicated otherwise, all measurements were made at the 4-hour time point. (B) *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 between the groups indicated; §§P < 0.01 vs. adrenalectomy plus corticosterone at time zero. (D) Anion gap. (E–I) Plasma insulin, leptin, corticosterone, ACTH, and IGF-1 concentrations. (J) Whole-body glucose turnover. (K–M) Whole-body palmitate, glycerol, and βOHB turnover. (N and O) Liver acetyl and malonyl CoA concentrations. In all panels, data are the mean ± SEM of n = 8 (control), n = 11 (adrenalectomy), n = 6 (adrenalectomy plus corticosterone), or n = 6 (adrenalectomy plus sucrose water) per group. Unless otherwise specified, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 vs. controls; §P < 0.05, §§P < 0.01, §§§P < 0.001, §§§§P < 0.0001 vs. adrenalectomized rats; ##P < 0.01, ###P < 0.001, ####P < 0.0001 vs. adrenalectomy plus corticosterone–treated rats. Data were compared using ANOVA with Bonferroni’s multiple comparisons test.
Figure 5
Figure 5. Insulin and feeding abrogate leptin’s effects to lower plasma glucose.
(A and B) Plasma glucose and insulin during a glucose tolerance test in T1D rats with fasting plasma insulin of approximately 15 pM as compared with those with fasting plasma insulin of approximately 70 pM. (C–F) Plasma glucose, NEFA, βOHB, and anion gap before and after an infusion of insulin to achieve plasma concentrations of approximately 70 pM. (G–J) Plasma glucose, NEFA, βOHB, and anion gap in fed rats with food withdrawn at the start of the study, before and after an infusion of insulin to achieve plasma concentrations of approximately 70 pM. (A–C, and G) *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 between groups by 2-tailed unpaired Student’s t test. (D–F and H–J) *P < 0.05, **P < 0.01, ****P < 0.0001 vs. the same group at time zero by 2-tailed paired Student’s t test. Data are the mean ± SEM of n = 6 per group (panels A–F) or n = 10 (fed, insulin 15 pM to 70 pM) and n = 11 (fed, insulin 15 pM to 70 pM + leptin) per group (panels G–J).
Figure 6
Figure 6. The chronic effect of leptin to suppress hyperglycemia in T1D mice is pleotropic.
(A and B) Plasma glucose and leptin concentrations in mice infused for 2 weeks with leptin or saline (control). (C and D) Plasma corticosterone and glucagon. (E) Water drinking. (F) Food intake. (G and H) Liver and skeletal muscle TAG concentrations. (A–H) Data are the mean ± SEM of n = 10 (control) or n = 12 (leptin-treated) per group. (I and J) Liver and skeletal muscle DAG concentrations, n = 8 (control) or n = 10 (leptin-treated) per group. *P < 0.05, **P < 0.01, ***P < 0.001 by 2-tailed unpaired Student’s t test.
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Comment in

  • How does leptin restore euglycemia in insulin-deficient diabetes?

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