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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-09-0043v1 JOE-09-0043v2 201/3/377    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Klieverik, L. Articles by Kalsbeek, A. Search for Related Content PubMed PubMed Citation Articles by Klieverik, L. Articles by Kalsbeek, A.

L Klieverik, Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
E Foppen, Netherlands Institute for Neuroscience, Amsterdam, Netherlands
M Ackermans, Department of Clinical Chemistry, Laboratory of Endocrinology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
M Serlie, Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
H Sauerwein, Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
T Scanlan, Department of Physiology and Pharmacology, School of Medicine, Oregon Health and Science University, Portland, United States
D Grandy, Department of Physiology and Pharmacology, School of Medicine, Oregon Health and Science University, Portland, United States
E Fliers, Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
A Kalsbeek, Netherlands Institute for Neuroscience, Amsterdam, Netherlands

Correspondence: Lars Klieverik, Email: L.P.Klieverik{at}amc.uva.nl

Abstract

Thyronamines are naturally occurring, chemical relatives of thyroid hormone. Systemic administration of synthetic 3-iodothyronamine (T1AM) and - to a lesser extent - thyronamine (T0AM), leads to acute bradycardia, hypothermia, decreased metabolic rate and hyperglycemia. This profile led us to hypothesize that the central nervous system is among the principal targets of thyronamines.

We investigated whether a low dose intracerebroventricular (icv) infusion of synthetic thyronamines recapitulates the changes in glucose metabolism that occur following intraperitoneal (ip) thyronamine administration.

Plasma glucose, glucoregulatory hormones and endogenous glucose production (EGP) using stable isotope dilution were monitored in rats before and 120 min after an ip (50 mg/kg) or icv (0.5 mg/kg) bolus infusion of T1AM, T0AM, or vehicle. To identify peripheral effects of centrally administered thyronamines, drug-naive rats were also infused intravenously with low dose (0.5 mg/kg) thyronamines.

Systemic T1AM rapidly increased EGP and plasma glucose, increased plasma glucagon, and corticosterone, but failed to change plasma insulin. Compared to ip-administered T1AM, a

100-fold lower dose administered centrally induced a more pronounced acute EGP increase and hyperglucagonemia while plasma insulin tended to decrease. Both systemic and central infusions of T0AM caused smaller increases in EGP, plasma glucose and glucagon compared with T1AM. Neither T1AM nor T0AM influenced any of these parameters upon low dose intravenous administration.

We conclude that central administration of low dose thyronamines suffices to induce the acute alterations in glucoregulatory hormones and glucose metabolism following systemic thyronamine infusion. Our data indicate that thyronamines can act centrally to modulate glucose metabolism.