CLINICAL STUDY IGF-I increases the recruitment of GLUT4 and GLUT3 glucose transporters on cell surface in hyperthyroidism George Dimitriadis 1 , Eirini Maratou 2 , Eleni Boutati 1 , Anastasios Kollias 1 , Katerina Tsegka 1 , Maria Alevizaki 3 , Melpomeni Peppa 1 , Sotirios A Raptis 1,2 and Dimitrios J Hadjidakis 1 1 Second Department of Internal Medicine, Research Institute and Diabetes Center, University General Hospital ‘Attikon’, Athens University, 1 Rimini Street, 12462 Haidari, Greece, 2 Hellenic National Center for Research, Prevention and Treatment of Diabetes Mellitus and its Complications, 10675 Athens, Greece and 3 Department of Clinical Therapeutics, 11528 Athens University, Athens, Greece (Correspondence should be addressed to G Dimitriadis; Email: gdimi@ath.forthnet.gr, gdimitr@med.uoa.gr) Abstract Objective: In hyperthyroidism, tissue glucose disposal is increased to adapt to high energy demand. Our aim was to examine the regulation of glucose transporter (GLUT) isoforms by IGF-I in monocytes from patients with hyperthyroidism. Design and methods: Blood (20 ml) was drawn from 21 healthy and 10 hyperthyroid subjects. The abundance of GLUT isoforms on the monocyte plasma membrane was determined in the absence and presence of IGF-I (0.07, 0.14, and 0.7 nM) using flow cytometry. Anti-CD14-phycoerythrin monocional antibody was used for monocyte gating. GLUT isoforms were determined after staining the cells with specific antisera to GLUT3 and GLUT4. Results: In monocytes from the euthyroid subjects, IGF-I increased the abundance of GLUT3 and GLUT4 on the monocyte surface by 25 and 21% respectively (P!0.0005 with repeated measures ANOVA). Hyperthyroidism increased the basal monocyte surface GLUT3 and GLUT4; in these cells, IGF-I had a marginal but highly significant effect (PZ0.003, with repeated measures ANOVA) on GLUT3 (11%) and GLUT4 (10%) translocation on the plasma membrane. Conclusions: In hyperthyroidism: 1) basal abundance of GLUT3 and GLUT4 on the plasma membrane is increased and 2) the sensitivity of the recruitment of GLUT3 and GLUT4 transporters on the plasma membrane in response to IGF-I is increased. These findings may contribute to the understanding of the mechanism by which hyperthyroidism increases glucose disposal in peripheral tissues. European Journal of Endocrinology 158 361–366 Introduction In hyperthyroidism, tissue metabolic rate increases significantly (1). To adapt to high energy demand, cellular rates of basal and insulin-stimulated glucose disposal are generally elevated to increase the rates of glucose oxidation and lactate formation; lactate is then used by the liver to increase the rates of gluconeogenesis and endogenous glucose production (1, 2). Insulin-like growth factor-I (IGF-I) has a structural similarity to insulin (3) and its metabolic effects are considered to be similar to those of insulin (4, 5). However, in contrast to insulin, IGF-I is ineffective in suppressing hepatic glucose production (6–8) and has a preferential effect to increase the rates of glycolysis in tissues such as muscle (5). The effects of IGF-I on glucose disposal in hyperthyroidism have never been investigated. In insulin- or IGF-I-sensitive tissues, three glucose transporter (GLUT) isoforms are expressed: GLUT1, GLUT3, and GLUT4. GLUT1 is responsible for basal glucose transport, while GLUT3 and GLUT4 are respon- sible for insulin- or IGF-I-stimulated glucose transport (9). The present study was designed to examine the effects of physiological and maximal levels of IGF-I on the regulation of GLUT3 and GLUT4 isoforms in monocytes from patients with hyperthyroidism. Monocytes are a suitable cell system for this investigation since they have IGF-I receptors that quickly respond to changes in IGF-I concentrations (10–12), and they express all GLUT isoforms involved in glucose transport in insulin- or IGF-I-sensitive tissues (12–14). Material and methods Twenty-one euthyroid subjects (age 37G2 years, body mass index 24G0.7 kg/m 2 , thyroxine (T 4 ) 8.3G 0.3 mg/dl, tri-iodothyronine (T 3 ) 1.3G0.06 ng/ml, thyro- trophin (TSH) 1.86G0.4 mIU/ml) and ten newly diag- nosed hyperthyroid subjects with Graves’ disease who received no treatment (age 41G2 years, BMI 29G 0.5 kg/m 2 ,T 4 13.1G0.9 mg/dl, T 3 2.88G0.3 ng/ml, TSH!0.005 mIU/ml) were used in this study. The subjects were randomly recruited from the outpatient endocrine European Journal of Endocrinology (2008) 158 361–366 ISSN 0804-4643 q 2008 Society of the European Journal of Endocrinology DOI: 10.1530/EJE-07-0532 Online version via www.eje-online.org