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P-42 NO IMPROVEMENT OF GLUCOSE TOLERANCE BY GROWTH HORMONE ADMINISTRATION IN INSULIN RESISTANT OLETF RAT
Poster presentations: Monday 13 November 2006 P-36 STANDARDIZED CENTILE CURVES OF BODY MASS INDEX FOR JAPANESE CHILDREN AND ADOLESCENTS BASED ON THE 1978–1981 NATIONAL SURVEY DATA Tomonobu Hasegawa1 ° , Mikako Inokuchi1 , Makoto Anzo1 , Nobutake Matsuo2 . 1 Keio University School of Medicine, Department of Pediatrics; 2 National Center for Child Health and Development, Japan Background: The prevalence of overweight among Japanese children and adolescents has steadily increased during the last 20 years. Aims: The aims of this study were to construct reference curves of body mass index (BMI) for contemporary Japanese children and adolescents and compare Japanese data with the foreign ones. Methods: BMI reference values were derived using the LMS method as based on height and weight data from cross-sectional national survey of Japanese children and adolescents conducted in 1978–1981 (14,012 boys and 13,781 girls, aged 1.5–18.5 years) collected by Japanese Ministry of International Trade and Industry. To compare the Japanese BMI reference data with British, Dutch, and US ones, the BMI centile curves of the two populations were superimposed with each other in the same graphs. Results: The Japanese BMI reference curves were constructed for clinical use. The centile values at the upper end of the spectrum apparently differed in British, Dutch, Japanese, and US children and adolescents. In contrast, the centile values at the lower end of the spectrum nearly overlapped with each other in the four populations. Conclusions: Overweight is concentrated in a subgroup of children and does not occur across the entire population of British, Dutch, Japanese, and US children, indicating a subgroup of genetically and/or environmentally more susceptible children in each country.
P-38 IGF-1, ARTERIAL SMOOTH MUSCLE AND ENDOTHELIAL CELL INTERACTIONS Thomas Ledet1 ° , Lise Wogensen1 , Lars Rasmussen1,2 . 1 Research Laboratory for Biochemical Pathology, Aarhus University; 2 Depart. of Clin. Chem., Denmark Diabetic macroangiopathy may be a forerunner facilitating the development of atherosclerosis. IGF-1 is believed to be regulated by growth hormone, that is increased in diabetes. The focus is put on human arterial smooth muscle cells (HuVSMCs) and IGF-1 and on the interaction with endothelial cells (HUVECs). The adhesion to type I and IV collagen of HuVSMCs is evaluated after directly and indirectly addition of IGF-1. The indirectly IGF-1 effect is acquired using conditioned HUVECs medium to the HuVSMCs. The conditioned medium is obtained from IGF-1 primed HUVECs which medium is collected in the period subsequent to priming and added to HuVSMCs. The expression of av /b3 integrin is measured and neutralizing antibody used to estimate the significance of the integrin for the adhesion. Finally PI-3 kinase, HSP90 and NF-ú B inhibitors are used to scrutinize possible pathways responsible for the adhesion of HuVSMCs after IGF-1 treatment. The adhesion of HuVSMCs is increased significantly to collagen type I, and IV (2p < 0,05) whereas indirectly treatment reduces the adhesion to type I and IV collagen (2p < 0,01). This reduction can not be ascribed to an acute effect of NO due to the experimental conditions. The expression of av /b3 integrin is elevated after IGF-1 addition and neutralizing antibody to av /b3 integrin decreases the adhesion of HuVSMCs (2p < 0,01). The records from the use of inhibitors of the intracellular pathways indicate that HSP90 and NF-ˆeB and not PI-3 kinase may be involved in the stimulatory effect of IGF-1. In conclusion IGF-1 may participate in the development of diabetic macroangiopathy and consequently in the increase of atherosclerosis in diabetes through its effect on HuVSMCs adhesion which can be modulated by non-NO action(s) of HUVECs.
S47
Metabolism P-40 MORPHOLOGICAL PECULIARITIES OF HEART AND CORONARY VESSELS DAMAGE IN TYPE 2 DIABETES MELLITUS ASSOCIATED GROWTH HORMONE DEFICIENCY Andrey L Davydov ° , Acshot M Mkrtum’yan, Anna V Koroleva, L’udmila Y Baranova. Moscow State Medical Stomatological University, Department of Endocrinology, Senior Research Officer, Russia At present great attention is paid to investigation of cardiovascular complications in type 2 diabetes patents.The aim of the work was to study morphological peculiarities of heart and coronary vessels damage in type 2 DM with GH deficiency. Materials and Methods: We studied endomiocardial bioptates of 7 patients with type 2 DM with GH deficiency and without coronary atherosclerosis obtained during coronarography and ventriculo-graphy. After special treatment the sections of different thickness (thin and ultrathin) were examined under light and electronic microscopes. Results: We revealed morphological peculiarities of myocardium and coronary vessels damage in type 2 DM patients with GH deficiency without clinical signs of atherosclerosis and ischemic heart disease, in particular, pronounced fatty degeneration of cardiomiocites, accumulation of glycogen in them, micromitochondriosis, miofibril lysis, sarcoplasmic reticulum defects, mitochondria destruction with crysts loss, apoptosis signs as well as arterioles and small and medium arteries changes, namely, pronounced edema of endotheliocytes, occurrence of fenestrated capillaries that are not normally characteristic of myocardium, and hypertrophy of unstriated muscle cells. These changes were responsible for decrease in useful heart work and disturbed coronary vessels function. These changes were not found in patients with type 2 diabetes mellitus without obvious GH deficiency; generally, areas of fatty degeneration and mitochondrial respiratory ensembles defect were observed. Conclusion: The morphological peculiarities of myocardium and coronary arteries damage can be indicative of united pathogenetic mechanisms of development of such diseases as type 2 DM, atherosclerosis, ischemic heart disease, and can be responsible for early development of failing heart in type 2 DM patients with GH deficiency without coronary atherosclerosis. P-42 NO IMPROVEMENT OF GLUCOSE TOLERANCE BY GROWTH HORMONE ADMINISTRATION IN INSULIN RESISTANT OLETF RAT Dong-Sun Kim ° , Tae-Wha Kim, Joo-Won Lee, Ju-Seop Kang. Dept. of Internal Medicine, Hanyang University College of Medicine, Korea The effects of growth hormone on glucose metabolism are complex, yielding conflicting results ranging from insulin-like to diabetogenic. Recently, short-term low-dose GH administration has been reported to improve post-load glucose tolerance in subjects with IGT and the metabolic syndrome. We investigated the effect of long-term, low dose GH administration in Long-Evans Tokushima Fatty (OLETF) rats which characteristically begin to gain weight rapidly from 5 weeks of age, show insulin resistance at 8 to 9 weeks, and finally develop obese type 2 diabetes. OLETF rats and LETO rats (control rats showing normal glucose metabolism) received either GH s.c. twice a day (150 ng/g BW for 13−18 weeks of age, and then 750 ng/g BW for 19−26 weeks of age) or vehicle. At 26 weeks, in LETO rats (LV) GH treatment group (LGH) showed increased serum IGF-I levels (2.7-fold) compared to vehicle treatment group, but GH treatment group in OLETF rats (OGH) did not. But serum IGF-I concentrations
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Growth Hormone & IGF Research 16 (2006) Suppl B
of OLETF rats with vehicle treatment group (OV) was 3.6-fold higher to those of LV. Serum insulin concentrations were 3.7-fold higher in OV than LV, but were not changed in OLETF rats by GH administration. GH administration did not cause a significant change in fasting blood glucose levels either in LETO or OLETF rats. Area under curve (AUC) of serum glucose levels during intraperitoneal glucose tolerance tests showed no difference between GH and vehicle treatment group either in LETO or OLETF rats. AUC of glucose concentrations during insulin tolerance tests after GH treatment showed no difference in OLETF rats, while it tends to increase in LETO rats compared to vehicle treatment group. These results suggest that GH administration does not prevent to progress to diabetes in the model of insulin resistant OLETF rats.
Aging P-44 GROWTH HORMONE INCREASES FoxO1 PROTEIN LEVELS AND THE EXPRESSION OF ITS TARGET GENES IN ADIPOSE TISSUE Hidenori Fukuoka1 ° , Yutaka Takahashi1 , Junko Nakae2 , Nishizawa Hitoshi1 , Mari Imanaka1 , Ryoko Takeno1 , Kentaro Takahashi1 , Keiji Iida1 , Yasuhiko Okimura3 , Hidesuke Kaji4 , Kazuo Chihara1 . 1 Division of Endocrinology/Metabolism, Neurology and Hematology/Oncology Department of Clinical Molecular Medicine Kobe University Graduate school of Medicine; 2 Dept of Diabetes, Digestive, and Kidney Diseases, Kobe University Graduate School of Medicine; 3 Kobe University Faculty of Health Sciences; 4 College of Nursing Art and Science, University of Hyogo, Japan Introduction: FoxO1 (Forkhead box O1) plays key roles in regulating metabolism, cell cycle, cell death, and oxidative stress response in the down stream of the insulin action. AIMS: The purpose of the present work is to examine whether FoxO1 is regulated by growth hormone (GH). Materials and methods: We examined FoxO1 protein levels in adipose tissue in GH deficient rat (spontaneous dwarf rat; SDR) using immuno blot analysis. 3T3L1 adipocytes were treated with insulin (100 nM 15 min) in the presence or absence of GH (100 ng/ml 12h). Then FoxO1 and phospho- FoxO1 protein levels were analyzed. Also, mRNA levels of FoxO1 itself and its target genes were analyzed, using quantitative real time PCR (QR-PCR) Results: In the adipose tissue in SDR, FoxO1 protein levels were decreased. In 3T3L1 adipocyte, FoxO1 protein levels were increased by GH treatment, while insulin-induced phosphorylation of FoxO1 was not attenuated in the presence of GH. QR-PCR revealed that FoxO1 mRNA level was not changed after GH treatment. Further, GH treatment increased mRNA level of FoxO1-target genes including p27kip, gadd45 and bim. Insulin decreased the expression of the FoxO1-target genes. Interestingly, GH pretreatment suppressed insulin-induced reduction of the expression of FoxO1-target genes. Conclusions: GH increased FoxO1 protein in adipose tissue in vitro and in vivo. These data suggest that GH exerts its physiological action in part via regulatory the FoxO1 protein level. Also, it may be related to GH-induced insulin resistance.
Cancer P-46 SEMINAL FLUID AS A LOCAL SOURCE OF IGF-I IN THE PROSTATE: IMPLICATIONS FOR PROSTATE CANCER Christian Sell1 ° , Krzysztof Reiss2 , Fernando Garcia1 . 1 Drexel University College of Medicine; 2 Temple University, USA Background: The insulin-like growth factors are potent mitogens and survival factors that appear to be involved in cellular transformation and the development of cancer.
Abstracts, 3rd Int. Congress of GRS & IGF Society In human populations, epidemiological studies suggest that elevated circulating levels of IGF-I are associated with an increased risk for prostate cancer. However, there have been conflicting reports regarding this correlation. Among the possible reasons for these conflicting reports is that the serum levels of IGF-I do not accurately reflect the local concentrations of IGF-I in the prostate. We have identified a potential source of local IGF-I in the peripheral zone of the prostate. The seminal ducts open into the urethra in the peripheral zone and we find that seminal vesicle fluid (SVF) contains relatively high levels of IGF-I. Hypothesis: Chronic stimulation of basal cells in the prostate by local IGF-I produced in the seminal vesicle provides an initiating stimulus for prostate cancer. We have confirmed earlier reports that SVF contains high levels of IGF-I. We have examined the potential local consequences of SVF derived IGF-I in the prostate, identifying the activated IGF-I receptor in regions of basal cell (BC) hyperplasia which occur primarily in the peripheral zone of the prostate downstream of the seminal ducts. Specifically, we find that the IGF-I receptor is expressed and activated in p63 positive cells within areas of IBC hyperplasia. In vitro, we find that SVF and promotes the proliferation of normal and malignant prostate cells. We also find that addition of SVF to CD133 positive prostate cancer prostate tumor initiating cells drives proliferation in these cells. These results suggest that IGF-I contained with in the seminal vesicle fluid serves as an initiating factor in the development of prostate cancer. P-48 TUMOR-DRIVEN ACTIVATION OF THE CIRCULATING GH-IGF SYSTEM RESULTS IN INCREASED SERUM IGF-1 LEVELS OF HEPATIC ORIGIN IN THE TRAMP MOUSE MODEL OF PROSTATE CANCER Makoto Anzo1 ° , Laura Cobb1 , Hemal Mehta1 , David Hwang1 , Shoshana Yakar2 , Derek LeRoith2 , Pinchas Cohen1 . 1 Division of Pediatric Endocrinology, David Geffen School of Medicine at UCLA; 2 Mount Sinai School of Medicine, USA Prostate cancer and other malignancies have been associated with increased levels of circulating IGF-1. We have shown that TRAMP (transgenic adenocarcinoma mouse prostate), a model of prostate cancer with prostate specific overexpression of the SV40 T antigen, has elevated serum IGF-1 levels. We hypothesized that this elevation was a result of IGF-1 secretion by the cancerous cells as these tumors had a significant increase in Igf-1 mRNA expression. To test this, we derived a novel model (LID-TRAMP mice) that lacks hepatic IGF-1 production, by crossing the TRAMP with the liver-specific IGF-1 deficient (LID) mice, and measured the levels of murine GH-IGF axis analytes by novel, specific, murine ELISA assays developed in our laboratory. LID-TRAMP serum IGF-1 levels were dramatically reduced (from 186±12 ng/ml in TRAMP to 14±2 ng/ml in LID-TRAMP) and did not differ significantly from those of LID mice, suggesting that the IGF-1 excess in TRAMP is of hepatic origin. TRAMP mice also displayed 30−50% higher IGFBP-3, ALS, as well as GH levels, compatible with a general activation of the systemic GH-IGF axis. This observation implies a possible tumor-derived source of GH or a GH secretagogue. Western immunoblots of prostates from TRAMP were negative for mouse GH or GHRH, but positive for ghrelin. These results suggest that the increased serum IGF-1 in TRAMP mice is derived from the liver and imply that production of ghrelin within the tumor may lead to increased GH secretion, activating hepatic production of the ternary complex of IGF-1, a process that may affect tumor progression.
P-38 IGF-1, ARTERIAL SMOOTH MUSCLE AND ENDOTHELIAL CELL INTERACTIONS Thomas Ledet1 ° , Lise Wogensen1 , Lars Rasmussen1,2 . 1 Research Laboratory for Biochemical Pathology, Aarhus University; 2 Depart. of Clin. Chem., Denmark Diabetic macroangiopathy may be a forerunner facilitating the development of atherosclerosis. IGF-1 is believed to be regulated by growth hormone, that is increased in diabetes. The focus is put on human arterial smooth muscle cells (HuVSMCs) and IGF-1 and on the interaction with endothelial cells (HUVECs). The adhesion to type I and IV collagen of HuVSMCs is evaluated after directly and indirectly addition of IGF-1. The indirectly IGF-1 effect is acquired using conditioned HUVECs medium to the HuVSMCs. The conditioned medium is obtained from IGF-1 primed HUVECs which medium is collected in the period subsequent to priming and added to HuVSMCs. The expression of av /b3 integrin is measured and neutralizing antibody used to estimate the significance of the integrin for the adhesion. Finally PI-3 kinase, HSP90 and NF-ú B inhibitors are used to scrutinize possible pathways responsible for the adhesion of HuVSMCs after IGF-1 treatment. The adhesion of HuVSMCs is increased significantly to collagen type I, and IV (2p < 0,05) whereas indirectly treatment reduces the adhesion to type I and IV collagen (2p < 0,01). This reduction can not be ascribed to an acute effect of NO due to the experimental conditions. The expression of av /b3 integrin is elevated after IGF-1 addition and neutralizing antibody to av /b3 integrin decreases the adhesion of HuVSMCs (2p < 0,01). The records from the use of inhibitors of the intracellular pathways indicate that HSP90 and NF-ˆeB and not PI-3 kinase may be involved in the stimulatory effect of IGF-1. In conclusion IGF-1 may participate in the development of diabetic macroangiopathy and consequently in the increase of atherosclerosis in diabetes through its effect on HuVSMCs adhesion which can be modulated by non-NO action(s) of HUVECs.
S47
Metabolism P-40 MORPHOLOGICAL PECULIARITIES OF HEART AND CORONARY VESSELS DAMAGE IN TYPE 2 DIABETES MELLITUS ASSOCIATED GROWTH HORMONE DEFICIENCY Andrey L Davydov ° , Acshot M Mkrtum’yan, Anna V Koroleva, L’udmila Y Baranova. Moscow State Medical Stomatological University, Department of Endocrinology, Senior Research Officer, Russia At present great attention is paid to investigation of cardiovascular complications in type 2 diabetes patents.The aim of the work was to study morphological peculiarities of heart and coronary vessels damage in type 2 DM with GH deficiency. Materials and Methods: We studied endomiocardial bioptates of 7 patients with type 2 DM with GH deficiency and without coronary atherosclerosis obtained during coronarography and ventriculo-graphy. After special treatment the sections of different thickness (thin and ultrathin) were examined under light and electronic microscopes. Results: We revealed morphological peculiarities of myocardium and coronary vessels damage in type 2 DM patients with GH deficiency without clinical signs of atherosclerosis and ischemic heart disease, in particular, pronounced fatty degeneration of cardiomiocites, accumulation of glycogen in them, micromitochondriosis, miofibril lysis, sarcoplasmic reticulum defects, mitochondria destruction with crysts loss, apoptosis signs as well as arterioles and small and medium arteries changes, namely, pronounced edema of endotheliocytes, occurrence of fenestrated capillaries that are not normally characteristic of myocardium, and hypertrophy of unstriated muscle cells. These changes were responsible for decrease in useful heart work and disturbed coronary vessels function. These changes were not found in patients with type 2 diabetes mellitus without obvious GH deficiency; generally, areas of fatty degeneration and mitochondrial respiratory ensembles defect were observed. Conclusion: The morphological peculiarities of myocardium and coronary arteries damage can be indicative of united pathogenetic mechanisms of development of such diseases as type 2 DM, atherosclerosis, ischemic heart disease, and can be responsible for early development of failing heart in type 2 DM patients with GH deficiency without coronary atherosclerosis. P-42 NO IMPROVEMENT OF GLUCOSE TOLERANCE BY GROWTH HORMONE ADMINISTRATION IN INSULIN RESISTANT OLETF RAT Dong-Sun Kim ° , Tae-Wha Kim, Joo-Won Lee, Ju-Seop Kang. Dept. of Internal Medicine, Hanyang University College of Medicine, Korea The effects of growth hormone on glucose metabolism are complex, yielding conflicting results ranging from insulin-like to diabetogenic. Recently, short-term low-dose GH administration has been reported to improve post-load glucose tolerance in subjects with IGT and the metabolic syndrome. We investigated the effect of long-term, low dose GH administration in Long-Evans Tokushima Fatty (OLETF) rats which characteristically begin to gain weight rapidly from 5 weeks of age, show insulin resistance at 8 to 9 weeks, and finally develop obese type 2 diabetes. OLETF rats and LETO rats (control rats showing normal glucose metabolism) received either GH s.c. twice a day (150 ng/g BW for 13−18 weeks of age, and then 750 ng/g BW for 19−26 weeks of age) or vehicle. At 26 weeks, in LETO rats (LV) GH treatment group (LGH) showed increased serum IGF-I levels (2.7-fold) compared to vehicle treatment group, but GH treatment group in OLETF rats (OGH) did not. But serum IGF-I concentrations
S48
Growth Hormone & IGF Research 16 (2006) Suppl B
of OLETF rats with vehicle treatment group (OV) was 3.6-fold higher to those of LV. Serum insulin concentrations were 3.7-fold higher in OV than LV, but were not changed in OLETF rats by GH administration. GH administration did not cause a significant change in fasting blood glucose levels either in LETO or OLETF rats. Area under curve (AUC) of serum glucose levels during intraperitoneal glucose tolerance tests showed no difference between GH and vehicle treatment group either in LETO or OLETF rats. AUC of glucose concentrations during insulin tolerance tests after GH treatment showed no difference in OLETF rats, while it tends to increase in LETO rats compared to vehicle treatment group. These results suggest that GH administration does not prevent to progress to diabetes in the model of insulin resistant OLETF rats.
Aging P-44 GROWTH HORMONE INCREASES FoxO1 PROTEIN LEVELS AND THE EXPRESSION OF ITS TARGET GENES IN ADIPOSE TISSUE Hidenori Fukuoka1 ° , Yutaka Takahashi1 , Junko Nakae2 , Nishizawa Hitoshi1 , Mari Imanaka1 , Ryoko Takeno1 , Kentaro Takahashi1 , Keiji Iida1 , Yasuhiko Okimura3 , Hidesuke Kaji4 , Kazuo Chihara1 . 1 Division of Endocrinology/Metabolism, Neurology and Hematology/Oncology Department of Clinical Molecular Medicine Kobe University Graduate school of Medicine; 2 Dept of Diabetes, Digestive, and Kidney Diseases, Kobe University Graduate School of Medicine; 3 Kobe University Faculty of Health Sciences; 4 College of Nursing Art and Science, University of Hyogo, Japan Introduction: FoxO1 (Forkhead box O1) plays key roles in regulating metabolism, cell cycle, cell death, and oxidative stress response in the down stream of the insulin action. AIMS: The purpose of the present work is to examine whether FoxO1 is regulated by growth hormone (GH). Materials and methods: We examined FoxO1 protein levels in adipose tissue in GH deficient rat (spontaneous dwarf rat; SDR) using immuno blot analysis. 3T3L1 adipocytes were treated with insulin (100 nM 15 min) in the presence or absence of GH (100 ng/ml 12h). Then FoxO1 and phospho- FoxO1 protein levels were analyzed. Also, mRNA levels of FoxO1 itself and its target genes were analyzed, using quantitative real time PCR (QR-PCR) Results: In the adipose tissue in SDR, FoxO1 protein levels were decreased. In 3T3L1 adipocyte, FoxO1 protein levels were increased by GH treatment, while insulin-induced phosphorylation of FoxO1 was not attenuated in the presence of GH. QR-PCR revealed that FoxO1 mRNA level was not changed after GH treatment. Further, GH treatment increased mRNA level of FoxO1-target genes including p27kip, gadd45 and bim. Insulin decreased the expression of the FoxO1-target genes. Interestingly, GH pretreatment suppressed insulin-induced reduction of the expression of FoxO1-target genes. Conclusions: GH increased FoxO1 protein in adipose tissue in vitro and in vivo. These data suggest that GH exerts its physiological action in part via regulatory the FoxO1 protein level. Also, it may be related to GH-induced insulin resistance.
Cancer P-46 SEMINAL FLUID AS A LOCAL SOURCE OF IGF-I IN THE PROSTATE: IMPLICATIONS FOR PROSTATE CANCER Christian Sell1 ° , Krzysztof Reiss2 , Fernando Garcia1 . 1 Drexel University College of Medicine; 2 Temple University, USA Background: The insulin-like growth factors are potent mitogens and survival factors that appear to be involved in cellular transformation and the development of cancer.
Abstracts, 3rd Int. Congress of GRS & IGF Society In human populations, epidemiological studies suggest that elevated circulating levels of IGF-I are associated with an increased risk for prostate cancer. However, there have been conflicting reports regarding this correlation. Among the possible reasons for these conflicting reports is that the serum levels of IGF-I do not accurately reflect the local concentrations of IGF-I in the prostate. We have identified a potential source of local IGF-I in the peripheral zone of the prostate. The seminal ducts open into the urethra in the peripheral zone and we find that seminal vesicle fluid (SVF) contains relatively high levels of IGF-I. Hypothesis: Chronic stimulation of basal cells in the prostate by local IGF-I produced in the seminal vesicle provides an initiating stimulus for prostate cancer. We have confirmed earlier reports that SVF contains high levels of IGF-I. We have examined the potential local consequences of SVF derived IGF-I in the prostate, identifying the activated IGF-I receptor in regions of basal cell (BC) hyperplasia which occur primarily in the peripheral zone of the prostate downstream of the seminal ducts. Specifically, we find that the IGF-I receptor is expressed and activated in p63 positive cells within areas of IBC hyperplasia. In vitro, we find that SVF and promotes the proliferation of normal and malignant prostate cells. We also find that addition of SVF to CD133 positive prostate cancer prostate tumor initiating cells drives proliferation in these cells. These results suggest that IGF-I contained with in the seminal vesicle fluid serves as an initiating factor in the development of prostate cancer. P-48 TUMOR-DRIVEN ACTIVATION OF THE CIRCULATING GH-IGF SYSTEM RESULTS IN INCREASED SERUM IGF-1 LEVELS OF HEPATIC ORIGIN IN THE TRAMP MOUSE MODEL OF PROSTATE CANCER Makoto Anzo1 ° , Laura Cobb1 , Hemal Mehta1 , David Hwang1 , Shoshana Yakar2 , Derek LeRoith2 , Pinchas Cohen1 . 1 Division of Pediatric Endocrinology, David Geffen School of Medicine at UCLA; 2 Mount Sinai School of Medicine, USA Prostate cancer and other malignancies have been associated with increased levels of circulating IGF-1. We have shown that TRAMP (transgenic adenocarcinoma mouse prostate), a model of prostate cancer with prostate specific overexpression of the SV40 T antigen, has elevated serum IGF-1 levels. We hypothesized that this elevation was a result of IGF-1 secretion by the cancerous cells as these tumors had a significant increase in Igf-1 mRNA expression. To test this, we derived a novel model (LID-TRAMP mice) that lacks hepatic IGF-1 production, by crossing the TRAMP with the liver-specific IGF-1 deficient (LID) mice, and measured the levels of murine GH-IGF axis analytes by novel, specific, murine ELISA assays developed in our laboratory. LID-TRAMP serum IGF-1 levels were dramatically reduced (from 186±12 ng/ml in TRAMP to 14±2 ng/ml in LID-TRAMP) and did not differ significantly from those of LID mice, suggesting that the IGF-1 excess in TRAMP is of hepatic origin. TRAMP mice also displayed 30−50% higher IGFBP-3, ALS, as well as GH levels, compatible with a general activation of the systemic GH-IGF axis. This observation implies a possible tumor-derived source of GH or a GH secretagogue. Western immunoblots of prostates from TRAMP were negative for mouse GH or GHRH, but positive for ghrelin. These results suggest that the increased serum IGF-1 in TRAMP mice is derived from the liver and imply that production of ghrelin within the tumor may lead to increased GH secretion, activating hepatic production of the ternary complex of IGF-1, a process that may affect tumor progression.