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PL11 Growth hormone: From starvation to obesity
S28
Oral Presentations / Growth Hormone & IGF Research 22 (2012) S1–S31
was optimized by CSII for 2 days before the study and subjects were studied after an overnight fast using a constant insulin infusion (0.5mU/kg x min) and a variable glucose infusion under euglycemic clamp conditions. We studied the effects on glucose infusion rate (GIR), serum levels of IGF-I, GH, IGFBP-1, IGFBP-3, ALS, Insulin and by micro dialysis (mdIGF-I) the levels of IGF-I in muscle and fat tissue. Steady state GIR before (−60 – 0 min) placebo/IGF-1 bolus was similar (2.4±0.5 vs. 2.2±1.4 mg/kg·min). IGF-1 increased GIR to 3.0±1.6 (p = 0.06), 4.4±1.2 (p ≤ 0.001), 5.0±2.2 (p ≤ 0.001) and 5.1±2.4 mg/kg·min (p ≤ 0.001), respectively, during the 2nd, 3rd, 4th and 5th hour from injection whereas GIR was unchanged after the placebo injection [2.7±0.8 (p = 0.56), 2.5±0.9 (p = 0.95), 2.4±0.9 (p = 0.97) and 2.1±0.8 mg/kg·min (p = 0.35), respectively]. Results obtained from the present study demonstrate that rhIGF-1 could be an adjuvant therapy in type 1 diabetics as it potently induces glucose utilization under constant insulin concentrations. A more prolonged increase in glucose utilization was seen in our patients at this recommended “growth promoting” dose of IGF-1 than would be expected from the changes in serum IGF-I levels in other severe IGF-I deficient states. PL11 Growth hormone: From starvation to obesity A. Klibanski1 . 1 M.D. Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States The relationship between body weight and GH secretion is a complex one involving multiple neuroendocrine signals and body composition depots. At one extreme, anorexia nervosa (AN), a common psychiatric disorder characterized by chronic self-induced starvation, is associated with the development of a state of acquired growth hormone resistance, characterized by low insulinlike growth factor (IGF)-I and elevated growth hormone (GH) levels, which may be mediated in part by fibroblast growth factor21. Adolescent girls and women with AN have increases in both basal and pulsatile GH secretion coupled with low levels of IGF-I. Elevations in GH secretion in starvation, likely the result of feedback and stimulation of GHRH due to low circulating IGF-I levels, have led to the concept of a nutritionally-mediated state of acquired GH resistance at the liver in AN in which starvation impairs GH action both acutely and chronically. We have shown that administration of supraphysiologic rhGH in women with AN for 12 weeks does not increase IGF-1 levels but does result in decreases in fat mass and percent body fat, supporting the role for an IGF-1 independent lipolytic effect of GH. Women with AN have significantly elevated levels of the orexigenic hormone ghrelin, which may also contribute to increased GH secretion. The elevated levels of ghrelin have been proposed to be an adaptive response to prevent hypoglycemia in the setting of severe calorie restriction. FGF-21, a member of the fibroblast growth factor family, is produced in both the liver and in human adipocytes. Serum FGF-21 levels correlate positively with BMI and are higher in overweight and obese individuals. However, elevations in hepatic FGF-21 may be an adaptive mechanism to induce ketogenesis and decrease metabolic activity and energy expenditure in a fasting state. In a mouse model, FGF-21 overexpression leads to a state of GH resistance. At the other extreme of the spectrum, obesity, particularly visceral adiposity, is associated with a relative GH deficiency as determined by a decreased GH response to GH stimulation testing compared to lean controls with a variable but overall effect of decreasing circulating IGF-1 levels. Findings in obesity show relatively decreased ghrelin levels in association with relative GH deficiency. As in AN, changes in orexigenic and anorexigenic hormones linked to GH secretion typically, but do not always, normalize with weight normalization. Decreased “GH action” via disruption of the GH-IGF-I axis in the context of both GH resistance and relative GH deficiency is an
important factor in mediating the bone loss characteristic of both AN as well as that associated with visceral adiposity. A new avenue of research has been the impact of fat depots and the GH/IGF-1 axis on bone marrow fat and bone mineral density at both ends of the nutritional spectrum. PL12 Growth hormone and IGF-1 in mouse models of growth and metabolism D. LeRoith1 , S. Yakar2 . 1 Mt. Sinai School of Medicine, Division of Endocrinology, Diabetes and Bone Diseases, New York City, United States; 2 NYU, New York City, United States The GH/IGF-1 system is involved in longitudinal growth especially peri-pubertally and bone-formation throughout life. Many of the functions on growth and metabolism of GH are mediated by IGF-1; however there GH functions that are IGF-1-independent and conversely, IGF-1 has functions that are GH-independent. We have studied these functions in mouse models use the transgenic and gene-deletion technologies. Reductions in circulating IGF-1 levels, seen in the liver-specific IGF-1 genedeletion (LID) mice and the ALS knockout mice, resulted in reductions in bone accrual and slender more mechanically inferior bones. In contrast, the mice that have their IGF-1 gene replaced by an IGF-1 that has reduced affinity for IGFBPs, the increased total body “free” IGF-1, resulted in more robust, stronger bones with increases in all morphological traits. These latter findings also support the findings of the total IGFBP-3 knock-out mouse (IGFBP3KO) that has a more robust bone phenotype probably due to increased free IGF-1. Thus circulating and local IGF-1 play a role in bone structure. GH’s effects can be seen independent of liver production of IGF-1. In the LID mice, the elevated GH maybe compensating for the lowered circulating IGF-1 in maintaining bone accrual. Indeed, when the elevated GH levels are reduced using pegvisomat, reductions in femoral length and cortical bone formation. Thus both GH and IGF-1 are important for bone growth and bone formation. Finally, we used tissue specific, gene-deletion GH receptor knockouts to study the effect on metabolism. Liver GHRKO shows an alteration in lipid metabolism whereas skleletal muscle specific GHRKO leads to an improvement of muscle glucose metabolism even in the face of high-fat diet-induced obesity. Overall these studies show combined GH/IGF-1 effects on these parameters and many independent effects on growth, bone structure and whole body metabolism.
OR11: Hot topics OR11-1 Biochemical characterisation of insulin-like growth factor II isoforms associated with tumorigenesis S.A. Greenall1 , L. Cosgrove2 , R.C. Baxter3 , T.E. Adams1 . 1 CSIRO, Materials Science and Engineering, Parkville, Australia; 2 CSIRO, Molecular Health Technologies, Adelaide, Australia; 3 Kolling Institute of Medical Research, St Leonards, Australia Elevated expression and secretion of insulin-like growth factor II (IGF-II) and its precursor forms (big- and pro-IGF-II) are commonly associated with tumorigenesis. Normally, IGF-II is sequestered by binding and internalisation by IGF-IIR, its cognate receptor, or by binding the IGF binding proteins (IGFBP). This can occur by formation of binary complex or, more commonly, ternary complex with IGFBP-3 or IGFBP-5 and the acid labile subunit (ALS). Recently, our laboratory presented in vivo evidence that cancer-associated IGF-II isoforms may have unique biological properties which enable them to escape sequestration, rendering them bioavailable [1]. As yet, the properties of individual species of IGF-II isoforms have yet to be explored, due to either heterogeneous populations
Oral Presentations / Growth Hormone & IGF Research 22 (2012) S1–S31
was optimized by CSII for 2 days before the study and subjects were studied after an overnight fast using a constant insulin infusion (0.5mU/kg x min) and a variable glucose infusion under euglycemic clamp conditions. We studied the effects on glucose infusion rate (GIR), serum levels of IGF-I, GH, IGFBP-1, IGFBP-3, ALS, Insulin and by micro dialysis (mdIGF-I) the levels of IGF-I in muscle and fat tissue. Steady state GIR before (−60 – 0 min) placebo/IGF-1 bolus was similar (2.4±0.5 vs. 2.2±1.4 mg/kg·min). IGF-1 increased GIR to 3.0±1.6 (p = 0.06), 4.4±1.2 (p ≤ 0.001), 5.0±2.2 (p ≤ 0.001) and 5.1±2.4 mg/kg·min (p ≤ 0.001), respectively, during the 2nd, 3rd, 4th and 5th hour from injection whereas GIR was unchanged after the placebo injection [2.7±0.8 (p = 0.56), 2.5±0.9 (p = 0.95), 2.4±0.9 (p = 0.97) and 2.1±0.8 mg/kg·min (p = 0.35), respectively]. Results obtained from the present study demonstrate that rhIGF-1 could be an adjuvant therapy in type 1 diabetics as it potently induces glucose utilization under constant insulin concentrations. A more prolonged increase in glucose utilization was seen in our patients at this recommended “growth promoting” dose of IGF-1 than would be expected from the changes in serum IGF-I levels in other severe IGF-I deficient states. PL11 Growth hormone: From starvation to obesity A. Klibanski1 . 1 M.D. Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States The relationship between body weight and GH secretion is a complex one involving multiple neuroendocrine signals and body composition depots. At one extreme, anorexia nervosa (AN), a common psychiatric disorder characterized by chronic self-induced starvation, is associated with the development of a state of acquired growth hormone resistance, characterized by low insulinlike growth factor (IGF)-I and elevated growth hormone (GH) levels, which may be mediated in part by fibroblast growth factor21. Adolescent girls and women with AN have increases in both basal and pulsatile GH secretion coupled with low levels of IGF-I. Elevations in GH secretion in starvation, likely the result of feedback and stimulation of GHRH due to low circulating IGF-I levels, have led to the concept of a nutritionally-mediated state of acquired GH resistance at the liver in AN in which starvation impairs GH action both acutely and chronically. We have shown that administration of supraphysiologic rhGH in women with AN for 12 weeks does not increase IGF-1 levels but does result in decreases in fat mass and percent body fat, supporting the role for an IGF-1 independent lipolytic effect of GH. Women with AN have significantly elevated levels of the orexigenic hormone ghrelin, which may also contribute to increased GH secretion. The elevated levels of ghrelin have been proposed to be an adaptive response to prevent hypoglycemia in the setting of severe calorie restriction. FGF-21, a member of the fibroblast growth factor family, is produced in both the liver and in human adipocytes. Serum FGF-21 levels correlate positively with BMI and are higher in overweight and obese individuals. However, elevations in hepatic FGF-21 may be an adaptive mechanism to induce ketogenesis and decrease metabolic activity and energy expenditure in a fasting state. In a mouse model, FGF-21 overexpression leads to a state of GH resistance. At the other extreme of the spectrum, obesity, particularly visceral adiposity, is associated with a relative GH deficiency as determined by a decreased GH response to GH stimulation testing compared to lean controls with a variable but overall effect of decreasing circulating IGF-1 levels. Findings in obesity show relatively decreased ghrelin levels in association with relative GH deficiency. As in AN, changes in orexigenic and anorexigenic hormones linked to GH secretion typically, but do not always, normalize with weight normalization. Decreased “GH action” via disruption of the GH-IGF-I axis in the context of both GH resistance and relative GH deficiency is an
important factor in mediating the bone loss characteristic of both AN as well as that associated with visceral adiposity. A new avenue of research has been the impact of fat depots and the GH/IGF-1 axis on bone marrow fat and bone mineral density at both ends of the nutritional spectrum. PL12 Growth hormone and IGF-1 in mouse models of growth and metabolism D. LeRoith1 , S. Yakar2 . 1 Mt. Sinai School of Medicine, Division of Endocrinology, Diabetes and Bone Diseases, New York City, United States; 2 NYU, New York City, United States The GH/IGF-1 system is involved in longitudinal growth especially peri-pubertally and bone-formation throughout life. Many of the functions on growth and metabolism of GH are mediated by IGF-1; however there GH functions that are IGF-1-independent and conversely, IGF-1 has functions that are GH-independent. We have studied these functions in mouse models use the transgenic and gene-deletion technologies. Reductions in circulating IGF-1 levels, seen in the liver-specific IGF-1 genedeletion (LID) mice and the ALS knockout mice, resulted in reductions in bone accrual and slender more mechanically inferior bones. In contrast, the mice that have their IGF-1 gene replaced by an IGF-1 that has reduced affinity for IGFBPs, the increased total body “free” IGF-1, resulted in more robust, stronger bones with increases in all morphological traits. These latter findings also support the findings of the total IGFBP-3 knock-out mouse (IGFBP3KO) that has a more robust bone phenotype probably due to increased free IGF-1. Thus circulating and local IGF-1 play a role in bone structure. GH’s effects can be seen independent of liver production of IGF-1. In the LID mice, the elevated GH maybe compensating for the lowered circulating IGF-1 in maintaining bone accrual. Indeed, when the elevated GH levels are reduced using pegvisomat, reductions in femoral length and cortical bone formation. Thus both GH and IGF-1 are important for bone growth and bone formation. Finally, we used tissue specific, gene-deletion GH receptor knockouts to study the effect on metabolism. Liver GHRKO shows an alteration in lipid metabolism whereas skleletal muscle specific GHRKO leads to an improvement of muscle glucose metabolism even in the face of high-fat diet-induced obesity. Overall these studies show combined GH/IGF-1 effects on these parameters and many independent effects on growth, bone structure and whole body metabolism.
OR11: Hot topics OR11-1 Biochemical characterisation of insulin-like growth factor II isoforms associated with tumorigenesis S.A. Greenall1 , L. Cosgrove2 , R.C. Baxter3 , T.E. Adams1 . 1 CSIRO, Materials Science and Engineering, Parkville, Australia; 2 CSIRO, Molecular Health Technologies, Adelaide, Australia; 3 Kolling Institute of Medical Research, St Leonards, Australia Elevated expression and secretion of insulin-like growth factor II (IGF-II) and its precursor forms (big- and pro-IGF-II) are commonly associated with tumorigenesis. Normally, IGF-II is sequestered by binding and internalisation by IGF-IIR, its cognate receptor, or by binding the IGF binding proteins (IGFBP). This can occur by formation of binary complex or, more commonly, ternary complex with IGFBP-3 or IGFBP-5 and the acid labile subunit (ALS). Recently, our laboratory presented in vivo evidence that cancer-associated IGF-II isoforms may have unique biological properties which enable them to escape sequestration, rendering them bioavailable [1]. As yet, the properties of individual species of IGF-II isoforms have yet to be explored, due to either heterogeneous populations