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Department of Diabetes and Endocrinology, Blacktown Hospital, Blacktown, New South Wales, Australia
Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, New South Wales, Australia
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Department of Diabetes and Endocrinology, Blacktown Hospital, Blacktown, New South Wales, Australia
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Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales, Australia
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Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
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Department of Diabetes and Endocrinology, Blacktown Hospital, Blacktown, New South Wales, Australia
School of Medicine, UNSW Sydney, Sydney, New South Wales, Australia
Translational Health Research Institute, Penrith, New South Wales, Australia
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Department of Diabetes and Endocrinology, Blacktown Hospital, Blacktown, New South Wales, Australia
Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
School of Medicine, UNSW Sydney, Sydney, New South Wales, Australia
Translational Health Research Institute, Penrith, New South Wales, Australia
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Context
Androgen deprivation therapy (ADT) in prostate cancer results in muscular atrophy, due to loss of the anabolic actions of testosterone. Recently, we discovered that testosterone acts on the hepatic urea cycle to reduce amino acid nitrogen elimination. We now hypothesize that ADT enhances protein oxidative losses by increasing hepatic urea production, resulting in muscle catabolism. We also investigated whether progressive resistance training (PRT) can offset ADT-induced changes in protein metabolism.
Objective
To investigate the effect of ADT on whole-body protein metabolism and hepatic urea production with and without a home-based PRT program.
Design
A randomized controlled trial.
Patients and intervention
Twenty-four prostate cancer patients were studied before and after 6 weeks of ADT. Patients were randomized into either usual care (UC) (n = 11) or PRT (n = 13) starting immediately after ADT.
Main outcome measures
The rate of hepatic urea production was measured by the urea turnover technique using 15N2-urea. Whole-body leucine turnover was measured, and leucine rate of appearance (LRa), an index of protein breakdown and leucine oxidation (Lox), a measure of irreversible protein loss, was calculated.
Results
ADT resulted in a significant mean increase in hepatic urea production (from 427.6 ± 18.8 to 486.5 ± 21.3; P < 0.01) regardless of the exercise intervention. Net protein loss, as measured by Lox/Lra, increased by 12.6 ± 4.9% (P < 0.05). PRT preserved lean body mass without affecting hepatic urea production.
Conclusion
As early as 6 weeks after initiation of ADT, the suppression of testosterone increases protein loss through elevated hepatic urea production. Short-term PRT was unable to offset changes in protein metabolism during a state of profound testosterone deficiency.
Department of Diabetes and Endocrinology, Blacktown Hospital, New South Wales, Australia
Garvan Institute of Medical Research, New South Wales, Australia
School of Medical Sciences, University of New South Wales, New South Wales, Australia
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Department of Diabetes and Endocrinology, Blacktown Hospital, New South Wales, Australia
Department of Diabetes and Endocrinology, Westmead Hospital, New South Wales, Australia
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Department of Diabetes and Endocrinology, Blacktown Hospital, New South Wales, Australia
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Department of Diabetes and Endocrinology, Blacktown Hospital, New South Wales, Australia
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Faculty of Medicine, Health and Human Sciences, Macquarie University, New South Wales, Australia
Crown Princess Mary Cancer Centre, Westmead Hospital, New South Wales, Australia
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Endocrine Research Unit, Department of Endocrinology, Odense University Hospital & Department of Clinical Research, Faculty of Health, University of Southern Denmark, Odense, Denmark
Steno Diabetes Center Odense, Odense University Hospital & Department of Clinical Research, Faculty of Health, University of Southern Denmark, Odense, Denmark
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Endocrine Research Unit, Department of Endocrinology, Odense University Hospital & Department of Clinical Research, Faculty of Health, University of Southern Denmark, Odense, Denmark
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Objective
Androgen deprivation therapy (ADT), a principal therapy in patients with prostate cancer, is associated with the development of obesity, insulin resistance, and hyperinsulinemia. Recent evidence indicates that metformin may slow cancer progression and improves survival in prostate cancer patients, but the mechanism is not well understood. Circulating insulin-like growth factors (IGFs) are bound to high-affinity binding proteins, which not only modulate the bioavailability and signalling of IGFs but also have independent actions on cell growth and survival. The aim of this study was to investigate whether metformin modulates IGFs, IGF-binding proteins (IGFBPs), and the pregnancy-associated plasma protein A (PAPP-A) – stanniocalcin 2 (STC2) axis.
Design and methods
In a blinded, randomised, cross-over design, 15 patients with prostate cancer on stable ADT received metformin and placebo treatment for 6 weeks each. Glucose metabolism along with circulating IGFs and IGFBPs was assessed.
Results
Metformin significantly reduced the homeostasis model assessment as an index of insulin resistance (HOMA IR) and hepatic insulin resistance. Metformin also reduced circulating IGF-2 (P < 0.05) and IGFBP-3 (P < 0.01) but increased IGF bioactivity (P < 0.05). At baseline, IGF-2 correlated significantly with the hepatic insulin resistance (r2= 0.28, P < 0.05). PAPP-A remained unchanged but STC2 declined significantly (P < 0.05) following metformin administration. During metformin treatment, change in HOMA IR correlated with the change in STC2 (r2= 0.35, P < 0.05).
Conclusion
Metformin administration alters many components of the circulating IGF system, either directly or indirectly via improved insulin sensitivity. Reduction in IGF-2 and STC2 may provide a novel mechanism for a potential metformin-induced antineoplastic effect.
