Insulin-like growth factor role in determining the anti-cancer effect of metformin: RCT in prostate cancer patients

Vita Birzniece; Vita Birzniece; Mark McLean; Navneeta Reddy; Haleh Shahidipour; Amy Hayden; Howard Gurney; Glenn Stone; Rikke Hjortebjerg; Jan Frystyk

doi:10.1530/EC-21-0375

Endocrine Connections (May 2022)

Insulin-like growth factor role in determining the anti-cancer effect of metformin: RCT in prostate cancer patients

Vita Birzniece,
Vita Birzniece,
Mark McLean,
Navneeta Reddy,
Haleh Shahidipour,
Amy Hayden,
Howard Gurney,
Glenn Stone,
Rikke Hjortebjerg,
Jan Frystyk

Affiliations

Vita Birzniece: School of Medicine, Western Sydney University, New South Wales, Australia; 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
Vita Birzniece: School of Medicine, Western Sydney University, New South Wales, Australia; Department of Diabetes and Endocrinology, Blacktown Hospital, New South Wales, Australia; Department of Diabetes and Endocrinology, Westmead Hospital, New South Wales, Australia
Mark McLean: School of Medicine, Western Sydney University, New South Wales, Australia; Department of Diabetes and Endocrinology, Blacktown Hospital, New South Wales, Australia
Navneeta Reddy: Department of Diabetes and Endocrinology, Blacktown Hospital, New South Wales, Australia
Haleh Shahidipour: School of Medicine, Western Sydney University, New South Wales, Australia; Department of Diabetes and Endocrinology, Blacktown Hospital, New South Wales, Australia
Amy Hayden: School of Medicine, Western Sydney University, New South Wales, Australia; Faculty of Medicine, Health and Human Sciences, Macquarie University, New South Wales, Australia; Crown Princess Mary Cancer Centre, Westmead Hospital, New South Wales, Australia
Howard Gurney: Crown Princess Mary Cancer Centre, Westmead Hospital, New South Wales, Australia
Glenn Stone: School of Computing, Engineering and Mathematics, Western Sydney University, New South Wales, Australia
Rikke Hjortebjerg: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 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
Jan Frystyk: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Endocrine Research Unit, Department of Endocrinology, Odense University Hospital & Department of Clinical Research, Faculty of Health, University of Southern Denmark, Odense, Denmark

DOI: https://doi.org/10.1530/EC-21-0375
Journal volume & issue: Vol. 11, no. 4
pp. 1 – 11

Abstract

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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 assessmen t 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 ins ulin resistance (r2 = 0.28, P < 0.05). PAPP-A remained unchanged but STC2 declined significa ntly (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.

Published in Endocrine Connections

ISSN: 2049-3614 (Online)
Publisher: Bioscientifica
Country of publisher: United Kingdom
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the endocrine glands. Clinical endocrinology
Website: http://www.endocrineconnections.com/

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