Clinical Endocrinology

Exploring the pathophysiology of hypogonadism in men with type 2 diabetes: Kisspeptin-10 stimulates serum testosterone and LH secretion in men with type 2 diabetes and mild biochemical hypogonadism

Authors

  • Jyothis T. George,

    Corresponding author
    • MRC Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
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  • Johannes D. Veldhuis,

    1. Endocrine Research Unit, Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota, USA
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  • Manuel Tena-Sempere,

    1. Department of Cell Biology, Physiology and Immunology & CIBER Fisiopatologia de la Obesidad y Nutrición, University of Cordoba, Cordoba, Spain
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  • Robert P. Millar,

    1. MRC/UCT, Receptor Biology and Reproductive Health Group, Division of Medical Biochemistry, University of Cape Town, Observatory, South Africa
    2. Mammal Research Institute, University of Pretoria, Pretoria, South Africa
    3. Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK
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  • Richard A. Anderson

    1. MRC Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
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Correspondence: Jyothis T George, MRC Centre for Reproductive Health, The Queen's Medical Research Institute, Edinburgh, EH16 4TJ, United Kingdom. E-mail: j.george@ed.ac.uk

Abstract

Rationale

Low serum testosterone is commonly observed in men with type 2 diabetes (T2DM), but the neuroendocrine pathophysiology remains to be elucidated.

Objectives

The hypothalamic neuropeptide kisspeptin integrates metabolic signals with the reproductive axis in animal models. We hypothesized that administration of exogenous kisspeptin-10 will restore luteinizing hormone (LH) and testosterone secretion in hypotestosteronaemic men with T2DM.

Participants

Five hypotestosteronaemic men with T2DM (age 33·6 ± 3 years, BMI 40·6 ± 6·3, total testosterone 8·5 ± 1·0 nmol/l, LH 4·7 ± 0·7 IU/l, HbA1c 7·4±2%, duration of diabetes <5 years) and seven age-matched healthy men.

Experiment 1

Mean LH increased in response to intravenous administration of kisspeptin-10 (0·3 mcg/kg bolus) both in healthy men (5·5 ± 0·8 to 13·9 ± 1·7 IU/l P < 0·001) and in men with T2DM (4·7 ± 0·7 to 10·7 ± 1·2 IU/l = 0·02) with comparable ΔLH (P = 0·18).

Experiment 2

Baseline 10-min serum sampling for LH and hourly testosterone measurements were performed in four T2DM men over 12 h. An intravenous infusion of kisspeptin-10 (4 mcg/kg/h) was administered for 11 h, 5 days later. There were increases in LH (3·9 ± 0·1 IU/l to 20·7 ± 1·1 IU/l P = 0·03) and testosterone (8·5 ± 1·0 to 11·4 ± 0·9 nmol/l, P = 0·002). LH pulse frequency increased from 0·6 ± 0·1 to 0·9 ± 0 pulses/h (P = 0·05) and pulsatile component of LH secretion from 32·1 ± 8·0 IU/l to 140·2 ± 23·0 IU/l (P = 0·007).

Conclusions

Kisspeptin-10 administration increased LH pulse frequency and LH secretion in hypotestosteronaemic men with T2DM in this proof-of-concept study, with associated increases in serum testosterone. These data suggest a potential novel therapeutic role for kisspeptin agonists in enhancing endogenous testosterone secretion in men with T2DM and central hypogonadism.

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