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
George JT, Veldhuis JD, Tena-Sempere M, Millar RP, Anderson RA. Clin Endocrinol (Oxf). 2012 Nov 15. doi: 10.1111/cen.12103. [Epub ahead of print]

Source

MRC Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4TJ, 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 hypothesised that administration of exogenous kisspeptin-10 will restore luteinising 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, HbA(1c) 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) in both healthy men (5.5±0.8 to 13.9±1.7 IU/L P <0.001) and in T2DM (4.7±0.7 to 10.7±1.2 IU/L P=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 hours. An intravenous infusion of kisspeptin-10 (4 mcg/kg/hr) was administered for 11 hours, 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/hr (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.