Abstract
Low serum testosterone is commonly observed in men with type 2 diabetes (T2DM), but the neuroendocrine pathophysiology remains to be elucidated. 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. Five hypotestosteronaemic men with T2DM (age 33·6±3years, BMI 40·6±6·3, total testosterone 8·5±1·0nmol/l, LH 4·7±0·7 IU/l, HbA1c 7·4±2%, duration of diabetes <5years) and seven age-matched healthy men. EXPERIMENT 1: Mean LH increased in response to intravenous administration of kisspeptin-10 (0·3mcg/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 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 12h. An intravenous infusion of kisspeptin-10 (4mcg/kg/h) was administered for 11h, 5days 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±0·9nmol/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). 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.
Published Version
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