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

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 center dot 6 +/- 3years, BMI 40 center dot 6 +/- 6 center dot 3, total testosterone 8 center dot 5 +/- 1 center dot 0nmol/l, LH 4 center dot 7 +/- 0 center dot 7 IU/l, HbA1c 7 center dot 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 center dot 3mcg/kg bolus) both in healthy men (5 center dot 5 +/- 0 center dot 8 to 13 center dot 9 +/- 1 center dot 7 IU/l P<0 center dot 001) and in men with T2DM (4 center dot 7 +/- 0 center dot 7 to 10 center dot 7 +/- 1 center dot 2 IU/l P=0 center dot 02) with comparable LH (P=0 center dot 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 center dot 9 +/- 0 center dot 1 IU/l to 20 center dot 7 +/- 1 center dot 1 IU/l P=0 center dot 03) and testosterone (8 center dot 5 +/- 1 center dot 0 to 11 center dot 4 +/- 0 center dot 9nmol/l, P=0 center dot 002). LH pulse frequency increased from 0 center dot 6 +/- 0 center dot 1 to 0 center dot 9 +/- 0 pulses/h (P=0 center dot 05) and pulsatile component of LH secretion from 32 center dot 1 +/- 8 center dot 0 IU/l to 140 center dot 2 +/- 23 center dot 0 IU/l (P=0 center dot 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.