AimsTo investigate the effect of kisspeptin on glucose‐stimulated insulin secretion and appetite in humans.Materials and methodsIn 15 healthy men (age: 25.2 ± 1.1 years; BMI: 22.3 ± 0.5 kg m−2), we compared the effects of 1 nmol kg−1 h−1 kisspeptin versus vehicle administration on glucose‐stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose‐stimulated insulin secretion in vitro in human pancreatic islets and a human β‐cell line (EndoC‐βH1 cells).ResultsKisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose load, and modulated serum metabolites. In keeping with this, kisspeptin increased glucose‐stimulated insulin secretion from human islets and a human pancreatic cell line in vitro. In addition, kisspeptin administration did not alter gut hormones, appetite or food intake in healthy men.ConclusionsCollectively, these data demonstrate for the first time a beneficial role for kisspeptin in insulin secretion in humans in vivo. This has important implications for our understanding of the links between reproduction and metabolism in humans, as well as for the ongoing translational development of kisspeptin‐based therapies for reproductive and potentially metabolic conditions.

Objective: To stop smoking is commonly associated with significant weight gain, but the mechanisms for this are poorly understood. We assessed the effects of smoking cessation on body weight, insulin sensitivity, b-cell function, and appetite. Subjects and methods: Twenty-seven long-term smokers (nZ27; nine females/18 males, 28G1 years, 22.9G0.6 kg/m 2 )attending an ambulatory smoking cessation program in a community hospital in Vienna, Austria were examined at baseline (Visit A; still smoking) and after a minimum of 3 months of smoking abstinence (Visit B; nZ14); relapsed smokers were not followed up. Participants underwent 3-h oral glucose tolerance tests and body composition measurements at each study visit. Fasting (QUICKI) and dynamic (oral glucose insulin sensitivity (OGIS)) insulin sensitivity and b-cell secretion (insulinogenic index 140 (IGI40)) were calculated. Food intake was quantified with a free choice buffet. Fasting plasma concentrations of neuropeptide-Y (NPY), peptide-YY (PYY), glucagon-like peptide 1 (GLP1), leptin, ghrelin, and visfatin were measured. Results: After O3 months' smoking abstinence, body weight, and fat mass were increased (C4 and C22% respectively, P!0.05) and fasting insulin sensitivity deteriorated (QUICKI: post, 0.37G0.02 vs baseline, 0.41G0.2; P!0.05), while OGIS remained unchanged throughout. IGI40 increased by 31% after O3 months' smoking abstinence (P!0.01). Carbohydrate ingestion increased after stopping smoking (P!0.05). NPY fasting levels were increased after O3 months (P!0.05), PYY, GLP1, leptin, ghrelin, and visfatin were unchanged. Conclusion: Smoking cessation is associated with transient metabolic changes including increased b-cell secretion in response to glucose and fasting insulin resistance. These alterations may be associated with or contribute to the body weight gain after smoking cessation.

BACKGROUND. Kisspeptin is a key regulator of hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is essential for reproductive health. A specific kisspeptin receptor (KISS1R) agonist could significantly expand the potential clinical utility of therapeutics targeting the kisspeptin pathway. Herein, we investigate the effects of a KISS1R agonist, MVT-602, in healthy women and in women with reproductive disorders. METHODS. We conducted in vivo and in vitro studies to characterize the action of MVT-602 in comparison with native kisspeptin-54 (KP54). We determined the pharmacokinetic and pharmacodynamic properties of MVT-602 (doses 0.01 and 0.03 nmol/kg) versus KP54 (9.6 nmol/kg) in the follicular phase of healthy women (n = 9), and in women with polycystic ovary syndrome (PCOS; n = 6) or hypothalamic amenorrhea (HA; n = 6). Further, we investigated their effects on KISS1Rmediated inositol monophosphate (IP 1) and Ca 2+ signaling in cell lines and on action potential firing of GnRH neurons in brain slices. RESULTS. In healthy women, the amplitude of luteinizing hormone (LH) rise was similar to that after KP54, but peaked later (21.4 vs. 4.7 hours; P = 0.0002), with correspondingly increased AUC of LH exposure (169.0 vs. 38.5 IU•h/L; P = 0.0058). LH increases following MVT-602 were similar in PCOS and healthy women, but advanced in HA (P = 0.004). In keeping with the clinical data, MVT-602 induced more potent signaling of KISS1R-mediated IP 1 accumulation and a longer duration of GnRH neuron firing than KP54 (115 vs. 55 minutes; P = 0.0012). CONCLUSION. Taken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders. TRIAL REGISTRATION. International Standard Randomised Controlled Trial Number (ISRCTN) Registry, ISRCTN21681316.