The effects of kisspeptin on β‐cell function, serum metabolites and appetite in humans

Abstract

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.

Kisspeptin and Glucose Homeostasis

“…Furthermore, in this study, incubation of human donor islets and a human pancreatic β-cell line (EndoC-βH1) with different concentrations of kisspeptin produced dose-dependent increases in insulin secretion. 22 This confirms findings from animal studies that kisspeptin (presumably acting via the kisspeptin receptor on β-cells) has a direct effect on βcells. However, kisspeptin may also enhance GSIS by increasing sex-steroid hormone levels (via its well-established potent stimulatory effects on the hypothalamic-pituitarygonadal axis 43,44 ), as both androgens (acting via the androgen receptor on β-cells 45 ) and estrogens (acting via pancreatic estrogen receptor-α 46 and/or the G protein-coupled estrogen receptor 47 ) stimulate insulin secretion.…”

“…23,30 Additionally, in healthy men, administration of kisspeptin resulted in similar plasma glucagon levels to vehicle administration. 22 More recent immunostaining data show that both kisspeptin and GPR54 specifically co-localize to the insulin expressing β-cells and are minimally expressed in the other islet endocrine cells, 24 consistent with the primary role of kisspeptin within the islets being the modulation of insulin secretion.…”

“…24 Additionally, in a study of 261 people without diabetes who underwent oral glucose tolerance testing, after adjustments for age, gender, and body mass index, there was a weak but significant negative correlation between plasma kisspeptin levels and the insulinogenic index (standardized coefficient β ¼ À0.105, p ¼ 0.03), a measure of insulin secretion. 41 A recently published interventional study demonstrated that kisspeptin increased GSIS in healthy men by 15% in response to an intravenous glucose bolus and it increased the disposition index 22 (a composite measure of β-cell function that is inversely associated with the risk of progression from normoglycemia to impaired glucose tolerance and/or progression from impaired glucose tolerance to type 2 diabetes 42 ). Consistent with in vivo primate studies, 39 in this human study, kisspeptin stimulated insulin secretion only when glucose levels were elevated, 22 suggesting a role for kisspeptin in the correction of hyperglycemia.…”

“…Additionally, the stimulatory effects of kisspeptin on the reproductive system could also improve glucose homeostasis, as hypogonadism results in increased insulin resistance, reduced insulin secretion, and increased body weight, 48 which have detrimental effects on glucose homeostasis. As the stimulatory effect on insulin secretion by kisspeptin has been demonstrated only in healthy men, 22 further studies are required to characterize the effects of kisspeptin on insulin secretion in other populations such as people with hypogonadism and/or people with diabetes.…”

Viral and bacterial infection elicit distinct changes in plasma lipids in febrile children

“…Lipidomic analysis was carried out as previously described [25]. Briefly, 50 μl of water were added to 50 μl of plasma, vortexed and shaken for 5 min at 1,400 rpm at 4°C.…”