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Context: The combination of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) has been proposed as a potential treatment for diabetes and obesity. However, the combined effects of these hormones, PYY3–36 and GLP-17–36 amide, on glucose homeostasis are unknown. Objective: This study sought to investigate the acute effects of PYY3–36 and GLP-17–36 amide, individually and in combination, on insulin secretion and sensitivity. Setting and Design: Using a frequently sampled iv glucose tolerance test (FSIVGTT) and minimal modeling, this study measured the effects of PYY3–36 alone, GLP-17–36 amide alone, and a combination of PYY3–36 and GLP-17–36 amide on acute insulin response to glucose (AIRg) and insulin sensitivity index (SI) in 14 overweight human volunteers, studied in a clinical research facility. Results: PYY3–36 alone caused a small but nonsignificant increase in AIRg. GLP-17–36 amide alone and the combination of PYY3–36 and GLP-17–36 amide did increase AIRg significantly. No significant differences in SI were observed with any intervention. Conclusions: PYY3–36 lacks any significant acute effects on first-phase insulin secretion or SI when tested using an FSIVGTT. Both GLP-17–36 amide alone and the combination of PYY3–36 and GLP-17–36 amide increase first-phase insulin secretion. There does not seem to be any additive or synergistic effect between PYY3–36 and GLP-17–36 amide on first-phase insulin secretion. Neither hormone alone nor the combination had any significant effects on SI.

Background Kisspeptin is a hypothalamic neuropeptide playing a physiological role in human reproduction. Genetic over-activation of kisspeptin causes precocious puberty in children. Concentrations of circulating kisspeptin are low in adults. The concentrations of plasma kisspeptin in boys and girls have not been studied previously. Methods Blood was obtained from 51 children and 63 adults. Plasma samples were analysed using radioimmunoassay. Children were aged 2–18 years, and attending hospital for a medically requested blood test unrelated to reproductive development. Data on pubertal status were not collected due to ethical reasons. Results Mean plasma kisspeptin was significantly higher in children when compared with adults (mean plasma kisspeptin in pmol/L: 12.3 ± 0.9, adults; 40.9 ± 3.3, children, P Conclusions We report that circulating kisspeptin is elevated in both boys and girls when compared with adults. Furthermore both boys and girls may have distinct, age-dependent concentrations of circulating kisspeptin. Further studies may determine if plasma kisspeptin could be used as a clinically useful biochemical marker of reproductive development in children.

Background Despite NIH clinical recommendations, many clinicians are reluctant to replace vitamin D in patients with hypercalcaemia with primary hyperparathyroidism (PHP) due to concerns over aggravating hypercalcaemia. Furthermore, the optimum level of vitamin D replacement in PHP remains unclear. Methods We performed a large retrospective study to determine whether a relationship exists between serum 25-hydroxyvitamin D levels, calcium and other important biochemical markers in patients with PHP. Serum, plasma and urinary biochemical measurements were collected from 251 patients with hypercalcaemia diagnosed with PHP. Results When examining overall mean circulating levels during clinical follow-up, serum 25-hydroxyvitamin D correlated highly significantly with plasma parathyroid hormone (PTH) (r = −0·23, P = 0·0003) and serum phosphate (r = 0·16, P = 0·0119). No significant relationship was observed between serum calcium and 25-hydroxyvitamin D (r = 0·002, P = 0·98). Mean plasma PTH during clinical follow-up was 51% lower in patients with serum 25-hydroxyvitamin D > 60 nm when compared with patients who had 25-hydroxyvitamin D 60 nm have significantly reduced PTH hypersecretion when compared with patients with deficient vitamin D levels, without exhibiting worse hypercalcaemia.

Glucagon and glucagon-like peptide (GLP)-1 are the primary products of proglucagon processing from the pancreas and gut, respectively. Giving dual agonists with glucagon and GLP-1 activity to diabetic, obese mice causes enhanced weight loss and improves glucose tolerance by reduction of food intake and by increase in energy expenditure (EE). We aimed to observe the effect of a combination of glucagon and GLP-1 on resting EE and glycemia in healthy human volunteers. In a randomized, double-blinded crossover study, 10 overweight or obese volunteers without diabetes received placebo infusion, GLP-1 alone, glucagon alone, and GLP-1 plus glucagon simultaneously. Resting EE—measured using indirect calorimetry—was not affected by GLP-1 infusion but rose significantly with glucagon alone and to a similar degree with glucagon and GLP-1 together. Glucagon infusion was accompanied by a rise in plasma glucose levels, but addition of GLP-1 to glucagon rapidly reduced this excursion, due to a synergistic insulinotropic effect. The data indicate that drugs with glucagon and GLP-1 agonist activity may represent a useful treatment for type 2 diabetes and obesity. Long-term studies are required to demonstrate that this combination will reduce weight and improve glycemia in patients.

The global obesity epidemic has resulted in significant morbidity and mortality. However, the medical treatment of obesity is limited. Gastric bypass is an effective surgical treatment but carries signifi cant perioperative risks. The gut hormones, peptide tyrosine tyrosine (PYY) and glucagon-like peptide 1 (GLP-1), are elevated following gastric bypass and have been shown to reduce food intake. They may provide new therapeutic targets. This review article provides an overview of the central control of food intake and the role of PYY and GLP-1 in appetite control. Key translational animal and human studies are reviewed. (Gut Liver 2012;6:10-20)

The obesity epidemic has a direct impact on every aspect of health. Current strategies to treat obesity are limited and there is a need to pioneer novel solutions. Anorectic gut hormones, physiologically secreted post-prandially to mediate satiety, have recently emerged as potential therapeutic targets in obesity. Peptide tyrosine tyrosine (PYY) is one such anorectic gut hormone, secreted from entero-endocrine L cells, which acts on neuropeptide Y (NPY) receptors within the central appetite circuit. Since the first intravenous administration of PYY to man nearly a decade ago, a number of translational studies and clinical trials have ensued with a view to developing this peptide as a treatment for obesity. This review reports on the current state of play of this on-going research.

Summary Obesity is a major public health issue worldwide. Understanding how the brain controls appetite offers promising inroads toward new therapies for obesity. Peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) are coreleased postprandially and reduce appetite and inhibit food intake when administered to humans. However, the effects of GLP-1 and the ways in which PYY and GLP-1 act together to modulate brain activity in humans are unknown. Here, we have used functional MRI to determine these effects in healthy, normal-weight human subjects and compared them to those seen physiologically following a meal. We provide a demonstration that the combined administration of PYY3-36 and GLP-17-36 amide to fasted human subjects leads to similar reductions in subsequent energy intake and brain activity, as observed physiologically following feeding., Highlights ► Coadministration of PYY3-36 and GLP-17-36 amide reduces food intake and brain activity ► The reduction in brain activity is notable in areas that control appetitive behavior ► Changes in food intake and brain activity are similar to that observed after a meal

Functional magnetic resonance imaging (fMRI) has provided the opportunity to safely investigate the workings of the human brain. This paper focuses on its use in the field of human appetitive behaviour and its impact in obesity research. In the present absence of any safe or effective centrally acting appetite suppressants, a better understanding of how appetite is controlled is vital for the development of new antiobesity pharmacotherapies. Early functional imaging techniques revealed an attenuation of brain reward area activity in response to visual food stimuli when humans are fed—in other words, the physiological state of hunger somehow increases the appeal value of food. Later studies have investigated the action of appetite modulating hormones on the fMRI signal, showing how the attenuation of brain reward region activity that follows feeding can be recreated in the fasted state by the administration of anorectic gut hormones. Furthermore, differences in brain activity between obese and lean individuals have provided clues about the possible aetiology of overeating. The hypothalamus acts as a central gateway modulating homeostatic and nonhomeostatic drives to eat. As fMRI techniques constantly improve, functional data regarding the role of this small but hugely important structure in appetite control is emerging.

Background Kisspeptin (encoded by the KISS1 gene) is a crucial regulator of normal reproductive function. In human beings, KISS1 deletion results in a failure to go through puberty whereas activating mutations result in central precocious puberty. Administration of kisspeptin induces ovulation in rodents and sheep, but whether exogenous kisspeptin can alter the menstrual cycle in healthy women is not known. This study aimed to determine the effects of kisspeptin administration on the menstrual cycle in healthy women. Methods A prospective, single-blinded, one-way crossover study at Imperial College, London, was performed. Five healthy female volunteers aged 24–37 years were recruited through adverts in the local press. They each received twice-daily subcutaneous injections of kisspeptin-54 or saline for 7 days during days 7 to 14 of their menstrual cycle. All women underwent serial assessments of basal reproductive hormones, ultrasound measurements, and luteinising hormone (LH) pulsatility, as well assessment of acute sensitivity to gonadotrophin-releasing hormone (GnRH) and kisspeptin injection. Because of the intensive protocol, women attended for assessments every 2–3 days throughout the cycle, rather than daily, to minimise stress and enhance compliance. Ethics approval was granted by the Hammersmith and Queen Charlotte's and Chelsea Hospitals Research Ethics Committee (registration number 05/Q0406/142). Findings Kisspeptin-54 treatment shortened the menstrual cycle (mean length of menstrual cycle: saline 28·6 days [SE 3·1] vs kisspeptin 26·8 [3·1], p=0·0043), advanced the onset of highest recorded serum LH (mean menstrual day of highest recorded LH 15·2 [SE 2·9] vs 13·0 [4·1], p=0·0372), and advanced the onset of the luteal phase of the menstrual cycle (mean menstrual day of progesterone increase 18·0 [SE 2·1] vs 15·8 [2·0], p=0·0402). On menstrual day 15, the largest ovarian follicle had a significantly higher diameter after kisspeptin-54 than after saline (mean diameter of largest follicle saline 10·0 mm [SE 4·4] vs kisspeptin 15·5 mm [2·2], p=0·04). LH pulsatility was maintained during kisspeptin-54 treatment. Sensitivity to exogenous kisspeptin-54 and exogenous GnRH was maintained during twice-daily kisspeptin-54 administration. Interpretation We have shown, for the first time to our knowledge using biochemical and radiological data, that exogenous kisspeptin-54 advances the menstrual cycle in healthy women. These data have important therapeutic implications for the use of kisspeptin in the treatment of women with reproductive disorders. Even though participants attended every 2–3 days rather than daily, statistical significance in key parameters was still achieved, confirming the strength of the data. In addition, use of both biochemical and radiological data allowed detailed analysis of the underlying physiological processes. Funding Wellcome Trust, National Institute for Health Research, UK Medical Research Council.

Functional magnetic resonance imaging has become a powerful tool to investigate the neuroendocrinology of appetite. In a recent study, we demonstrated that the brain activation pattern seen following the infusion of the anorectic gut hormones PYY3–36 and GLP-17–36 amide to fasted individuals resembles the brain activation pattern seen in the physiological satiated state. This commentary discusses the significance of these findings and compares them with other landmark studies in the field, with specific reference to the brain areas involved in appetite regulation. We highlight the importance of this type of research in order to pave the way for the development of efficacious and safe anti-obesity therapies.