Akila De Silva

The Gut Hormones PYY3-36 and GLP-17-36 amide Reduce Food Intake and Modulate Brain Activity in Appetite Centers in Humans

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.

Gut Hormones and Appetite Control: A Focus on PYY and GLP-1 as Therapeutic Targets in Obesity.

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 significant 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.

Coadministration of Glucagon-Like Peptide-1 During Glucagon Infusion in Humans Results in Increased Energy Expenditure and Amelioration of Hyperglycemia

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 Use of Functional MRI to Study Appetite Control in the CNS

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.

Increasing LH Pulsatility in Women With Hypothalamic Amenorrhoea Using Intravenous Infusion of Kisspeptin-54

Background: Hypothalamic amenorrhea (HA) is the one of the most common causes of period loss in women of reproductive age and is associated with deficient LH pulsatility. High-dose kisspeptin-54 acutely stimulates LH secretion in women with HA, but chronic administration causes desensitization. GnRH has paradoxical effects on reproductive activity; we therefore hypothesized that a dose-dependent therapeutic window exists within which kisspeptin treatment restores the GnRH/LH pulsatility in women with HA. Aim: The aim of the study was to determine whether constant iv infusion of kisspeptin-54 temporarily increases pulsatile LH secretion in women with HA. Methods: Five patients with HA each underwent six assessments of LH pulsatility. Single-blinded continuous iv infusion of vehicle or kisspeptin-54 (0.01, 0.03, 0.10, 0.30, or 1.00 nmol/kg/h) was administered. The LH pulses were detected using blinded deconvolution. Results: Kisspeptin increased LH pulsatility in all patients with HA, with peak responses observed at different doses in each patient. The mean peak number of pulses during infusion of kisspeptin-54 was 3-fold higher when compared with vehicle (number of LH pulses per 8 h: 1.6 ± 0.4, vehicle; 5.0 ± 0.5, kisspeptin-54, P < .01 vs vehicle). The mean peak LH pulse secretory mass during kisspeptin-54 was 6-fold higher when compared with vehicle (LH pulse secretory mass in international units per liter: 3.92 ± 2.31, vehicle; 23.44 ± 12.59, kisspeptin-54; P < .05 vs vehicle). Conclusions: Kisspeptin-54 infusion temporarily increases LH pulsatility in women with HA. Furthermore, we have determined the dose range within which kisspeptin-54 treatment increases basal and pulsatile LH secretion in women with HA. This work provides a basis for studying the potential of kisspeptin-based therapies to treat women with HA.

Translational studies on PYY as a novel target in obesity.

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.

Effects of neurokinin B administration on reproductive hormone secretion in healthy men and women.

Background: Neurokinin B (NKB) is a member of the tachykinin family of peptides. Inactivating mutations in the tachykinin 3 or tachykinin 3 receptor gene are associated with pubertal failure and congenital hypogonadotrophic hypogonadism in humans. This suggests that NKB may have a critical role in human reproduction. The effects of NKB administration have not been investigated previously in humans. Aim: The aim of this study was to determine the effects of iv administration of NKB on gonadotrophin secretion in healthy male and female volunteers. Methods: A total of 23 healthy men and 11 healthy women participated in the study. After an initial dose-finding study (study 1), men received a 4-hour infusion of vehicle (gelofusin) followed by a 4-hour infusion of NKB (2.56 or 5.12 nmol/kg/h) (study 2), and an 8-hour infusion of vehicle or NKB during different visits (study 3). Healthy women underwent a dose-finding study consisting of a 3-hour NKB administration during the follicular phase of the menstrual cycle, and the maximum dose of NKB was also tested during the preovulatory and midluteal phases of menstrual cycle (study 4). Results: Mean LH, FSH, and T secretion were not significantly altered during a 90-minute infusion of NKB (0.4–5.12 nmol/kg/h), or a 4-hour infusion of NKB (5.12 nmol/kg/h). No alterations in gonadotrophin secretion or LH pulsatility were observed during an 8-hour infusion of NKB when compared with vehicle. Doses of 0.64–5.12 nmol/kg/h NKB did not significantly alter LH, FSH, or estradiol secretion in healthy women during the follicular phase of the menstrual cycle. Finally, 5.12 nmol/kg/h did not significantly alter reproductive hormone secretion during the preovulatory or midluteal phases of the menstrual cycle. Conclusions: This is the first clinical study of NKB administration. None of the doses of NKB tested were associated with significant alterations in reproductive hormone secretion in healthy male or female volunteers. These novel data add to our understanding of the physiological actions of NKB in human reproduction.

Combination of Peptide YY3–36 with GLP-17–36 amide Causes an Increase in First-Phase Insulin Secretion after IV Glucose

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.

Age-dependent elevations in plasma kisspeptin are observed in boys and girls when compared with adults

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 < 0.001 vs. adults). Overall mean concentrations of plasma kisspeptin were not significantly different between sexes (mean plasma kisspeptin in pmol/L: 39.5 ± 3.2, boys; 44.3 ± 6.3, girls, P = 0.48). In both sexes, concentrations of plasma kisspeptin increased with age to peak concentrations between 9 and 12 years of age, before decreasing beyond 12 years of age to adulthood. Plasma kisspeptin concentrations were highly significantly elevated in both girls and boys aged 9–12 when compared with adults (mean plasma kisspeptin in pmol/L: 59.5 ± 18.3, girls, P < 0.01 vs. adult women; 43.8 ± 6.2, boys, P < 0.001 vs. adult men). 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.

Associations of serum 25‐hydroxyvitamin D with circulating PTH, phosphate and calcium in patients with primary hyperparathyroidism

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.