Can encapsulated glutamine increase GLP-1 secretion, improve glucose tolerance, and reduce meal size in healthy volunteers? A randomised, placebo-controlled, cross-over trial.

BACKGROUND: Obesity is a global concern and can be effectively treated with bariatric surgery, which is expensive and invasive. Weight loss after surgery has been attributed to increased nutrient delivery to the lower small intestine with release of satiety-promoting gut hormones such as glucagon-like peptide 1 (GLP-1). We aimed to assess whether glutamine, a potent secretagogue of GLP-1 in vivo, increases GLP-1 release, improves glucose tolerance, or reduces meal size in volunteers. METHODS: A single-centre, randomised, double blind, placebo-controlled, cross-over study was performed in Cambridge, UK, studying the effects of a single dose of encapsulated ileal-release glutamine (6 g) and placebo (microcrystalline cellulose) in healthy adult volunteers. Volunteers were recruited for each endpoint and received each regimen in random order (performed by electronic random number generation). The primary outcome was within-person GLP-1 in venous blood (concentrations and area under the curve). Secondary outcomes were glucose tolerance (measured with an oral glucose tolerance test given after 90 min) and meal size (ad-libitum meal given at 120 min). Inclusion of 8-10 participants for each endpoint would achieve 90% power with α at 0·05. Significance testing was done with the paired t test. Participants gave written informed consent and the study was approved by the local research ethics committee. This trial is registered with the ISRCTN register, number ISRCTN10757078. FINDINGS: 11 men and 13 women were recruited (aged 22-58 years, body-mass index 18·5-31·8 kg/m(2)). Ten patients were assigned to assessment of GLP-1, eight to assessment of glucose tolerance, and ten for meal size. Some volunteers participated in more than one part of the study. Ingestion of 6 g glutamine was associated with increased GLP-1 concentrations after 90 min compared with placebo (mean 3·2 pmol/L [SD 0·86] vs 2·1 [0·65], p=0·004), increased insulin concentrations after 90 min (70·9 [37·9] vs 51·5 [23·1], p=0·048), and increased meal size at 120 min (542 g eaten [188] vs 481 [193], p=0·008). No safety concerns were identified after the ingestion of glutamine. INTERPRETATION: This trial shows that a single oral dose of encapsulated glutamine can promote increased secretion of GLP-1 and is associated with increased insulin release. However, the effect size was small and unlikely to be clinically useful. Glutamine was associated with increased meal size, an undesirable effect, perhaps because the orexigenic effects of insulin release predominated over the anorexigenic effects of GLP-1 release after administration of glutamine. FUNDING: European Union's Seventh Framework Programme, Wellcome Trust Translational Medicine & Therapeutics Programme, National Institute for Health Research.

Accelerated waning of the humoral response to COVID-19 vaccines in obesity.

Obesity is associated with an increased risk of severe Coronavirus Disease 2019 (COVID-19) infection and mortality. COVID-19 vaccines reduce the risk of serious COVID-19 outcomes; however, their effectiveness in people with obesity is incompletely understood. We studied the relationship among body mass index (BMI), hospitalization and mortality due to COVID-19 among 3.6 million people in Scotland using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) surveillance platform. We found that vaccinated individuals with severe obesity (BMI > 40 kg/m2) were 76% more likely to experience hospitalization or death from COVID-19 (adjusted rate ratio of 1.76 (95% confidence interval (CI), 1.60-1.94). We also conducted a prospective longitudinal study of a cohort of 28 individuals with severe obesity compared to 41 control individuals with normal BMI (BMI 18.5-24.9 kg/m2). We found that 55% of individuals with severe obesity had unquantifiable titers of neutralizing antibody against authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus compared to 12% of individuals with normal BMI (P = 0.0003) 6 months after their second vaccine dose. Furthermore, we observed that, for individuals with severe obesity, at any given anti-spike and anti-receptor-binding domain (RBD) antibody level, neutralizing capacity was lower than that of individuals with a normal BMI. Neutralizing capacity was restored by a third dose of vaccine but again declined more rapidly in people with severe obesity. We demonstrate that waning of COVID-19 vaccine-induced humoral immunity is accelerated in individuals with severe obesity. As obesity is associated with increased hospitalization and mortality from breakthrough infections, our findings have implications for vaccine prioritization policies.

Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial.

This study investigated the effect of subcutaneously administered oxyntomodulin on body weight in healthy overweight and obese volunteers. Participants self-administered saline or oxyntomodulin subcutaneously in a randomized, double-blind, parallel-group protocol. Injections were self-administered for 4 weeks, three times daily, 30 min before each meal. The volunteers were asked to maintain their regular diet and level of physical exercise during the study period. Subjects' body weight, energy intake, and levels of adipose hormones were assessed at the start and end of the study. Body weight was reduced by 2.3 +/- 0.4 kg in the treatment group over the study period compared with 0.5 +/- 0.5 kg in the control group (P = 0.0106). On average, the treatment group had an additional 0.45-kg weight loss per week. The treatment group demonstrated a reduction in leptin and an increase in adiponectin. Energy intake by the treatment group was significantly reduced by 170 +/- 37 kcal (25 +/- 5%) at the initial study meal (P = 0.0007) and by 250 +/- 63 kcal (35 +/- 9%) at the final study meal (P = 0.0023), with no change in subjective food palatability. Oxyntomodulin treatment resulted in weight loss and a change in the levels of adipose hormones consistent with a loss of adipose tissue. The anorectic effect was maintained over the 4-week period. Oxyntomodulin represents a potential therapy for obesity.

The effect of bariatric surgery on gastrointestinal and pancreatic peptide hormones.

Bariatric surgery for obesity has proved to be an extremely effective method of promoting long-term weight reduction with additional beneficial metabolic effects, such as improved glucose tolerance and remission of type 2 diabetes. A range of bariatric procedures are in common use, including gastric banding, sleeve gastrectomy and the Roux-en-Y gastric bypass. Although the mechanisms underlying the efficacy of bariatric surgery are unclear, gastrointestinal and pancreatic peptides are thought to play an important role. The aim of this review is to summarise the effects of different bariatric surgery procedures upon gastrointestinal and pancreatic peptides, including ghrelin, gastrin, cholecystokinin (CCK), glucose-dependent insulinotropic hormone (GIP), glucagon-like peptide 1 (GLP-1), peptide YY (PYY), oxyntomodulin, insulin, glucagon and somatostatin.

Peptide YY3-36 and glucagon-like peptide-17-36 inhibit food intake additively.

Peptide YY (PYY) and glucagon like peptide (GLP)-1 are cosecreted from intestinal L cells, and plasma levels of both hormones rise after a meal. Peripheral administration of PYY(3-36) and GLP-1(7-36) inhibit food intake when administered alone. However, their combined effects on appetite are unknown. We studied the effects of peripheral coadministration of PYY(3-36) with GLP-1(7-36) in rodents and man. Whereas high-dose PYY(3-36) (100 nmol/kg) and high-dose GLP-1(7-36) (100 nmol/kg) inhibited feeding individually, their combination led to significantly greater feeding inhibition. Additive inhibition of feeding was also observed in the genetic obese models, ob/ob and db/db mice. At low doses of PYY(3-36) (1 nmol/kg) and GLP-1(7-36) (10 nmol/kg), which alone had no effect on food intake, coadministration led to significant reduction in food intake. To investigate potential mechanisms, c-fos immunoreactivity was quantified in the hypothalamus and brain stem. In the hypothalamic arcuate nucleus, no changes were observed after low-dose PYY(3-36) or GLP-1(7-36) individually, but there were significantly more fos-positive neurons after coadministration. In contrast, there was no evidence of additive fos-stimulation in the brain stem. Finally, we coadministered PYY(3-36) and GLP-1(7-36) in man. Ten lean fasted volunteers received 120-min infusions of saline, GLP-1(7-36) (0.4 pmol/kg.min), PYY(3-36) (0.4 pmol/kg.min), and PYY(3-36) (0.4 pmol/kg.min) + GLP-1(7-36) (0.4 pmol/kg.min) on four separate days. Energy intake from a buffet meal after combined PYY(3-36) + GLP-1(7-36) treatment was reduced by 27% and was significantly lower than that after either treatment alone. Thus, PYY(3-36) and GLP-1(7-36), cosecreted after a meal, may inhibit food intake additively.

Low-dose pancreatic polypeptide inhibits food intake in man.

Pancreatic polypeptide (PP) is a gut hormone released from the pancreas in response to food ingestion and remains elevated for up to 6 h postprandially. Plasma levels are elevated in patients with pancreatic tumours. An intravenous infusion of PP has been reported to reduce food intake in man, suggesting that PP is a satiety hormone. We investigated whether a lower infusion rate of PP would induce significant alterations in energy intake. The study was randomised and double-blinded. Fourteen lean fasted volunteers (five men and nine women) received 90 min infusions of PP (5 pmol/kg per min) and saline on two separate days. The dose chosen was half that used in a previous human study which reported a decrease in appetite but at supra-physiological levels of PP. One hour after the end of the infusion, a buffet lunch was served and energy intake measured. PP infusion was associated with a significant 11 % reduction in energy intake compared with saline (2440 (se 200) v. 2730 (se 180) kJ; P<0 x 05). Preprandial hunger as assessed by a visual analogue score was decreased in the PP-treated group compared to saline. These effects were achieved with plasma levels of PP within the pathophysiological range of pancreatic tumours.

Neuroendocrine control of food intake.

PURPOSE OF REVIEW: Obesity is a major public health problem and substantially increases the risk of type 2 diabetes, hypertension, stroke, cardiovascular, respiratory problems, gall bladder disease, osteoarthritis and sleep apnoea, as well as certain cancers. The prevalence of obesity is rapidly increasing worldwide. However, for individuals weight is regulated within a narrow range. This regulation depends on energy intake (in the form of food) and energy expenditure. Recently, there has been a remarkable increase in our understanding of the homeostatic mechanisms that control food intake and energy homeostasis. RECENT FINDINGS: There is increased understanding of the central regulation of appetite. In particular, this includes new knowledge about the hypothalamus and brainstem and their relation to food intake regulation. Peripheral hormones (notably adipostat factors and gut hormones) have now been found to be important in food intake regulation. SUMMARY: Complex central circuitry controls food intake. Circulating hormones, in particular the gut hormones have unexpectedly been found to be very important in appetite control. The gut hormones are thus new and exciting targets for future obesity therapies.

Repeated ICV administration of oxyntomodulin causes a greater reduction in body weight gain than in pair-fed rats.

Oxyntomodulin (OXM) is a product of proglucagon processing in the intestine and the central nervous system. We reported that intracerebroventricular (ICV) and intranuclear administration of OXM caused an inhibition of food intake in rats (Dakin CL, Gunn I, Small CJ, Edwards CM, Hay DL, Smith DM, Ghatei MA, and Bloom SR. Endocrinology 142: 4244-4250, 2001). In this study, we investigated the effect of twice-daily ICV administration of OXM, 1 nmol, for 7 days. A pair-fed control was included. These animals were restricted to the food intake of the OXM group but injected twice daily with saline. OXM-treated animals gained significantly less weight than either control group (day 8: OXM, 12.2 +/- 1.9 g vs. pair fed, 21.0 +/- 2.1 g; P < 0.005). OXM treatment caused a reduction in epididymal white adipose tissue (OXM, 1.13 +/- 0.03 g vs. pair fed, 1.29 +/- 0.04 g; P < 0.05) and interscapular brown adipose tissue (OXM, 0.15 +/- 0.01 g vs. pair fed, 0.18 +/- 0.01 g; P < 0.05) and increased core temperature compared with saline control, suggestive of enhanced energy expenditure. The food restriction-induced suppression in plasma TSH, seen in the pair-fed group, was prevented by OXM, potentially via increased release of hypothalamic TRH. In summary, ICV OXM causes reduced body weight gain and body adiposity following chronic administration.