Per M. Hellström

Prandial subcutaneous injections of glucagon-like peptide-1 cause weight loss in obese human subjects

Recombinant glucagon-like peptide-1 (7-36)amide (rGLP-1) was recently shown to cause significant weight loss in type 2 diabetics when administered for 6 weeks as a continuous subcutaneous infusion. The mechanisms responsible for the weight loss are not clarified. In the present study, rGLP-1 was given for 5 d by prandial subcutaneous injections (PSI) (76 nmol 30 min before meals, four times daily; a total of 302.4 nmol/24 h) or by continuous subcutaneous infusion (CSI) (12.7 nmol/h; a total of 304.8 nmol/24 h). This was performed in nineteen healthy obese subjects (mean age 44.2 (sem 2.5) years; BMI 39.0 (sem 1.2) kg/m(2)) in a prospective randomised, double-blind, placebo-controlled, cross-over study. Compared with the placebo, rGLP-1 administered as PSI and by CSI generated a 15 % reduction in mean food intake per meal (P=0.02) after 5 d treatment. A weight loss of 0.55 (sem 0.2) kg (P<0.05) was registered after 5 d with PSI of rGLP-1. Gastric emptying rate was reduced during both PSI (P<0.001) and CSI (P<0.05) treatment, but more rapidly and to a greater extent with PSI of rGLP-1. To conclude, a 5 d treatment of rGLP-1 at high doses by PSI, but not CSI, promptly slowed gastric emptying as a probable mechanism of action of increased satiety, decreased hunger and, hence, reduced food intake with an ensuing weight loss.

Ghrelin stimulates motility in the small intestine of rats through intrinsic cholinergic neurons

BACKGROUND AND PURPOSE Ghrelin is a peptide discovered in endocrine cells of the stomach. Since ghrelin mRNA expression and plasma levels are elevated in the fasting state, we investigated the effects of ghrelin on the interdigestive migrating myoelectric complex (MMC) in the small intestine in vivo and compared with motor effects of ghrelin in vitro. METHODS Sprague-Dawley rats were supplied with a venous catheter and bipolar electrodes in the duodenum and jejunum for electromyography of small intestine in awake rats. In organ baths, isometric contractions of segments of rat jejunum were studied. RESULTS Ghrelin dose-dependently shortened the MMC cycle length at all three recording points. At the duodenal site, the interval shortened from 17.2+/-2.0 to 9.9+/-0.8 min during infusion of ghrelin (1000 pmol kg(-1) min(-1)) and at the jejunal site from 17.5+/-2.2 to 10.5+/-0.8 min. Ghrelin contracted the muscle strips with a pD2 of 7.97+/-0.47. Atropine (10(-6) M) in vitro and (1 mg kg(-1)) in vivo blocked the effect of ghrelin. CONCLUSION Ghrelin stimulates interdigestive motility through cholinergic neurons. Ghrelin also stimulates motility, in vitro, suggesting that ghrelin receptors are present in the intestinal neuromuscular tissue and mediate its effects via cholinergic mechanisms.

Intestinal microflora stimulates myoelectric activity of rat small intestine by promoting cyclic initiation and aboral propagation of migrating myoelectric complex

Microbial modulation of myoelectric activity in small intestine was studied. Germ-free male Sprague-Dawley rats were equipped with bipolar electrodes from the duodenojejunal junction to the midpoint of small intestine. Prior to and one week after introduction of conventional intestinal microflora, 32±5% and 61±5% (mean±se), respectively, of activity fronts of the migrating myoelectric complex reached the midpoint (P<0.05), and the interval between activity fronts in proximal jejunum was reduced from 31.2±2.0 min to 17.5±0.8 min, respectively (P<0.01). The pattern of propagation was more regular after conventionalization. Slow-wave frequency in proximal jejunum was 38.5±1.2/min in germ-free rats and 43.0±0.8/min in conventional rats (P<0.01), but introduction of microflora failed to increase the frequency in germ-free rats. The frequency of spike potentials succeeding jejunal infusion of 5 ml of 12.5% glucose remained unchanged after conventionalization. Statistical analyses showed that the interval between activity fronts varied mainly within rats, whereas the propagation velocity showed statistically significant variability between rats (P<0.01), regardless of intestinal microflora. Luminal control by the resident microflora is important for physiological cycling and aboral propagation of the migrating myoelectric complex, but seems to be of no major consequence for postprandial myoelectric response.

Peripheral and central signals in the control of eating in normal, obese and binge-eating human subjects

The worldwide increase in the incidence of obesity is a consequence of a positive energy balance, with energy intake exceeding expenditure. The signalling systems that underlie appetite control are complex, and the present review highlights our current understanding of key components of these systems. The pattern of eating in obesity ranges from over-eating associated with binge-eating disorder to the absence of binge-eating. The present review also examines evidence of defects in signalling that differentiate these sub-types. The signalling network underlying hunger, satiety and metabolic status includes the hormonal signals leptin and insulin from energy stores, and cholecystokinin, glucagon-like peptide-1, ghrelin and peptide YY3-36 from the gastrointestinal tract, as well as neuronal influences via the vagus nerve from the digestive tract. This information is routed to specific nuclei of the hypothalamus and brain stem, such as the arcuate nucleus and the solitary tract nucleus respectively, which in turn activate distinct neuronal networks. Of the numerous neuropeptides in the brain, neuropeptide Y, agouti gene-related peptide and orexin stimulate appetite, while melanocortins and alpha-melanocortin-stimulating hormone are involved in satiety. Of the many gastrointestinal peptides, ghrelin is the only appetite-stimulating hormone, whereas cholecystokinin, glucagon-like peptide-1 and peptide YY3-36 promote satiety. Adipose tissue provides signals about energy storage levels to the brain through leptin, adiponectin and resistin. Binge-eating has been related to a dysfunction in the ghrelin signalling system. Moreover, changes in gastric capacity are observed, and as gastric capacity is increased, so satiety signals arising from gastric and post-gastric cues are reduced. Understanding the host of neuropeptides and peptide hormones through which hunger and satiety operate should lead to novel therapeutic approaches for obesity; potential therapeutic strategies are highlighted.

Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis.

Background  TZP‐101 is a synthetic, selective ghrelin agonist in development for gastroparesis.

Peripheral administration of GLP-2 to humans has no effect on gastric emptying or satiety

Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are secreted in parallel to the circulation after a meal. Intravenous (IV) GLP-1 has an inhibitory effect on gastric emptying, hunger and food intake in man. In rodents, central administration of GLP-2 increases satiety similar to GLP-1. The aim of the present study was to assess the effect of IV administered GLP-2 on gastric emptying and feelings of hunger in human volunteers. In eight (five men) healthy subjects (age 31.1+/-2.9 years and BMI 24.1+/-1.0 kg m(-2)), scintigraphic solid gastric emptying, hunger ratings (VAS) and plasma concentrations of GLP-2 were studied during infusion of saline or GLP-2 (0.75 and 2.25 pmol kg(-1) min(-1)) for a total of 180 min. Concentrations of GLP-2 were elevated to a maximum of 50 and 110 pmol l(-1) for 0.75 and 2.25 pmol kg(-1) min(-1) infusion of GLP-2, respectively. There was no effect of GLP-2 on either the lag phase (29.5+/-4.4, 26.0+/-5.2 and 21.2+/-3.6 min for saline, GLP-2 0.75 or 2.25 pmol kg(-1) min(-1), respectively) or the half emptying time (84.5+/-6.1, 89.5+/-17.8 and 85.0+/-7.0 min for saline, GLP-2 0.75 or 2.25 pmol kg(-1) min(-1), respectively). The change in hunger rating after the meal to 180 min was also unaffected by infusion of GLP-2. GLP-2 does not seem to mediate the ileal brake mechanism.

Technology Insight: calprotectin, lactoferrin and nitric oxide as novel markers of inflammatory bowel disease

Distinguishing patients with inflammatory bowel disease from those with irritable bowel syndrome can be difficult. A simple and reliable test that detects intestinal inflammation would therefore be very useful in the clinic. If such a test parameter correlated with the intensity of the inflammatory reaction it could also be used to monitor disease activity. Calprotectin, lactoferrin and nitric oxide are produced and released locally in much greater quantities in the inflamed gut than in the noninflamed gut. These compounds can be readily measured in fecal samples (calprotectin and lactoferrin) or directly in the intestinal lumen (nitric oxide gas). Here, we discuss what is known about these markers, how they could be used in clinical practice and how they can complement existing techniques used for the diagnosis and monitoring of inflammatory bowel disease.

A novel tachykinin NK2 receptor antagonist prevents motility-stimulating effects of neurokinin A in small intestine

MEN 11420 (nepadutant) is a potent, selective and competitive antagonist of tachykinin NK2 receptors. The objective of the present study was to assess the capability of the drug to antagonize the stimulatory effects of neurokinin A (NKA) on gastrointestinal motility, as well as to change the fasting migrating motor complex (MMC). Thirty‐four male volunteers were randomized to treatment with either placebo or MEN 11420 in a double‐blinded manner. Effects of MEN 11420 (8 mg intravenously) were evaluated as changes in phases I, II and III of MMC, as well as contraction frequency, amplitude and motility index during baseline conditions and during stimulation of motility using NKA (25 pmol kg−1 min−1 intravenously). NKA preceded by placebo increased the fraction of time occupied by phase II, increased contraction frequency, amplitude and motility index. MEN 11420 effectively antagonized the motility‐stimulating effects of NKA. MEN 11420 reduced the phase II‐stimulating effect of NKA. In addition, the stimulatory effect of NKA on contraction frequency and amplitude, as well as motility index were inhibited by MEN 11420. MEN 11420 did not affect the characteristics of MMC during saline infusion. Plasma levels of MEN 11420 peaked during the first hour after infusion and decreased to less than half during the first 2 h. In conclusion, intravenous MEN 11420 effectively inhibited NKA‐stimulated, but not basal gastrointestinal motility, and was well tolerated by all subjects.

Correlation between Peptide YY-Induced Myoelectric Activity and Transit of Small-Intestinal Contents in Rats

The effect of peptide YY (PYY) on the myoelectric activity of the small intestine was studied in relation to the transit of a 51Cr marker solution in fasted conscious rats. The myoelectric activity was recorded by means of bipolar electrodes implanted at 5, 20, and 35 cm from the pylorus. The marker was administered in the duodenum immediately after an activity front of a migrating myoelectric complex (MMC) had passed the first recording site. Under control conditions, the propagation of one activity front over the three recording levels was accompanied by the propulsion of 90.2 +/- 11.4% of the total radioactivity as one portion distal to the third electrode site. The median peak of the radioactivity was recovered at a distance approximately twice that propagated by an activity front. Intravenous infusion of PYY (50 pmol X kg-1 X min-1) had no effect on the occurrence of the MMC in the duodenum but interrupted its distal propagation and almost totally abolished the spiking activity in the jejunum. In comparison with controls, the transport of the marker was significantly retarded, and the median peak of the radioactivity was recovered proximal to the third electrode site. The results indicate that the small-intestinal contents are propelled as one portion in front of a propagating activity front. The inhibition of the activity front by PYY may account for the delay in the transit of the small-intestinal contents.(ABSTRACT TRUNCATED AT 250 WORDS)

Interactions between gastric emptying and satiety, with special reference to glucagon-like peptide-1

The slowing of gastric emptying is an important mechanism for the satiating effect of gut peptide signaling. After food intake, cholecystokinin (CCK), as well as glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2), are released from the gastrointestinal tract to mediate satiety. In humans, CCK and the GLP-1 have been found to cause satiety in both normal and obese subjects. This satiating effect may be caused by the peptides circulating as hormones with direct effects in the central nervous system, or indirect effects through signals mediated either via the vagus nerve or by activation of vagal afferent fibers due to slow gastric emptying. These peptides also cause gastric relaxation, considered an additional component in the satiating effect of the peptides. To conclude, after food intake, gut peptides may act in concert as neurohormonal satiety signals acting directly in the brain or indirectly via the vagus nerve, as well as through gastric sensory mechanisms to limit food intake.