Background/Aims-Studies in animals suggest a physiological role for glucagonlike peptide-1-(7-36)-amide (GLP-1) in regulating satiety. The role of GLP-1 in regulating food intake in man has, however, not been investigated. Subjects-Sixteen healthy male subjects were examined in a double blind placebo controlled fashion. Methods-The eVect of graded intravenous doses (0, 0.375, 0.75, and 1.5 pmol/ kg/min) of synthetic human GLP-1 on food intake and feelings of hunger and satiety was tested in healthy volunteers. Results-Graded GLP-1 infusions resulted in a dose dependent reduction in food intake (maximal inhibition 35%, p<0.001 v control) and a similar reduction in calorie intake (32%; p<0.001). Fluid ingestion was also reduced by GLP-1 (18% reduction, p<0.01). No overt side eVects were produced by GLP-1, but subjects experienced less hunger and early fullness in the period before a meal during GLP-1 infusion at the highest dose (p<0.05). Conclusions-Intravenous infusions of GLP-1 decrease spontaneous food intake even at physiological plasma concentrations, implying an important role for GLP-1 in the regulation of the early satiety response in humans. (Gut 1999;44:81-86)

Glucagon-like peptide-1-(7-36)-amide (GLP-1) is involved in satiety control and glucose homeostasis. Animal studies suggest a physiological role for GLP-1 in water and salt homeostasis. This study's aim was to define the effects of GLP-1 on water and sodium excretion in both healthy and obese men. Fifteen healthy subjects and 16 obese men (mean body mass index, 36 kg/m2) were examined in a double-blind, placebo-controlled, crossover study to demonstrate the effects of a 3-h infusion of GLP-1 on urinary sodium excretion, urinary output, and the glomerular filtration rate after an i.v. 9.9-g salt load. Infusion of GLP-1 evoked a dose-dependent increase in urinary sodium excretion in healthy subjects (from 74 +/- 8 to 143 +/- 18 mmol/180 min, P = 0.0013). In obese men, there was a significant increase in urinary sodium excretion (from 59 to 96 mmol/180 min, P = 0.015), a decrease in urinary H+ secretion (from 1.1 to 0.3 pmol/180 min, P = 0.013), and a 6% decrease in the glomerular filtration rate (from 151 +/- 8 to 142 +/- 8 ml/min, P = 0.022). Intravenous infusions of GLP-1 enhance sodium excretion, reduce H+ secretion, and reduce glomerular hyperfiltration in obese men. These findings suggest an action at the proximal renal tubule and a potential renoprotective effect.

Glucagon-like peptide-1-(7—36) amide (GLP-1) is an incretin hormone of the enteroinsular axis. Recent experimental evidence in animals and healthy subjects suggests that GLP-1 has a role in controlling appetite and energy intake in humans. We have therefore examined in a double-blind, placebo-controlled, crossover study in 12 patients with diabetes type 2 the effect of intravenously infused GLP-1 on appetite sensations and energy intake. On 2 days, either saline or GLP-1 (1.5 pmol ⋅ kg−1 ⋅ min−1) was given throughout the experiment. Visual analog scales were used to assess appetite sensations; furthermore, food and fluid intake of a test meal were recorded, and blood was sampled for analysis of plasma glucose and hormone levels. GLP-1 infusion enhanced satiety and fullness compared with placebo ( P = 0.028 for fullness and P = 0.026 for hunger feelings). Energy intake was reduced by 27% by GLP-1 ( P = 0.034) compared with saline. The results demonstrate a marked effect of GLP-1 on appetite by showing enhanced satiety and reduced energy intake in patients with diabetes type 2.

Nutritional risk screening may be able to predict mortality and morbidity after surgery for colorectal cancer. However, the diverse results reflect either the imprecision of the tests or the small sample size.

Seven studies have now been published pertaining to the acute effect of iv administration of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake. In four of these studies energy intake was significantly reduced following the glucagon-like peptide-1 infusion compared with saline. In the remaining studies, no significant effect of glucagon-like peptide-1 could be shown. Lack of statistical power or low glucagon-like peptide-1 infusion rate may explain these conflicting results. Our aim was to examine the effect of glucagon-like peptide-1 on subsequent energy intake using a data set composed of subject data from previous studies and from two as yet unpublished studies. Secondly, we investigated whether the effect on energy intake is dose dependent and differs between lean and overweight subjects. Raw subject data on body mass index and ad libitum energy intake were collected into a common data set (n = 115), together with study characteristics such as infusion rate, duration of infusion, etc. From four studies with comparable protocol the following subject data were included if available: plasma concentrations of glucagon-like peptide-1, subjective appetite measures, well-being, and gastric emptying rate of a meal served at the start of the glucagon-like peptide-1 infusion. Energy intake was reduced by 727 kJ (95% confidence interval, 548-908 kJ) or 11.7% during glucagon-like peptide-1 infusion. Although the absolute reduction in energy intake was higher in lean (863 kJ) (634-1091 kJ) compared with overweight subjects (487 kJ) (209-764 kJ) (P = 0.05), the relative reduction did not differ between the two groups (13.2% and 9.3%, respectively). Stepwise regression analysis showed that the glucagon-like peptide-1 infusion rate was the only independent predictor of the reduction in energy intake during glucagon-like peptide-1 (7-36) amide infusion (r = 0.4, P < 0.001). Differences in mean plasma glucagon-like peptide-1 concentration on the glucagon-like peptide-1 and placebo day (n = 43) were related to differences in feelings of prospective consumption (r = 0.40, P < 0.01), fullness (r = 0.38, P < 0.05), and hunger (r = 0.26, P = 0.09), but not to differences in ad libitum energy intake. Gastric emptying rate was significantly lower during glucagon-like peptide-1 infusion compared with saline. Finally, well-being was not influenced by the glucagon-like peptide-1 infusion. Glucagon-like peptide-1 infusion reduces energy intake dose dependently in both lean and overweight subjects. A reduced gastric emptying rate may contribute to the increased satiety induced by glucagon-like peptide-1.

ABSTRACT:Efflux transporters such as P-glycoprotein and multidrug resistance-associated proteins (MRPs) in the intestinal wall restrict intestinal drug transport. To overcome this limitation for enteral drug absorption, galenical targeting approaches have been proposed for site-specific luminal drug release in segments of the gut, where expression of the respective absorption-limiting transporter is minimal. Therefore, expression of multidrug resistance gene 1 (MDR1) and MRP1-5 was systematically investigated in 10 healthy subjects. Biopsies were taken from different segments of the gastrointestinal tract (from duodenum and terminal ileum, as well as ascending, transverse, descending, and sigmoid colon). Gene expression was investigated by quantitative real-time PCR (TaqMan). MRP3 appeared to be the most abundantly expressed transporter in investigated parts of the human intestine, except for the terminal ileum, where MDR1 showed the highest expression. The ranking of transporter gene expression in the duodenum was MRP3 Ͼ Ͼ MDR1 > MRP2 > MRP5 > MRP4 > MRP1. In the terminal ileum, the ranking order was as follows: MDR1 > MRP3 Ͼ Ͼ MRP1 Ϸ MRP5 Ϸ MRP4 > MRP2. In all segments of the colon (ascending, transverse, descending, and sigmoid colon), the transporter gene expression showed the following order: MRP3 Ͼ Ͼ MDR1 > MRP4 Ϸ MRP5 > MRP1 Ͼ Ͼ MRP2. We have shown, for the first time, systematic site-specific expression of MDR1 and MRP mRNA along the gastrointestinal tract in humans. All transporters showed alterations in their expression levels from the duodenum to sigmoid colon. The most pronounced changes were observed for MRP2, with high levels in the small intestine and hardly any expression in colonic segments. This knowledge may be useful to develop new targeting strategies for enteral drug delivery.Efflux transporters in the intestinal wall form a barrier to cellular accumulation of toxins as well as to drug absorption (Schinkel, 1997). Important efflux proteins in the gut are P-glycoprotein [gene product of the multidrug resistance 1 (MDR1) gene] and multidrug resistanceassociated protein (MRP) transporters. They belong to the superfamily of ATP-binding cassette (ABC) transporters. ABC transporters mediate the translocation of a wide variety of substances across cellular membranes using ATP hydrolysis (Horio et al., 1988;Senior et al., 1995). The expression of ABC transporter genes is widespread throughout many tissues, most notably in excretory sites such as the liver, kidney, blood-brain barrier, and intestine. Therefore, they play a critical role in absorption and tissue distribution of orally administered drugs (Schuetz et al., 1998;Ambudkar et al., 1999). Due to their broad substrate specificity, they may influence the pharmacokinetics of many chemically unrelated substances (e.g., HIV drugs, anticancer drugs, endogenous compounds) (Lee et al., 1997;Schinkel, 1998;Schuetz et al., 1999;Borst et al., 2000). MDR1 preferentially extrudes large hydrophobic, positively charged molecules, whereas the members of th...

Intraduodenal fat inhibits gastric emptying and exerts early satiation in animals and humans, but it is not clear whether the effects are mediated by cholecystokinin (CCK) in humans. Here, we tested whether CCK-A receptors mediate the inhibition of fat on food intake. Two sequential, double-blind, crossover studies were performed in 24 male subjects. First, subjects received either intraduodenal fat or saline together with a preload of either water or banana shake. Second, 12 subjects received either intraduodenal fat or saline perfusion plus a concomitant infusion of saline or loxiglumide, a specific CCK-A receptor antagonist, together with a preload of banana shake. In both studies, subjects were free to eat and drink as much as they wished. Fat induced a reduction in calorie intake (P < 0.05) compared with controls. Furthermore, a decrease in hunger feelings was observed. Infusion of loxiglumide abolished the effects of fat. Duodenal fat interacts with an appetizer to modulate energy intake in humans. This effect is mediated by CCK-A receptors.

In previous studies with glucagon-like peptide-1 (GLP-1) we have observed that this peptide modulates fluid intake and increases renal sodium excretion in healthy volunteers and in patients with diabetes mellitus type 2. The effect of GLP-1 on thirst, water intake and on osmoregulation has, however, not been examined in detail in humans. Methods: Seventeen healthy male subjects were enrolled in two double-blind, placebo-controlled studies. In study part A, 8 volunteers participated in a protocol with an intravenous salt load of 26.7 ± 0.9 g comparing the effect of an infusion of GLP-1 (1.5 pmol/kg × min) to isotonic saline (placebo). Sodium excretion and water intake were measured. In part B, 9 volunteers were challenged with an oral salt load of 27.7 ± 0.5 g; sodium excretion and water intake were determined comparing an infusion of GLP-1 (1.5 pmol/kg × min) to isotonic saline (placebo). In part C, intestinal biopsies along the gastrointestinal tract were obtained from 14 healthy subjects. Expression of human GLP-1 receptor mRNA was measured by real-time polymerase chain reaction. Results: In study part A, an increase in renal sodium excretion was demonstrated: FeNa rose from 1.6 ± 0.3 (placebo) to 2.7 ± 0.2% (GLP-1; p = 0.0005). There was no difference in water consumption between the two treatments: 1,291 ± 69 (saline) vs. 1,228 ± 74 ml (GLP-1; p = 0.49). In part B, an oral salt challenge of 27.7 ± 0.5 g led to an increased renal excretion of sodium during GLP-1: FeNa increased from 1.6 ± 0.2% (placebo) to 2.0 ± 0.2% (GLP-1; p = 0.012). In contrast to part A, oral water intake was reduced by 36% under GLP-1 treatment: 1,848 ± 331 ml (placebo) vs. 1,181 ± 177 ml (GLP-1; p = 0.0414). Three subjects in part B did not finish treatment with GLP-1 because of diarrhea. Human GLP-1 receptor mRNA expression was highest in the proximal human small intestine compared to terminal ileum and colon (p < 0.02). Conclusions: GLP-1 acts on renal tissue reducing sodium absorption, probably via similar sodium transporters, which also may be localized in the gastrointestinal tract. This hypothesis needs to be confirmed by further studies.