Juergen Drewe

Glucagon-like peptide-1: a potent regulator of food intake in humans

Background/Aims Studies in animals suggest a physiological role for glucagon-like 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 effect 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 vcontrol) 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 effects 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.

Improvement in glucose metabolism after bariatric surgery: comparison of laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy: a prospective randomized trial.

Background:The exclusion of the proximal small intestine is thought to play a major role in the rapid improvement in the metabolic control of diabetes after gastric bypass. Objective:In this randomized, prospective, parallel group study, we sought to evaluate and compare the effects of laparoscopic Roux-en-Y gastric bypass (LRYGB) with those of laparoscopic sleeve gastrectomy (LSG) on fasting, and meal-stimulated insulin, glucose, and glucagon-like peptide-1 (GLP-1) levels. Methods:Thirteen patients were randomized to LRYGB and 14 patients to LSG. The mostly nondiabetic patients were evaluated before, and 1 week and 3 months after surgery. A standard test meal was given after an overnight fast, and blood samples were collected before and after food intake in both groups for insulin, GLP-1, glucose, PYY, and ghrelin concentrations. This trial was registered in www.clinicaltrials.gov (NCT00356213) before the first patient was randomized. Results:Body weight and body mass index decreased markedly (P < 0.002) and comparably after either procedure. Excess BMI loss was similar at 3 months (43.3 ± 12.1% vs. 39.4 ± 9.4%, P > 0.36). After surgery, patients had markedly increased postprandial plasma insulin and GLP-1 levels, respectively (P < 0.01) after both of these surgical procedures, which favor improved glucose homeostasis. Compared with LSG, LRYGB patients had early and augmented insulin responses as early as 1-week postoperative; potentially mediating improved early glycemic control. After 3 months, no significant difference was observed with respect to insulin and GLP-1 secretion between the 2 procedures. Conclusion:Both procedures markedly improved glucose homeostasis: insulin, GLP-1, and PYY levels increased similarly after either procedure. Our results do not support the idea that the proximal small intestine mediates the improvement in glucose homeostasis.

The role of long chain fatty acids in regulating food intake and cholecystokinin release in humans

BACKGROUND AND AIMS The mechanism of intraduodenal fat induced inhibition of food intake is still unclear. Therefore, we tested the ability of duodenal fatty acids to suppress food intake at a lunchtime meal; in addition, we were interested to test if these effects were mediated by cholecystokinin (CCK) A receptors. SUBJECTS AND METHODS Three sequential double blind, three period crossover studies were performed in 12 healthy males each: (1) subjects received intraduodenal fat with or without 120 mg of tetrahydrolipstatin, an inhibitor of gastrointestinal lipases, or saline; (2) volunteers received intraduodenal long chain fatty acids, medium chain fatty acids, or saline; (3) subjects received long chain fatty acids or saline together with concomitant intravenous infusions of saline or loxiglumide, a specific CCK-A receptor antagonist. The effect of these treatments on food intake and feelings of hunger was quantified. RESULTS Intraduodenal fat perfusion significantly (p<0.05) reduced calorie intake. Inhibition of fat hydrolysis abolished this effect. Only long chain fatty acids significantly (p<0.05) decreased calorie intake, whereas medium chain fatty acids were ineffective. Infusion of loxiglumide abolished the effect of long chain fatty acids. CONCLUSIONS Generation of long chain fatty acids through hydrolysis of fat is a critical step for fat induced inhibition of food intake; the signal is mediated via CCK-A receptors.

Safety of propofol for conscious sedation during endoscopic procedures in high-risk patients–a prospective, controlled study

OBJECTIVE:Propofol, a rapidly-acting hypnotic agent, is increasingly being used for endoscopic sedation. Serious adverse effects, including respiratory and cardiovascular depression, make many endoscopists reluctant to use propofol in critically ill patients. This study characterizes propofols safety profile in consecutive high-risk patients (American Society of Anesthesiologists [ASA] classes III and IV) compared with matched subjects (ASA classes I and II).METHODS:During a 19-month period, 1370 at risk-patients were sedated with propofol, of whom 47% (614 ASA III, 28 ASA IV) were age matched with 642 consecutive patients of the same gender and age assigned to ASA classes I and II and undergoing the same endoscopic procedures (395 gastroscopies, 201 colonoscopies, 14 combined). Registered nurses performed all sedations by propofol dose titration while carefully monitoring arterial oxygen saturation, heart rate, and blood pressure.RESULTS:No major complications occurred among the critically ill patients. There was, however, an increased risk for a short relevant oxygen desaturation (<90%) of 3.6% for ASA III and IV versus 1.7% for ASA I and II (p = 0.036). In four versus one case, short mask ventilation was necessary. Also, a greater proportion of patients showed a ≥5% oxygen saturation decrease. There was no pronounced influence on arterial pressure or heart rate and no perforations in 336 colonoscopies.CONCLUSIONS:With careful monitoring, propofol sedation during GI endoscopies is safe, even for high-risk patients. Considering their higher comorbidity and tendency toward oxygen desaturation, they need particularly careful monitoring, and the required dose is, on mean, 10–20% lower than in ASA classes I and II.

Inhibition of food intake in response to intestinal lipid is mediated by cholecystokinin in humans

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.

P‐Glycoprotein and Surfactants: Effect on Intestinal Talinolol Absorption

Surfactants used in pharmaceutical formulations can modulate drug absorption by multiple mechanisms including inhibition of intestinal P‐glycoprotein (P‐gp). Our objective was to analyze the effect of 2 surfactants with different affinity for P‐gp in vitro on the intestinal absorption and bioavailability of the P‐gp substrate talinolol in humans.

Glucagon-Like Peptide-1 Is Involved in Sodium and Water Homeostasis in Humans

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.

Effect of intravenous human gastrin-releasing peptide on food intake in humans

BACKGROUND/AIMS Bombesin and gastrin-releasing peptide (GRP) are closely related peptides. Both have been proposed to serve as a satiety signal in animals. METHODS To explore further the role of GRP in humans, its effects on satiety and eating behavior were investigated by infusion of GRP into healthy men at three dosages (10, 40, and 160 pmol/kg per hour) and compared with saline infusions. RESULTS GRP produced a significant reduction in calorie intake (P < 0.05) but only a 19% (nonsignificant) reduction in food intake. Fluid ingestion was not affected by GRP. No overt side effects were produced by GRP, but subjects experienced d less hunger and early fullness in the premeal period during GRP infusion but not when receiving saline (P < 0.05-0.01). CONCLUSIONS This study shows that intravenous infusions of GRP can decrease spontaneous food intake at concentrations that produce physiological effects, such as stimulation of acid or pancreatic secretion or gallbladder contraction. The data imply that GRP-like peptides can act as satiety signals in humans, confirming data previously reported in animals.

Patient-controlled versus nurse-administered sedation with propofol during colonoscopy. A prospective randomized trial.

OBJECTIVES:Patient-controlled sedation (PCS) with propofol, is well tolerated and reduces recovery time and staff required during endoscopic interventions. “Who” administers the drug proves economically crucial. With the aim of maintaining safety, medical quality, and patient satisfaction, this study investigates PCS versus nurse-administered propofol sedation (NAPS) in a cohort of consecutive patients.METHODS:One hundred and fourteen patients, aged 22–90 yr, undergoing only colonoscopy participated in this prospective randomized trial. Patients were randomly assigned to either PCS or NAPS. If patients declined randomization for different reasons of reluctance to PCS they were assigned to a standard nurse-sedated control group. All patients received pethidine presedation for analgesia. Visual analogue scales followed patient anxiety level, tolerability, pain, and satisfaction, and endoscopists assessment of the procedure.RESULTS:Given the choice, 35% of the patients who were rather younger and more anxious declined randomization to PCS. The mean total dose of propofol needed in this group was higher, but the patients had a tendency to rate the global tolerance and the pain of the examination as less comfortable compared to the two randomized groups. Self-administration of propofol created a significantly different drug profile and higher medication costs. With regard to the safety parameters there was no difference between PCS and NAPS. In their global assessments, the patients and endoscopists tended to prefer NAPS.CONCLUSIONS:Individual patient characteristics and attitudes toward self-control are crucial for PCS. While being a viable option for patients who are able and willing to handle, this technique is not applicable in a considerable portion of everyday patients.

Oral administration of glucagon-like peptide 1 or peptide YY 3-36 affects food intake in healthy male subjects

BACKGROUND Peripheral infusion of glucagon-like peptide 1 (GLP-1) or peptide YY 3-36 (PYY3-36) reduces food intake in healthy, obese, and diabetic subjects. In vivo, both peptides are cosecreted from intestinal L cells; GLP-1 is subject to rapid breakdown by dipeptidyl peptidase IV, and together with PYY3-36 it is likely to be degraded in the liver before entering the systemic circulation. The largest concentrations are observed in the splanchnic blood rather than in the systemic circulation. OBJECTIVE In contrast with peripheral infusion, oral delivery of sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) mimics endogenous secretion. We aimed to investigate how this affects food intake. DESIGN Twelve healthy male subjects were studied in a randomized, double-blind, placebo-controlled, 4-way crossover trial. Each subject received in random order 2.0 mg GLP-1, 1.0 mg PYY3-36, or 2.0 mg GLP-1 plus 1.0 mg PYY3-36; the peptides were mixed with SNAC. The placebo treatment was the delivery agent alone. Food intake during an ad libitum test meal was measured. RESULTS Both peptides were rapidly absorbed from the gut, leading to plasma concentrations several times higher than those in response to a normal meal. GLP-1 alone, but not PYY3-36, reduced total energy intake significantly, with marked effects on glucose homeostasis. Coadministration of both peptides reduced total energy intake by 21.5% and fullness at meal onset (P < 0.05) but not total 24-h energy intake. CONCLUSION The results show a marked effect of orally administered GLP-1 and PYY3-36 on appetite by showing enhanced fullness at meal onset and reduced energy intake. This trial was registered at clinicaltrials.gov as NCT00822705.