N-acyl taurines are endogenous lipid messengers that improve glucose homeostasis.

Fatty acid amide hydrolase (FAAH) degrades 2 major classes of bioactive fatty acid amides, the N-acylethanolamines (NAEs) and N-acyl taurines (NATs), in central and peripheral tissues. A functional polymorphism in the human FAAH gene is linked to obesity and mice lacking FAAH show altered metabolic states, but whether these phenotypes are caused by elevations in NAEs or NATs is unknown. To overcome the problem of concurrent elevation of NAEs and NATs caused by genetic or pharmacological disruption of FAAH in vivo, we developed an engineered mouse model harboring a single-amino acid substitution in FAAH (S268D) that selectively disrupts NAT, but not NAE, hydrolytic activity. The FAAH-S268D mice accordingly show substantial elevations in NATs without alterations in NAE content, a unique metabolic profile that correlates with heightened insulin sensitivity and GLP-1 secretion. We also show that N-oleoyl taurine (C18:1 NAT), the most abundant NAT in human plasma, decreases food intake, improves glucose tolerance, and stimulates GPR119-dependent GLP-1 and glucagon secretion in mice. Together, these data suggest that NATs act as a class of lipid messengers that improve postprandial glucose regulation and may have potential as investigational metabolites to modify metabolic disease.

Effects of liraglutide on gallbladder emptying: A randomized, placebo-controlled trial in adults with overweight or obesity.

AIMS: Treatment with liraglutide 3.0 mg has been associated with gallbladder-related adverse events. To conduct a single-centre, double-blind, 12-week trial comparing the effect of 0.6 mg liraglutide and steady-state liraglutide 3.0 mg with placebo on gallbladder emptying in adults with body mass index (BMI) ≥27 kg/m2 and without diabetes. METHODS: Participants were randomized 1:1 to once-daily subcutaneous liraglutide (n = 26) or placebo (n = 26), starting at 0.6 mg with 0.6-mg weekly increments to 3.0 mg, with nutritional and physical activity counselling. A 600-kcal (23.7 g fat) liquid meal test was performed at baseline, after the first dose and after 12 weeks. The primary endpoint was the 12-week maximum postprandial gallbladder ejection fraction (GBEFmax ), measured over 240 minutes after starting the meal. RESULTS: Baseline characteristics were similar between groups (mean ± SD overall age 47.6 ± 10.0 years, BMI 32.6 ±3.4 kg/m2 , 50% women). Mean 12-week GBEFmax (treatment difference -3.7%, 95% confidence interval [CI] -13.1, 5.7) and area under the GBEF curve in the first 60 minutes (-390% × min, 95% CI -919, 140) did not differ for liraglutide 3.0 mg (n = 23) vs placebo (n = 24). The median (range) time to GBEFmax was 151 (11-240) minutes with liraglutide 3.0 mg and 77 (22-212) minutes with placebo. Similar findings were noted after the first 0.6-mg liraglutide dose. Gastrointestinal disorders, notably nausea and constipation, were the most frequently reported adverse events. CONCLUSIONS: Treatment with liraglutide did not affect the GBEFmax but appeared to prolong the time to GBEFmax .

Gastric Aspiration Improves Postprandial Glucose Tolerance Without Causing a Compensatory Increase in Appetite and Food Intake.

INTRODUCTION: AspireAssist® allows aspiration of ~30% of an ingested meal through a percutaneous gastrostomy tube, reducing caloric uptake. We evaluated the acute effects of gastric aspiration on postprandial glucose tolerance, responses of gluco-regulatory and appetite-regulating hormones, appetite sensations, and food intake. METHODS: Seven AspireAssist®-treated individuals underwent two separate experimental days each involving a mixed meal test (MMT) with double-blinded aspiration and sham aspiration, respectively. Seven age and body mass index (BMI)-matched controls underwent one MMT. MMTs were followed by an ad libitum meal. RESULTS: Postprandial glucose tolerance was improved during aspiration vs. sham visits (median [interquartile range] baseline-subtracted area under the curve (bsAUC) 170 [88.4;356] vs. 388 [239;456] mmol/L × min, p = 0.025). Reduced responses (bsAUCs) of C-peptide (113 [28.4;224] vs. 302 [215;433] nmol/L × min, p = 0.014), cholecystokinin (223 [59.4;402] vs. 467 [416;546] pmol/L × min, p = 0.005), glucose-dependent insulinotropic polypeptide (4.63 [1.49;9.04] vs. 15.4 [9.59;18.9] nmol/L × min, p = 0.025), and glucagon-like peptide 1 (532.8 [274.5;1,278] vs. 1,296 [746.2;1,618] pmol/L × min, p = 0.032) were observed during aspiration vs. sham visits. Responses of glucagon, gastrin, ghrelin and peptide YY, appetite sensations, and ad libitum food intake were unaffected by aspiration. Responses of plasma glucose, gut hormones, appetite sensations, and food intake were similar during sham and control visits. CONCLUSION: Gastric aspiration improved postprandial glucose tolerance without causing compensatory increases in appetite or food intake, pointing to acute beneficial metabolic effects of aspiration therapy together with previously reported body weight-lowering effects.

Glucagon-Like Peptide 2 Inhibits Postprandial Gallbladder Emptying in Man: A Randomized, Double-Blinded, Crossover Study.

INTRODUCTION: A recent study in mice points to the gut-derived hormone glucagon-like peptide 2 (GLP-2) as an important regulator of gallbladder motility inducing gallbladder relaxation and refilling. In this study, we evaluated the effect of exogenous GLP-2 on postprandial gallbladder motility in healthy men. METHODS: In a randomized, double-blinded, placebo-controlled, crossover study, we evaluated the effect of 4-hour intravenous infusions of high-dose GLP-2 (10 pmol × kg × min), low-dose GLP-2 (1 pmol × kg × min), and placebo (saline) on postprandial gallbladder motility. A 300-kcal liquid-mixed meal (added 1.5 g of acetaminophen for indirect measurement of gastric emptying) was served 30 minutes after start of intravenous infusions. Gallbladder volume was assessed by ultrasonography. RESULTS: Fifteen healthy men, age 24.3 (22.4-26.1) years (mean [95% confidence interval]) and body mass index 22.5 (21.7-23.4) kg × m, were included. Basal plasma GLP-2 concentration was 14 (11-17) pmol/L. During low-dose and high-dose GLP-2 infusions, steady-state postprandial plasma GLP-2 concentrations amounted to 201 (188-214) and 2,658 (2,443-2,873) pmol/L, respectively, compared with maximum postprandial plasma GLP-2 concentration of 34 (25-44) pmol/L during placebo. Gallbladder emptying (assessed as baseline-subtracted area under the curve for gallbladder volume) was reduced by low-dose GLP-2 (-0.8 [0.7-1.9] L × min, P < 0.0001) and nearly abolished by high-dose GLP-2 (1.3 [-1.7 to 0.01] L × min, P = 0.029) compared to placebo (-2.0 [-2.8 to -1.1] L × min). Compared to placebo, gastric emptying was reduced by high-dose GLP-2 (P = 0.0060 and 0.019), whereas low-dose GLP-2 did not affect gastric emptying (P = 0.13 and 0.85). DISCUSSION: Exogenous GLP-2 exerts a dose-dependent inhibitory effect on postprandial gallbladder emptying in healthy men.