Liraglutide changes postprandial responses of gut hormones involved in the regulation of gallbladder motility

Aim

Liraglutide treatment is associated with gallbladder-related disorders and has been shown to delay postprandial gallbladder refilling. The gut hormones cholecystokinin (CCK), fibroblast growth factor 19 (FGF19) and glucagon-like peptide 2 (GLP-2), are known to regulate gallbladder motility and may be implicated in gallbladder-related disorders associated with liraglutide treatment.

Materials and Methods

In a double-blind, 12-week trial, 52 participants [50% male, age 47.6 ± 10.0 years, body mass index 32.6 ± 3.4 kg/m² (mean ± standard deviation)] with obesity were randomized 1:1 to once-daily subcutaneous liraglutide (escalated from 0.6 mg to 3.0 mg once-daily) or placebo. During liquid meal tests performed at baseline, after the first dose and following 12 weeks of treatment, we evaluated postprandial gallbladder dynamics and plasma responses of CCK, FGF19 and GLP-2.

Results

Liraglutide reduced postprandial FGF19 after the first dose [area under the curve (AUC)_{0-240 min} 24.8 vs. 48.0 min × ng/ml, treatment ratio (TR) (95% confidence interval) 0.52 (0.39; 0.69)] and following 12 weeks of treatment [AUC_{0-240 min} 33.7 vs. 48.5 ng/ml × min, TR 0.69 (0.52; 0.93)]. Liraglutide also reduced postprandial GLP-2 responses (AUC_{0-240 min} 3650 vs. 4894 min × pmol/L, TR 0.75 (0.62; 0.90)] following the first dose as well as after 12 weeks [AUC_{0-240 min} 3760 vs. 4882 min × pmol/L, TR 0.77 (0.60; 0.99)]. Liraglutide increased postprandial responses of CCK after the first dose [AUC_{0-240 min} 762 vs. 670 min × pmol/L; TR 1.14 (0.97; 1.33)] and following 12 weeks of treatment [AUC_{0-240 min} 873 vs. 628 min × pmol/L; TR 1.39 (1.12; 1.73)].

Conclusion

Compared with placebo, treatment with liraglutide decreased postprandial FGF19 and GLP-2 concentrations and increased postprandial CCK concentrations, which may explain the delayed postprandial gallbladder refilling observed in individuals with obesity treated with liraglutide.     

Weight change and risk of obesity-related complications: A retrospective population-based cohort study of a UK primary care database

Aims

To examine associations between weight loss/gain and risk of developing 13 obesity-related complications (ORCs), stratified by baseline body mass index (BMI).

Materials and Methods

In this retrospective cohort study, we included adults with obesity (>30 kg/m²) from the UK Clinical Practice Research Datalink GOLD database with weight change (−50% to +50%) between Years 1 and 4 (N = 418 774 [median follow-up: 7 years]). Associations between weight change, baseline BMI and risk of developing ORCs during follow-up were assessed using Cox proportional hazard models.

Results

The impact of weight change on ORCs was generally dependent on baseline BMI. Four clear patterns were seen across the 13 outcomes. Pattern 1 showed greatest weight loss benefit for people with low baseline BMI (type 2 diabetes, sleep apnoea, hypertension and dyslipidaemia); Pattern 2 showed most weight loss benefit at lower baseline BMI but no significant weight loss effect at higher baseline BMI (asthma, hip/knee osteoarthritis and polycystic ovary syndrome); Pattern 3 showed benefit in most cardiovascular diseases with weight loss (chronic kidney disease, heart failure, atrial fibrillation and venous thromboembolism), but no additional benefit with >10% weight loss; Pattern 4 showed no clear relationship between weight change and unstable angina/myocardial infarction and depression. We found similar but opposite patterns for weight gain.

Conclusions

Weight loss benefit is dependent on weight loss magnitude and initial BMI, and weight gain is associated with a similar risk increase. Four patterns of association were identified between degree of weight change, baseline BMI and 13 ORCs.     

Folic acid supplementation at lower doses increases oxidative stress resistance and longevity in <Emphasis Type="Italic">Caenorhabditis elegans</Emphasis>

Folic acid (FA) is an essential nutrient that the human body needs but cannot be synthesized on its own. Fortified foods and plant food sources such as green leafy vegetables, beans, fruits, and juices are good sources of FA to meet the daily requirements of the body. The aim was to evaluate the effect of dietary FA levels on the longevity of well-known experimental aging model Caenorhabditis elegans. Here, we show for first time that FA extends organism life span and causes a delay in aging. We observed that FA inhibits mechanistic target of rapamycin (mTOR) and insulin/insulin growth factor 1 (IGF-1) signaling pathways to control both oxidative stress levels and life span. The expression levels of stress- and life span-relevant gerontogenes, viz. daf-16, skn-1, and sir. 2.1, and oxidative enzymes, such as glutathione S-transferase 4 (GST-4) and superoxide dismutase 3 (SOD-3), were also found to be highly enhanced to attenuate the intracellular reactive oxygen species (ROS) damage and to delay the aging process. Our study promotes the use of FA to mitigate abiotic stresses and other aging-related ailments.     

Randomised trial of amnioinfusion during labour with meconium stained amniotic fluid

Objective To assess the effect of amnioinfusion during labour with meconium stained amniotic fluid on caesarean section rate and perinatal outcome.
Design Prospective randomised controlled study.
Setting A tertiary care teaching hospital in India.
Population Women in labour at term with meconium stained amniotic fluid.
Methods Two hundred women in labour with ≥37 weeks gestation, single cephalic presentation with moderate or thick meconium were randomised to control and amnioinfusion groups at a 1:1 ratio. Amnioinfusion was performed using 500mL of normal saline over a period of 30 minutes in a study group. The control group received routine care. Both groups had intermittent auscultation of fetal heart rate during labour.
Main outcome measures The primary outcome measure was caesarean section rate. Secondary outcome measures were meconium aspiration syndrome, 1 minute and 5 minute apgar  <7  , hypoxic ischaemic encephalopathy, neonatal intensive care unit admission, meconium at the level of vocal cords.
Results The caesarean section rate in the amnioinfusion group was less than the control group (RR 0.47; 95% CI 0.24–0.93). Amnioinfusion was associated with a significant decrease in the incidence of meconium at the vocal cords (   P = 0.001  ); improvement in 1 minute apgar scores (   P <0.05  ), respiratory distress (   P = 0.002  ) and fewer admissions to nursery compared with the controls. This sample size was inadequate to study the impact on meconium aspiration syndrome.
Conclusion Amnioinfusion in an under resourced labour ward decreases caesarean section rates and fetal morbidity.     

Field measurement of the effective dominance of an insecticide resistance in anopheline mosquitos

Anopheles culicifacies that were susceptible, heterozygous, or homozygous resistant to HCH and dieldrin were differentially marked with fluorescent dusts and released twice weekly into village huts in Pakistan that had been sprayed with four different dosages of HCH to see which of the genotypes died and which survived. The three highest dosages killed all three genotypes in the first four weeks, and heterozygotes and susceptibles for at least 12 weeks. The lowest dosage killed all the susceptibles throughout the period, and all but 0.07% of the heterzygotes. Thus the resistance is effectively recessive at the higher dosages and unlikely to be selected rapidly, as long as the gene frequency is low to start with and the houses are sprayed regularly. Similar releases of partially and completely resistant A. stephensi, and completely resistant A. subpictus, showed greater survival rates on exposure to the high HCH dosages than the same genotypes of A. culicifacies.     

A point survey of periurban and urban malaria in Karachi

A point survey of malaria in Karachi revealed a concentration of malaria cases in the periurban perimeter and marginal areas where immigrating groups, including Afghan refugees and Biharis from Bangladesh are concentrated. Populations of Anopheles stephensi, Karachi's main vector, were low, and were feeding chiefly on buffaloes which are also concentrated along the periurban perimeter. Maintenance of malaria transmission in periurban zones may depend on immigration of susceptibles, bovid hosts which help maintain zoophilic vector populations, and mosquito breeding sites in water tanks or buffalo hoofprints. The vector's switch to man-biting behaviour may occur either due to a 'spillover' effect from buffalo corrals to surrounding houses, or when buffaloes become less available for biting. Four types of chromosome inversions were found in the Karachi An. stephensi; as this species is not a vector in similar habitats in Lahore and Pondicherry where such inversions are not prevalent, it is likely that its status as a vector is related to chromosomal polymorphism influencing behaviour.     

Melioidosis in Pahang, Malaysia

We conducted a retrospective review of 135 patients with melioidosis in Pahang from January 2000 to June 2003. Patients were mostly male (78.5%) and Malay (83%) with a median age of 51 years. Seventy four percent of patients were diabetic. Common presentations were pneumonia (40.7%), septicaemic without obvious source of infection (19.3%) and multiple organ involvement (15.6%). Only 32.7% were given appropriate antibiotics empirically. The overall mortality was 54% with most deaths (65%) occurring within 48 hours of admission. Patients with pneumonia, multiple organ involvement and septicaemic of unknown source had higher mortality as compared to patients with subcutaneous, musculoskeletal or single internal organ involvement without pneumonia (p < 0.001). The relapse rate was 19.2%.