Amylin as a Future Obesity Treatment.

Obesity is defined as abnormal or excessive fat accumulation that contributes to detrimental health impacts. One-third of the population suffers from obesity, and it is important to consider obesity as a chronic disease requiring chronic treatment. Amylin is co-secreted with insulin from ß pancreatic cells upon nutrient delivery to the small intestine as a satiety signal, acts upon sub-cortical homeostatic and hedonic brain regions, slows gastric emptying, and suppresses post-prandial glucagon responses to meals. Therefore, new pharmacological amylin analogues can be used as potential anti-obesity medications in individuals who are overweight or obese. In this narrative review, we analyse the efficacy, potency, and safety of amylin analogues. The synthetic amylin analogue pramlintide is an approved treatment for diabetes mellitus which promotes better glycaemic control and small but significant weight loss. AM833 (cagrilintide), an investigational novel long-acting acylated amylin analogue, acts as a non-selective amylin receptor. This calcitonin G protein-coupled receptor agonist can serve as an attractive novel treatment for obesity, resulting in reduction of food intake and significant weight loss in a dose-dependent manner.

Clinical Impact of Liraglutide as a Treatment of Obesity.

Obesity is defined as a chronic, complex, relapsing disease characterized by excessive adipose tissue. Obesity impacts an individual's health by increasing complications such as prediabetes, type 2 diabetes mellitus (T2DM), hypertension, dyslipidemia, metabolic syndrome, cardiovascular disease, nonalcoholic fatty liver disease (NAFLD), cancers (eg endometrial), and obstructive sleep apnea (OSA). With the increase of obesity prevalence and its negative influences on individuals' quality of life, there is a great need for therapy with a purpose to produce sustainable weight loss of more than 10% in order to improve or even reverse the progress of obesity related complications. The GLP-1 analogue, liraglutide reduce food consumption, promote weight reduction and improve metabolic functions. The primary mechanism of GLP-1 effect on food intake, metabolism, and weight reduction is mainly due to its actions on peripheral (vagal) and central pathways and activation of hindbrain and hypothalamus. The average weight reduction induced by liraglutide was significant and the weight loss was maintained as long as the patients on therapy. Liraglutide has advantages on weight loss maintenance and promoting cardiovascular disease (CVD) risk reduction, by decreasing systolic blood pressure and glycemic index. In this review, we aim to explain the mechanism of action of Liraglutide, its pharmacokinetic properties, its clinical impact on obesity and its safety and tolerability.

Liraglutide Does Not Adversely Impact Fat-Free Mass Loss.

OBJECTIVES: This study aimed to examine fat-free mass (FFM) loss between successful responders to lifestyle intervention alone compared with lifestyle intervention plus liraglutide 3.0 mg. An additional objective was to examine the effects of varying resistance training frequencies (days per week) on FFM retention. METHODS: This prospective study examined patients with BMI ≥ 35 kg/m2 receiving treatment in a tertiary care obesity clinic. Body composition (dual-energy x-ray absorptiometry) was captured at baseline and after 16 weeks of treatment. Exercise-related data (aerobic minutes per week and resistance training frequency) were captured at week 16. A total of 78 individuals were examined in two groups, the first with lifestyle intervention alone (n = 19) and the second with lifestyle intervention plus liraglutide 3.0 mg (n = 59). Linear mixed-effects models were used to examine between-group differences. RESULTS: Compared with lifestyle intervention alone, participants on liraglutide lost more weight (-12.2 kg vs. -9.7 kg, P = 0.048) and FFM (-2.3 kg vs. -1.5 kg, P = 0.06). After controlling for weight loss, there was no difference in FFM loss between groups (0.14 kg/wk vs. -0.09 kg/wk, P = 0.12). Absolute weight loss (kilograms) was associated with FFM loss (kilograms) (ρ = 0.58, P < 0.0001). Exercise did not increase weight loss, and resistance training frequency (days per week) did not attenuate FFM loss. CONCLUSIONS: Liraglutide does not have effects on FFM beyond what can be expected from total weight loss. Resistance training did not attenuate FFM loss in the liraglutide or lifestyle-alone groups. To ameliorate FFM loss after liraglutide, a new strategy may be needed that may combine exercise with specific nutritional interventions.

Prevalence and Risk Factors of Hypoxemia after Coronary Artery Bypass Grafting: The Time to Change Our Conceptions.

Background: Acute hypoxemia is the main characteristic of acute respiratory distress syndrome (ARDS), which is one of the most critical complications of coronary artery bypass grafting (CABG). Given the dearth of data on acute hypoxemia, we sought to determine its prevalence and risk factors among post-CABG patients. Methods: This cross-sectional study was conducted on on-pump CABG patients in Tehran Heart Center in 2 consecutive months in 2012. The effects of arterial blood gas variables, age, gender, the duration of the pump and cross-clamping, the ejection fraction, the creatinine level, and the body mass index on the prevalence of hypoxemia at the cutoff points of ARDS and acute lung injury were assessed. Results: Out of a total of 232 patients who remained in the study, 174 (75.0%) cases were male. The mean age was 60.60±9.42 years, and the mean body mass index was 27.15±3.93 kg/m2. None of the patients expired during the current admission. The ratio of partial pressure arterial oxygen to the fraction of inspired oxygen (PaO2/FiO2) 1 hour after admission to the intensive care unit (ICU), before extubation, and at 4 hours after extubation was less than 300 mmHg in 66.6%, 72.2%, and 86.6% of the patients and less than 200 mmHg in 20.8% 17.7%, and 30.2% of the patients, respectively. Among the different variables, only a heavier weight was associated with a PaO2/FiO2 ratio of less than 300 mmHg at 1 hour after ICU admission and at 4 hours after extubation (P=0.001). A rise in the cross-clamp time showed a significant association with the risk of a PaO2/FiO2 ratio of less than 200 mmHg at 4 hours after extubation (P=0.014). Conclusion: This study shows that hypoxemia following CABG is very common in the first 48 postoperative hours, although it is a benign and transient event. The high prevalence may affect the accuracy of the ARDS criteria and their positive or negative predictive value.

The Role of the Small Bowel in Unintentional Weight Loss after Treatment of Upper Gastrointestinal Cancers.

Upper gastrointestinal (GI) cancers are responsible for significant mortality and morbidity worldwide. To date, most of the studies focused on the treatments' efficacy and post-treatment survival rate. As treatments improve, more patients survive long term, and thus the accompanying complications including unintentional weight loss are becoming more important. Unintentional weight loss is defined as >5% of body weight loss within 6-12 months. Malignancies, particularly GI cancers, are diagnosed in approximately 25% of patients who present with unintentional weight loss. Whereas some recent studies discuss pathophysiological mechanisms and new promising therapies of cancer cachexia, there is a lack of studies regarding the underlying mechanism of unintentional weight loss in patients who are tumor free and where cancer cachexia has been excluded. The small bowel is a central hub in metabolic regulation, energy homeostasis, and body weight control throughout the microbiota-gut-brain axis. In this narrative review article, the authors discussed the impacts of upper GI cancers' treatment modalities on the small bowel which may lead to unintentional weight loss and some new promising therapeutic agents to treat unintentional weight loss in long term survivors after upper GI operations with curative intent.

Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis.

Macrophages specialize in removing lipids and debris present in the atherosclerotic plaque. However, plaque progression renders macrophages unable to degrade exogenous atherogenic material and endogenous cargo including dysfunctional proteins and organelles. Here we show that a decline in the autophagy-lysosome system contributes to this as evidenced by a derangement in key autophagy markers in both mouse and human atherosclerotic plaques. By augmenting macrophage TFEB, the master transcriptional regulator of autophagy-lysosomal biogenesis, we can reverse the autophagy dysfunction of plaques, enhance aggrephagy of p62-enriched protein aggregates and blunt macrophage apoptosis and pro-inflammatory IL-1ß levels, leading to reduced atherosclerosis. In order to harness this degradative response therapeutically, we also describe a natural sugar called trehalose as an inducer of macrophage autophagy-lysosomal biogenesis and show trehalose's ability to recapitulate the atheroprotective properties of macrophage TFEB overexpression. Our data support this practical method of enhancing the degradative capacity of macrophages as a therapy for atherosclerotic vascular disease.

Non-alcoholic fatty liver disease (NAFLD) and 10-year risk of cardiovascular diseases.

BACKGROUND AND AIMS: The association between cardiovascular diseases (CVD) and non-alcoholic fatty liver disease (NAFLD) was confirmed by a large body of evidence. This study was conducted to determine the association between NAFLD and 10-year CVD risk. METHODS: This study utilized the data of 2804 subjects aged 40-74 years from a cohort study of northern Iran. Two CVD risk assessment tools, American College of Cardiology/American Heart Association and Framingham general cardiovascular risk profile for use in primary care, were utilized to determine the 10-year CVD risk in patients with NAFLD and the individuals without this condition. The mean risks were compared between these two groups. RESULTS: Using ACC/AHA approach, the mean risk in male participants suffering NAFLD was 14.2%, while in men without NAFLD was 11.7% (P-value < 0.0001). Using Framingham approach, the mean risks were 16.0 and 12.7% in men with and without NAFLD, respectively (P-value < 0.0001). Using ACC/AHA approach, the mean risks in female participants with and without NAFLD were 6.7 and 4.6%, respectively (P-value < 0.0001). Applying Framingham approach, the mean risk was 8.2% in women with NAFLD and 5.4% in women without NAFLD (P-value < 0.0001). CONCLUSION: The individuals with NAFLD had a higher risk of 10-year CVD events than individuals without NAFLD, according to both ACC/AHA tool and primary care version of Framingham tool. A large proportion of NAFLD patients fulfill the criteria of statin therapy recommendation, suggesting that statin therapy could reduce 10-year CVD risk in NAFLD patients.

Epidemiological features of irritable bowel syndrome and its subtypes among Iranian adults.

BACKGROUND: The epidemiological features of irritable bowel syndrome (IBS) have not been properly investigated in Iran. Also, worldwide there is limited knowledge about the characteristics of IBS subtypes. The aim of the study was to explore the epidemiological features of IBS and its subtypes among Iranian adults. METHODS: This is a cross-sectional study in Iranian adults living in Isfahan province. Demographic characteristics and common gastrointestinal symptoms were assessed using a self-administered modified Persian version of the Rome III questionnaire. RESULTS: In 4763 subjects aged 19-70 years the overall prevalence of IBS was 21.5%. IBS was more prevalent in women than men (24.0 vs. 18.3%, P<0.001). In multivariate analysis, being married was associated with 27% increased odds of IBS (95% confidence interval: 1.03-1.57, P<0.05). However, IBS was not associated with age (P=0.71) or educational attainment (P=0.61). Constipation-predominant IBS (IBS-C) was the most prevalent subtype of IBS followed by mixed IBS (IBS-M), diarrhea-predominant IBS (IBS-D), and unsubtyped IBS. Female gender was associated with IBS-C while male gender was associated with IBS-D and IBS-M. CONCLUSION: IBS is highly prevalent among Iranian adults, affecting particularly women in whom IBS-C is the most prevalent subtype.

Thioflavin T effect in diabetic Wistar rats: reporting the antihyperglycemic property of an amyloid probing dye.

BACKGROUND: Thioflavin T (ThT) is a well-known probe of amyloid fibrils with a benzothiazole core structure. As a compound with partial inhibitory effect on alpha-amylase, the results of oral ThT administration were investigated on a streptozotocin (STZ)-induced rat model of diabetes. METHODS: STZ was administered intraperitoneally for induction of diabetes. Afterwards, doses of 2, 8, 16, and 32 mg/kg of ThT were used in diabetic and non-diabetic rats. Blood glucose levels, lipid profiles, alpha-amylase activity, food and water intake and urine volume were assessed. Docking was also performed to evaluate the inhibitory effect of ThT on alpha-amylase. RESULTS: Upon treatment with ThT, blood glucose levels and lipid profile of diabetic rats improved significantly. Furthermore, alpha-amylase serum levels of treated animals decreased compared to the control group, suggesting a possible effect of ThT on this digestive enzyme. On the other hand, the food intake of treated animals showed a decrease. ThT effects were also seen to some extent in the non-diabetic group. CONCLUSION: ThT is suggested to be a potentially useful compound in treatment and prevention of diabetes and associated complications.