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#29034530   2017/10/16 Save this To Up

Gene expression and morphological changes in the intestinal mucosa associated with increased permeability induced by short-term fasting in chickens.

Short-term fasting for 4.5 and 9 hr has been demonstrated to increase intestinal permeability (IP) in chickens. This study aimed to investigate the effects of 0, 4.5, 9 and 19.5 hr fasting on intestinal gene expression and villus-crypt architecture of enterocytes in jejunal and ileal samples. On day 38, Ross-308 male birds were fasted according to their group and then euthanised. Two separate intestinal sections (each 2 cm long, jejunum and ileum) were collected. One section was utilised for villus height and crypt depth measurements. The second section was snap-frozen in liquid nitrogen for quantitative polymerase chain reaction (qPCR) analysis of tight junction proteins (TJP) including claudin-1, claudin-3, occludin, zonula occludens (ZO-1, ZO-2), junctional adhesion molecules (JAM) and E-cadherin. Additionally genes involved in enterocyte protection including glucagon-like peptide (GLP-2), heat-shock protein (HSP-70), intestinal alkaline phosphatase (IAP), mammalian target of rapamycin (mTOR), toll-like receptors (TLR-4), mucin (MUC-2), cluster differentiation (CD-36) and fatty acid-binding protein (FABP-6) were also analysed. Normally distributed data were analysed using one-way analysis of variance ANOVA. Other data were analysed by non-parametric one-way ANOVA. Villus height and crypt depth were increased (p < .05) only in the ileum after fasting for 4.5 and 9 hr compared with non-fasting group. mRNA expression of claudin-3 was significantly reduced in the ileum of birds fasted for 9 and 19.5 hr, suggesting a role in IP modulation. However, all other TJP genes examined were not statistically different from control. Nevertheless, ileal FABP-6 of all fasted groups was significantly reduced, which could possibly be due to reduced bile acid production during fasting.

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#29033597   2017/10/16 Save this To Up

Reasons for discontinuation of GLP1 receptor agonists: data from a real-world cross-sectional survey of physicians and their patients with type 2 diabetes.

Nonadherence to glucagon-like peptide-1 receptor agonists (GLP1 RAs) is relatively common among patients with type 2 diabetes mellitus (T2DM). This study sought to identify reasons why patients discontinue GLP1 RAs.

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#29031728   2017/10/16 Save this To Up

Single-cell RNA-sequencing reveals a distinct population of proglucagon-expressing cells specific to the mouse upper small intestine.

To identify sub-populations of intestinal preproglucagon-expressing (PPG) cells producing Glucagon-like Peptide-1, and their associated expression profiles of sensory receptors, thereby enabling the discovery of therapeutic strategies that target these cell populations for the treatment of diabetes and obesity.

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#29031718   2017/10/16 Save this To Up

Gαs regulates Glucagon-Like Peptide 1 Receptor-mediated cyclic AMP generation at Rab5 endosomal compartment.

Upon activation, G protein coupled receptors (GPCRs) associate with heterotrimeric G proteins at the plasma membrane to initiate second messenger signaling. Subsequently, the activated receptor experiences desensitization, internalization, and recycling back to the plasma membrane, or it undergoes lysosomal degradation. Recent reports highlight specific cases of persistent cyclic AMP generation by internalized GPCRs, although the functional significance and mechanistic details remain to be defined. Cyclic AMP generation from internalized Glucagon-Like Peptide-1 Receptor (GLP-1R) has previously been reported from our laboratory. This study aimed at deciphering the molecular mechanism by which internalized GLP-R supports sustained cyclic AMP generation upon receptor activation in pancreatic beta cells.

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#29031717   2017/10/16 Save this To Up

Lipid nanoparticle delivery of glucagon receptor siRNA improves glucose homeostasis in mouse models of diabetes.

Hyperglucagonemia is present in many forms of diabetes and contributes to hyperglycemia, and glucagon suppression can ameliorate diabetes in mice. Leptin, a glucagon suppressor, can also reverse diabetes in rodents. Lipid nanoparticle (LNP) delivery of small interfering RNA (siRNA) effectively targets the liver and is in clinical trials for the treatment of various diseases. We compared the effectiveness of glucagon receptor (Gcgr)-siRNA delivered via LNPs to leptin in two mouse models of diabetes.

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#29025878   2017/10/13 Save this To Up

Elevated Postoperative Endogenous GLP-1 Levels Mediate Effects of Roux-en-Y Gastric Bypass on Neural Responsivity to Food Cues.

It has been suggested that weight reduction and improvements in satiety after Roux-en-Y gastric bypass (RYGB) are partly mediated via postoperative neuroendocrine changes. Glucagon-like peptide-1 (GLP-1) is a gut hormone secreted after food ingestion and is associated with appetite and weight reduction, mediated via effects on the central nervous system (CNS). Secretion of GLP-1 is greatly enhanced after RYGB. We hypothesized that postoperative elevated GLP-1 levels contribute to the improved satiety regulation after RYGB via effects on the CNS.

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#29024408   2017/10/12 Save this To Up

Effects of glucagon-like peptide-1 (GLP-1) receptor agonists on cardiovascular risk factors: a narrative review of head-to-head comparisons.

Cardiovascular (CV) disease is the leading cause of death and morbidity in patients with type 2 diabetes. Five CV risk factors (blood pressure, resting heart rate [HR], body weight, cholesterol levels and blood glucose) are monitored routinely as safety and efficacy endpoints in randomised clinical trials for diabetes therapies. To determine if different glucagon-like peptide-1 receptor agonists (GLP-1RAs) had varying effects on these CV risk factors, we reviewed 16 head-to-head trials directly comparing GLP-1RAs that included at least one of the five factors. Few trials reported statistical differences between GLP-1RAs in terms of systolic blood pressure (SBP), body weight and total cholesterol. Liraglutide increased heart rate versus its comparators in three separate trials. All GLP-1RAs reduced glycated haemoglobin (HbA1c), but exenatide twice daily and lixisenatide had statistically smaller effects compared with other GLP-1RAs. These descriptive data indicate that individual GLP-1RAs affect CV risk factors differently, potentially due to their individual pharmacokinetics and/or size. Short-acting GLP-1RAs appeared to result in smaller changes in SBP and total cholesterol compared with continuous-acting treatments, while large GLP-1RAs had a reduced effect on body weight compared with small GLP-1RAs. For glycaemic control, short-acting GLP-1RAs had a greater impact on post-prandial glucose levels versus continuous-acting GLP-1RAs, but for fasting plasma glucose levels and HbA1c, continuous-acting treatments had the greater effect. No differentiating trends were obvious in HR data. These diverse actions of GLP-1RAs on CV risk factors should aid individualised patient treatment.

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#29022064   2017/10/12 Save this To Up

Proinflammatory switch from Gαs to Gαi signaling by Glucagon-like peptide-1 receptor in murine splenic monocyte following burn injury.

Glucagon-like peptide-1 (GLP-1)-based therapy via G protein-coupled receptor (GPCR) GLP-1R, to attenuate hyperglycemia in critical care has attracted great attention. However, the exaggerated inflammation by GLP-1R agonist, Exendin-4, in a mouse model of burn injury was quite unexpected. Recent studies found that GPCR might elicit proinflammatory effects by switching from Gαs to Gαi signaling in the immune system. Thus, we aimed to investigate the possible Gαs to Gαi switch in GLP-1R signaling in monocyte following burn injury.

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#28991933   2017/10/09 Save this To Up

Addressing Unmet Needs With Injectable Medications in Type 2 Diabetes Treatment: Using Combinations of a Basal Insulin and a Glucagon-Like Peptide-1 Receptor Agonist.

This article presents the rationale and data for combining a basal insulin with a GLP-1RA, including as fixed-ratio products.

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#28991932   2017/10/09 Save this To Up

Addressing Unmet Needs With Injectable Medications in Type 2 Diabetes Treatment: Glucagon-Like Peptide-1 Receptor Agonists.

Since 2005, four new GLP-1RAs (liraglutide, albiglutide, dulaglutide, and lixisenatide) and a once-weekly formulation of exenatide were approved for the treatment of persons with T2DM. Another GLP-1RA, semaglutide, is under review by the FDA, as is exenatide administered via an osmotic mini-pump.

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