Agonist-induced membrane nanodomain clustering drives GLP-1 receptor responses in pancreatic beta cells.

The glucagon-like peptide-1 receptor (GLP-1R), a key pharmacological target in type 2 diabetes (T2D) and obesity, undergoes rapid endocytosis after stimulation by endogenous and therapeutic agonists. We have previously highlighted the relevance of this process in fine-tuning GLP-1R responses in pancreatic beta cells to control insulin secretion. In the present study, we demonstrate an important role for the translocation of active GLP-1Rs into liquid-ordered plasma membrane nanodomains, which act as hotspots for optimal coordination of intracellular signaling and clathrin-mediated endocytosis. This process is dynamically regulated by agonist binding through palmitoylation of the GLP-1R at its carboxyl-terminal tail. Biased GLP-1R agonists and small molecule allosteric modulation both influence GLP-1R palmitoylation, clustering, nanodomain signaling, and internalization. Downstream effects on insulin secretion from pancreatic beta cells indicate that these processes are relevant to GLP-1R physiological actions and might be therapeutically targetable.

Of Mice Not Men? Actions of Interleukin-6 on Glucose Tolerance.

In mice, interleukin-6 (IL-6) improves glucose tolerance via stimulation of glucagon-like peptide 1 (GLP-1) secretion. In this issue of Cell Metabolism, Lang Lehrskov et al. (2018) demonstrate that IL-6 infusion has GLP-1-dependent and -independent actions with opposing effects on glucose tolerance, resulting in an overall improvement in healthy male volunteers but no improvement in male patients with diabetes.

RAMP2 Influences Glucagon Receptor Pharmacology via Trafficking and Signaling.

Endogenous satiety hormones provide an attractive target for obesity drugs. Glucagon causes weight loss by reducing food intake and increasing energy expenditure. To further understand the cellular mechanisms by which glucagon and related ligands activate the glucagon receptor (GCGR), we investigated the interaction of the GCGR with receptor activity modifying protein (RAMP)2, a member of the family of receptor activity modifying proteins. We used a combination of competition binding experiments, cell surface enzyme-linked immunosorbent assay, functional assays assessing the Gαs and Gαq pathways and ß-arrestin recruitment, and small interfering RNA knockdown to examine the effect of RAMP2 on the GCGR. Ligands tested were glucagon; glucagonlike peptide-1 (GLP-1); oxyntomodulin; and analog G(X), a GLP-1/glucagon coagonist developed in-house. Confocal microscopy was used to assess whether RAMP2 affects the subcellular distribution of GCGR. Here we demonstrate that coexpression of RAMP2 and the GCGR results in reduced cell surface expression of the GCGR. This was confirmed by confocal microscopy, which demonstrated that RAMP2 colocalizes with the GCGR and causes significant GCGR cellular redistribution. Furthermore, the presence of RAMP2 influences signaling through the Gαs and Gαq pathways, as well as recruitment of ß-arrestin. This work suggests that RAMP2 may modify the agonist activity and trafficking of the GCGR, with potential relevance to production of new peptide analogs with selective agonist activities.

Prognostic benefit of surgery following chemoradiotherapy for squamous cell carcinoma of the oesophagus.

A best evidence topic in surgery was written according to a structured protocol. The question addressed was whether patients who have undergone chemoradiotherapy (CRT) for locally advanced squamous cell carcinoma of the oesophagus benefit from surgical resection. 505 papers were found using the reported search, of which 5 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group, study type, relevant outcomes and results of these papers are tabulated. Of these five studies, two were randomised controlled trials. These demonstrated that there was no survival benefit in adding surgery to patients who have undergone CRT for oesophageal cancer. The remaining three observational studies suggest that surgery may have a prognostic benefit for patients who show a partial, but not complete response to CRT. We conclude that for patients who are complete responders to induction CRT, surgery adds no survival benefit. With regard to partial responders there is weak evidence suggesting that there may be some benefit in surgery after CRT, but further trials are needed to clarify the survival benefit (if any) of adding oesophagectomy to CRT for this sub-group.

Functional outcomes following laparoscopic and open rectal resection for cancer.

A best evidence topic was written according to a structured protocol. The question addressed whether laparoscopic approach confers a difference in functional outcome compared to conventional open resectional surgery for rectal cancer. 246 papers were found using the reported search, of which five represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group, study type, relevant outcomes and key results of these papers are tabulated. Of these five studies, none showed any difference in post-operative urinary function between patients undergoing laparoscopic or open surgery. The two randomised studies reported either a trend or a significant difference in favour of open surgery for sexual outcome in men. Three more recent, case-control studies showed differences in favour of laparoscopic surgery for sexual function in men. We conclude that there is no evidence to suggest that laparoscopic approach makes any difference to post-operative urinary function. The data relating to sexual function in men is contradictory, and as none of the studies available have generated high level evidence and further trials are required to clarify whether laparoscopic approach confers an advantage or disadvantage in terms of sexual function for men post-operatively. In terms of sexual function in women, the available data is far too scarce to satisfactorily determine whether laparoscopy is superior to open surgery.