Incretin-based therapies: new treatments for type 2 diabetes in the new millennium

The advent of ‘incretin-based therapies’ – GLP-1 agonists and dipeptidyl-peptidase-4 inhibitors – which result in improvements in glycemic control comparable to those with existing oral hypoglycemic agents, and potentially improve cardiovascular and pancreatic β-cell function, represents a major therapeutic advance in the management of type 2 diabetes. Gastrointestinal adverse effects occur commonly with GLP-1 agonists, and rarely with DPP-4 inhibitors, but are dose-dependent and usually transient. The low risk of hypoglycemia, and beneficial or neutral effects on body weight, render GLP-1 agonists and DPP-4 inhibitors suitable alternatives to insulin secretagogues and insulin in overweight and elderly patients. Incretin-based therapies also improve quality of life in patients with type 2 diabetes, and may be cost-effective in the long term

Effects of GLP-1 and Incretin-Based Therapies on Gastrointestinal Motor Function

Glucagon-like peptide 1 (GLP-1) is a hormone secreted predominantly by the distal small intestine and colon and released in response to enteral nutrient exposure. GLP-1-based therapies are now used widely in the management of type 2 diabetes and have the potential to be effective antiobesity agents. Although widely known as an incretin hormone, there is a growing body of evidence that GLP-1 also acts as an enterogastrone, with profound effects on the gastrointestinal motor system. Moreover, the effects of GLP-1 on gastrointestinal motility appear to be pivotal to its effect of reducing postprandial glycaemic excursions and may, potentially, represent the dominant mechanism. This review summarizes current knowledge of the enterogastrone properties of GLP-1, focusing on its effects on gut motility at physiological and pharmacological concentrations, and the motor actions of incretin-based therapies. While of potential importance, the inhibitory action of GLP-1 on gastric acid secretion is beyond the scope of this paper

The effects of a whey protein and guar gum-containing preload on gastric emptying, glycaemia, small intestinal absorption and blood pressure in healthy older subjects

A whey protein/guar gum preload reduces postprandial glycaemia in type 2 diabetes through slowing gastric emptying. However, gastric emptying has previously been assessed using a stable isotope breath test technique, which cannot discriminate between slowing of gastric emptying and small intestinal absorption. This preload also may be useful in the management of postprandial hypotension. We evaluated the effects of a whey protein/guar preload on gastric emptying, glucose absorption, glycaemic/insulinaemic and blood pressure (BP) responses to an oral glucose load. Eighteen healthy older participants underwent measurements of gastric emptying (scintigraphy), plasma glucose and insulin, glucose absorption, superior mesenteric artery (SMA) flow, BP and heart rate (HR) after ingesting a 50 g glucose drink, with or without the preload. The preload reduced plasma glucose (p = 0.02) and serum 3-O-methylglucose (3-OMG) (p = 0.003), and increased plasma insulin (p = 0.03). There was no difference in gastric emptying or BP between the two days. The reduction in plasma glucose on the preload day was related to the reduction in glucose absorption (r = 0.71, p = 0.002). In conclusion, the glucose-lowering effect of the preload may relate to delayed small intestinal glucose absorption and insulin stimulation, rather than slowing of gastric emptying.publishedVersio

Exploring the measurement of markedness and its relationship with other linguistic variables

Antonym pair members can be differentiated by each word's markedness-that distinction attributable to the presence or absence of features at morphological or semantic levels. Morphologically marked words incorporate their unmarked counterpart with additional morphs (e.g., "unlucky" vs. "lucky"); properties used to determine semantically marked words (e.g., "short" vs. "long") are less clearly defined. Despite extensive theoretical scrutiny, the lexical properties of markedness have received scant empirical study. The current paper employs an antonym sequencing approach to measure markedness: establishing markedness probabilities for individual words and evaluating their relationship with other lexical properties (e.g., length, frequency, valence). Regression analyses reveal that markedness probability is, as predicted, related to affixation and also strongly related to valence. Our results support the suggestion that antonym sequence is reflected in discourse, and further analysis demonstrates that markedness probabilities, derived from the antonym sequencing task, reflect the ordering of antonyms within natural language. In line with the Pollyanna Hypothesis, we argue that markedness is closely related to valence; language users demonstrate a tendency to present words evaluated positively ahead of those evaluated negatively if given the choice. Future research should consider the relationship of markedness and valence, and the influence of contextual information in determining which member of an antonym pair is marked or unmarked within discourse

Intercomparison of long-term sea surface temperature analyses using the GHRSST Multi-Product Ensemble (GMPE) system

Six global, gridded, gap-free, daily sea surface temperature (SST) analyses covering a period of at least 20 years have been intercompared: ESA SST CCI anal- ysis long-term product v1.0, MyOcean OSTIA reanalysis v1.0, CMC 0.2 degree, AVHRR ONLY Daily 1/4 degree OISST v2.0, HadISST2.1.0.0 and MGDSST. A seventh SST product of the ensemble median of all six has also been produced using the GMPE (Group for High Resolution SST Multi-Product Ensemble) sys- tem. Validation against independent near-surface Argo data, a long timeseries of moored buoy data from the tropics and anomalies to the GMPE median have been used to examine the temporal and spatial homogeneity of the analyses. A comparison of the feature resolution of the analyses has also been undertaken. A summary of relative strengths and weaknesses of the SST datasets is presented, intended to help users to make an informed choice of which analysis is most suitable for their proposed application

Gut Mechanisms Linking Intestinal Sweet Sensing to Glycemic Control

Copyright © 2018 Kreuch, Keating, Wu, Horowitz, Rayner and Young. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Sensing nutrients within the gastrointestinal tract engages the enteroendocrine cell system to signal within the mucosa, to intrinsic and extrinsic nerve pathways, and the circulation. This signaling provides powerful feedback from the intestine to slow the rate of gastric emptying, limit postprandial glycemic excursions, and induce satiation. This review focuses on the intestinal sensing of sweet stimuli (including low-calorie sweeteners), which engage similar G-protein-coupled receptors (GPCRs) to the sweet taste receptors (STRs) of the tongue. It explores the enteroendocrine cell signals deployed upon STR activation that act within and outside the gastrointestinal tract, with a focus on the role of this distinctive pathway in regulating glucose transport function via absorptive enterocytes, and the associated impact on postprandial glycemic responses in animals and humans. The emerging role of diet, including low-calorie sweeteners, in modulating the composition of the gut microbiome and how this may impact glycemic responses of the host, is also discussed, as is recent evidence of a causal role of diet-induced dysbiosis in influencing the gut-brain axis to alter gastric emptying and insulin release. Full knowledge of intestinal STR signaling in humans, and its capacity to engage host and/or microbiome mechanisms that modify glycemic control, holds the potential for improved prevention and management of type 2 diabetes

A T8.5 Brown Dwarf Member of the Xi Ursae Majoris System

The Wide-field Infrared Survey Explorer has revealed a T8.5 brown dwarf (WISE J111838.70+312537.9) that exhibits common proper motion with a solar-neighborhood (8 pc) quadruple star system - Xi Ursae Majoris. The angular separation is 8.5 arc-min, and the projected physical separation is about 4000 AU. The sub-solar metallicity and low chromospheric activity of Xi UMa A argue that the system has an age of at least 2 Gyr. The infrared luminosity and color of the brown dwarf suggests the mass of this companion ranges between 14 and 38 Jupiter masses for system ages of 2 and 8 Gyr respectively.Comment: AJ in press, 12 pages LaTeX with 6 figures. More astrometric data and a laser guide star adaptive optics image adde

Satellite-based time-series of sea-surface temperature since 1981 for climate applications

A climate data record of global sea surface temperature (SST) spanning 1981–2016 has been developed from 4 × 10^12 satellite measurements of thermal infra-red radiance. The spatial area represented by pixel SST estimates is between 1 km^2 and 45 km^2. The mean density of good-quality observations is 13 km^−2 yr^−1. SST uncertainty is evaluated per datum, the median uncertainty for pixel SSTs being 0.18 K. Multi-annual observational stability relative to drifting buoy measurements is within 0.003 K yr^−1 of zero with high confidence, despite maximal independence from in situ SSTs over the latter two decades of the record. Data are provided at native resolution, gridded at 0.05° latitude-longitude resolution (individual sensors), and aggregated and gap-filled on a daily 0.05° grid. Skin SSTs, depth-adjusted SSTs de-aliased with respect to the diurnal cycle, and SST anomalies are provided. Target applications of the dataset include: climate and ocean model evaluation; quantification of marine change and variability (including marine heatwaves); climate and ocean-atmosphere processes; and specific applications in ocean ecology, oceanography and geophysics

Gut Mechanisms Linking Intestinal Sweet Sensing to Glycemic Control

Sensing nutrients within the gastrointestinal tract engages the enteroendocrine cell system to signal within the mucosa, to intrinsic and extrinsic nerve pathways, and the circulation. This signaling provides powerful feedback from the intestine to slow the rate of gastric emptying, limit postprandial glycemic excursions, and induce satiation. This review focuses on the intestinal sensing of sweet stimuli (including low-calorie sweeteners), which engage similar G-protein-coupled receptors (GPCRs) to the sweet taste receptors (STRs) of the tongue. It explores the enteroendocrine cell signals deployed upon STR activation that act within and outside the gastrointestinal tract, with a focus on the role of this distinctive pathway in regulating glucose transport function via absorptive enterocytes, and the associated impact on postprandial glycemic responses in animals and humans. The emerging role of diet, including low-calorie sweeteners, in modulating the composition of the gut microbiome and how this may impact glycemic responses of the host, is also discussed, as is recent evidence of a causal role of diet-induced dysbiosis in influencing the gut-brain axis to alter gastric emptying and insulin release. Full knowledge of intestinal STR signaling in humans, and its capacity to engage host and/or microbiome mechanisms that modify glycemic control, holds the potential for improved prevention and management of type 2 diabetes