Saxagliptin for the treatment of type 2 diabetes mellitus: assessing cardiovascular data

Patients with type 2 diabetes mellitus (T2DM) are at high risk for cardiovascular (CV) disease; however, conclusive evidence that glycemic control leads to improved cardiovascular outcomes is lacking. Saxagliptin is a potent, selective dipeptidyl peptidase-4 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Saxagliptin was evaluated in a series of phase III trials as monotherapy; add-on therapy to metformin, a sulfonylurea, or a thiazolidinedione; and as initial therapy in combination with metformin. Saxagliptin consistently improved glycemic control (as reflected by significant decreases in glycated hemoglobin, fasting plasma glucose, and postprandial glucose compared with controls) and was generally well tolerated. In these analyses, saxagliptin had clinically neutral effects on body weight, blood pressure, lipid levels, and other markers of CV risk compared with controls. A retrospective meta-analysis of 8 phase II and phase III trials found no evidence that saxagliptin increases CV risk in patients with T2DM (Cox proportional hazard ratio, 0.43; 95% CI, 0.23-0.80 for major adverse cardiovascular events retrospectively adjudicated). Instead, it raised the hypothesis that saxagliptin may reduce the risk of major adverse CV events. A long-term CV outcome trial, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-THrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) is currently ongoing to determine whether saxagliptin reduces CV risk in T2DM

Oleate induces K_ATP channel-dependent hyperpolarisation in mouse hypothalamic glucose-excited neurones without altering cellular energy charge

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.The unsaturated fatty acid, oleate exhibits anorexigenic properties reducing food intake and hepatic glucose output. However, its mechanism of action in the hypothalamus has not been fully determined. This study investigated the effects of oleate and glucose on GT1-7 mouse hypothalamic cells (a model of glucose-excited (GE) neurons) and mouse arcuate nucleus (ARC) neurons. Whole-cell and perforated patch-clamp recordings, immunoblotting and cell energy status measures were used to investigate oleate- and glucose-sensing properties of mouse hypothalamic neurons. Oleate or lowered glucose concentration caused hyperpolarization and inhibition of firing of GT1-7 cells by the activation of ATP-sensitive K(+) channels (KATP). This effect of oleate was not dependent on fatty acid oxidation or raised AMP-activated protein kinase activity or prevented by the presence of the UCP2 inhibitor genipin. Oleate did not alter intracellular calcium, indicating that CD36/fatty acid translocase may not play a role. However, oleate activation of KATP may require ATP metabolism. The short-chain fatty acid octanoate was unable to replicate the actions of oleate on GT1-7 cells. Although oleate decreased GT1-7 cell mitochondrial membrane potential there was no change in total cellular ATP or ATP/ADP ratios. Perforated patch and whole-cell recordings from mouse hypothalamic slices demonstrated that oleate hyperpolarized a subpopulation of ARC GE neurons by KATP activation. Additionally, in a separate small population of ARC neurons, oleate application or lowered glucose concentration caused membrane depolarization. In conclusion, oleate induces KATP-dependent hyperpolarization and inhibition of firing of a subgroup of GE hypothalamic neurons without altering cellular energy charge.This work was supported by: grants from the Wellcome Trust (grant number 068692) to M.L.J. Ashford; from Juvenile Diabetes Research Foundation (JDRF) to R.J. McCrimmon and Fellowships to C. Beall (JDRF; 3-576-2010 and Diabetes UK 13/0004647

A ligament influences the diversification of damselfishes (Pomacentridae)

The Pomacentridae (damselfishes) is one of the most successful families of reef-associated fishes (386 species). In 1981, Stiassny described a synapomorphic trait of the Pomacentridae: the cerato-mandibular ligament (CML) joining the hyoid bar (ceratohyal) to the internal part of the mandible (coronoid process of the articulo-angular). Here, we highlight that this ligament is lacking in at least 18 damselfish species from different subclades (i.e. Chrominae, Abudefdufinae and Pomacentrinae) and we explore the impact of its disappearance on lineage, morphological and ecological diversification through their evolutionary history. Using a time-calibrated phylogeny including 208 species, we found no support for different rates of lineage diversification between species that lack the CML and the others. Yet, the CML clearly governs a part of the morphological diversity in damselfishes. Indeed, the body and mandible shapes differ significantly between species without CML and the others. Evolutionary modeling of some phenotypic traits (i.e. body and mandible shape) mainly supports models with two rates of morphological diversification across the time-tree with the species without CML having a higher rate of morphological diversification than the others. Mapping the diet of all studied species illustrates that damselfishes lacking CML are highly zooplanktivorous species. Their shapes suggest they feed on planktonic copepods with a higher contribution of ram-feeding (i.e. predator movement towards prey) in comparison with the other planktivorous damselfishes. Finally, the CML could have promoted easy shifts among the three main trophic guilds in damselfishes (i.e. grazers, zooplanktivorous and omnivorous) during evolution but the disappearance of the CML allowed a functional specialization linked to prey-capture strategies. These results support the primary role of the CML in the evolution and diversification of pomacentrids

Tempo and mode of eco-morphological evolution in damselfishes (Pomacentridae)

Coral reef fishes represent one of the most outstandingly diverse assemblages of vertebrates on the planet but our understanding of their mode of diversification remains limited. Here we test whether the damselfishes (Pomacentridae), one of the most species-rich families of reef-associated fishes, adaptively radiated during their evolutionary history. Tests of the tempo of lineage diversification using a time-calibrated phylogeny including 208 species did not support the expected pattern of rapid inital diversification that slowed through time as predicted by macroevolutionary theory. Evolutionary modeling of trophic traits similarly rejected the hypothesis of early among-lineage partitioning of ecologically relevant phenotypic diversity. Instead, damselfishes are shown to have experienced iterative convergent radiations wherein subclades converge on similar trophic strategies (i.e. pelagic feeders, benthic feeders, intermediate) and morphologies. We discuss that regionalization of coral reefs, bipartite life cycle of reef fishes, competition and functional constraints are good candidate of causal factors underlying the iterative ecological radiation and convergent evolution of damselfishes

Effect of evolutionary miniaturization on the tempo and mode of diversification - An example from marine angelfishes

Evolutionary change in body size is a widespread phenomenon in animals. Numerous studies have highlighted evolutionary miniaturization, referring to the evolution of small body size, in various taxa. As other traits shift, decrease in size can be viewed as a morphological novelty that enables colonization of new “adaptive zones” and subsequent diversification (i.e. a “key innovation”). Thus, evolution to small body size is hypothesized to influence lineage, morphological and ecological diversification. Until now, few studies have tested this hypothesis and current supports are mixed. Here, we present a quantitative analysis of the radiation of Pomacanthidae (angelfishes), an iconic coral reef fish family where small taxa, the so called “pygmy angelfishes” of the genus Centropyge, appear to have evolved three-times. If an evolutionary decrease in size has acted as a key innovation during the evolutionary history of Pomacanthidae, we predict that diversification rates would be the highest in clades of pygmy angelfishes. We produced a time-calibrated phylogeny including 67 species, collected ecological data and quantified the body shape of 80 species using geometric morphometrics. Then, we tested the prediction by modelling macroevolutionary dynamics of diversification using the Bayesian Analysis of Macroevolutionary Mixture (BAMM) framework. BAMM results do not support a common macroevolutionary regime for every pigmy angelfish clades. Only the clade Centropyge Xiphypops shows higher rates of lineage and morphological diversification than the other clades of angelfishes. We show that miniaturization has few effects on the rate of diversification. The shifts in the tempo of diversification observed in C. Xiphypops might instead be related to a functional innovation of the feeding apparatus. Using the Pomacanthidae, we illustrate that miniaturization may not be a main factor in triggering increased of diversification rates at the family level