Incretin-Based Therapies for the Treatment of Type 2 Diabetes: Evaluation of the Risks and Benefits

Limited evidence suggests that GLP-I may also preserve ventricular function and improve outcomes in human subjects with heart failure or myocardial infarction (11,12). [...] both exenatide and liraglutide reduce blood pressure, body weight, and plasma lipid profiles in subjects with type 2 diabetes (13), raising the hope that longterm treatment with these agents may reduce the incidence of cardiovascular events.\n However, two safety issues have been raised - pancreatitis and medullary carcinoma of the thyroid

Seismic slip on an upper-plate normal fault during a large subduction megathrust rupture

Quantification of stress accumulation and release during subduction zone seismic cycles requires an understanding of the distribution of fault slip during earthquakes. Reconstructions of slip are typically constrained to a single, known fault plane. Yet, slip has been shown to occur on multiple faults within the subducting plate1 owing to stress triggering2, resulting in phenomena such as earthquake doublets3. However, rapid stress triggering from the plate interface to faults in the overriding plate has not been documented. Here we analyse seismic data from the magnitude 7.1 Araucania earthquake that occurred in the Chilean subduction zone in 2011. We find that the earthquake, which was reported as a single event in global moment tensor solutions4, 5, was instead composed of two ruptures on two separate faults. Within 12?s a thrust earthquake on the plate interface triggered a second large rupture on a normal fault 30?km away in the overriding plate. This configuration of partitioned rupture is consistent with normal-faulting mechanisms in the ensuing aftershock sequence. We conclude that plate interface rupture can trigger almost instantaneous slip in the overriding plate of a subduction zone. This shallow upper-plate rupture may be masked from teleseismic data, posing a challenge for real-time tsunami warning systems

Slab segmentation controls the interplate slip motion in the SW Hellenic subduction: New insight from the 2008Mw 6.8 Methoni interplate earthquake

We present an integrated approach of the seismic structure and activity along the offshore SW Hellenic subduction from combined observations of marine and land seismic stations. Our imaging of the slab top topography from teleseismic receiver function analysis at ocean bottom seismometers supports a trenchward continuation of the along-dip slab faults beneath the Peloponnesus. We further show that their morphostructural control accounts for the backstepping of the thrust contact of the Mediterranean Ridge accretionary wedge over the upper plate. Local seismic activity offshore SW Peloponnesus constrained by ocean bottom seismometer observations reveals a correlation with specific features of the forearc: the Matapan Troughs. We study the Mw6.8 14.02.2008 interplate earthquake offshore SW Peloponnesus and show that its nucleation, rupture zone, and aftershocks sequence are confined to one slab panel between two adjacent along-dip faults and are thus controlled by not only the offshore slab top segmentation but also the upper plate sea-bottom morphology

Brain Glucagon-Like Peptide-1 Regulates Arterial Blood Flow, Heart Rate, and Insulin Sensitivity

OBJECTIVE— To ascertain the importance and mechanisms underlying the role of brain glucagon-like peptide (GLP)-1 in the control of metabolic and cardiovascular function. GLP-1 is a gut hormone secreted in response to oral glucose absorption that regulates glucose metabolism and cardiovascular function. GLP-1 is also produced in the brain, where its contribution to central regulation of metabolic and cardiovascular homeostasis remains incompletely understood

GLP-1R Agonist Liraglutide Activates Cytoprotective Pathways and Improves Outcomes After Experimental Myocardial Infarction in Mice

OBJECTIVE—Glucagon-like peptide-1 receptor (GLP-1R) ago-nists are used to treat type 2 diabetes, and transient GLP-1 administration improved cardiac function in humans after acute myocardial infarction (MI) and percutaneous revascularization. However, the consequences of GLP-1R activation before isch-emic myocardial injury remain unclear. RESEARCH DESIGN AND METHODS—We assessed the pathophysiology and outcome of coronary artery occlusion in normal and diabetic mice pretreated with the GLP-1R agonist liraglutide. RESULTS—Male C57BL/6 mice were treated twice daily for 7 days with liraglutide or saline followed by induction of MI. Survival was significantly higher in liraglutide-treated mice. Lira-glutide reduced cardiac rupture (12 of 60 versus 46 of 60; P 0.0001) and infarct size (21 2 % versus 29 3%, P 0.02) an

Incretin-based therapy: a powerful and promising weapon in the treatment of type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a progressive multisystemic disease that increases significantly cardiovascular morbidity and mortality. It is associated with obesity, insulin resistance, beta-cell dysfunction, and hyperglucagonemia, the combination of which typically leads to hyperglycemia. Incretin-based treatment modalities, and in particular glucagon-like peptide 1 (GLP-1) receptor agonists, are able to successfully counteract several of the underlying pathophysiological abnormalities of T2DM. The pancreatic effects of GLP-1 receptor agonists include glucose-lowering effects by stimulating insulin secretion and inhibiting glucagon release in a strictly glucose-dependent manner, increased beta-cell proliferation, and decreased beta-cell apoptosis. GLP-1 receptors are widely expressed throughout human body; thus, GLP-1-based therapies exert pleiotropic and multisystemic effects that extend far beyond pancreatic islets. A large body of experimental and clinical data have suggested a considerable protective role of GLP-1 analogs in the cardiovascular system (decreased blood pressure, improved endothelial and myocardial function, functional recovery of failing and ischemic heart, arterial vasodilatation), kidneys (increased diuresis and natriuresis), gastrointestinal tract (delayed gastric emptying, reduced gastric acid secretion), and central nervous system (appetite suppression, neuroprotective properties). The pharmacologic use of GLP-1 receptor agonists has been shown to reduce bodyweight and systolic blood pressure, and significantly improve glycemic control and lipid profile. Interestingly, weight reduction induced by GLP-1 analogs reflects mainly loss of abdominal visceral fat. The critical issue of whether the emerging positive cardiometabolic effects of GLP-1 analogs can be translated into better clinical outcomes for diabetic patients in terms of long-term hard endpoints, such as cardiovascular morbidity and mortality, remains to be elucidated with prospective, large-scale clinical trials