Exenatide once-weekly (EQW [2 mg s.c.]) is under development as monotherapy as an adjunct to diet and exercise or as a combination therapy with an oral antidiabetes drug(s) in adults with type 2 diabetes. This longacting formulation contains the active ingredient of the original exenatide twice-daily (EBID) formulation encapsulated in 0.06-mm-diameter microspheres of medical-grade poly-(d,l-lactide-co-glycolide) (PLG). After mechanical suspension and subcutaneous injection by the patient, EQW microspheres hydrate in situ and adhere to one another to form an amalgam. A small amount of loosely bound surface exenatide, typically less than 1%, releases in the first few hours, whereas drug located in deeper interstices diffuses out more slowly (time to maximum, *2 weeks). Fully encapsulated exenatide (i.e., drug initially inaccessible to diffusion) releases over a still longer period (time to maximum, *7 weeks) as the PLG matrix hydrolyzes into lactic acid and glycolic acid, which are subsequently eliminated as carbon dioxide and water. For EQW, plasma exenatide concentrations reach the therapeutic range by 2 weeks and steady state by 6-7 weeks. This gradual approach to steady state seems to improve tolerability, as nausea is less frequent with EQW than EBID. EQW administrations may be associated with palpable skin nodules that generally resolve without further medical intervention. In comparative trials, EQW improved hemoglobin A1c more than EBID, sitagliptin, pioglitazone, or insulin glargine and reduced fasting plasma glucose more than EBID. Weight loss due to EQW or EBID was similar. EQW is the first glucose-lowering agent that is administered once weekly.

The major goal in the treatment of type 2 diabetes mellitus is to control the hyperglycaemia characteristic of the disease. However, treatment with common therapies such as insulin or insulinotrophic sulphonylureas (SU), while effective in reducing hyperglycaemia, may impose a greater risk of hypoglycaemia, as neither therapy is self-regulated by ambient blood glucose concentrations. Hypoglycaemia has been associated with adverse physical and psychological outcomes and may contribute to negative cardiovascular events; hence minimization of hypoglycaemia risk is clinically advantageous. Stimulation of insulin secretion from pancreatic β-cells by glucagon-like peptide 1 receptor (GLP-1R) agonists is known to be glucose-dependent. GLP-1R agonists potentiate glucose-stimulated insulin secretion and have little or no activity on insulin secretion in the absence of elevated blood glucose concentrations. This ‘glucose-regulated’ activity of GLP-1R agonists makes them useful and potentially safer therapeutics for overall glucose control compared to non-regulated therapies; hyperglycaemia can be reduced with minimal hypoglycaemia. While the inherent mechanism of action of GLP-1R agonists mediates their glucose dependence, studies in rats suggest that SUs may uncouple this dependence. This hypothesis is supported by clinical studies showing that the majority of events of hypoglycaemia in patients treated with GLP-1R agonists occur in patients treated with a concomitant SU. This review aims to discuss the current understanding of the mechanisms by which GLP-1R signalling promotes insulin secretion from pancreatic β-cells via a glucose-dependent process.

All of the incretin-based therapies in the present meta-analysis were associated with significant reductions from baseline in HbA(1c) and FPG. Further direct comparative studies between the GLP-1RAs and the DPP-4 inhibitors and within the GLP-1RA class are justified.

Background-Human atherosclerotic lesions contain elevated levels of urokinase plasminogen activator (uPA), expressed predominantly by macrophages. Methods and Results-To test the hypothesis that macrophage-expressed uPA contributes to the progression and complications of atherosclerosis, we generated transgenic mice with macrophage-targeted overexpression of uPA. The uPA transgene was bred into the apolipoprotein E-null background, and transgenic mice and nontransgenic littermate controls were fed an atherogenic diet. uPA-transgenic mice had significantly elevated uPA activity in the atherosclerotic artery wall, of a magnitude similar to elevations reported in atherosclerotic human arteries. Compared with littermate controls, uPA-transgenic mice had accelerated atherosclerosis, dilated aortic roots, occlusive proximal coronary artery disease, myocardial infarcts, and early mortality. Conclusions-These data support the hypothesis that overexpression of uPA by artery wall macrophages is atherogenic and suggest that uPA inhibitors might be therapeutically useful.

Abstract-Fas ligand (FasL) is expressed by cells of the arterial wall and is present in human atherosclerotic lesions.However, the role of FasL in modifying the initiation and progression of atherosclerosis is unclear.

Background-Elevated plasma levels of plasminogen activator inhibitor type 1 (PAI-1) are associated with myocardial infarction, atherosclerosis, and restenosis. PAI-1 is increased in atherosclerotic arteries and failed vein grafts. No experimental data, however, support a causal relationship between elevated PAI-1 expression and vascular lesions. Paradoxically, data generated in PAI-1 knockout mice suggest that PAI-1 might decrease lesion formation after arterial injury and that PAI-1 gene transfer might prevent restenosis. Methods and Results-Using the rat carotid balloon injury model and a PAI-1-expressing adenoviral vector, we tested whether elevated arterial PAI-1 expression would alter neointima formation. Compared with control-transduced arteries, neointima formation in PAI-1-transduced arteries was initially retarded. By 14 days, however, the intimas of PAI-1-transduced arteries were significantly larger than intimas of control-transduced arteries (1.6Ϯ0.1ϫ10 5 versus 1.2Ϯ0.1ϫ10 5 m 2 , nϭ18 to 19, PϽ0.03). PAI-1 expression in individual arteries correlated with increased cell proliferation at 4 and 8 days after injury (Rϭ0.6, PϽ0.02 and PϽ0.006). PAI-1 expression also correlated with fibrin(ogen) accumulation (Rϭ0.77, PϽ0.001), and fibrin(ogen) accumulation correlated strongly with proliferation (Rϭ0.86, PϽ0.00001). Conclusions-Increased expression of PAI-1 in the artery wall promotes neointima growth after balloon injury. Therefore, despite encouraging data generated in other animal models, PAI-1 is not a promising agent for gene therapy to prevent restenosis. Moreover, our data associate elevated PAI-1 expression with fibrin(ogen) accumulation and increased cell proliferation. These data suggest a mechanism to explain the association between elevated PAI-1 expression and the progression of arterial disease.

Overexpression of urokinase plasminogen activator (uPA) in endothelial cells can decrease intravascular thrombosis. However, expression of uPA is increased in atherosclerotic human arteries, which suggests that uPA might accelerate atherogenesis. To investigate whether elevated uPA expression accelerates atherogenesis, we cloned a rabbit uPA cDNA and expressed it in carotid arteries of cholesterol-fed rabbits. uPA gene transfer increased artery-wall uPA activity for at least 1 week, with a return to baseline by 2 weeks. One week after gene transfer, uPA-transduced arteries were constricted, with significantly smaller lumens and thicker walls, but no difference in intimal or medial mass. Two weeks after gene transfer, uPA-and control-transduced arteries were morphologically indistinguishable. By 4 weeks, however, uPA-transduced arteries had 70% larger intimas than control-transduced arteries (P < 0.01) and smaller lumens (P < 0.05). Intimal lesions appeared to be of similar composition in uPA-and control-transduced arteries, except that degradation of elastic laminae was evident in uPA-transduced arteries. These data suggest that elevated uPA expression in atherosclerotic arteries contributes to intimal growth and constrictive remodeling leading to lumen loss. Antagonists of uPA activity might, therefore, be useful in limiting intimal growth and preventing constrictive remodeling. Overexpression of uPA in endothelial cells to prevent intravascular thrombosis must be reconsidered, because this intervention could worsen underlying vascular disease.

Regions of the negative strands of the satellite RNAs of chicory yellow mottle virus (sCYMV1) and arabis mosaic virus (sArMV) have similarity in sequence and predicted secondary structure compared to the tobacco ringspot virus satellite RNA (sTRSV) hairpin ribozyme, suggesting that they may also be catalytic RNAs of a similar type. Our experiments show that the hairpin ribozyme-like sequences derived from sCYMV1 and sArMV have high phosphodiesterase activity. The Kcat values determined are similar to that of the highly active native sTRSV hairpin ribozyme under the same conditions, although the Km values are much higher. The Km of the sArMV ribozyme was reduced 3-fold, with no change in kcat, by extending substrate hybridization in helix 2. Additionally, the three hairpin ribozymes prefer different GUX sequences on the immediate 3'-side of the cleavage site. The sTRSV hairpin ribozyme cleaves GUX substrates with catalytic efficiencies in the relative order GUC >> GUU > GUG = GUA. The sCYMV1 ribozyme cleaves GUA > GUC, GUG, GUU. The sArMV ribozyme prefers GUA > GUG > GUU > GUC. The functional domain, regulating substrate selection at this position, must reside in the nucleotides that vary between the ribozyme--substrate complexes. The sTRSV ribozyme is most efficient at cleaving GUC complexes, while the sCYMV1 and sArMV ribozymes are most efficient for cleaving GUA-containing sequences.