Sustainability certification systems as guidelines for early-phase urban design processes

The German Sustainable Building Council (Deutsche Gesellschaft für Nachhaltiges Bauen or DGNB) has one of the most comprehensive sustainability certification systems for urban districts (UD). Their explicit aim is that the system should impact the very earliest design decisions. The Technical University of Denmark has tested the DGNB-UD system in two experimental design projects for similar locations to find out how it can be used in the early-phase design process. This paper describes these two independent design processes, compares them and discusses their general features. We found that DGNB-UD addresses a broad sustainable focus and can be used as a tool for setting sustainability goals from the very first design steps. The system tends to promote multifunctional compromise solutions that meet several criteria at the same time. Using the DGNB-UD certification system in the early design phases therefore does have some effect on the urban design in terms of a bias towards certain design traits. </jats:p

The Discovery and Development of Liraglutide and Semaglutide

The discovery of glucagon-like peptide-1 (GLP-1), an incretin hormone with important effects on glycemic control and body weight regulation, led to efforts to extend its half-life and make it therapeutically effective in people with type 2 diabetes (T2D). The development of short- and then long-acting GLP-1 receptor agonists (GLP-1RAs) followed. Our article charts the discovery and development of the long-acting GLP-1 analogs liraglutide and, subsequently, semaglutide. We examine the chemistry employed in designing liraglutide and semaglutide, the human and non-human studies used to investigate their cellular targets and pharmacological effects, and ongoing investigations into new applications and formulations of these drugs. Reversible binding to albumin was used for the systemic protraction of liraglutide and semaglutide, with optimal fatty acid and linker combinations identified to maximize albumin binding while maintaining GLP-1 receptor (GLP-1R) potency. GLP-1RAs mediate their effects via this receptor, which is expressed in the pancreas, gastrointestinal tract, heart, lungs, kidneys, and brain. GLP-1Rs in the pancreas and brain have been shown to account for the respective improvements in glycemic control and body weight that are evident with liraglutide and semaglutide. Both liraglutide and semaglutide also positively affect cardiovascular (CV) outcomes in individuals with T2D, although the precise mechanism is still being explored. Significant weight loss, through an effect to reduce energy intake, led to the approval of liraglutide (3.0 mg) for the treatment of obesity, an indication currently under investigation with semaglutide. Other ongoing investigations with semaglutide include the treatment of non-alcoholic fatty liver disease (NASH) and its use in an oral formulation for the treatment of T2D. In summary, rational design has led to the development of two long-acting GLP-1 analogs, liraglutide and semaglutide, that have made a vast contribution to the management of T2D in terms of improvements in glycemic control, body weight, blood pressure, lipids, beta-cell function, and CV outcomes. Furthermore, the development of an oral formulation for semaglutide may provide individuals with additional benefits in relation to treatment adherence. In addition to T2D, liraglutide is used in the treatment of obesity, while semaglutide is currently under investigation for use in obesity and NASH

Treatment with glucagon-like peptide-1 receptor agonists and incidence of dementia:Data from pooled double-blind randomized controlled trials and nationwide disease and prescription registers

INTRODUCTION: People with type 2 diabetes have increased risk of dementia. Glucagon‐like peptide‐1 (GLP‐1) receptor agonists (RAs) are among the promising therapies for repurposing as a treatment for Alzheimer's disease; a key unanswered question is whether they reduce dementia incidence in people with type 2 diabetes. METHODS: We assessed exposure to GLP‐1 RAs in patients with type 2 diabetes and subsequent diagnosis of dementia in two large data sources with long‐term follow‐up: pooled data from three randomized double‐blind placebo‐controlled cardiovascular outcome trials (15,820 patients) and a nationwide Danish registry‐based cohort (120,054 patients). RESULTS: Dementia rate was lower both in patients randomized to GLP‐1 RAs versus placebo (hazard ratio [HR]: 0.47 (95% confidence interval [CI]: 0.25–0.86) and in the nationwide cohort (HR: 0.89; 95% CI: 0.86–0.93 with yearly increased exposure to GLP‐1 RAs). DISCUSSION: Treatment with GLP‐1 RAs may provide a new opportunity to reduce the incidence of dementia in patients with type 2 diabetes

Semaglutide treatment attenuates vessel remodelling in ApoE-/- mice following vascular injury and blood flow perturbation.

BACKGROUND AND AIMS Randomized clinical studies have shown a reduction in cardiovascular outcomes with glucagon-like peptide 1 receptor agonist (GLP-1RA) treatment with the hypothesized mechanisms being an underlying effect on atherosclerosis. Here, we aimed to assess the pharmacological effects of semaglutide in an atheroprone murine model that recapitulates central mechanisms related to vascular smooth muscle cell (VSMC) phenotypic switching and endothelial dysfunction known to operate within the atherosclerotic plaque. METHODS In study A, we employed an electrical current to the carotid artery in ApoE-/- mice to induce severe VSMC injury and death, after which the arteries were allowed to heal for 4 weeks. In study B, a constrictive cuff was added for 6 h at the site of the healed segment to induce a disturbance in blood flow. RESULTS Compared to vehicle, semaglutide treatment reduced the intimal and medial area by ∼66% (p = 0.007) and ∼11% (p = 0.0002), respectively. Following cuff placement, expression of the pro-inflammatory marker osteopontin and macrophage marker Mac-2 was reduced (p < 0.05) in the semaglutide-treated group compared to vehicle. GLP-1R were not expressed in murine carotid artery and human coronary vessels with and without atherosclerotic plaques, and semaglutide treatment did not affect proliferation of cultured primary human VSMCs. CONCLUSIONS Semaglutide treatment reduced vessel remodelling following electrical injury and blood flow perturbation in an atheroprone mouse model. This effect appears to be driven by anti-inflammatory and -proliferative mechanisms independent of GLP-1 receptor-mediated signalling in the resident vascular cells. This mechanism of action may be important for cardiovascular protection.This study was supported by a grant from the LifePharm Centre of In Vivo Pharmacology.S

Integrated Brain Atlas for Unbiased Mapping of Nervous System Effects Following Liraglutide Treatment

Light Sheet Fluorescence Microscopy (LSFM) of whole organs, in particular the brain, offers a plethora of biological data imaged in 3D. This technique is however often hindered by cumbersome non-Automated analysis methods. Here we describe an approach to fully automate the analysis by integrating with data from the Allen Institute of Brain Science (AIBS), to provide precise assessment of the distribution and action of peptide-based pharmaceuticals in the brain. To illustrate this approach, we examined the acute central nervous system effects of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide. Peripherally administered liraglutide accessed the hypothalamus and brainstem, and led to activation in several brain regions of which most were intersected