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

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes

Elevated tibiofemoral articular contact stress predicts risk for bone marrow lesions and cartilage damage at 30 months

OBJECTIVE: As cartilage loss and bone marrow lesions (BMLs) are associated with knee joint pain and structural worsening, this study assessed whether non-invasive estimates of articular contact stress may longitudinally predict risk for worsening of knee cartilage morphology and BMLs. DESIGN: This was a longitudinal cohort study of adults aged 50-79 years with risk factors for knee osteoarthritis. Baseline and follow-up measures included WORMS classification of knee cartilage morphology and BMLs. Tibiofemoral geometry was manually segmented on baseline MRI, and 3D tibiofemoral point clouds were registered into subject-specific loaded apposition using fixed-flexion knee radiographs. Discrete element analysis (DEA) was used to estimate mean and peak contact stresses for the medial and lateral compartments. The association of baseline contact stress with worsening cartilage and BMLs in the same sub-region over 30 months was assessed using conditional logistic regression. RESULTS: Subjects (N=38, 60.5% female) had a mean±SD age and BMI of 63.5±8.4 years and 30.5±3.7 kg/m(2) respectively. Elevated mean articular contact stress at baseline was associated with worsening cartilage morphology and worsening BMLs by 30-months, with OR (95%CI) of 4.0 (2.5, 6.4) and 6.6 (2.7, 16.5) respectively. Peak contact stress also was significantly associated with worsening cartilage morphology and BMLs {1.9 (1.5, 2.3) and 2.3 (1.5, 3.6)}(all p<0.0001). CONCLUSIONS: Detection of higher contact stress 30 months prior to structural worsening suggests an etiological role for mechanical loading. Estimation of articular contact stress with DEA is an efficient and accurate means of predicting sub-region-specific knee joint worsening and may be useful in guiding prognosis and treatment

Progress in nitrogen deposition monitoring and modelling

The chapter reviews progress in monitoring and modelling of atmospheric nitrogen (N) deposition at regional and global scales. The Working Group expressed confidence in the inorganic N wet deposition estimates in U.S., eastern Canada, Europe and parts of East Asia. But, long-term wet or dry N deposition information in large parts of Asia, South America, parts of Africa, Australia/Oceania, and oceans and coastal areas is lacking. Presently, robust estimates are only available for inorganic N as existing monitoring generally does not measure the complete suite of N species, impeding the closing of the atmospheric N budget. The most important species not routinely measured are nitrogen dioxide (NO2), ammonia (NH3), organic N and nitric acid (HNO3). Uncertainty is much higher in dry deposition than in wet deposition estimates. Inferential modelling (combining air concentrations with exchange rates) and direct flux measurements are good tools to estimate dry deposition; however, they are not widely applied. There is a lack of appropriate parameterizations for different land uses and compounds for input into inferential models. There is also a lack of direct dry deposition flux measurements to test inferential models and atmospheric model estimates