Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies

Perspective taking and systematic biases in object location memory.

The aim of the current study was to develop a novel task that allows for the quick assessment of spatial memory precision with minimal technical and training requirements. In this task, participants memorized the position of an object in a virtual room and then judged from a different perspective, whether the object has moved to the left or to the right. Results revealed that participants exhibited a systematic bias in their responses that we termed the reversed congruency effect. Specifically, they performed worse when the camera and the object moved in the same direction than when they moved in opposite directions. Notably, participants responded correctly in almost 100% of the incongruent trials, regardless of the distance by which the object was displaced. In Experiment 2, we showed that this effect cannot be explained by the movement of the object on the screen, but that it relates to the perspective shift and the movement of the object in the virtual world. We also showed that the presence of additional objects in the environment reduces the reversed congruency effect such that it no longer predicts performance. In Experiment 3, we showed that the reversed congruency effect is greater in older adults, suggesting that the quality of spatial memory and perspective-taking abilities are critical. Overall, our results suggest that this effect is driven by difficulties in the precise encoding of object locations in the environment and in understanding how perspective shifts affect the projected positions of the objects in the two-dimensional image

Running non-minimal inflation with stabilized inflaton potential

Abstract In the context of the Higgs model involving gauge and Yukawa interactions with the spontaneous gauge symmetry breaking, we consider $$\lambda \phi ^4$$ λ ϕ 4 inflation with non-minimal gravitational coupling, where the Higgs field is identified as the inflaton. Since the inflaton quartic coupling is very small, once quantum corrections through the gauge and Yukawa interactions are taken into account, the inflaton effective potential most likely becomes unstable. In order to avoid this problem, we need to impose stability conditions on the effective inflaton potential, which lead to not only non-trivial relations amongst the particle mass spectrum of the model, but also correlations between the inflationary predictions and the mass spectrum. For concrete discussion, we investigate the minimal $$B-L$$ B - L extension of the standard model with identification of the $$B-L$$ B - L Higgs field as the inflaton. The stability conditions for the inflaton effective potential fix the mass ratio amongst the $$B-L$$ B - L gauge boson, the right-handed neutrinos and the inflaton. This mass ratio also correlates with the inflationary predictions. In other words, if the $$B-L$$ B - L gauge boson and the right-handed neutrinos are discovered in the future, their observed mass ratio provides constraints on the inflationary predictions

Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis

BACKGROUND & AIMS: The prevalence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is increasing at an alarming rate. The role of bile acids in the development and progression of NAFLD to NASH and cirrhosis is poorly understood. This study aimed to quantify the bile acid metabolome in healthy subjects and patients with non-cirrhotic NASH under fasting conditions and after a standardized meal. METHODS: Liquid chromatography tandem mass spectroscopy was used to quantify 30 serum and 16 urinary bile acids from 15 healthy volunteers and 7 patients with biopsy-confirmed NASH. Bile acid concentrations were measured at two fasting and four post-prandial timepoints following a high-fat meal to induce gallbladder contraction and bile acid reabsorption from the intestine. RESULTS: Patients with NASH had significantly higher total serum bile acid concentrations than healthy subjects under fasting conditions (2.2- to 2.4-fold increase in NASH; NASH: 2595–3549 μM and healthy: 1171–1458 μM) and at all post-prandial time points (1.7- to 2.2-fold increase in NASH; NASH: 4444–5898 μM and healthy: 2634–2829 μM). These changes were driven by increased taurine- and glycine-conjugated primary and secondary bile acids. Patients with NASH exhibited greater variability in their fasting and post-prandial bile acid profile. CONCLUSIONS: Results indicate that patients with NASH have higher fasting and post-prandial exposure to bile acids, including the more hydrophobic and cytotoxic secondary species. Increased bile acid exposure may be involved in liver injury and the pathogenesis of NAFLD and NASH