N-acyl taurines and acylcarnitines cause an imbalance in insulin synthesis and secretion provoking β cell dysfunction in type 2 diabetes.

The processes contributing to β cell dysfunction in type 2 diabetes (T2D) are uncertain, largely because it is difficult to access β cells in their intact immediate environment. We examined the pathophysiology of β cells under T2D progression directly in pancreatic tissues. We used MALDI imaging of Langerhans islets (LHIs) within mouse tissues or from human tissues to generate in situ-omics data, which we supported with in vitro experiments. Molecular interaction networks provided information on functional pathways and molecules. We found that stearoylcarnitine accumulated in β cells, leading to arrest of insulin synthesis and energy deficiency via excessive β-oxidation and depletion of TCA cycle and oxidative phosphorylation metabolites. Acetylcarnitine and an accumulation of N-acyl taurines, a group not previously detected in β cells, provoked insulin secretion. Thus, β cell dysfunction results from enhanced insulin secretion combined with an arrest of insulin synthesis

A double-blind, randomized, multicenter study of MP4OX for treatment of perioperative hypotension in patients undergoing primary hip arthroplasty under spinal anesthesia

Background: MP4OX (oxygenated polyethylene glycol-modified hemoglobin) is a novel oxygen therapeutic agent specifically developed to perfuse and oxygenate tissue at risk for ischemia and hypoxia. In this study, we investigated the ability of MP4OX to treat hypotensive episodes. In addition, the tolerability profile of MP4OX in a large surgical population was established. Methods: Patients from 21 study sites in 5 countries, scheduled to undergo primary hip arthroplasty under spinal anesthesia, were randomized in a double-blind manner to receive MP4OX or hydroxyethyl starch (HES) solution (Voluven®; HES 130/0.4). Patients received the first 250-mL dose of investigational product when systolic blood pressure decreased to the predefined dosing trigger. A second 250-mL dose was given only if the systolic blood pressure decreased to the same trigger level after administration of the first dose. The primary efficacy outcome was total duration of all hypotensive episodes during surgery and the first 6 hours after skin closure. Results: Of the 474 patients randomized, 405 reached the dosing trigger and received at least 1 dose. The mean total duration of all hypotensive episodes was significantly shorter (P < 0.0001) in the MP4OX group (52.4 ± 71.50 minutes; range, 3-442 minutes) compared with the HES group (137.6 ± 120.21 minutes; range, 5-435 minutes). The overall incidence of adverse events (AEs) in the intent-to-treat population was similar between the MP4OX and HES groups (75.2% vs 73.4%; P = 0.733). Transient increases in laboratory values were reported in more patients in the MP4OX group versus HES controls for aspartate aminotransferase (13.4% vs 7.4%; P = 0.052), alanine aminotransferase (6.9% vs 4.9%; P = 0.409), lipase (9.7% vs 3.6%; P = 0.015), and troponin (8.1% vs 2.0%; P = 0.006). There was no significant difference in the incidence of serious AEs reported (6.4% in MP4OX group vs 3.0% in HES controls; P = 0.106). Certain AEs did occur more frequently in the MP4OX group, including nausea (23.8% vs 14.3%; P = 0.016), bradycardia (14.9% vs 5.9%; P = 0.003), hypertension (8.4% vs 2.5%; P = 0.009), and oliguria (5.9% vs 1.5%; P = 0.019). The composite morbidity and ischemia end points did not reveal any differences between the 2 treatment groups. Conclusions: Administration of MP4OX achieved the end point of treating perioperative hypotension in patients undergoing primary hip arthroplasty under spinal anesthesia. The study was not powered to demonstrate clinical benefit based on the composite morbidity or ischemia outcomes. Although efficacy end points with sufficient power were met, MP4OX is not being proposed for use in routine surgery where the risk-benefit profile would not be favorable based on the safety profile demonstrated in this study. Copyright © 2011 International Anesthesia Research Society.SCOPUS: ar.jinfo:eu-repo/semantics/publishe