Here, we investigated the effects of exercise training on glucose- and cholinergic-induced insulin secretion in pancreatic islets from obese and lean rats. Male Wistar rats were treated with monosodium glutamate (MSG) for the first 5 days of life, while control (CON) rats received saline. At 21 days, the rats were divided into exercised (EXE) and sedentary (SED) groups. The EXE rats swam for 30 min, 3 times/week, for 10 weeks. After this, MSG-SED rats showed hyperglycemia, hypertriglyceridemia and hyperinsulinemia. Besides, islets from MSG-SED rats exhibited increased glucose-stimulated insulin secretion (GSIS), followed by impaired glucose sensitivity, absence of glucose amplifying pathway and weak cholinergic response. In contrast, adiposity, hyperinsulinemia and hypertriglyceridemia were reduced in MSG-EXE rats. Moreover, islets from MSG-EXE rats exhibited lower GSIS and improved islet glucose sensitivity, without restoration of the glucose-amplifying pathway or alteration in the weak cholinergic effect of these islets. In islets from CON-EXE rats we also observed reduced GSIS and absence of glucose-amplifying effects and an accentuated reduction in cholinergic insulinotropic responses, without effect on glucose sensitivity in pancreatic islets from this group. Neither obesity nor exercise modified Muscarinic Receptor 3 (M3R) immunocontent or its downstream pathways (PKC and PKA). Moreover, only CON-EXE showed increased GSIS in the presence of calcium blocker, Thapsigargin. In conclusion, swimming training reduces GSIS and cholinergic responsiveness in isolated pancreatic islets from lean and hypothalamic obese rats, which could be due to the inhibition of glucose amplifying pathways.

Vancomycin and daptomycin are often used in outpatient parenteral antimicrobial therapy for gram-positive coverage. Vancomycin's narrow therapeutic window poses challenges. We retrospectively assessed acute kidney injury (AKI) and other adverse drug events in outpatient parenteral antimicrobial therapy patients receiving vancomycin or daptomycin at home after hospital discharge. Among 191 patients included, AKI was the most common adverse drug event. Early antibiotic discontinuation and AKI were more frequent in the vancomycin group. Vancomycin use (odds ratio [OR], 4.57; 95% confidence interval [CI], 1.02-20.51); p = 0.04], female sex (OR, 3.28; 95%CI, 1.41-7.67; P < .01), and longer hospitalization (OR, 1.06; 95%CI, 1.01-1.11; P = .02] independently predicted moderate-to-severe AKI. In the vancomycin group, trough concentrations increased after discharge, and were higher in female compared to male patients, and in those who developed moderate-to-severe AKI compared to those who did not. Female sex (OR, 8.37; 95%CI, 2.35-29.82; P < .01) and higher concentrations (OR, 1.12; 95%CI, 1.05-1.19; P < .01) predicted moderate-to-severe AKI in patients receiving vancomycin. In conclusion, premature antibiotic discontinuations and nephrotoxicity are more frequent in patients treated at home with vancomycin compared to daptomycin. Among patients receiving vancomycin, plasma concentrations increased after hospital discharge and predicted moderate-to-severe AKI. Women had higher vancomycin concentrations and higher risk for AKI.

Adipose tissue inflammation is closely associated with the development of obesity and insulin resistance. Free fatty acids (FFAs) are a major inducer of obesity-related insulin resistance. Previously, we reported that endoplasmic reticulum (ER) stress potentially mediated retinal inflammation in diabetic retinopathy. The unfolded protein response (UPR) protects cells against damage induced by oxidative stress. X-box binding protein 1 (XBP1) plays a major role in protecting cells by modulating the UPR. However, the link between ER stress and adipocyte inflammation has been poorly investigated. In the present study, we found that pretreatment of 3T3-L1 adipocytes with a low dose of ER stress inducer tunicamycin inhibited FFA-induced upregulated expression of inflammatory cytokines. In addition, FFAs induced phosphorylation of the p65 subunit of NF-κB was largely inhibited by pretreatment with tunicamycin in 3T3-L1 adipocytes. Knockdown of XBP1 by siRNA markedly mitigated the protective effects of preconditioning against inflammation. Conversely, overexpression of XBP1 alleviated FFA-induced phosphorylation of IκB-α, IKKα/β, and NF-κB, which was accompanied by decreased inflammatory cytokine expression. Collectively, these results imply a beneficial role of ER stress preconditioning in protecting against FFA-induced 3T3-L1 adipocyte inflammation, which is likely mediated through inhibition of the IKK/NF-κB pathway via XBP1.