Alternative splicing variant of the scaffold protein APPL1 suppresses hepatic adiponectin signaling and function.

Adiponectin is an adipocyte-derived hormone with antidiabetic activities that include increasing the sensitivity of cells to insulin. Adaptor protein containing pleckstrin homology domain, phosphotyrosine-binding domain, and leucine zipper motif (APPL1) stimulates adiponectin signaling and promotes adiponectin's insulin-sensitizing effects by binding to two adiponectin receptors, AdipoR1 and AdipoR2, and the insulin receptor. In this study, we report an alternative splicing variant of APPL1 (APPL1sv) that is highly expressed in mouse liver, pancreas, and spleen tissues. The expression levels of APPL1sv in liver tissues were enhanced in a mouse model of obesity and diabetic dyslipidemia (i.e. db/db mice) and reduced in calorie-restricted mice compared with ad libitum-fed mice. APPL1sv overexpression or suppression inhibited or enhanced, respectively, adiponectin-stimulated phosphorylation of AMP protein kinase (AMPK) in mouse hepatocytes. We also found that APPL1sv binds to AdipoR1 and AdipoR2 under basal conditions and that adiponectin treatment reduces this binding. Overexpression of APPL1sv blocked adiponectin-induced interactions of APPL1 with the adiponectin receptors. Moreover, adenovirus-mediated and short hairpin RNA-based suppression of APPL1sv greatly reduced high fat diet-induced insulin resistance and hepatic glucose production in mice. Our study identifies a key suppressor of hepatic adiponectin signaling and insulin sensitivity, a finding that may shed light on identifying effective therapeutic targets for treating insulin resistance and type 2 diabetes.

Combined carotid endarterectomy and coronary artery bypass grafting versus coronary artery bypass grafting alone: a retrospective review of outcomes at our institution.

BACKGROUND: It remains controversial whether patients with concomitant carotid and coronary disease should undergo operative repair separately or in combination. METHODS: Patients with documented cerebrovascular disease undergoing coronary artery bypass grafting (CABG) alone were matched by propensity scoring with patients undergoing combined carotid endarterectomy (CEA)/CABG procedures and compared for the occurrence of stroke, myocardial infarction (MI), and mortality. RESULTS: Of the 4943 patients undergoing CABG, 908 had known cerebrovascular disease. Among these, 134 underwent concomitant CEA, and these were propensity matched with 134 patients undergoing CABG only. No differences were observed in the perioperative risks of stroke (4% vs 3%, odds ratio [OR] 1.5, 95% confidence interval [CI] 0.4-5.5), MI (0.7% vs 0.7%, not significant [NS]), or combined cardiovascular events (6% vs 10%, OR 0.5, 95% CI [0.2-1.3]), although mortality (1% vs 8%, OR 0.2, 95% CI [0.04-0.8] was higher with CABG only. DISCUSSION: Addition of CEA to CABG did not significantly alter the risk of perioperative stroke relative to propensity-matched patients undergoing CABG alone.