Rabbit Anti-Human IRS1 (Phospho-Tyr896) polyclonal antibody

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, accompanied by memory loss and cognitive impairments, and there is no effective treatment for it at present. Since type 2 diabetes (T2DM) has been identified as a risk factor for AD, the incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP), promising antidiabetic agents for the treatment of type 2 diabetes, have been tested in models of neurodegenerative disease including AD and achieved good results. Here we show for the first time the potential neuroprotective effect of a novel dual GLP-1/GIP receptor agonist (DA-JC4) in the icy. streptozotocin (STZ)-induced AD rat model. Treatment with DA-JC4 (10 nmol/kg ip.) once-daily for 14 days after STZ intracerebroventricular (ICV) administration significantly prevented spatial learning deficits in a Y-maze test and Morris water maze tests, and decreased phosphorylated tau levels in the rat cerebral cortex and hippocampus. DA-JC4 also alleviated the chronic inflammation response in the brain (GFAP-positive astrocytes, IBA1-positive microglia). Apoptosis was reduced as shown in the reduced ratio of pro-apoptotic BAX to anti-apoptotic Bcl-2 levels. Importantly, insulin signaling was re-sensitized as evidenced by a reduction of phospho-IRS1(Ser1101) levels and phospho-Akt(ser473) up-regulation. In conclusion, the novel dual agonist DA-JC4 shows promise as a novel treatment for sporadic AD, and reactivating insulin signaling pathways may be a key mechanism that prevents disease progression in AD. (C) 2017 Elsevier B.V. All rights reserved.

Very little is known about how long-term (>6 months) adaptation to a low-carbohydrate, high-fat (LCHF) diet affects insulin signaling in healthy, well-trained individuals. This study compared glucose tolerance; skeletal muscle glucose transporter 4 (GLUT4) and insulin receptor substrate 1 (IRS1) content; and muscle enzyme activities representative of the main energy pathways (3-hydroxyacetyl-CoA dehydrogenase, creatine kinase, citrate synthase, lactate dehydrogenase, phosphofructokinase, phosphorylase) in trained cyclists who followed either a long-term LCHF or a mixed-macronutrient (Mixed) diet. On separate days, a 2-hr oral glucose tolerance test was conducted, and muscle samples were obtained from the vastus lateralis of fasted participants. The LCHF group had reduced glucose tolerance compared with the Mixed group, as plasma glucose concentrations were significantly higher throughout the oral glucose tolerance test and serum insulin concentrations peaked later (LCHF, 60 min; Mixed, 30 min). Whole-body insulin sensitivity was not statistically significantly different between groups (Matsuda index: LCHF, 8.7 +/- 3.4 vs. Mixed, 12.9 +/- 4.6; p = .08). GLUT4 (LCHF: 1.13 +/- 0.24; Mixed: 1.44 +/- 0.16; p = .026) and IRS1 (LCHF: 0.25 +/- 0.13; Mixed: 0.46 +/- 0.09; p = .016) protein content was lower in LCHF muscle, but enzyme activities were not different. We conclude that well-trained cyclists habituated to an LCHF diet had reduced glucose tolerance compared with matched controls on a mixed diet. Lower skeletal muscle GLUT4 and IRS1 contents may partially explain this finding. This could possibly reflect an adaptation to reduced habitual glucose availability rather than the development of a pathological insulin resistance.