| Title |
Brain GLP-1/IGF-1 Signaling and Autophagy Mediate Exendin-4 Protection Against Apoptosis in Type 2 Diabetic Rats
|
|---|---|
| Published in |
Molecular Neurobiology, June 2017
|
| DOI | 10.1007/s12035-017-0622-3 |
| Pubmed ID | |
| Authors |
Emanuel Candeias, Inês Sebastião, Susana Cardoso, Cristina Carvalho, Maria Sancha Santos, Catarina Resende Oliveira, Paula I. Moreira, Ana I. Duarte |
| Abstract |
Type 2 diabetes (T2D) is a modern socioeconomic burden, mostly due to its long-term complications affecting nearly all tissues. One of them is the brain, whose dysfunctional intracellular quality control mechanisms (namely autophagy) may upregulate apoptosis, leading to cognitive dysfunction and Alzheimer disease (AD). Since impaired brain insulin signaling may constitute the crosslink between T2D and AD, its restoration may be potentially therapeutic herein. Accordingly, the insulinotropic anti-T2D drugs from glucagon-like peptide-1 (GLP-1) mimetics, namely, exendin-4 (Ex-4), could be a promising therapy. In line with this, we hypothesized that peripherally administered Ex-4 rescues brain intracellular signaling pathways, promoting autophagy and ultimately protecting against chronic T2D-induced apoptosis. Thus, we aimed to explore the effects of chronic, continuous, subcutaneous (s.c.) exposure to Ex-4 in brain cortical GLP-1/insulin/insulin-like growth factor-1 (IGF-1) signaling, and in autophagic and cell death mechanisms in middle-aged (8 months old), male T2D Goto-Kakizaki (GK) rats. We used brain cortical homogenates obtained from middle-aged (8 months old) male Wistar (control) and T2D GK rats. Ex-4 was continuously administered for 28 days, via s.c. implanted micro-osmotic pumps (5 μg/kg/day; infusion rate 2.5 μL/h). Peripheral characterization of the animal models was given by the standard biochemical analyses of blood or plasma, the intraperitoneal glucose tolerance test, and the heart rate. GLP-1, insulin, and IGF-1, their downstream signaling and autophagic markers were evaluated by specific ELISA kits and Western blotting. Caspase-like activities and other apoptotic markers were given by colorimetric methods and Western blotting. Chronic Ex-4 treatment attenuated peripheral features of T2D in GK rats, including hyperglycemia and insulin resistance. Furthermore, s.c. Ex-4 enhanced their brain cortical GLP-1 and IGF-1 levels, and subsequent signaling pathways. Specifically, Ex-4 stimulated protein kinase A (PKA) and phosphoinositide 3-kinase (PI3K)/Akt signaling, increasing cGMP and AMPK levels, and decreasing GSK3β and JNK activation in T2D rat brains. Moreover, Ex-4 regulated several markers for autophagy in GK rat brains (as mTOR, PI3K class III, LC3 II, Atg7, p62, LAMP-1, and Parkin), ultimately protecting against apoptosis (by decreasing several caspase-like activities and mitochondrial cytochrome c, and increasing Bcl2 levels upon T2D). Altogether, this study demonstrates that peripheral Ex-4 administration may constitute a promising therapy against the chronic complications of T2D affecting the brain. |
X Demographics
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Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 2 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 2 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 76 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 76 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 12 | 16% |
| Student > Bachelor | 10 | 13% |
| Student > Master | 9 | 12% |
| Researcher | 8 | 11% |
| Professor | 5 | 7% |
| Other | 12 | 16% |
| Unknown | 20 | 26% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 16 | 21% |
| Biochemistry, Genetics and Molecular Biology | 8 | 11% |
| Neuroscience | 8 | 11% |
| Agricultural and Biological Sciences | 6 | 8% |
| Pharmacology, Toxicology and Pharmaceutical Science | 4 | 5% |
| Other | 7 | 9% |
| Unknown | 27 | 36% |
Attention Score in Context
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 02 May 2018.
All research outputs
#14,349,470
of 22,977,819 outputs
Outputs from Molecular Neurobiology
#1,833
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Outputs of similar age
#177,375
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Outputs of similar age from Molecular Neurobiology
#57
of 132 outputs
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