Depression, glycemic control and type 2 diabetes

<p>Abstract</p> <p>Background</p> <p>Comorbid depression in diabetes has been suggested as one of the possible causes of an inadequate glycemic control. The purpose of this study was to investigate the association between major depression and the glycemic control of type 2 diabetes mellitus (T2DM).</p> <p>Methods</p> <p>Seventy T2DM patients were evaluated. They underwent a psychiatric examination using the following instruments: Structured Clinical Interview for DSM-IV and Beck Depression Inventory. The diabetes status was assessed in the short-term (glycemia, glycated hemoglobin) clinical control.</p> <p>Results</p> <p>The presence of current depression was observed in 18.6% (13/70). In addition, type 2 diabetes patients who displayed depression evidenced higher levels of glycated hemoglobin (8.6 ± 2.0 vs. 7.5 ± 1.8; p = 0.05) when compared to those who did not exhibit a mood disorder.</p> <p>Conclusions</p> <p>In our sample, the presence of depression seems to impact on the short-term control of T2DM. The authors discuss the clinical utility of these findings in the usual treatment of diabetes.</p

Oligomerization of Cu,Zn-Superoxide Dismutase (SOD1) by Docosahexaenoic Acid and Its Hydroperoxides In Vitro: Aggregation Dependence on Fatty Acid Unsaturation and Thiols.

Docosahexaenoic acid (C22:6, n-3, DHA) is a polyunsaturated fatty acid highly enriched in the brain. This fatty acid can be easily oxidized yielding hydroperoxides as primary products. Cu, Zn-Superoxide dismutase (SOD1) aggregation is a common hallmark of Amyotrophic Lateral Sclerosis (ALS) and the molecular mechanisms behind their formation are not completely understood. Here we investigated the effect of DHA and its hydroperoxides (DHAOOH) on human SOD1 oligomerization in vitro. DHA induced the formation of high-molecular-weight (HMW) SOD1 species (>700 kDa). Aggregation was dependent on free thiols and occurred primarily with the protein in its apo-form. SOD1 incubation with DHA was accompanied by changes in protein structure leading to exposure of protein hydrophobic patches and formation of non-amyloid aggregates. Site-directed mutagenesis studies demonstrated that Cys 6 and Cys 111 in wild-type and Cys 6 in ALS-linked G93A mutant are required for aggregation. In contrast, DHAOOH did not induce HMW species formation but promoted abnormal covalent dimerization of apo-SOD1 that was resistant to SDS and thiol reductants. Overall, our data demonstrate that DHA and DHAOOH induce distinct types of apo-SOD1 oligomerization leading to the formation of HMW and low-molecular-weight species, respectively

Aggregation of apo-SOD1 WT and G93A in the presence of different fatty acids analyzed by size-exclusion chromatography.

<p>Typical chromatograms obtained for the incubations of apo-SOD1 WT (A) or G93A mutant (B) with different fatty acids. All incubations were performed with 10 μM of the protein and 250 μM of each fatty acid at 37°C for 24 h. Arrows indicate the SOD1 main peak and brackets indicate the SOD1 oligomers. Chromatograms are representative of at least 3 independent experiments.</p

Role of Cys 6 and Cys 111 on DHA induced apo-SOD1 aggregation.

<p>C6S and C111S mutants of apo-SOD1 (10 μM) WT (<b>A</b>) and G93A (<b>B</b>) were incubated in the absence and presence of DHA (250 μM). Percentages of aggregates formed in the incubation were determined by size-exclusion chromatography analysis. The results were presented by means ± standard deviations of three experiments. Significant differences are indicated with * when <i>p<0</i>.<i>01</i>. Dots represent individual values.</p

Nature of the apo-SOD1 aggregates formed in the presence of DHA or DHAOOH.

<p>Representative bis-ANS fluorescence spectra obtained for the control incubations containing DHA, DHAOOH or H₂O₂ without the protein (A); and for the incubations containing the (B) apo-SOD1 WT or (C) apo-SOD1 G93A incubated in the presence of DHA, DHAOOH or H₂O₂. Transmission electronic microscopy (TEM) of the apo-SOD1 WT or G93A mutant incubated with DHA (D). Two sets of images, one with the scale bar of 500 nm (upper panel) and the other of 100 nm (lower panel) are shown. Images are representative of two experiments. Representative visible spectra of congo red (CR) in the absence and presence of apo-SOD1 WT or G93A mutant pre-incubated with DHA or DHAOOH. Samples were added to the CR solution to give a final concentration of 6 μM of CR. All incubations were conducted in the presence of 10 μM protein and 250 μM of the lipid or H₂O₂ at 37°C for 24 h.</p

Analysis of apo-SOD1 aggregates by size-exclusion chromatography.

<p>Apo-SOD1 WT incubated in the absence (<b>A</b>) and presence of 250 μM of DHA (<b>B</b>), DHAOOH <b>(C)</b> or H₂O₂<b>(D)</b>. Apo-SOD1 G93A incubated in the absence <b>(E)</b> and presence of 250 μM of DHA <b>(F)</b>, DHAOOH <b>(G)</b>, or H₂O₂<b>(H)</b>. All experiments were conducted in the presence of 10 μM of the protein at 37°C for 24 h. The colored lines represent the incubation times: 2 h (black), 6 h (red) and 24 h (blue). Chromatograms are representative at least 3 independent experiments.</p