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      The Effects of Antidepressants “Fluoxetine and Imipramine” on Vascular Abnormalities and Toll Like Receptor-4 Expression in Diabetic and Non-Diabetic Rats Exposed to Chronic Stress

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          Abstract

          Several studies reveal that diabetes doubles the odds of comorbid depression with evidence of a pro-inflammatory state underlying its vascular complications. Indeed, little information is available about vascular effects of antidepressant drugs in diabetes. Method: We investigated the effect of chronic administration of fluoxetine “FLU” and imipramine “IMIP” on behavioral, metabolic and vascular abnormalities in diabetic and non-diabetic rats exposed to chronic restraint stress (CRS). Results: Both diabetes and CRS induced depressive-like behavior which was more prominent in diabetic/depressed rats; this was reversed by chronic treatment with FLU and IMIP in a comparable manner. Diabetic and non-diabetic rats exposed to CRS exhibited abnormalities in glucose homeostasis, lipid profile and vascular function, manifested by decreased endothelium-dependent relaxation, increased systolic blood pressure and histopathological atherosclerotic changes. Vascular and metabolic dysfunctions were associated with significant increase in aortic expression of TLR-4, and pro-inflammatory cytokines (TNF-α and IL-1ß). FLU ameliorated these metabolic, vascular and inflammatory abnormalities, while IMIP induced either no change or even worsening of some parameters. Conclusion: FLU has favorable effect over IMIP on metabolic, vascular and inflammatory aberrations associated with DM and CRS in Wistar rats, clarifying the preference of FLU over IMIP in management of comorbid depression in diabetic subjects.

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          The prevalence of comorbid depression in adults with diabetes: a meta-analysis.

          Judy Anderson, P Lustman, Melvin E. Clouse … (2001)
          To estimate the odds and prevalence of clinically relevant depression in adults with type 1 or type 2 diabetes. Depression is associated with hyperglycemia and an increased risk for diabetic complications; relief of depression is associated with improved glycemic control. A more accurate estimate of depression prevalence than what is currently available is needed to gauge the potential impact of depression management in diabetes. MEDLINE and PsycINFO databases and published references were used to identify studies that reported the prevalence of depression in diabetes. Prevalence was calculated as an aggregate mean weighted by the combined number of subjects in the included studies. We used chi(2) statistics and odds ratios (ORs) to assess the rate and likelihood of depression as a function of type of diabetes, sex, subject source, depression assessment method, and study design. A total of 42 eligible studies were identified; 20 (48%) included a nondiabetic comparison group. In the controlled studies, the odds of depression in the diabetic group were twice that of the nondiabetic comparison group (OR = 2.0, 95% CI 1.8-2.2) and did not differ by sex, type of diabetes, subject source, or assessment method. The prevalence of comorbid depression was significantly higher in diabetic women (28%) than in diabetic men (18%), in uncontrolled (30%) than in controlled studies (21%), in clinical (32%) than in community (20%) samples, and when assessed by self-report questionnaires (31%) than by standardized diagnostic interviews (11%). The presence of diabetes doubles the odds of comorbid depression. Prevalence estimates are affected by several clinical and methodological variables that do not affect the stability of the ORs.
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            The association of comorbid depression with mortality in patients with type 2 diabetes.

            W Katon, C Rutter, G. Simón … (2005)
            We assessed whether patients with comorbid minor and major depression and type 2 diabetes had a higher mortality rate over a 3-year period compared with patients with diabetes alone. In a large health maintenance organization (HMO), 4,154 patients with type 2 diabetes were surveyed and followed for up to 3 years. Patients initially filled out a written questionnaire, and HMO-automated diagnostic, laboratory, and pharmacy data and Washington State mortality data were collected to assess diabetes complications and deaths. Cox proportional hazards regression models were used to calculate adjusted hazard ratios of death for each group compared with the reference group. There were 275 (8.3%) deaths in 3,303 patients without depression compared with 48 (13.6%) deaths in 354 patients with minor depression and 59 (11.9%) deaths among 497 patients with major depression. A proportional hazards model with adjustment for age, sex, race/ethnicity, and educational attainment found that compared with the nondepressed group, minor depression was associated with a 1.67-fold increase in mortality (P = 0.003), and major depression was associated with a 2.30-fold increase (P < 0.0001). In a second model that controlled for multiple potential mediators, both minor and major depression remained significant predictors of mortality. Among patients with diabetes, both minor and major depression are strongly associated with increased mortality. Further research will be necessary to disentangle causal relationships among depression, behavioral risk factors (adherence to medical regimens), diabetes complications, and mortality.
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              Elevated Toll-Like Receptor 4 Expression and Signaling in Muscle From Insulin-Resistant Subjects

              Sara Reyna, Sangeeta Ghosh, Puntip Tantiwong … (2008)
              OBJECTIVE— Tall-like receptor (TLR)4 has been implicated in the pathogenesis of free fatty acid (FFA)-induced insulin resistance by activating inflammatory pathways, including inhibitor of κB (IκB)/nuclear factor κB (NFκB). However, it is not known whether insulin-resistant subjects have abnormal TLR4 signaling. We examined whether insulin-resistant subjects have abnormal TLR4 expression and TLR4-driven (IκB/NFκB) signaling in skeletal muscle. RESEARCH DESIGN AND METHODS— TLR4 gene expression and protein content were measured in muscle biopsies in 7 lean, 8 obese, and 14 type 2 diabetic subjects. A primary human myotube culture system was used to examine whether FFAs stimulate IκB/NFκB via TLR4 and whether FFAs increase TLR4 expression/content in muscle. RESULTS— Obese and type 2 diabetic subjects had significantly elevated TLR4 gene expression and protein content in muscle. TLR4 muscle protein content correlated with the severity of insulin resistance. Obese and type 2 diabetic subjects also had lower IκBα content, an indication of elevated IκB/NFκB signaling. The increase in TLR4 and NFκB signaling was accompanied by elevated expression of the NFκB-regulated genes interleukin (IL)-6 and superoxide dismutase (SOD)2. In primary human myotubes, acute palmitate treatment stimulated IκB/NFκB, and blockade of TLR4 prevented the ability of palmitate to stimulate the IκB/NFκB pathway. Increased TLR4 content and gene expression observed in muscle from insulin-resistant subjects were reproduced by treating myotubes from lean, normal-glucose-tolerant subjects with palmitate. Palmitate also increased IL-6 and SOD2 gene expression, and this effect was prevented by inhibiting NFκB. CONCLUSIONS— Abnormal TLR4 expression and signaling, possibly caused by elevated plasma FFA levels, may contribute to the pathogenesis of insulin resistance in humans.
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                Author and article information

                Contributors
                Leonardo Barbosa Moraes Resstel: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 31 March 2015
                Publication date Collection: 2015
                Volume: 10
                Issue: 3
                Electronic Location Identifier: e0120559
                Affiliations
                [1 ]Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
                [2 ]Department of Histology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
                [3 ]Clinical Pharmacology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
                University of São Paulo, BRAZIL
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SA. Performed the experiments: MH SA NE. Analyzed the data: SA MH. Contributed reagents/materials/analysis tools: SA MH NE SS. Wrote the paper: SA MH.

                Article
                Publisher ID: PONE-D-14-37547
                DOI: 10.1371/journal.pone.0120559
                PMC ID: 4380417
                PubMed ID: 25826421
                SO-VID: 66d3de78-3cfe-4fee-97cb-f71065d65923
                Copyright statement: Copyright @ 2015
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                Date received : 22 August 2014
                Date accepted : 5 February 2015
                Page count
                Figures: 10, Tables: 4, Pages: 25
                Funding
                The authors have no support or funding to report.
                Categories
                Subject: Research Article
                Custom metadata
                Data Availability All relevant data are within the paper.

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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