scholarly journals Glucose-dependent insulinotropic polypeptide inhibits cardiac hypertrophy and fibrosis in diabetic mice via suppression of TGF-β2

2021 ◽  
Vol 18 (2) ◽  
pp. 147916412199903
Author(s):  
Munenori Hiromura ◽  
Yusaku Mori ◽  
Michishige Terasaki ◽  
Hideki Kushima ◽  
Tomomi Saito ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
High Glucose ◽  
Transforming Growth Factor ◽  
Mrna Levels ◽  
Diabetic Mice ◽  
Rt Pcr ◽  
Superoxide Generation ◽  
Increased Risk ◽  
Glycation End Products ◽  
Patients With Diabetes

Diabetic cardiomyopathy is associated with an increased risk for heart failure and death in patients with diabetes. We investigated here whether and how GIP attenuated cardiac hypertrophy and fibrosis in diabetic mice with obesity. Diabetic db/db mice at 7 weeks old were infused with vehicle or GIP (50 nmol/kg/day) for 6 weeks, and hearts were collected for histological and RT-PCR analyzes. Cardiomyocytes isolated from neonatal mice were incubated with or without 300 nM [D-Ala2]-GIP, 30 mM glucose, or 100 μg/mL advanced glycation end products (AGEs) for RT-PCR and lucigenin assays. Compared with non-diabetic mice, diabetic mice exhibited larger left ventricle wall thickness and cardiomyocyte sizes and more fibrotic areas in association with up-regulation of myosin heavy chain β (β-Mhc) and transforming growth factor-beta2 (Tgf-β2) mRNA levels, all of which were inhibited by GIP infusion. High glucose increased NADPH oxidase-driven superoxide generation and up-regulated β-Mhc, Tgf-β2, and receptor for AGEs mRNA levels in cardiomyocytes, and augmented the AGE-induced β-Mhc gene expression. [D-Ala2]-GIP attenuated all of the deleterious effects of high glucose and/or AGEs on cardiomyocytes. Our present findings suggest that GIP could inhibit cardiac hypertrophy and fibrosis in diabetic mice via suppression of TGF-β2.

scholarly journals MicroRNA-133a impairs perfusion recovery after hindlimb ischemia in diabetic mice

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Lingdan Chen ◽  
Chunli Liu ◽  
Dejun Sun ◽  
Tao Wang ◽  
Li Zhao ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Endothelial Cells ◽  
Arterial Disease ◽  
Tube Formation ◽  
Cgmp Level ◽  
Diabetic Mice ◽  
Rt Pcr ◽  
Patients With Diabetes ◽  
Peripheral Arterial ◽  
Ischemic Muscle

Objective: Peripheral arterial disease (PAD) patients with diabetes mellitus suffer from impaired neovascularization after ischemia which results in poorer outcomes. MicroRNA (miR)-133a is excessively expressed in endothelial cells under diabetic conditions. Here, we test whether diabetes-induced miR-133a up-regulation is involved in the impaired capability of neovascularization in experimental PAD models. Methods and results: MiR-133a level was measured by quantitative RT-PCR and showed a higher expression level in the ischemic muscle from diabetic mice when compared with nondiabetic mice. Knockdown of miR-133a using antagomir improved perfusion recovery and angiogenesis in experimental PAD model with diabetes day 21 after HLI. On the other hand, overexpression of miR-133a impaired perfusion recovery. Ischemic muscle was harvested day 7 after experimental PAD for biochemical test, miR-133a antagonism resulted in reduced malondialdehyde, and it increased GTP cyclohydrolase 1 (GCH1), and cyclic guanine monophosphate (cGMP) levels. In cultured endothelial cells, miR-133a antagonism resulted in reduced reactive oxygen species level, and it increased tube formation, nitric oxide (NO), and cGMP level. Moreover, miR-133a antagonism-induced angiogenesis was abolished by GCH1 inhibitor. In contrary, miR-133a overexpression impairs angiogenesis and it reduces GCH1, NO, and cGMP levels in nondiabetic models. Conclusion: Diabetes mellitus-induced miR-133a up-regulation impairs angiogenesis in PAD by reducing NO synthesis in endothelial cells. MiR-133a antagonism improves postischemic angiogenesis.

scholarly journals Pathobiology of renal-specific oxidoreductase/myo-inositol oxygenase in diabetic nephropathy: its implications in tubulointerstitial fibrosis

2010 ◽  
Vol 298 (6) ◽  
pp. F1393-F1404 ◽  
Author(s):  
Ping Xie ◽  
Lin Sun ◽  
Peter J. Oates ◽  
Satish K. Srivastava ◽  
Yashpal S. Kanwar
Keyword(s):  
Diabetic Nephropathy ◽  
Aldose Reductase ◽  
High Glucose ◽  
Transforming Growth Factor ◽  
Polyol Pathway ◽  
Renal Tubules ◽  
Erk Phosphorylation ◽  
Glycation End Products ◽  
Fibronectin Expression ◽  
Si Rna

Renal-specific oxido-reductase/ myoinositol oxygenase (RSOR/MIOX) is expressed in renal tubules. It catabolizes myo-inositol and its expression is increased in diabetic mice and in LLC-PK1 cells under high-glucose ambience. Aldose reductase (AR) is another aldo-keto reducase that is expressed in renal tubules. It regulates the polyol pathway and plays an important role in glucose metabolism, osmolyte regulation, and ECM pathobiology via the generation of advanced glycation end products, reactive oxygen species, and activation of transforming growth factor (TGF)-β. In view of the similarities between AR and RSOR/MIOX, the pathobiology of RSOR/MIOX and some of the cellular pathways affected by its overexpression were investigated. An increased expression of fibronectin was noted by transfection of LLC-PK1 cells with pcDNA3.1-RSOR/MIOX. Similar changes were observed in LLC-PK1 cells under high-glucose ambience, and they were notably lessened by RSOR/MIOX-small interfering (si) RNA treatment. The changes in tubulointerstitial fibronectin expression were also observed in the kidneys of db/db mice having high levels of RSOR. The pcDNA3.1-RSOR/MIOX transfectants had an increased NADH/NAD+ ratio, PKC and TGF-β activity, Raf1:Ras association, and p-ERK phosphorylation. These changes were significantly reduced by the inhibitors of PKC, aldose reductase, Ras farnesylation, and MEK1. Similar increases in various the above-noted parameters were observed under high-glucose ambience. Such changes were partially reversed with RSOR-siRNA treatment. Expression of E-cadherin and vimentin paralleled in cells overexpressing RSOR/MIOX or subjected to high-glucose ambience. These studies suggest that RSOR/MIOX modulates various downstream pathways affected by high-glucose ambience, and conceivably it plays a role in the pathobiology of tubulointerstitium in diabetic nephropathy.

scholarly journals Amelioration of renal alterations in obese type 2 diabetic mice by vasohibin-1, a negative feedback regulator of angiogenesis

2011 ◽  
Vol 300 (4) ◽  
pp. F873-F886 ◽  
Author(s):  
Daisuke Saito ◽  
Yohei Maeshima ◽  
Tatsuyo Nasu ◽  
Hiroko Yamasaki ◽  
Katsuyuki Tanabe ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Therapeutic Efficacy ◽  
Transforming Growth Factor ◽  
Angiogenesis Inhibitor ◽  
Therapeutic Effects ◽  
Mrna Levels ◽  
Diabetic Mice ◽  
Protein Levels ◽  
Type 2 Diabetic

The involvement of VEGF-A as well as the therapeutic efficacy of angiogenesis inhibitors in diabetic nephropathy have been reported. We recently reported the therapeutic effects of vasohibin-1 (VASH-1), an endogenous angiogenesis inhibitor, in a type 1 diabetic nephropathy model (Nasu T, Maeshima Y, Kinomura M, Hirokoshi-Kawahara K, Tanabe K, Sugiyama H, Sonoda H, Sato Y, Makino H. Diabetes 58: 2365–2375, 2009). In this study, we investigated the therapeutic efficacy of VASH-1 on renal alterations in obese mice with type 2 diabetes. Diabetic db/db mice received intravenous injections of adenoviral vectors encoding human VASH-1 (AdhVASH-1) and were euthanized 8 wk later. AdhVASH-1 treatment resulted in significant suppression of glomerular hypertrophy, glomerular hyperfiltration, albuminuria, increase in the CD31+ glomerular endothelial area, F4/80+ monocyte/macrophage infiltration, the accumulation of type IV collagen, and mesangial matrix. An increase in the renal levels of VEGF-A, VEGFR-2, transforming growth factor (TGF)-β1, and monocyte chemoattractant protein-1 in diabetic animals was significantly suppressed by AdhVASH-1 (immunoblotting). AdhVASH-1 treatment significantly recovered the loss and altered the distribution patterns of nephrin and zonula occludens (ZO)-1 and suppressed the increase in the number of fibroblast-specific protein-1 (FSP-1+) and desmin+ podocytes in diabetic mice. In vitro, recombinant human VASH-1 (rhVASH-1) dose dependently suppressed the upregulation of VEGF induced by high ambient glucose (25 mM) in cultured mouse podocytes. In addition, rhVASH-1 significantly recovered the mRNA levels of nephrin and the protein levels of ZO-1 and P-cadherin and suppressed the increase in protein levels of desmin, FSP-1, Snail, and Slug in podocytes under high-glucose condition. Taken together, these results suggest the potential use of VASH-1 as a novel therapeutic agent in type 2 diabetic nephropathy mediated via antiangiogenic effects and maintenance of podocyte phenotype in association with antiproteinuric effects.

scholarly journals Role of Parathyroid Hormone-Related Protein in the Decreased Osteoblast Function in Diabetes-Related Osteopenia

Endocrinology ◽  
2009 ◽  
Vol 150 (5) ◽  
pp. 2027-2035 ◽  
Author(s):  
Daniel Lozano ◽  
Luis F. de Castro ◽  
Sonia Dapía ◽  
Irene Andrade-Zapata ◽  
Félix Manzarbeitia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Glucose ◽  
Ex Vivo ◽  
Mrna Levels ◽  
Diabetic Mice ◽  
Related Protein ◽  
Matrix Mineralization ◽  
Parathyroid Hormone Related Protein ◽  
Marrow Ablation

A deficit in bone formation is a major factor in diabetes-related osteopenia. We examined here whether diabetes-associated changes in osteoblast phenotype might in part result from a decrease in PTH-related protein (PTHrP). We used a bone marrow ablation model in diabetic mice by multiple streptozotocin injections. PTHrP (1–36) (100 μg/kg, every other day) or vehicle was administered to mice for 13 d starting 1 wk before marrow ablation. Diabetic mice showed bone loss in both the intact femur and the regenerating tibia on d 6 after ablation; in the latter, this was related to decreased bone-forming cells, osteoid surface, and blood vessels, and increased marrow adiposity. Moreover, a decrease in matrix mineralization occurred in ex vivo bone marrow cultures from the unablated tibia from diabetic mice. These skeletal alterations were associated with decreased gene expression (by real-time PCR) of Runx2, osterix, osteocalcin, PTHrP, the PTH type 1 receptor, vascular endothelial growth factor and its receptors, and osteoprotegerin to receptor activator of nuclear factor-κB ligand mRNA ratio, and increased peroxisome proliferator-activated receptor-γ2 mRNA levels. Similar changes were induced by hyperosmotic (high glucose or mannitol) medium in osteoblastic MC3T3-E1 cells, which were mimicked by adding a neutralizing anti-PTHrP antibody or PTH type 1 receptor antagonists to these cells in normal glucose medium. PTHrP (1–36) administration reversed these changes in both intact and regenerating bones from diabetic mice in vivo, and in MC3T3-E1 cells exposed to high glucose. These findings strongly suggest that PTHrP has an important role in the altered osteoblastic function related to diabetes.

scholarly journals Localization and regulation of pancreatic selenoprotein P

2012 ◽  
Vol 50 (1) ◽  
pp. 31-42 ◽  
Author(s):  
Holger Steinbrenner ◽  
Anna-Lena Hotze ◽  
Bodo Speckmann ◽  
Antonio Pinto ◽  
Helmut Sies ◽  
...  
Keyword(s):  
Real Time ◽  
High Glucose ◽  
Sodium Selenate ◽  
Selenoprotein P ◽  
Mrna Levels ◽  
Rt Pcr ◽  
Β Cells ◽  
Β Cell ◽  
Gene Reporter Assay ◽  
Insulinoma Cells

Progressive loss of pancreatic β-cell mass is a crucial feature of type 2 diabetes mellitus. As β-cells express very low amounts of the antioxidant enzymes catalase and glutathione peroxidase (GPx), they appear to be particularly vulnerable to oxidative damage in the pathogenesis of diabetes. Here, we investigated the pancreatic expression pattern and regulation of selenoprotein P (Sepp1), which may serve as an additional antioxidant enzyme inside and outside of cells. Sepp1 was detected in rodent pancreas by immunofluorescence and real-time RT-PCR. Regulation of Sepp1 biosynthesis in INS-1 rat insulinoma cells was investigated by real-time RT-PCR, luciferase gene reporter assay, and immunoblotting. Sepp1 and Gpx1 gene expressions in rat pancreas were 58 and 22% respectively of the liver values. Pancreatic Sepp1 expression was restricted to the endocrine tissue, with Sepp1 being present in the α- and β-cells of mouse islets. In INS-1 insulinoma cells, Sepp1 expression was stimulated by the selenium compound sodium selenate and diminished in the presence of high glucose (16.7 vs 5 mM) concentrations. Sepp1 mRNA stability was also lowered at 16.7 mM glucose. Moreover, Sepp1 mRNA levels were decreased in isolated murine islets cultured in high-glucose (22 mM) medium compared with normal glucose (5.5 mM) medium. Pancreatic Sepp1 expression was elevated upon treatment of mice with the β-cell toxin streptozotocin. This study shows that pancreatic islets express relatively high levels of Sepp1 that may fulfill a function in antioxidant protection of β-cells. Downregulation of Sepp1 expression by high glucose might thus contribute to glucotoxicity in β-cells.

scholarly journals Telomere dynamics during aging in polygenic left ventricular hypertrophy

2016 ◽  
Vol 48 (1) ◽  
pp. 42-49 ◽  
Author(s):  
Francine Z. Marques ◽  
Scott A. Booth ◽  
Priscilla R. Prestes ◽  
Claire L. Curl ◽  
Lea M. D. Delbridge ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricular Hypertrophy ◽  
Cardiac Hypertrophy ◽  
Telomere Length ◽  
Ventricular Hypertrophy ◽  
Telomerase Activity ◽  
Left Ventricular ◽  
Mrna Levels ◽  
Control Strain ◽  
Increased Risk

Short telomeres are associated with increased risk of cardiovascular disease. Here we studied cardiomyocyte telomere length at key ages during the ontogeny of cardiac hypertrophy and failure in the hypertrophic heart rat (HHR) and compared these with the normal heart rat (NHR) control strain. Key ages corresponded with the pathophysiological sequence beginning with fewer cardiomyocytes (2 days), leading to left ventricular hypertrophy (LVH) (13 wk) and subsequently progression to heart failure (38 wk). We measured telomere length, tissue activity of telomerase, mRNA levels of telomerase reverse transcriptase ( Tert) and telomerase RNA component ( Terc), and expression of the telomeric regulator microRNA miR-34a. Cardiac telomere length was longer in the HHR compared with the control strain at 2 days and 38 wk, but shorter at 13 wk. Neonatal HHR had higher cardiac telomerase activity and expression of Tert and miR-34a. Telomerase activity was not different at 13 or 38 wk. Tert mRNA and Terc RNA were overexpressed at 38 wk, while miR-34a was overexpressed at 13 wk but downregulated at 38 wk. Circulating leukocytes were strongly correlated with cardiac telomere length in the HHR only. The longer neonatal telomeres in HHR are likely to reflect fewer fetal and early postnatal cardiomyocyte cell divisions and explain the reduced total cardiomyocyte complement that predisposes to later hypertrophy and failure. Although shorter telomeres were a feature of cardiac hypertrophy at 13 wk, they were not present at the progression to heart failure at 38 wk.

scholarly journals Involvement of p300/CBP and epigenetic histone acetylation in TGF-β1-mediated gene transcription in mesangial cells

2013 ◽  
Vol 304 (5) ◽  
pp. F601-F613 ◽  
Author(s):  
Hang Yuan ◽  
Marpadga A. Reddy ◽  
Guangdong Sun ◽  
Linda Lanting ◽  
Mei Wang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Histone Acetylation ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Mrna Levels ◽  
Creb Binding Protein ◽  
Diabetic Mice ◽  
Plasminogen Activator Inhibitor 1 ◽  
Tgf Β1 ◽  
Pai 1

Transforming growth factor-β1 (TGF-β1)-induced expression of plasminogen activator inhibitor-1 (PAI-1) and p21 in renal mesangial cells (MCs) plays a major role in glomerulosclerosis and hypertrophy, key events in the pathogenesis of diabetic nephropathy. However, the involvement of histone acetyl transferases (HATs) and histone deacetylases (HDACs) that regulate epigenetic histone lysine acetylation, and their interaction with TGF-β1-responsive transcription factors, are not clear. We evaluated the roles of histone acetylation, specific HATs, and HDACs in TGF-β1-induced gene expression in rat mesangial cells (RMCs) and in glomeruli from diabetic mice. Overexpression of HATs CREB binding protein (CBP) or p300, but not p300/CBP-activating factor, significantly enhanced TGF-β1-induced PAI-1 and p21 mRNA levels as well as transactivation of their promoters in RMCs. Conversely, they were significantly attenuated by HAT domain mutants of CBP and p300 or overexpression of HDAC-1 and HDAC-5. Chromatin immunoprecipitation assays showed that TGF-β1 treatment led to a time-dependent enrichment of histone H3-lysine9/14-acetylation (H3K9/14Ac) and p300/CBP occupancies around Smad and Sp1 binding sites at the PAI-1 and p21 promoters. TGF-β1 also enhanced the interaction of p300 with Smad2/3 and Sp1 and increased Smad2/3 acetylation. High glucose-treated RMCs exhibited increased PAI-1 and p21 levels, and promoter H3K9/14Ac, which were blocked by TGF-β1 antibodies. Furthermore, increased PAI-1 and p21 expression was associated with elevated promoter H3K9/14Ac levels in glomeruli from diabetic mice. Thus TGF-β1-induced PAI-1 and p21 expression involves interaction of p300/CBP with Smads and Sp1, and increased promoter access via p300/CBP-induced H3K9/14Ac. This in turn can augment glomerular dysfunction linked to diabetic nephropathy.

Stimulation of TGF-β type II receptor by high glucose in mouse mesangial cells and in diabetic kidney

2000 ◽  
Vol 278 (5) ◽  
pp. F830-F838 ◽  
Author(s):  
Motohide Isono ◽  
András Mogyorósi ◽  
Dong Cheol Han ◽  
Brenda B. Hoffman ◽  
Fuad N. Ziyadeh
Keyword(s):  
High Glucose ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Kidney Cortex ◽  
Mrna Levels ◽  
Type Ii ◽  
Diabetic Kidney ◽  
Normal Glucose ◽  
Cells Cultured ◽  
Stimulation Of

Transforming growth factor-β (TGF-β) is important in the pathogenesis of diabetic nephropathy, but little is known about the regulation of the ligand-binding TGF-β type II signaling receptor (TβIIR). There were significant increases in TβIIR protein and mRNA levels in kidney cortex after 1–6 wk of streptozotocin-induced diabetes. Mouse mesangial cells cultured in high glucose demonstrated significantly increased TβIIR protein and mRNA levels compared with normal glucose. This effect was independent of stimulation of TGF-β bioactivity by high glucose. Consistent with transcriptional activation by high glucose, the half-life (∼4 h) of TβIIR mRNA was not affected by glucose concentration. Moreover, mouse mesangial cells transiently transfected with reporter constructs containing the first 47- or 274-bp promoter fragments of TβIIR demonstrated significantly increased reporter activity in high glucose. Cells grown in high glucose demonstrated increased responsiveness to a relatively small dose of exogenous TGF-β1 (0.5 ng/ml): [3H]proline incorporation and α1(IV) collagen mRNA were significantly greater in cells cultured in high than in normal glucose. Hence, the expression of TβIIR is increased in the diabetic kidney and in mesangial cells cultured in high glucose, primarily because of stimulation of gene transcription. TβIIR upregulation by high ambient glucose may contribute to the increased sensitivity of mesangial cells to the profibrogenic action of TGF-β1.

scholarly journals Mechanism of Albuminuria Reduction by Chymase Inhibition in Diabetic Mice

2020 ◽  
Vol 21 (20) ◽  
pp. 7495
Author(s):  
Kentaro Terai ◽  
Denan Jin ◽  
Kenji Watase ◽  
Akihisa Imagawa ◽  
Shinji Takai
Keyword(s):  
Oxidative Stress ◽  
Transforming Growth Factor ◽  
Fasting Blood Glucose ◽  
Transforming Growth Factor Β ◽  
Treated Group ◽  
Oxidative Stress Marker ◽  
Mrna Levels ◽  
Diabetic Mice ◽  
Nadph Oxidase 4 ◽  
Significant Difference

Chymase has several functions, such as angiotensin II formation, which can promote diabetic kidney disease (DKD). In this study, we evaluated the effect of the chymase inhibitor TY-51469 on DKD in diabetic db/db mice. Diabetic mice were administered TY-51469 (10 mg/kg/day) or placebo for 4 weeks. No significant difference was observed in body weight and fasting blood glucose between TY-51469- and placebo-treated groups. However, a significant reduction in urinary albumin/creatinine ratio was observed in the TY-51469-treated group compared with the placebo-treated group. In the renal extract, chymase activity was significantly higher in placebo-treated mice than in non-diabetic db/m mice, but it was reduced by treatment with TY-51469. Both NADPH oxidase 4 expression and the oxidative stress marker malondialdehyde were significantly augmented in the placebo-treated group, but they were attenuated in the TY-51469-treated group. Significant increases of tumor necrosis factor-α and transforming growth factor-β mRNA levels in the placebo-treated group were significantly reduced by treatment with TY-51469. Furthermore, the expression of nephrin, which is a podocyte-specific protein, was significantly reduced in the placebo-treated group, but it was restored in the TY-51469-treated group. These findings demonstrated that chymase inhibition reduced albuminuria via attenuation of podocyte injury by oxidative stress.

scholarly journals Fluoxetine Attenuated Anxiety-Like Behaviors in Streptozotocin-Induced Diabetic Mice by Mitigating the Inflammation

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Peng Yuan ◽  
Jian Zhang ◽  
Liang Li ◽  
Zhendi Song
Keyword(s):  
Glial Cells ◽  
Cognitive Deficit ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Astrocyte Activation ◽  
High Anxiety ◽  
Increased Risk ◽  
Patients With Diabetes ◽  
The Status ◽  
Anxiety Levels

Patients with diabetes mellitus (DM) showed an increased risk of anxiety. High anxiety levels are also shown to increase stress of diabetic patients, which may contribute to poor clinical outcomes. The mechanisms underlying the development of anxiety disorders in diabetic patients remain unknown. As a result, there are no available treatments yet. Here, we tested the hypothesis that glial cells in the hippocampal area of DM mice might be responsible for their anxiety-like behaviors. Furthermore, we postulated that treatment with antidepressant, fluoxetine, could reduce anxiety behaviors and prevent the dysregulation of glial cells (oligodendrocyte and astrocyte) in DM mice. Diabetic mice were administered a single injection of streptozotocin (STZ), followed by treatment with fluoxetine. Mice were then tested on Y maze, open field, dark and light transition, and elevated plus maze tests to measure the status of anxiety and cognition. After completing these behavioral tests, mice were sacrificed and western blot was used to detect the oligodendrocyte and astrocyte maker proteins in hippocampal tissues. Emphasis was directed towards adult oligodendrocyte precursor cells (OPCs) and their marker protein to measure their proliferation and differentiation. We found that fluoxetine could effectively mitigate the level of anxiety and attenuate the cognitive dysfunction in diabetic mice. Meanwhile, fluoxetine inhibited astrocyte activation in mice exposed to STZ, prevented the loss of myelin basic protein (MBP), and affected the function of OPCs in these diabetic mice. The results suggested that the changes of these glial cells in the brains of diabetic mice might be related to the high anxiety levels and cognitive deficit in DM mice. Fluoxetine could ameliorate the high anxiety level and prevent cognitive deficit via inhibiting astrocyte activation and repairing the oligodendrocyte damage.

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