Diabetes Promotes Mild Osteoarthritis in The Streptozotocin‐ Induced Diabetic Mouse Model
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Rios Arce, Naiomy↗
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MicroRNAs as biomarkers of diabetic retinopathy and disease progression
Diabetes mellitus, together with its complications, has been increasing in prevalence worldwide. Its complications include cardiovascular disease (e.g., myocardial infarction, stroke), neuropathy, nephropathy, and eye complications (e.g., glaucoma, cataracts, retinopathy, and macular edema). In patients with either type 1 or type 2 diabetes mellitus, diabetic retinopathy is the leading cause of visual impairment or blindness. It is characterized by progressive changes in the retinal microvasculature. The progression from nonproliferative diabetic retinopathy to a more advanced stage of moderate to severe nonproliferative diabetic retinopathy and proliferative diabetic retinopathy occurs very quickly after diagnosis of mild nonproliferative diabetic retinopathy. The etiology of diabetic retinopathy is unclear, and present treatments have limited effectiveness. Currently diabetic retinopathy can only be diagnosed by a trained specialist, which reduces the population that can be examined. A screening biomarker of diabetic retinopathy with high sensitivity and specificity would aid considerably in identifying those individuals in need of clinical assessment and treatment. The majority of the studies reviewed identified specific microRNAs in blood serum/plasma able to distinguish diabetic patients with retinopathy from those without retinopathy and for the progresion of the disease from nonproliferative diabetic retinopathy to proliferative diabetic retinopathy. In addition, certain microRNAs in vitreous humor were dysregulated in proliferative diabetic retinopathy compared to controls. A very high percentage of patients with diabetic retinopathy develop Alzheimer’s disease. Thus, identifying diabetic retinopathy by measurement of suitable biomarkers would also enable better screening and treatment of those individuals at risk of Alzheimer’s disease.
59 BASIC BIOLOGICAL SCIENCES↗
Resveratrol alleviates diabetes-induced testicular dysfunction by inhibiting oxidative stress and c-Jun N-terminal kinase signaling in rats
Diabetes adversely affects reproductive functions in humans and animals. The present study investigated the effects of Resveratrol on diabetes-induced alterations in oxidative stress, c-Jun N-terminal kinase (JNK) signaling and apoptosis in the testis. Adult male Wistar rats (13–15 weeks; n = 6/group) were segregated into 1) normal control, 2) Resveratrol-treated (5 mg/kg; ip; given during last 3 weeks), 3) Streptozotocin-induced diabetic and, 4) Resveratrol-treated diabetic groups, and euthanized on day 42 after the confirmation of diabetes. Resveratrol did not normalize blood glucose levels in diabetic rats. Resveratrol supplementation recovered diabetes-induced decreases in reproductive organ weights, sperm count and motility, intra-testicular levels of superoxide dismutase, catalase, and glutathione peroxidase and an increase in 4-hydroxynonenal activities (P < 0.05). Resveratrol also recovered diabetes-induced increases in JNK signaling pathway proteins, namely, ASK1 (apoptosis signal-regulating kinase 1), JNKs (46 and 54 kDa isoforms) and p-JNK to normal control levels (P < 0.05). Interestingly, the expression of a down-stream target of ASK1, MKK4 (mitogen-activated protein kinase kinase 4) and its phosphorylated form (p-MKK4) did not change in experimental groups. Resveratrol inhibited diabetes-induced increases in AP-1 (activator protein-1) components, c-Jun and ATF2 (activating transcription factor 2), but not their phosphorylated forms, to normal control levels (P < 0.05). Further, Resveratrol inhibited diabetes-induced increase in cleaved-caspase-3 to normal control levels. In conclusion, Resveratrol alleviates diabetes-induced apoptosis in testis by modulating oxidative stress, JNK signaling pathway and caspase-3 activities, but not by inhibiting hyperglycemia, in rats. These results suggest that Resveratrol supplementation may be a useful strategy to treat diabetes-induced testicular dysfunction. - Highlights: • Resveratrol up-regulates glutathione peroxidase and catalase levels in the testis. • Diabetes up-regulates oxidative stress and JNK pathway in the testis. • Resveratrol inhibits diabetes-induced oxidative stress and JNK pathway. • Resveratrol mitigates diabetes-induced apoptosis of testicular cells. • Resveratrol treatment alleviates diabetes-induced testicular dysfunction.
60 APPLIED LIFE SCIENCES↗
Renin-Angiotensin System (RAS) in Hematopoietic Stem/Progenitor Cells (HS/PC) Predicts Vaso-Reparative Dysfunction and Progression of Diabetic Retinopathy (DR)
Purpose: We tested the hypothesis that loss of angiotensin converting enzyme 2 (ACE2) within diabetic HS/PCs (Hematopoietic Stem/Progenitor Cells) would be detrimental to HS/PC reparative function, and alter their ability to contribute to vascular remodeling in human subjects and rodent models of DR (Diabetic Retinopathy). Methods: Subjects (n52) were recruited as controls (n13) or diabetics (n39) with either no DR, mild non-proliferative DR (NPDR), moderate NPDR, severe NPDR or proliferative DR (PDR). Fluorescein angiograms were analyzed using Vessel Generation Analysis (VESGEN) software in a cohort of subjects. CD34+ HS/PCs were isolated from peripheral blood. RAS (Renin-Angiotensin System) gene expression and migration was measured. Diabetic ACE2 knockout (KO)C57BL6-Ins2 (Akita) mice at 3, 6 and 9 months of diabetes were compared to age-matched controls. Bone marrow HS/PC populations were analyzed by flow cytometry and migration and proliferation studies performed. Results: ACE2 gene expression in human CD34+ cells from diabetics without DR was increased compared to controls (p0.0437). Mas receptor mRNA was also increased in diabetics without DR, but reduced with the onset of NPDR (p0.0002), suggesting a loss of compensation. DR was associated with CD34+ cell migratory dysfunction. By VESGEN analysis, vessel density measured by several confirming parameters in early NPDR (n3) was greater than in normal retina (n6) in both arteries and veins, which suggests active retinal remodeling. ACE2KO-Akita and Akita cohorts showed reduced retinal thickness by OCT (Optical Coherence Tomography) at 9 months of diabetes. Absence of ACE2 in 9-month Akita mice led to an accelerated increase in acellular capillaries compared to diabetic alone. Electroretinogram (ERG) in ACE2KO-Akita mice resulted in persistent deterioration of the neural retina. Reparative function studies showed that ACE2KO exacerbated diabetes-induced impairment of LK (Low Potassium) cell migration and proliferative functions as early as 3-month of diabetes (p0.0019). Conclusions: Retinopathy and adverse vascular remodeling in subjects with diabetes was associated with a loss of the protective arm of RAS in HS/PCs. Loss of ACE2 exacerbated vascular dysfunction in diabetic mice.
retina↗
Protection by sulforaphane from type 1 diabetes-induced testicular apoptosis is associated with the up-regulation of Nrf2 expression and function
Diabetes-induced testicular apoptosis is predominantly due to increased oxidative stress. The nuclear factor-erythroid 2-related factor 2 (Nrf2), as a master transcription factor in controlling anti-oxidative systems, is able to be induced by sulforaphane (SFN). To examine whether SFN prevents testicular apoptosis, type 1 diabetic mouse model was induced with multiple low-dose streptozotocin. Diabetic and age-matched control mice were treated with and without SFN at 0.5 mg/kg daily in five days of each week for 3 months and then kept until 6 months. Diabetes significantly increased testicular apoptosis that was associated with endoplasmic reticulum stress and mitochondrial cell death pathways, shown by the increased expression of C/EBP homologous protein (CHOP), cleaved caspase-12, Bax to Bcl2 expression ratio, and cleaved caspase-3. Diabetes also significantly increased testicular oxidative damage, inflammation and fibrosis, and decreased germ cell proliferation. All these diabetic effects were significantly prevented by SFN treatment for the first 3 months, and the protective effect could be sustained at 3 months after SFN treatment. SFN was able to up-regulate Nrf2 expression and function. The latter was reflected by the increased phosphorylation of Nrf2 at Ser40 and expression of Nrf2 downstream antioxidants at mRNA and protein levels. These results suggest that type 1 diabetes significantly induced testicular apoptosis and damage along with increasing oxidative stress and cell death and suppressing Nrf2 expression and function. SFN is able to prevent testicular oxidative damage and apoptosis in type 1 diabetes mice, which may be associated with the preservation of testicular Nrf2 expression and function under diabetic condition. - Highlights: • Sulforaphane (SFN) could attenuate diabetes-induced germ cell apoptosis. • SFN could preserve germ cell proliferation under diabetic conditions. • SFN testicular protection was sustained until 3 months after administration. • SFN prevents testicular oxidative damage and inflammation in diabetic mice. • SFN testicular protection from diabetic damage is associated with Nrf2 activation.
60 APPLIED LIFE SCIENCES↗
Protective effects of tocotrienols against lipid-induced nephropathy in experimental type-2 diabetic rats by modulation in TGF-β expression
Dyslipidemia is common in patients with diabetes mellitus (DM) and is considered a risk factor for the progression of diabetic nephropathy (DN). Hyperlipidemia and hyperglycemia act synergistically to induce renal injury. The present study was designed to investigate the protective effects of tocotrienols as tocotrienol-rich fraction (TRF) extracted from palm (PO) and rice bran oils (RBO) against lipid induced nephropathy in type-2 diabetic rats and its probable molecular mechanism. Male Wistar rats (175–200 g) were divided into four groups. The first group served as diabetic control, while the second and third groups received PO-TRF and RBO-TRF, respectively by gavage over a period of sixteen weeks post-induction of diabetes. The fourth group comprised of age-matched rats that served as normal control. The effects of TRF on serum lipid profile, oxidative stress markers, expression of TGF-β, fibronectin and collagen type IV were analyzed in the kidney of diabetic rats. Treatment with PO-TRF and RBO-TRF significantly improved glycemic status, serum lipid profile and renal function in type-2 diabetic rats. In addition, TRF supplementation down-regulated the expression of TGF-β, fibronectin and collagen type IV in the kidney of diabetic rats. Transforming growth factor-β (TGF-β) plays a critical role in progression of DN, but its modulation by tocotrienols in DN remains unexplored. TRF ameliorated lipid induced nephropathy in type-2 diabetes by its hypoglycemic, hypolipidemic and antioxidant activities as well as by modulation of TGF-β to prevent increased expression of collagen type IV and fibrinogen. We finally propose a mechanism for the expression of molecular markers that are significant in the events leading to diabetic nephropathy and its modulation by tocotrienols/TRF. - Highlights: • The nephroprotective effect of TRF in type-2 diabetic rats was investigated. • Treatment with TRF improved glycemic status, lipid profile and renal functions in rats. • TRF down-regulated the expression of TGF-β, fibronectin and collagen in rats' kidney. • TRF ameliorated nephropathy by hypoglycemic, hypolipidemic and antioxidant activity. • Tocotrienols modulate the expression of TGF-β in DN in type-2 diabetic rats.
60 APPLIED LIFE SCIENCES↗
Dipeptidyl peptidase-4 inhibitor ameliorates early renal injury through its anti-inflammatory action in a rat model of type 1 diabetes
Highlights: •DPP-4 inhibitor decreased urinary albumin excretion in a rat of type 1 diabetes. •DPP-4 inhibitor ameliorated histlogical changes of diabetic nephropathy. •DPP-4 inhibitor has reno-protective effects through anti-inflammatory action. •DPP-4 inhibitor is beneficial on diabetic nephropathy besides lowering blood glucose. -- Abstract: Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors are incretin-based drugs in patients with type 2 diabetes. In our previous study, we showed that glucagon-like peptide-1 (GLP-1) receptor agonist has reno-protective effects through anti-inflammatory action. The mechanism of action of DPP-4 inhibitor is different from that of GLP-1 receptor agonists. It is not obvious whether DPP-4 inhibitor prevents the exacerbation of diabetic nephropathy through anti-inflammatory effects besides lowering blood glucose or not. The purpose of this study is to clarify the reno-protective effects of DPP-4 inhibitor through anti-inflammatory actions in the early diabetic nephropathy. Materials and methods: Five-week-old male Sprague–Dawley (SD) rats were divided into three groups; non-diabetes, diabetes and diabetes treated with DPP-4 inhibitor (PKF275-055; 3 mg/kg/day). PKF275-055 was administered orally for 8 weeks. Results: PKF275-055 increased the serum active GLP-1 concentration and the production of urinary cyclic AMP. PKF275-055 decreased urinary albumin excretion and ameliorated histological change of diabetic nephropathy. Macrophage infiltration was inhibited, and inflammatory molecules were down-regulated by PKF275-055 in the glomeruli. In addition, nuclear factor-κB (NF-κB) activity was suppressed in the kidney. Conclusions: These results indicate that DPP-4 inhibitor, PKF275-055, have reno-protective effects through anti-inflammatory action in the early stage of diabetic nephropathy. The endogenous biological active GLP-1 might be beneficial on diabetic nephropathy besides lowering blood glucose.
60 APPLIED LIFE SCIENCES↗
Impaired Therapeutic Capacity of Autologous Stem Cells in a Model of Type 2 Diabetes
Abstract Endogenous stem cells in the bone marrow respond to environmental cues and contribute to tissue maintenance and repair. In type 2 diabetes, a multifaceted metabolic disease characterized by insulin resistance and hyperglycemia, major complications are seen in multiple organ systems. To evaluate the effects of this disease on the endogenous stem cell population, we used a type 2 diabetic mouse model (db/db), which recapitulates these diabetic phenotypes. Bone marrow-derived mesenchymal stem cells (MSCs) from db/db mice were characterized in vitro using flow cytometric cell population analysis, differentiation, gene expression, and proliferation assays. Diabetic MSCs were evaluated for their therapeutic potential in vivo using an excisional splint wound model in both nondiabetic wild-type and diabetic mice. Diabetic animals possessed fewer MSCs, which were proliferation and survival impaired in vitro. Examination of the recruitment response of stem and progenitor cells after wounding revealed that significantly fewer endogenous MSCs homed to the site of injury in diabetic subjects. Although direct engraftment of healthy MSCs accelerated wound closure in both healthy and diabetic subjects, diabetic MSC engraftment produced limited improvement in the diabetic subjects and could not produce the same therapeutic outcomes as in their nondiabetic counterparts in vivo. Our data reveal stem cell impairment as a major complication of type 2 diabetes in mice and suggest that the disease may stably alter endogenous MSCs. These results have implications for the efficiency of autologous therapies in diabetic patients and identify endogenous MSCs as a potential therapeutic target.
Shin, Laura↗
Development and validation of a diabetes risk score among two populations
The purpose of this study was to assess the validity of a practical diabetes risk score amongst two heterogenous populations, a working population and a non-working population. Study population 1 (n = 2,089) participated in a large-scale screening program offered to retired workers to discover previously undetected/incipient chronic illness. Study population 2 (n = 3,293) was part of a Colorado worksite wellness program health risk assessment. We assessed the relationship between a continuous diabetes risk score at baseline and development of diabetes in the future using logistic regression. Receiver operating curves and sensitivity/specificity of the models were calculated. Across both study populations, we observed that participants with diabetes at follow-up had higher diabetes risk scores at baseline than participants who did not have diabetes at follow-up. On average, the odds ratio of developing diabetes in the future was 1.38 (95% CI: 1.26–1.50, p < 0.0001) for study population 1 and 1.68 (95% CI: 1.45–1.95, p-value < 0.0001) for study population 2. These findings indicate that the diabetes risk score may be generalizable to diverse individuals, and thus potentially a population level diabetes screening tool. Minimally-invasive diabetes risk scores can aid in the identification of sub-populations of individuals at risk for diabetes.
60 APPLIED LIFE SCIENCES↗
Targeted metabolomic analysis identifies increased serum levels of GABA and branched chain amino acids in canine diabetes
Introduction Dogs with naturally occurring diabetes mellitus represent a potential model for human type 1 diabetes, yet signifcant knowledge voids exist in terms of the pathogenic mechanisms underlying the canine disorder. Untargeted metabolomic studies from a limited number of diabetic dogs identifed similarities to humans with the disease. Objective To expand and validate earlier metabolomic studies, identify metabolites that difer consistently between diabetic and healthy dogs, and address whether certain metabolites might serve as disease biomarkers. Methods Untargeted metabolomic analysis via liquid chromatography-mass spectrometry was performed on serum from diabetic (n=15) and control (n=15) dogs. Results were combined with those of our previously published studies using identical methods (12 diabetic and 12 control dogs) to identify metabolites consistently diferent between the groups in all 54 dogs. Thirty-two candidate biomarkers were quantifed using targeted metabolomics. Biomarker concentrations were compared between the groups using multiple linear regression (corrected P<0.0051 considered signifcant). Results Untargeted metabolomics identifed multiple persistent diferences in serum metabolites in diabetic dogs compared with previous studies. Therefore, targeted metabolomics showed increases in gamma amino butyric acid, valine, leucine, isoleucine, citramalate, and 2-hydroxyisobutyric acid in diabetic versus control dogs while indoxyl sulfate, N-acetyl-L-aspartic acid, kynurenine, anthranilic acid, tyrosine, glutamine, and tauroursodeoxycholic acid were decreased. Conclusion Several of these fndings parallel metabolomic studies in both human diabetes and other animal models of this disease. Given recent studies on the role of GABA and branched chain amino acids in human diabetes, the increase in serum concentrations in canine diabetes warrants further study of these metabolites as potential biomarkers, and to identify similarity in mechanisms underlying this disease in humans and dogs.
59 BASIC BIOLOGICAL SCIENCES↗
Overexpression of acetyl CoA carboxylase β exacerbates podocyte injury in the kidney of streptozotocin-induced diabetic mice
Highlights: • Podocyte-specific ACCβ overexpression causes severe podocyte injury in diabetic mice. • Podocyte-specific ACCβ overexpression increased proteinuria in diabetic mice. • AMPK activation ameliorates ACCβ overexpression-related podocyte injury. • Inhibition of ACCβ activity may serve as a therapy for diabetic nephropathy. A single nucleotide polymorphism (SNP) within the acetyl CoA carboxylase (ACC) β gene (ACACB), rs2268388, has been shown to be associated with susceptibility to development of proteinuria in patients with type 2 diabetes. To investigate the biological roles of ACCβ in the pathogenesis of diabetic nephropathy, we examined the effects of overexpression of ACACB using podocyte-specific ACACB-transgenic mice or ACACB-overexpressing murine podocytes. Podocyte-specific ACACB-transgenic mice or littermate mice were treated with streptozotocin (STZ) to induce diabetes, and 12 weeks after induction of diabetes, we examined the expression of podocyte markers to evaluate the degree of podocyte injury in these mice. We also examined the effects of ACCβ on podocyte injury in ACACB- or LacZ-overexpressing murine podocytes. Podocyte-specific ACACB overexpression did not cause visible podocyte injury in non-diabetic mice. In STZ-induced diabetic mice, ACACB-transgenic mice showed a significant increase in urinary albumin excretion, accompanied by decreased synaptopodin expression and podocin mislocalization in podocytes, compared with wild-type mice. In cultured murine podocytes, overexpression of ACACB significantly decreased synaptopodin expression and reorganized stress fibers under high glucose conditions, but not in normal glucose conditions. The decrease of synaptopodin expression and reorganized stress fibers observed in ACACB overexpressing cells cultured under high glucose conditions was reversed by a treatment of 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), activator of AMP-activated protein kinase (AMPK). The excess of ACCβ might contribute to exacerbation of podocyte injury in the kidney of an animal model for diabetes mellitus, and the AMPK/ACCβ pathway may be a novel therapeutic target for the prevention of diabetes-related podocyte injury.
60 APPLIED LIFE SCIENCES↗
Alpha-lipoic acid reduces retinal cell death in diabetic mice
Highlights: • α-LA reduces oxidative stress in diabetic mouse retinas. • α-LA increases p-AMPK, p-ACC, PPARδ, and SIRT3 in diabetic mouse retinas. • α-LA decreases OGT, TXNIP, and cleaved-PARP and -caspase-3 in diabetic mouse retinas. • α-LA decreases AMPK interaction with OGT, reducing retinal injuries in diabetic mice. Oxidative stress plays an important role in the development of diabetic retinopathy. Here, we examined whether α-lipoic acid (α-LA), a natural antioxidant, attenuated retinal injury in diabetic mice. The α-LA was orally administered to control mice or mice with streptozotocin-induced diabetes. We found that α-LA reduced oxidative stress, decreased and increased retinal 4-hydroxy-2-nonenal and glutathione peroxidase, respectively, and inhibited retinal cell death. Concomitantly, α-LA reversed the decreased activation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase, and increased the levels of peroxisome proliferator-activated receptor delta and sirtuin3 in diabetic mouse retinas, similar to results shown after metformin treatment of retinal pigment epithelial cells (RPE) exposed to high glucose. Moreover, α-LA lowered the levels of O-linked β-N-acetylglucosamine transferase (OGT) and thioredoxin-interacting protein (TXNIP) in diabetic retinas that were more pronounced after metformin treatment of RPE cells. Importantly, α-LA lowered interactions between AMPK and OGT as shown by co-immunoprecipitation analyses, and this was accompanied by less cell death as measured by double immunofluorescence staining by terminal deoxynucleotide transferase-mediated dUTP nick-end labelling and OGT or TXNIP in retinal ganglion cells. Consistently, α-LA lowered the levels of cleaved poly(ADP-ribose) polymerase and pro-apoptotic marker cleaved caspase-3 in diabetic retinas. Our results indicated that α-LA reduced retinal cell death partly through AMPK activation or OGT inhibition in diabetic mice.
60 APPLIED LIFE SCIENCES↗
Intrathecal circHIPK3 shRNA alleviates neuropathic pain in diabetic rats
Highlights: • CircHIPK3 was associated with diabetic neuropathic pain. • Silencing circHIPK3 alleviated neuropathic pain via increasing miR-124. Neuropathic pain is one of the most common diabetic complications and significantly decrease the quality of life. The aetiology of the painful diabetic neuropathic pain is not fully clear. Circular RNAs (circRNAs) have been identified as miRNA sponges and involved in various biological processes, including pain. CircHIPK3 is a circRNA that have been shown to be an oncogene or tumor suppressor to regulate cancer cells growth by sponging multiple miRNAs. However, the role of circHIPK3 in diabetic neuropathic pain remains unknown. The aim of the present study was to elucidate the possible role of circHIPK3 in the control of diabetic neuropathic pain. We found that circHIPK3 are highly abundant in serum from diabetes patients who suffered from neuropathic pain and in dorsal root ganglion from STZ-induced diabetes rats. Upregulation of circHIPK3 was positively associated with grade neuropathic pain in patients with type 2 diabetes. Silencing circHIPK3 alleviated neuropathic pain in diabetic rats, which was involved in neuroinflammation. Further mechanistic investigation demonstrated that circHIPK3 interacted with miR-124 and negatively regulated its expression. MiR-124 inhibitor can reverse circHIPK3 knockdown-mediated alleviation of neuropathic pain and inhibition of neuroinflammation in diabetic rats. We present the first evidence that intrathecal circHIPK3 shRNA treatment can be used to treat neuropathic pain of diabetic rats.
60 APPLIED LIFE SCIENCES↗
Leukocytic toll-like receptor 2 knockout protects against diabetes-induced cardiac dysfunction
Highlights: • TLR2 KO promotes the functional recovery of myocardium. • TLR2 KO maintains the balance of calcium. • TLR2 KO reduces cell apoptosis induced by oxidative stress. • TLR2 KO decreases the fibrosis of heart tissues in diabetic cardiomyopathy mice. Diabetic cardiomyopathy is characterized by the deterioration of the myocardial function. Emerging evidences have indicated that leukocytic toll-like receptor 2 (TLR2) played an important role in the development of diabetic cardiomyopathy. Our study aimed to investigate whether TLR2 knockout (KO) exerted a cardioprotective effect in vivo. The establishment of diabetes model was set up in mice via intraperitoneal injection of streptozotocin (STZ). Results demonstrated that blocking of TLR2 significantly suppressed the enhanced left ventricular end-diastolic dimension (LVEDD), left ventricular end systolic diameter (LVESD) and the reduced the heart rate in diabetic cardiomyopathy mice. The decreased resting cell length, PS, TPS and + dL/dt while increased TR90 and - dL/dt caused by diabetic cardiomyopathy were remarkably inhibited by TLR2 KO. Besides that, the alleviated ΔFFI (360/380), decreased SERCA2a and p-NFATc3 expressions, extended Ca{sup 2+} decay time and elevated Calcineurin A induced by diabetic cardiomyopathy were vastly repressed by TLR2 KO in cardiocytes. Moreover, TLR2 gene silence could ameliorate oxidative stress-induced apoptosis, evidences were the up-regulated superoxide generation and Bax/Bcl-2 expression while restrained GSH/GSSG ratio caused by diabetic cardiomyopathy were tremendously repressed in TLR2 KO mice. Furthermore, blocking of TLR2 remarkably attenuated the augmented fibrosis areas of heart tissues in mice with diabetic cardiomyopathy. The result of the enhanced α-SMA and collagenⅠ caused by diabetic cardiomyopathy were suppressed in heart tissues of TLR2 KO mice further validate it. All in all, our study demonstrated that diabetes-induced cardiac dysfunction could be attenuated by TLR2 KO.
60 APPLIED LIFE SCIENCES↗
Brain phosphoproteomic analysis identifies diabetes‐related substrates in Alzheimer's disease pathology in older adults
INTRODUCTION: Type 2 diabetes increases the risk of Alzheimer's disease (AD) dementia. Insulin signaling dysfunction exacerbates tau protein phosphorylation, a hallmark of AD pathology. However, the comprehensive impact of diabetes on patterns of AD-related phosphoprotein in the human brain remains underexplored. METHODS: We performed tandem mass tag–based phosphoproteome profiling in post mortem human brain prefrontal cortex samples from 191 deceased older adults with and without diabetes and pathologic AD. RESULTS: Among 7874 quantified phosphosites, microtubule-associated protein tau (MAPT) phosphorylated at T529 and T534 (isoform 8 T212 and T217) were more abundant in AD and showed differential associations with diabetes. Network analysis of co-abundance patterns uncovered synergistic interactions between AD and diabetes, with one module exhibiting higher MAPT phosphorylation (15 MAPT phosphosites) and another displaying lower MAP1B phosphorylation (22 MAP1B phosphosites). DISCUSSION: This study offers phosphoproteomics insights into AD in diabetes, shedding light on mechanisms that can inform the development of therapeutics for dementia. Highlights: The risk of Alzheimer's disease (AD) dementia is increased among older adults living with diabetes. The patterns of AD-related phosphoprotein in the human brain in older adults are differential among older adults living with diabetes. Microtubule-associated protein tau phosphorylated at T529 and T534 (isoform 8 T212 and T217) showed differential associations with diabetes. Phosphosite co-abundance networks of synergistic interactions between AD and diabetes were identified.
60 APPLIED LIFE SCIENCES↗
D-saccharic acid-1,4-lactone ameliorates alloxan-induced diabetes mellitus and oxidative stress in rats through inhibiting pancreatic beta-cells from apoptosis via mitochondrial dependent pathway
Oxidative stress plays a vital role in diabetic complications. To suppress the oxidative stress mediated damage in diabetic pathophysiology, a special focus has been given on naturally occurring antioxidants present in normal diet. D-saccharic acid 1,4-lactone (DSL), a derivative of D-glucaric acid, is present in many dietary plants and is known for its detoxifying and antioxidant properties. The aim of the present study was to evaluate the beneficial role of DSL against alloxan (ALX) induced diabetes in the pancreas tissue of Swiss albino rats. A dose-dependent study for DSL (20-120 mg/kg body weight) was carried out to find the effective dose of the compound in ALX-induced diabetic rats. ALX exposure elevated the blood glucose, glycosylated Hb, decreased the plasma insulin and disturbed the intra-cellular antioxidant machineries whereas oral administration of DSL at a dose of 80 mg/kg body weight restored these alterations close to normal. Investigating the mechanism of the protective activity of DSL we observed that it prevented the pancreatic {beta}-cell apoptosis via mitochondria-dependent pathway. Results showed decreased mitochondrial membrane potential, enhanced cytochrome c release in the cytosol and reciprocal regulation of Bcl-2 family proteins in the diabetic rats. These events were also found to be associated with increased level of Apaf-1, caspase 9, and caspase 3 that ultimately led to pancreatic {beta}-cell apoptosis. DSL treatment, however, counteracted these changes. In conclusion, DSL possesses the capability of ameliorating the oxidative stress in ALX-induced diabetes and thus could be a promising approach in lessening diabetic complications. Highlights: Black-Right-Pointing-Pointer Oxidative stress is suggested as a key event in the pathogenesis of diabetes. Black-Right-Pointing-Pointer D-saccharic acid 1,4-lactone (DSL) reduces the alloxan-induced diabetes mellitus. Black-Right-Pointing-Pointer DSL normalizes cellular antioxidant machineries disturbed due to alloxan toxicity. Black-Right-Pointing-Pointer DSL inhibits pancreatic {beta}-cells apoptosis via mitochondria-dependent pathway. Black-Right-Pointing-Pointer DSL could be a promising approach for the treatment of diabetes mellitus.
60 APPLIED LIFE SCIENCES↗
D-Saccharic acid 1,4-lactone protects diabetic rat kidney by ameliorating hyperglycemia-mediated oxidative stress and renal inflammatory cytokines via NF-κB and PKC signaling
Increasing evidence suggests that oxidative stress is involved in the pathogenesis of diabetic nephropathy (DN) and this can be attenuated by antioxidants. D-Saccharic acid 1,4-lactone (DSL) is known for its detoxifying and antioxidant properties. Our early investigation showed that DSL can ameliorate alloxan (ALX) induced diabetes mellitus and oxidative stress in rats by inhibiting pancreatic β-cell apoptosis. In the present study we, therefore, investigated the protective role of DSL against renal injury in ALX induced diabetic rats. ALX exposure (at a dose of 120 mg/kg body weight, i. p., once) elevated the blood glucose level, serum markers related to renal injury, the production of reactive oxygen species (ROS), and disturbed the intra-cellular antioxidant machineries. Oral administration of DSL (80 mg/kg body weight) restored all these alterations close to normal. In addition, DSL could also normalize the aldose reductase activity which was found to increase in the diabetic rats. Investigating the mechanism of its protective activity, we observed the activation of different isoforms of PKC along with the accumulation of matrix proteins like collagen and fibronectin. The diabetic rats also showed nuclear translocation of NF-κB and increase in the concentration of inflammatory cytokines in the renal tissue. The activation of mitochondria dependent apoptotic pathway was observed in the diabetic rat kidneys. However, treatment of diabetic rats with DSL counteracted all these changes. These findings, for the first time, demonstrated that DSL could ameliorate renal dysfunction in diabetic rats by suppressing the oxidative stress related signalling pathways. - Highlights: ► Sustained hyperglycemia and oxidative stress lead to diabetic renal injury. ► D-saccharic acid 1,4-lactone prevents renal damage in alloxan-induced diabetes. ► It restores intra-cellular antioxidant machineries and kidney apoptosis. ► DSL reduces hyperglycemia-mediated oxidative stress via NF-kB and PKC signaling. ► DSL may act as a beneficial agent in hyperglycemia induced renal disorder.
60 APPLIED LIFE SCIENCES↗
Selenite exacerbates hepatic insulin resistance in mouse model of type 2 diabetes through oxidative stress-mediated JNK pathway
Recent evidence suggests a potential pro-diabetic effect of selenite treatment in type 2 diabetics; however, the underlying mechanisms remain elusive. Here we investigated the effects and the underlying mechanisms of selenite treatment in a nongenetic mouse model of type 2 diabetes. High-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice were orally gavaged with selenite at 0.5 or 2.0 mg/kg body weight/day or vehicle for 4 weeks. High-dose selenite treatment significantly elevated fasting plasma insulin levels and insulin resistance index, in parallel with impaired glucose tolerance, insulin tolerance and pyruvate tolerance. High-dose selenite treatment also attenuated hepatic IRS1/Akt/FoxO1 signaling and pyruvate kinase gene expressions, but elevated the gene expressions of phosphoenolpyruvate carboxyl kinase (PEPCK), glucose 6-phosphatase (G6Pase), peroxisomal proliferator-activated receptor-γ coactivator 1α (PGC-1α) and selenoprotein P (SelP) in the liver. Furthermore, high-dose selenite treatment caused significant increases in MDA contents, protein carbonyl contents, and a decrease in GSH/GSSG ratio in the liver, concurrent with enhanced ASK1/MKK4/JNK signaling. Taken together, these findings suggest that high-dose selenite treatment exacerbates hepatic insulin resistance in mouse model of type 2 diabetes, at least in part through oxidative stress-mediated JNK pathway, providing new mechanistic insights into the pro-diabetic effect of selenite in type 2 diabetes. - Highlights: • Selenite exacerbates hepatic insulin resistance in HFD/STZ-induced diabetic mice. • Selenite elevates hepatic gluconeogenesis and reduces glycolysis in diabetic mice. • Selenite exacerbates hepatic oxidative stress and triggers JNK signaling pathway. • Selenite elevates hepatic selenoprotein P expression in diabetic mice.
60 APPLIED LIFE SCIENCES↗