Major Complication Of Diabetes Research Articles

Evaluation of a polymer-coated nanoparticle cream formulation of resiniferatoxin for the treatment of painful diabetic peripheral neuropathy.

Painful diabetic peripheral neuropathy (PDPN) is one of the major complications of diabetes. Currently, centrally acting drugs and topical analgesics are used for treating PDPN. These drugs have adverse effects; some are ineffective, and treatment with opioids is associated with use dependence and addiction. Recent research indicates that transient receptor potential vanilloid 1 (TRPV1) expressed in the peripheral sensory nerve terminals is an emerging target to treat pain associated with PDPN. Block of TRPV1 ion channel with specific antagonists, although effective as an analgesic, induced hyperthermia in clinical trials. However, TRPV1 agonists are useful to treat pain by virtue of their ability to cause Ca 2+ influx and subsequently leading to nerve terminal desensitization. Here, we report the effectiveness of an ultrapotent TRPV1 agonist, resiniferatoxin (RTX) nanoparticle, in a topical formulation (RTX-cream; RESINIZIN) that alleviates pain associated with DPN in animal models of diabetes. Resiniferatoxin causes nerve terminal depolarization block in the short term, which prevents pain during application and leading to nerve terminal desensitization/depletion in the long term resulting in long-lasting pain relief. Application of RTX cream to the hind limbs suppresses thermal hyperalgesia in streptozotocin-induced diabetic rats and mini pigs without any adverse effects as compared with capsaicin at therapeutic doses, which induces intense pain during application. Resiniferatoxin cream also decreases the expression of TRPV1 in the peripheral nerve endings and suppresses TRPV1-mediated calcitonin gene-related peptide release in the skin samples of diabetic rats and mini pigs. Our preclinical data confirm that RTX topical formulation is an effective treatment option for PDPN.

Advances for the treatment of lower extremity arterial disease associated with diabetes mellitus.

Lower extremity arterial disease (LEAD) is a major vascular complication of diabetes. Vascular endothelial cells dysfunction can exacerbate local ischemia, leading to a significant increase in amputation, disability, and even mortality in patients with diabetes combined with LEAD. Therefore, it is of great clinical importance to explore proper and effective treatments. Conventional treatments of diabetic LEAD include lifestyle management, medication, open surgery, endovascular treatment, and amputation. As interdisciplinary research emerges, regenerative medicine strategies have provided new insights to treat chronic limb threatening ischemia (CLTI). Therapeutic angiogenesis strategies, such as delivering growth factors, stem cells, drugs to ischemic tissues, have also been proposed to treat LEAD by fundamentally stimulating multidimensional vascular regeneration. Recent years have seen the rapid growth of tissue engineering technology; tissue-engineered biomaterials have been used to study the treatment of LEAD, such as encapsulation of growth factors and drugs in hydrogel to facilitate the restoration of blood perfusion in ischemic tissues of animals. The primary purpose of this review is to introduce treatments and novel biomaterials development in LEAD. Firstly, the pathogenesis of LEAD is briefly described. Secondly, conventional therapies and therapeutic angiogenesis strategies of LEAD are discussed. Finally, recent research advances and future perspectives on biomaterials in LEAD are proposed.

Abstract P3050: The Adropin-GPR19 Signaling Axis In Diabetic Cardiomyopathy

Background: Diabetic cardiomyopathy (DCM) is a major complication of diabetes and has been recognized as a cause of heart failure independent of other common risk factors for cardiac disease. In DCM, increased free fatty acid availability and decreased myocardial glucose uptake lead to a reliance on fatty acid oxidation for ATP generation. This loss of metabolic flexibility can reduce cardiac plasticity in response to stress. Energetic inefficiency in diabetic hearts may have profound implications for cardiac function under conditions of increased workload, and therefore therapeutic approaches are warranted. Alleviating metabolic inflexibility, by promoting cardiac glucose utilization, has been proposed as a potential strategy to reverse cardiomyopathy in diabetic and obese patients. Adropin is a liver- and brain-secreted peptide hormone shown to regulate fuel metabolism in a number of tissues, including the heart. Adropin levels are significantly reduced in obese and diabetic human subjects, and this decrease is linked to increased adiposity, insulin resistance, and impaired glucose tolerance. Our lab recently showed that adropin treatment restores glucose oxidation activity in vivo by reducing the expression of the mitochondrial acetyltransferase enzyme GCN5L1. The reduction in GCN5L1 abundance altered the acetylation and activity of fuel metabolism enzymes to favor glucose utilization; however, the mechanism that underlies this effect remains unknown. Our data suggests that the class A orphan G-coupled protein receptor, GPR19, acts as a putative cellular receptor for adropin in cardiac cells to regulate mitochondrial bioenergetic output. Hypothesis: We hypothesize that adropin-GPR19 signaling regulates GCN5L1 expression, which in turn promotes the deacetylation and activity of pyruvate dehydrogenase to restore glucose utilization in the diabetic heart. Methods: We used a novel whole-body GPR19 knockout mouse to perform a preliminary characterization of the effects of GPR19 depletion on cardiac and whole-body physiology. Using in vivo metabolic approaches, we report that GPR19 KO mice exhibit sex-dependent glucose intolerance, and display markers of altered cardiac energy metabolism. Conclusions: These findings further define the fundamental role of the adropin-GPR19 signaling pathway in the regulation of metabolic homeostasis, and thus highlight a potential target for therapeutic interventions in DCM.

Fibroblasts: Immunomodulatory factors in refractory diabetic wound healing.

Diabetes is a systemic disease in which patients with diabetes may develop peripheral neuropathy of the lower extremities and peripheral vascular disease due to long-term continuous exposure to high glucose. Delayed wound healing in diabetes is one of the major complications of diabetes. Slow wound healing in diabetic patients is associated with high glucose toxicity. When the condition deteriorates, the patient needs to be amputated, which seriously affects the quality of life and even endangers the life of the patient. In general, the delayed healing of diabetes wound is due to the lack of chemokines, abnormal inflammatory response, lack of angiogenesis and epithelial formation, and fibroblast dysfunction. The incidence of several chronic debilitating conditions is increasing in patients with diabetes, such as chronic renal insufficiency, heart failure, and hepatic insufficiency. Fibrosis is an inappropriate deposition of extracellular matrix (ECM) proteins. It is common in diabetic patients causing organ dysfunction. The fibrotic mechanism of diabetic fibroblasts may involve direct activation of permanent fibroblasts. It may also involve the degeneration of fibers after hyperglycemia stimulates immune cells, vascular cells, or organ-specific parenchymal cells. Numerous studies confirm that fibroblasts play an essential role in treating diabetes and its complications. The primary function of fibroblasts in wound healing is to construct and reshape the ECM. Nowadays, with the widespread use of single-cell RNA sequencing (scRNA-seq), an increasing number of studies have found that fibroblasts have become the critical immune sentinel cells, which can detect not only the activation and regulation of immune response but also the molecular pattern related to the injury. By exploring the heterogeneity and functional changes of fibroblasts in diabetes, the manuscript discusses that fibroblasts may be used as immunomodulatory factors in refractory diabetic wound healing, providing new ideas for the treatment of refractory diabetic wound healing.

Down-regulation of circCOL1A2 suppresses the dysfunction of diabetes-related retinal microvascular endothelial cells via miR-646/FGF7 axis

Purpose Diabetic retinopathy (DR), the major complication of diabetes, is the leading cause of vision loss and blindness globally. Altered circular RNAs (circRNAs) expression has been found to be involved in DR process. Hence, this work aimed to explore the role and mechanism of circCOL1A2 in DR. Methods Human retinal microvascular endothelial cells (RMECs) treated with high glucose (HG) were used for functional analysis. Levels of genes and proteins were detected using quantitative real-time polymerase chain reaction and western blotting. In vitro experiments were conducted by transwell, tube formation, CCK-8 assays, and ELISA, respectively. The binding interaction between miR-646 and circCOL1A2 or FGF7 (Fibroblast Growth Factor 7) was confirmed using dual-luciferase reporter and RIP assays. Results CircCOL1A2 was highly expressed in retinal tissues of DR patients and HG-induced RMECs. Then RMECs were exposed to HG treatment to mimic the diabetic conditions in vitro. Functionally, circCOL1A2 knockdown attenuated HG-evoked RMEC migration, proliferation, angiogenesis, blood-retina barrier (BRB) injury and inflammation. Mechanistically, circCOL1A2 functioned as a sponge for miR-646, and miR-646 directly targeted FGF7. Further rescue experiments showed that miR-646 inhibition abated the protective effects of circCOL1A2 knockdown on RMEC function under HG treatment. Besides that, miR-646 was decreased in HG-induced RMECs, re-expression of miR-646 reversed HG-evoked RMEC dysfunction, which was rescued by FGF7 overexpression. Conclusion CircCOL1A2 silencing can suppress HG-induced migration, proliferation, angiogenesis, BRB injury and inflammation in RMECs through miR-646/FGF7 axis, suggesting the potential involvement of circCOL1A2 in DR process.

Ursolic acid reduces NADPH oxidase expression and ensuing oxidative stress in diabetic kidney

Background and Aims : Diabetic kidney disease (DKD) is a major life-threatening complication of diabetes. Triterpenic acids elicit anti-hyperglycemic effects and prevent the dysfunction of pancreatic beta cells. The molecular basis of triterpenes action is not completely understood, particularly in DKD. This study aimed at investigating the potential of ursolic acid (UA), a pentacyclic triterpenoid, to modulate NADPH oxidase (Nox) expression, the key source of reactive oxygen species (ROS), in experimental DKD.

Nicotinamide mononucleotide improves spermatogenic function in streptozotocin-induced diabetic mice via modulating the glycolysis pathway.

Spermatogenic dysfunction is one of the major secondary complications of diabetes; however, the underlying mechanisms remain ill-defined, and there is no available drug or strategy for the radical treatment of diabetic spermatogenic dysfunction. Therefore, the objective of this study is to investigate the protective effects of nicotinamide mononucleotide (NMN) on testicular spermatogenic function in streptozotocin (STZ)-induced diabetic mice. The results show that oral administration of NMN significantly increases the body and testis weight and the number of sperms. Moreover, the abnormal sperm count and the rate of sperm malformation are significantly decreased compared with the saline-treated diabetic mice. Histological analysis reveals that NMN treatment significantly increases the area and diameter of seminiferous tubules, accompanied by an increased number of spermatogenic cells and sperms. Immunohistochemistry and qRT-PCR results show that NMN increases Bcl-2 expression and decreases Bax expression in the testis. NMN also increases the protein expression of Vimentin and the mRNA expressions of WT1 and GATA4. In addition, qRT-PCR, western blot analysis and immunohistochemistry results also show that NMN increases the expressions of glycolysis-related rate-limiting enzymes including HK2, PKM2, and LDHA. In summary, this study demonstrates the protective effects of NMN on the testis in an STZ-induced diabetic mice model. NMN exerts its protective effects via reducing spermatogenic cell apoptosis by regulating glycolysis of Sertoli cells in diabetic mice. This study provides an experimental basis for the future clinical application of NMN in diabetes-induced spermatogenic dysfunction.

790 Chronic skin wounds of genetically modified (db/db) and diet-induced diabetic mice have altered levels of TSG-6 and TSP-1

Chronic non-healing wounds are a major complication of diabetes. Effective communication between immune cells and the extracellular matrix (ECM) is crucial for regulating wound healing. Tumor necrosis factor-stimulated gene-6 (TSG-6) modifies the extracellular matrix (ECM) and regulates inflammation; Thrombospondin 1 (TSP-1) regulates angiogenesis and binds to TSG-6. In both TSG-6 and TSP-1 knockout mice, wound closure is delayed. We hypothesize that hyperglycemia causes dysregulation of TSG-6 and TSP-1, which together results in fewer heavy chain-hyaluronan complexes (HC-HA) in the ECM, an acceleration of leukocyte infiltration, a pro-inflammatory milieu, and wound healing delay.

Characterization Of Phyto-Synthesized Silver Nanoparticles And Their Antimicrobial Activity Against Diabetic Foot Ulcer Bacterial Isolates.

Diabetic Foot Ulcer (DFU) is one of the major complications of Diabetes. Patients with Diabetic Foot ulcers have a high susceptibility to microbial infections and are the leading cause of hospitalization and amputation of lower limbs. In the era of increased prevalence of bacterial resistance and outbreak of resistant infectious diseases, it is very essential to develop effective therapeutic strategies towards multi-drug resistant pathogens. The antimicrobial properties of silver nanoparticles have been well studied, therefore their use in biomedicine and pharmacology is a trend. Herein we present the use of Phyto-mediated synthesized AgNPs for the treatment of diabetic foot ulcers by topical administration. The nanoparticles were synthesized by reducing silver nitrate using Terminalia chebula fruit extract. The nanoparticles were analyzed and characterized using UV-Visible Spectrophotometer, FTIR, XRD, SEM with EDAX, TEM, and DLS. The synthesized silver nanoparticles were assayed for antimicrobial activity against five Diabetic Foot Ulcer bacterial isolates i.e. Escherichia coli, Klebsiella Pneumoniae, Pseudomonas aeruginosa, Streptococcus aureus, and Bacillus subtilis. The bactericidal property of synthesized nanoparticles was analyzed by the Agar well diffusion method, which revealed the remarkable antimicrobial effects against all the selective pathogenic bacterial isolates of Diabetic foot ulcers in the present study. These results constituted the basis for further studies on the use of plant-based silver nanoparticles for the treatment of Diabetic Foot ulcers from different origins.

A novel few-shot classification framework for diabetic retinopathy detection and grading

Diabetes Retinopathy (DR) is a major microvascular complication of diabetes. Computer-Aided Diagnosis (CAD) tools for DR management are primarily developed using Artificial Intelligence (AI) methods, such as machine and deep learning algorithms. DR diagnostic tools have been developed in recent years using deep learning models. Thus, these models require large amounts of data for training. Consequently, these huge amounts of data are not balanced due to fewer cases in the dataset. To solve the problems associated with training models with small datasets, such as overfitting and poor approximation, this paper proposes a paradigm called Few-Shot Learning (FSL) which uses a relatively small amount of training data to train the models effectively. This paper proposes a novel prototype network, a type of FSL classification network capable of grading and detecting DR based on attention. The DRNet framework uses episodic learning to train its model on few-shot classification tasks. We developed a DRNet based on the APTOS2019 dataset for diabetic detection and grading. In the proposed network, aggregated transformations and gradient activations of classes are leveraged to design the attention mechanism to capture image representations. As a result, the system achieves 99.73 % accuracy, 99.82 % sensitivity, 99.63 % specificity in DR detection, 98.18 % accuracy, 97.41% sensitivity, and 99.55% specificity in DR grading. An analysis of objective performance metrics and model interpretation shows that the proposed model can detect DR more efficiently and grade the severity more accurately when using unseen fundus images than existing state-of-the-art methods.Therefore, this tool could help provide a second opinion to an ophthalmologist about the severity level of DR.

Oxidative Stress and Lipid Peroxidation: Prospective Associations Between Ferroptosis and Delayed Wound Healing in Diabetic Ulcers.

Diabetic ulcers are one of the major complications of diabetes, and patients usually suffer from amputation and death due to delayed ulcer wound healing. Persistent inflammation and oxidative stress at the wound site are the main manifestations of delayed wound healing in diabetic ulcers. In addition, chronic hyperglycemia in patients can lead to circulatory accumulation of lipid peroxidation products and impaired iron metabolism pathways leading to the presence of multiple free irons in plasma. Ferroptosis, a newly discovered form of cell death, is characterized by intracellular iron overload and accumulation of iron-dependent lipid peroxides. These indicate that ferroptosis is one of the potential mechanisms of delayed wound healing in diabetic ulcers and will hopefully be a novel therapeutic target for delayed wound healing in diabetic patients. This review explored the pathogenesis of diabetic ulcer wound healing, reveals that oxidative stress and lipid peroxidation are common pathological mechanisms of ferroptosis and delayed wound healing in diabetic ulcers. Based on strong evidence, it is speculated that ferroptosis and diabetic ulcers are closely related, and have value of in-depth research. We attempted to clarify prospective associations between ferroptosis and diabetic ulcers in terms of GPX4, iron overload, ferroptosis inhibitors, AGEs, and HO-1, to provide new ideas for exploring the clinical treatment of diabetic ulcers.

Multi-Lesion Segmentation of Diabetic Retinopathy Using Deep Learning

Abstract: Diabetic Retinopathy (DR) and Diabetic Macular Edema (DME) are the two major complications of diabetes and have a significant impact on working individuals of the world population. DR doesn’t give any early symptoms. Therefore, it is important to diagnose DR at an early stage. The two above mentioned diseases usually depend on the presence and areas of lesions in fundus images. The four main related lesions include soft exudates, hard exudates,microaneurysms, and haemorrhages. Since lesions in retinal fundus images are a pivotal indicator of DR, analyzing retinal fundus images is the most popular method for DR screening. The examination of fundus images is time-consuming and small lesions are hard to observe. Therefore, adopting deep learning techniques for lesion segmentation is of great importance. In this project, we use one of the deep learning techniques called U-Net, which is a variant of Convolutional Neural Networks (CNN) for multiple lesion segmentation.

Predictive Capacity of Beat-to-Beat Blood Pressure Variability for Cardioautonomic and Vascular Dysfunction in Early Metabolic Challenge

Diabetic patients present established cardiovascular disease at the onset of diagnostic metabolic symptoms. While premature autonomic and vascular deterioration considered risk factors for major cardiovascular complications of diabetes, present in initial stages of metabolic impairment, their early detection remains a significant challenge impeding timely intervention. In the present study, we examine the utility of beat-to-beat blood pressure variability (BPV) parameters in capturing subtle changes in cardiac autonomic and vascular control distinguishing between various risk categories, independent of the average BP. A rat model of mild hypercaloric (HC) intake was used to represent the insidious cardiovascular changes associated with early metabolic impairment. Invasive hemodynamics were used to collect beat-to-beat BP time series in rats of either sex with different durations of exposure to the HC diet. Linear (standard deviation and coefficient of variation) and nonlinear (approximate entropy, ApEn, and self-correlation of detrended fluctuation analysis, α) BPV parameters were calculated to assess the impact of early metabolic impairment across sexes and feeding durations. HC-fed male, but not female, rats developed increased fat:lean ratio as well as hyperinsulinemia. Unlike linear parameters, multivariate analysis showed that HC-fed rats possessed lower ApEn and higher α, consistent with early changes in heart rate variability and blunting of parasympathetic baroreceptor sensitivity, particularly in males. Moreover, logistic regression demonstrated the superiority of nonlinear parameters of diastolic BPV in predicting a prediabetic disease state. Our findings support the use of nonlinear beat-to-beat BPV for early detection of cardiovascular derangements in the initial stages of metabolic impairment.

Neutralizing Staphylococcus aureus Virulence with AZD6389, a Three mAb Combination, Accelerates Closure of a Diabetic Polymicrobial Wound.

ABSTRACTNonhealing diabetic foot ulcers (DFU), a major complication of diabetes, are associated with high morbidity and mortality despite current standard of care. Since Staphylococcus aureus is the most common pathogen isolated from nonhealing and infected DFU, we hypothesized that S. aureus virulence factors would damage tissue, promote immune evasion and alter the microbiome, leading to bacterial persistence and delayed wound healing. In a diabetic mouse polymicrobial wound model with S. aureus, Pseudomonas aeruginosa, and Streptococcus pyogenes, we report a rapid bacterial proliferation, prolonged pro-inflammatory response and large necrotic lesions unclosed for up to 40 days. Treatment with AZD6389, a three-monoclonal antibody combination targeting S. aureus alpha toxin, 4 secreted leukotoxins, and fibrinogen binding cell-surface adhesin clumping factor A resulted in full skin re-epithelization 21 days after inoculation. By neutralizing multiple virulence factors, AZD6389 effectively blocked bacterial agglutination and S. aureus-mediated cell killing, abrogated S. aureus-mediated immune evasion and targeted the bacteria for opsonophagocytic killing. Neutralizing S. aureus virulence not only facilitated S. aureus clearance in lesions, but also reduced S. pyogenes and P. aeruginosa numbers, damaging inflammatory mediators and markers for neutrophil extracellular trap formation 14 days post initiation. Collectively, our data suggest that AZD6389 holds promise as an immunotherapeutic approach against DFU complications.IMPORTANCE Diabetic foot ulcers (DFU) represent a major complication of diabetes and are associated with poor quality of life and increased morbidity and mortality despite standard of care. They have a complex pathogenesis starting with superficial skin lesions, which often progress to deeper tissue structures up to the bone and ultimately require limb amputation. The skin microbiome of diabetic patients has emerged as having an impact on DFU occurrence and chronicity. DFU are mostly polymicrobial, and the Gram-positive bacterium Staphylococcus aureus detected in more than 95% of cases. S. aureus possess a collection of virulence factors which participate in disease progression and may facilitate growth of other pathogens. Here we show in a diabetic mouse wound model that targeting some specific S. aureus virulence factors with a multimechanistic antibody combination accelerated wound closure and promoted full skin re-epithelization. This work opens promising new avenues for the treatment of DFU.

Pyrroloquinoline quinone ameliorates renal fibrosis in diabetic nephropathy by inhibiting the pyroptosis pathway in C57BL/6 mice and human kidney 2 cells.

Diabetic nephropathy (DN), which is characterized by renal fibrosis, is a major complication of diabetes, a disease that afflicted more than 460 million people worldwide in 2019. Pyroptosis is an essential signaling pathway in DN-related injuries, such as renal fibrosis. Pyrroloquinoline quinone (PQQ) is a naturally occurring bioactive compound that protects human kidney 2 (HK-2) cells from oxidative stress-induced damage caused by high glucose concentrations. However, the nature and underlying mechanism of the effect of PQQ on DN-related renal fibrosis remains unclear. In this study, we evaluated whether PQQ has potential protective effects against renal fibrosis due to DN by establishing type 1 diabetes in mice via streptozotocin treatment and then inhibiting their pyroptosis signaling pathway. We found that compared to control mice, the area of renal fibrosis and injury were significantly increased in diabetic mice, and this was accompanied by increased levels of expression of collagen Ⅰ and transforming growth factor-β1; increased concentrations of the inflammatory cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α; and activation of the pyroptosis pathway components nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1, IL-1β, and IL-18. All of these changes were reversed by PQQ treatment. Analogously, we treated cultured HK-2 cells with a high concentration of glucose (35mmol/L), which caused these cells to exhibit significantly increased concentrations of reactive oxygen species (ROS), phosphorylated (p)-nuclear factor kappa B (NF-κB), p-IkappaB, NLRP3, caspase-1, IL-1β, and IL-18, and the loss of mitochondrial transmembrane potential. However, PQQ treatment significantly blunted these effects. In conclusion, in this study we demonstrated that PQQ attenuates renal fibrosis by alleviating mitochondrial dysfunction, reducing ROS production, and inhibiting the activation of the NF-κB/pyroptosis pathway under conditions of DN and hyperglycemia.

416-P: Mortality, Major Adverse Cardiovascular Events (MACE) and Diabetic Complications in Men with Hypogonadism and Type 2 Diabetes on Long-Term Testosterone Treatment: An Update from a Urological Registry Study

Background: Men with hypogonadism are at increased risk of MACE and mortality. Studies in men with T2DM show that testosterone therapy reduces both MACE and mortality. Methods: In a registry of 883 men with hypogonadism, 370 men (41.9%) have T2DM. 190 received TU 1000 mg/12 weeks (T-group) , 180 opted against treatment (CTRL) . All patients received standard diabetes treatment including lifestyle courses at a diabetes center. MACE, mortality, and diabetic complications were recorded and compared between groups. Results: Mean baseline age in the T-group and CTRL was 61.0±5.3 and 63.0±4.9 years. Mean follow-up in T-group and CTRL was 9.0 and 9.7 years. 71 patients (37.4%) in the T-group and 74 (41.1%) in CTRL had a history of cardiovascular disease (myocardial infarction MI, stroke, or coronary artery disease diagnosis) (p<0.05) . Baseline smoking prevalence was 41.6% (79 men) in the T-group and 37.4% (67 men) in CTRL (p=0.415) . The T-group had a worse baseline risk factor profile than CTRL: BMI (36.5±4.4 vs. 32.8±4.7 kg/m²) , systolic blood pressure (163.0±13.3 vs. 145.5±14.5 mmHg) , LDL (4.7±0.8 vs. 4.1±1.4 mmol/L) , HbA1c 9.5±1.4 vs. 7.8±0.7% (p<0.00for all) . Mortality: during the entire observation period, 21 patients (11.1%) died in the T-group vs. 62 (34.4%) in CTRL (p<0.0001) . Major adverse cardiovascular events (MACE) : in the T-group, there were no cases of MI or stroke. In CTRL, there were 62 cases of MI (34.4%) and 51 cases of stroke (28.3%) . Diabetic complications: in the T-group and CTRL, the incidence of retinopathy was 4 (2.1%) vs. 30 (16.7%) (p<0.0001) , nephropathy 1 (0.01%) vs. 7 (0.4%) (p=0.05) , polyneuropathy (5.3%) vs. 97 (53.9%) (p<0.0001) , diabetic foot syndrome 0 (0%) vs. 17 (9.4%) (p<0.0001) . Conclusions: Long-term treatment with TU in men with hypogonadism and T2DM reduces mortality, MACE, and diabetic complications, compared to untreated controls. Disclosure K.S.Haider: Other Relationship; Bayer AG. A.Haider: Other Relationship; Bayer AG. F.Saad: Consultant; Bayer AG, Stock/Shareholder; AbbVie Inc., Bayer AG, GlaxoSmithKline plc. Funding Bayer AG

1139-P: The Association between Age of Onset of Type 2 Diabetes and the Long-Term Risk for Major Diabetes-Related Complications

We evaluated the association between age of onset of type 2 diabetes and the risk for major diabetes complications. We included 1.1 million people with type 2 diabetes from the Australian diabetes registry, followed from 2010-2019. We evaluated the incidence of hospitalization for, or death from, myocardial infarction (MI) , stroke, and heart failure (HF) , and hospitalization for lower extremity amputation (LEA) ; the incidence of end-stage kidney disease (ESKD; including kidney replacement therapy or death from ESKD) ; and all-cause mortality (ACM) . Poisson regression was used to model rates by age of diabetes onset, current age, and diabetes duration. During 6.9 million person-years of follow-up, 72338, 46533, 101023, 20024, 13331, and 203542 MI, stroke, HF, LEA, ESKD, and ACM events occurred, respectively. The risk for all outcomes increased exponentially with diabetes duration (Figure) . The effects of age and duration differed for each: age was the stronger risk factor for MI, stroke, HF, and ACM, while duration was the predominant determinant of ESKD and LEA risk. At a given age, a 10-year younger age of onset was associated with a 1.1-1.5-fold increased risk of stroke and ACM, a 1.5-2-fold increased risk of MI and HF, and a 2-4-fold increased risk of LEA and ESKD. Thus, the increase in prevalence of young-onset type 2 diabetes may shift the burden of diabetes complications in coming decades. Disclosure J.I.Morton: None. P.Lazzarini: None. K.Polkinghorne: None. D.J.Magliano: None. J.E.Shaw: Advisory Panel; Abbott Diagnostics, AstraZeneca, Eli Lilly and Company, Pfizer Inc., Roche Diagnostics, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker's Bureau; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Sanofi. Funding JIM is supported by an Australian Government Research Training Program (RTP) Scholarship and Monash Graduate Excellence Scholarship. PAL is supported by a National Health and Medical Research Council Early Career Fellowship. DJM is supported by a National Health and Medical Research Council Senior Research Fellowship. JES is supported by a National Health and Medical Research Council Investigator Grant. This work is partially supported by the Victorian Government’s Operational Infrastructure Support Program.

TangShenWeiNing Formula Prevents Diabetic Nephropathy by Protecting Podocytes Through the SIRT1/HIF-1α Pathway.

BackgroundDiabetic nephropathy (DN) represents a major complication of diabetes, and podocyte injury has a critical function in DN development. TangShenWeiNing formula (TSWN) has been demonstrated to efficiently decrease proteinuria and protect podocytes in DN. This work aimed to explore the mechanism by which TSWN alleviates DN and protects podocytes.MethodsThe major bioactive components of TSWN were detected by mass spectrometry (MS) and pharmacological databases. Eight-week-old male C57BLKS/J db/m and db/db mice were provided pure water, valsartan, low dose TSWN, middle dose TSWN and high dose TSWN by gavage for 12 weeks, respectively.ResultsMS and network pharmacology analyses suggested that TSWN might prevent DN through the sirtuin (SIRT)1/hypoxia-inducible factor (HIF)-1α pathway. Diabetic mice showed elevated urinary albumin in comparison with non-diabetic mice, and TSWN decreased urinary albumin in diabetic mice. Histological injury increased in the kidney in diabetic mice, which could be improved by TSWN. Fibrosis and collagen I expression were induced in the diabetic mouse kidney in comparison with the non-diabetic mouse kidney; TSWN alleviated these effects. Apoptosis and cleaved caspase-3 were induced in the diabetic mouse kidney in comparison with the non-diabetic mouse kidney, and TSWN blunted these effects. Podocytes were damaged in the diabetic mouse kidney, which was improved by TSWN. Podocin and nephrin amounts were decreased in the diabetic mouse kidney in comparison with the non-diabetic mouse kidney, and podocalyxin was increased in urine of diabetic animals in comparison with non-diabetic counterparts. After TSWN treatment, podocin and nephrin were raised in the diabetic mouse kidney, and urinary podocalyxin was depressed in diabetic animals. Diabetic mice had lower SIRT1 and higher HIF-1α amounts in kidney specimens in comparison with non-diabetic mice, and TSWN promoted SIRT1 and inhibited HIF-1α in the diabetic mouse kidney. Moreover, co-staining of SIRT1 and podocin revealed that SIRT1 decreased in podocytes from diabetic mice in comparison with those from non-diabetic mice, and TSWN elevated SIRT1 in podocytes.ConclusionsThis study indicated that TSWN alleviates DN by improving podocyte injury through the SIRT1/HIF-1α pathway in diabetic mouse kidneys.

Targeting SLC7A11 improves efferocytosis by dendritic cells and wound healing in diabetes.

Chronic non-healing wounds are a major complication of diabetes, which affects 1 in 10 people worldwide. Dying cells in the wound perpetuate the inflammation and contribute to dysregulated tissue repair1-3. Here we reveal that the membrane transporter SLC7A11 acts as a molecular brake on efferocytosis, the process by which dying cells are removed, and that inhibiting SLC7A11 function can accelerate wound healing. Transcriptomics of efferocytic dendritic cells in mouse identified upregulation of several SLC7 gene family members. In further analyses, pharmacological inhibition of SLC7A11, or deletion or knockdown of Slc7a11 using small interfering RNA enhanced efferocytosis in dendritic cells. Slc7a11 was highly expressed in dendritic cells in skin, and single-cell RNA sequencing of inflamed skin showed that Slc7a11 was upregulated in innate immune cells. In a mouse model of excisional skin wounding, inhibition or loss of SLC7A11 expression accelerated healing dynamics and reduced the apoptotic cell load in the wound. Mechanistic studies revealed a link between SLC7A11, glucose homeostasis and diabetes. SLC7A11-deficient dendritic cells were dependent on aerobic glycolysis using glucose derivedfrom glycogen stores for increased efferocytosis; also, transcriptomics of efferocytic SLC7A11-deficient dendritic cells identified increased expression of genes linked to gluconeogenesis and diabetes. Further, Slc7a11 expression was higher in the wounds of diabetes-prone db/db mice, and targeting SLC7A11 accelerated their wound healing. The faster healing was also linked to the release of the TGFβ family member GDF15 from efferocytic dendritic cells. In sum, SLC7A11 is a negative regulator of efferocytosis, and removing this brake improves wound healing, with important implications for wound management in diabetes.

Speckle Tracking as Predictor of Coronary Artery Disease in Diabetic Female with Acute Chest Pain

Background: Cardiovascular disease is the most common reason of mortality and morbidity all-over the world and is the major complication of diabetes. Diabetes mellitus (DM) has reached epidemic proportions worldwide and the consequences of its diagnosis are as severe as a diagnosis of coronary artery disease (CAD). Females are more likely to develop atypical symptoms of coronary CAD than males later in life. Imaging of deformation by two-dimensional speckle-tracking echocardiography (2DSTE) has developed as a highly effective method for quantification of the function of myocardium.
 This research aimed to evaluate the accuracy of diagnosis using speckle tracking for prediction of the existence or absence of severe CAD in diabetic female with acute chest pain by using two-dimensional echocardiography.
 Methods: This study is a cohort prospective research which was carried out at the department of cardiology, Tanta University Hospitals and National Heart Institute from the duration of October 2019 to September 2020 on 60 diabetic female patients above 18 years old with acute chest pain may be prolonged for > 20 minutes or transient, changes in ECG in the form of depression of ST segment and/or inversion of T wave (ECG may be normal) and cardiac biomarkers (troponin and CKMB) may be elevated or normal.
 Results: 2D speckle tracking was good predictor for multi-vessels disease with 95% total accuracy, then for single vessels disease with 85% total accuracy and finally for double vessel disease stenosis with 80% accuracy as shown in table. Among Non-STEMI group, 2D speckle tracking was good predictor for multi-vessels disease with 95% total accuracy, then for single vessels disease with 80% total accuracy and finally for double vessel disease stenosis with 75% accuracy as shown in table.
 Conclusions: We found that speckle tracking is effective in predicting presence of CAD in diabetic female patients had acute chest pain and in prediction of affected vessels depending on the distribution of affected segments in longitudinal strain by GLS. In addition, it can be used as non-invasive test for patients with acute coronary syndrome.