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Diabetic encephalopathy (DE), a significant micro-complication of diabetes, manifests as neurochemical, structural, behavioral, and cognitive alterations. This condition is especially dangerous for the elderly because aging raises the risk of neurodegenerative disorders and cognitive impairment, both of which can be made worse by diabetes. Despite its severity, diagnosis of this disease is challenging, and there is a paucity of information on its pathogenesis. The pivotal roles of various cellular pathways, activated or influenced by hyperglycemia, insulin sensitivity, amyloid accumulation, tau hyperphosphorylation, brain vasculopathy, neuroinflammation, and oxidative stress, are widely recognized for contributing to the potential causes of diabetic encephalopathy. We also reviewed current pharmacological strategies for DE encompassing a comprehensive approach targeting metabolic dysregulations and neurological manifestations. Antioxidant-based therapies hold promise in mitigating oxidative stress-induced neuronal damage, while anti-diabetic drugs offer neuroprotective effects through diverse mechanisms, including modulation of insulin signaling pathways and neuroinflammation. Additionally, tissue engineering and nanomedicine-based approaches present innovative strategies for targeted drug delivery and regenerative therapies for DE. Despite significant progress, challenges remain in translating these therapeutic interventions into clinical practice, including long-term safety, scalability, and regulatory approval. Further research is warranted to optimize these approaches and address remaining gaps in the management of DE and associated neurodegenerative disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diabetic wounds pose a significant challenge in modern healthcare due to their chronic and complex nature, often resulting in delayed healing, infections, and, in severe cases, amputations. In recent years, nanotherapeutic approaches have emerged as promising strategies to address the unique pathophysiological characteristics of diabetic wounds. This review paper provides a comprehensive overview of the latest advancements in nanotherapeutics for diabetic wound treatment. We discuss various nanomaterials and delivery systems employed in these emerging therapies. Furthermore, we explore the integration of biomaterials to enhance the efficacy of nanotherapeutic interventions. By examining the current state-of-the-art research, challenges, and prospects, this review aims to offer valuable insights for researchers, clinicians, and healthcare professionals working in the field of diabetic wound care., Competing Interests: The authors declare that they have no competing interests in this work., (© 2024 Shi et al.)

Diabetic wounds, a prevalent diabetes complication, pose significant challenges in treatment. MicroRNA-engineered exosomes (miR-exo) are a promising new treatment for diabetic wounds; however, their mechanism remains to be completely understood. Therefore, we aimed to conduct a meta-analysis to evaluate the efficacy of miR-exo treatment in the management of diabetic wounds. To achieve this aim, academic databases, including PubMed, Embase, Web of Science, and the Cochrane Library, were searched for papers published before July 4, 2023. Outcome indicators (e.g., rate of wound healing, neovascular count, rate of re-epithelialization, deposition of collagen, breadth of scar, and inflammatory factors) were assessed. Six studies (total of 72 animals) met inclusion criteria and were analyzed. The amalgamated data revealed that miR-exo treatment exhibited superior results compared to those of control therapy. miR-exo treatment significantly enhanced the rate of wound healing, increased the number of neovascular formations, accelerated the rate of re-epithelialization, increased collagen deposition, reduced scar width, while significantly downregulating the expression of inflammatory factors. Our findings indicate that miR-exo treatment augments overall diabetic wound healing, especially when administered in conjunction with innovative dressings. To ascertain the optimal parameters for miR-exo treatment in managing diabetic wounds, future studies must encompass rigorous, large-scale, double-blinded clinical trials while incorporating long-term follow-up assessments for enhanced reliability and accuracy., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Diabetic wounds are more complex than normal chronic wounds because of factors such as hypoxia, reduced local angiogenesis, and prolonged inflammation phase. Fibrous proteins, including collagen, fibrin, laminin, fibronectin, elastin etc., possess excellent inherent properties that make them highly advantageous in the area of wound healing. Accumulating evidence suggests that they contribute to the healing process of diabetic wounds by facilitating the repair and remodel of extracellular matrix, stimulating the development of vascular and granulation tissue, and so on. However, there is currently a lack of a comprehensive review of the application of these proteins in diabetes wounds. An overview of fibrous protein characteristics and the alterations linked to diabetic wounds is given in this article's initial section. Next is a summary of the advanced applications of fibrous proteins in the last five years, including acellular dermal matrix, hydrogel, foam, scaffold, and electrospun nanofibrous membrane. These dressings have the ability to actively promote healing in addition to just covering wounds compared to traditional wound dressings like gauze or bandage. Research on fibrous proteins and their role in diabetic wound healing may result in novel therapeutic modalities that lower the incidence of diabetic wounds and thereby enhance the health of diabetic patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yan, Wang, Feng, Ni, Zhang, Cao, Zhou and Zhao.)

The remarkable potential of microRNAs (miRNAs) as a class of biotherapeutic agents in the treatment of diverse pathological conditions has garnered significant interest in recent years. To heal both acute and chronic wounds, miRNAs work by post-transcriptionally controlling various proteins and the pathways that are linked to them. Diabetes mellitus predisposes to several macro- and microvascular defects of end organs such as atherosclerosis, peripheral artery disease, retinopathy, nephropathy, neuropathy, and impaired wound healing. Here, miRNAs emerge as a beacon of hope, with the capacity to heal diabetic wounds by precisely modulating the expression of genes involved in the healing process. Despite the therapeutic promise, the journey to realizing the full potential of miRNAs is fraught with challenges. Their intrinsic instability and the inefficient delivery into target cells pose significant barriers to their clinical application. Consequently, a major focus of current research is the discovery of novel miRNAs and the development of innovative delivery systems that can effectively transport these nucleic acids into the cells where they are needed most. This review delves into the intricate roles that miRNAs play at various stages of diabetic wound healing, providing a comprehensive overview of the latest research findings. The review also addresses the obstacles and opportunities that come with translating miRNA-based strategies into clinical practice, offering a critical assessment of the field's advancements and the hurdles that remain to be overcome. SIGNIFICANCE STATEMENT: The potential of microRNA delivery using new biological or nonbiological carriers may create a revolutionary treatment method for chronic wounds of diabetes., (Copyright © 2024 by The Author(s).)

Erectile dysfunction is observed in about 50% of men. It has been found that diabetes mellitus increases its prevalence to 19-86.3%, necessitating attention to a therapeutic strategy. Among the available treatment methods, intracavernosal injections of mesenchymal stem cells have proven to be particularly effective., Objective: The purpose of study is to assess and analyse the effectiveness of their use in the treatment of erectile dysfunction in patients with diabetes mellitus., Materials and Methods: The literature search was conducted using systematic methods and analysis in databases such as Web of Science, Scopus, PubMed, Elsevier, and Springer, with 41 sources included for further review., Results: The study highlights microangiopathic and neuropathic links as key factors in erectile dysfunction development in diabetic patients, stemming from endothelial dysfunction and conductivity disturbances. Mesenchymal stem cell therapy from bone marrow, adipose tissue, and umbilical cord mitigates pathogenic impact through regenerative and anti-apoptotic effects. Due to this, most studies indicate high efficacy of the treatment and rapid therapeutic action through intracavernosal administration. Some studies suggest an increase in the body's receptor sensitivity to other drugs, such as sildenafil., Conclusion: From the perspective of further research on this issue, standardising the preparation of stem cells and the treatment method using a large sample size is essential to introduce such a method as an extremely promising therapy for this delicate issue in men into practical medicine. The practical value of the study lies in the systematisation of information on different sources of mesenchymal stem cells for treating erectile dysfunction., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Hajj is an obligatory duty for all healthy adult Muslims once in the lifetime subjected to the ability. Considering the 10.5 % global prevalence of diabetes coupled with the numbers of Muslims performing the Hajj, ∼ 1.8 million in 2023, it is estimated that Muslims with diabetes performing Hajj may exceed 340,000 this year. During Hajj the pattern and amount of their meal, fluid intake and physical activity are markedly altered. Many people with diabetes insist on doing the Hajj duty, thereby creating a medical challenge for themselves and their health care providers. It is therefore important that medical professionals be aware of the potential risks that may be associated with Hajj. People with diabetes may face many health hazards during Hajj including but not limited to the killer triad which might occur during Hajj: Hypoglycemia, Foot injury and Infections. Many precautions should be taken to prevent and treat these potentially serious complications. Risk stratification, medication adjustments, proper clinical assessment, and education before doing Hajj are crucial., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Wound healing is a sophisticated and orderly process of cellular interactions in which the body restores tissue architecture and functionality following injury. Healing of chronic diabetic wounds is difficult due to impaired blood circulation, a reduced immune response, and disrupted cellular repair mechanisms, which are often associated with diabetes. Stem cell-derived extracellular vesicles (SC-EVs) hold the regenerative potential, encapsulating a diverse cargo of proteins, RNAs, and cytokines, presenting a safe, bioactivity, and less ethical issues than other treatments. SC-EVs orchestrate multiple regenerative processes by modulating cellular communication, increasing angiogenesis, and promoting the recruitment and differentiation of progenitor cells, thereby potentiating the reparative milieu for diabetic wound healing. Therefore, this review investigated the effects and mechanisms of EVs from various stem cells in diabetic wound healing, as well as their limitations and challenges. Continued exploration of SC-EVs has the potential to revolutionize diabetic wound care., Competing Interests: The authors declare that they have no competing interests., (© 2024 Zhang et al.)

Background: Indigenous populations have increased risk of developing diabetes and experience poorer treatment outcomes than the general population. The FORGE AHEAD program partnered with First Nations communities across Canada to improve access to resources by developing community-driven primary healthcare models., Methods: This was an economic assessment of FORGE AHEAD using a payer perspective. Costs of diabetes management and complications during the 18-month intervention were compared to the costs prior to intervention implementation. Cost-effectiveness of the program assessed incremental differences in cost and number of resources utilization events (pre and post). Primary outcome was all-cause hospitalizations. Secondary outcomes were specialist visits, clinic visits and community resource use. Data were obtained from a diabetes registry and published literature. Costs are expressed in 2023 Can$., Results: Study population was ~ 60.5 years old; 57.2% female; median duration of diabetes of 8 years; 87.5% residing in non-isolated communities; 75% residing in communities < 5000 members. Total cost of implementation was $1,221,413.60 and cost/person $27.89. There was increase in the number and cost of hospitalizations visits from 8/$68,765.85 (pre period) to 243/$2,735,612.37. Specialist visits, clinic visits and community resource use followed this trend., Conclusion: Considering the low cost of intervention and increased care access, FORGE AHEAD represents a successful community-driven partnership resulting in improved access to resources., (© 2024. The Author(s).)

Aim: People with coexisting severe mental illness (SMI) and type 2 diabetes have a shorter life expectancy and poorer diabetes outcomes than those without SMI. This is partly explained by the separate treatment of diabetes and SMI, which occurs in parallel silos in many healthcare systems. The Steno Diabetes Center Sjaelland and Region Zealand established the Fusion Clinic to offer combined psychiatric and diabetes care delivered by both diabetes and mental healthcare professionals. This study describes how the clinic was established and the initial diabetes outcomes., Methods: The Fusion Clinic was co-designed by people with diabetes and SMI and healthcare professionals to improve the care of adults with diabetes and SMI. The clinic approach utilised the F-ACT model. The 63 people referred to the Fusion Clinic between 01.02.2020 and 01.01.2022 who attended the clinic for more than 6 months were included in this study. Diabetes outcomes were recorded in the electronic medical records (Sundhedsplatformen EPIC)., Results: There was a high prevalence of diabetes complications at baseline. Furthermore, 70% had one or more additional concomitant diseases, as well as SMI and diabetes. Assessment of diabetes complications and measurements of HbA 1c and lipid profile improved after referral to the clinic. HbA 1c declined during the first 6 months of attendance at the clinic., Conclusions: This model of service delivery has the potential to improve the quality of care for people with SMI and type 2 diabetes., (© 2023 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Stem cell-based therapies exhibit considerable promise in the treatment of diabetes and its complications. Extensive research has been dedicated to elucidate the characteristics and potential applications of adipose-derived stromal/stem cells (ASCs). Three-dimensional (3D) culture, characterized by rapid advancements, holds promise for efficacious treatment of diabetes and its complications. Notably, 3D cultured ASCs manifest enhanced cellular properties and functions compared to traditional monolayer-culture. In this review, the factors influencing the biological functions of ASCs during culture are summarized. Additionally, the effects of 3D cultured techniques on cellular properties compared to two-dimensional culture is described. Furthermore, the therapeutic potential of 3D cultured ASCs in diabetes and its complications are discussed to provide insights for future research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shi, Yang, Min, Kong, Hu, Zhang and Chen.)

Delayed wound healing is a major complication of diabetes, and is associated with impaired cellular functions. Current treatments are unsatisfactory. Based on the previous reports on microRNA expression in small extracellular vesicles (sEVs), miR-17-5p-engineered sEVs (sEVs 17-OE ) and encapsulated them in gelatin methacryloyl (GelMA) hydrogel for diabetic wounds treatment are fabricated. SEVs 17-OE are successfully fabricated with a 16-fold increase in miR-17-5p expression. SEVs 17-OE inhibited senescence and promoted the proliferation, migration, and tube formation of high glucose-induced human umbilical vein endothelial cells (HG-HUVECs). Additionally, sEVs 17-OE also performs a promotive effect on high glucose-induced human dermal fibroblasts (HG-HDFs). Mechanism analysis showed the expressions of p21 and phosphatase and tensin homolog (PTEN), as the target genes of miR-17-5p, are downregulated significantly by sEVs 17-OE . Accordingly, the downstream genes and pathways of p21 and PTEN, are activated. Next, sEVs 17-OE are loaded in GelMA hydrogel to fabricate a novel bioactive wound dressing and to evaluate their effects on diabetic wound healing. Gel-sEVs 17-OE effectively accelerated wound healing by promoting angiogenesis and collagen deposition. The cellular mechanism may be associated with local cell proliferation. Therefore, a novel bioactive wound dressing by loading sEVs 17-OE in GelMA hydrogel, offering an option for chronic wound management is successfully fabricated., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Background and Aims: Diabetic gastroparesis (DGp) is a common and preventable complication of uncontrolled diabetes mellitus (D.M.) and significantly affects the Quality of Life of patients. Diagnosis and management present as a clinical challenge due to the disease's complexity and limited effective therapeutic options. This review aims to comprehensively outline the pathogenesis, diagnosis, and management of diabetic gastroparesis, evaluating evolving approaches to guide clinicians and provide future recommendations., Methods: A literature review was conducted on scholarly databases of PubMed, Google Scholar, Scopus and Web of Science encompassing published articles, gray literature and relevant clinical guidelines. Data were synthesized and analyzed to provide a comprehensive overview of diabetic gastroparesis, focusing on pathogenesis, diagnosis, and management., Results: The review intricately explores the pathogenesis contributing to diabetic gastroparesis, emphasizing autonomic neuropathy, oxidative stress, inflammation, hormonal dysregulation, microbiota alterations, and gastrointestinal neuropathy. Primary management strategies are underscored, including lifestyle modifications, symptom relief, and glycemic control. The discussion encompasses pharmacological and surgical options, highlighting the importance of a multidisciplinary approach involving various healthcare professionals for comprehensive patient care., Conclusion: This review offers a thorough understanding of pathogenesis, diagnosis, and management of diabetic gastroparesis, underlining evolving approaches for clinicians. A multidisciplinary approach is crucial to address both the physical and mental health aspects of diabetes and its complications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Research Trust of DiabetesIndia (DiabetesIndia) and National Diabetes Obesity and Cholesterol Foundation (N-DOC). Published by Elsevier Ltd. All rights reserved.)

Diabetes is an ongoing global problem as it affects health of more than 537 million people around the world. Diabetes leaves many serious complications that affect patients and can cause death if not detected and treated promptly. Some of the complications of diabetes include impaired vascular system, increased risk of stroke, neurological diseases that cause pain and numbness, diseases related to the retina leading to blindness, and other complications affecting kidneys, heart failure, muscle weakness, muscle atrophy. All complications of diabetes seriously affect the health of patients. Recently, gene therapy has emerged as a viable treatment strategy for various diseases. DNA and RNA are among the target molecules that can change the structure and function of proteins and are effective methods of treating diseases, especially genetically inherited diseases. RNA therapeutics has attracted deep interest as it has been approved for application in the treatment of functional system disorders such as spinal muscular atrophy, and muscular dystrophy. In this review, we cover the types of RNA therapies considered for treatment of diabetes. In particular, we delve into the mechanism of action of RNA therapies for diabetes, and studies involving testing of these RNA therapies. Finally, we have highlighted the limitations of the current understanding in the mechanism of action of RNA therapies., (Copyright © 2024. Published by Elsevier Inc.)

Diabetes is a metabolic disorder whose prevalence has become a worrying condition in recent decades. Chronic diabetes can result in serious health conditions such as impaired kidney function, stroke, blindness, and myocardial infarction. Despite a variety of currently available treatments, cases of diabetes and its complications are on the rise. This review article provides a comprehensive account of the ameliorative effect of prebiotics and probiotics individually or in combination i.e. synbiotics on health complications induced by Type 2 Diabetes Mellitus (T2DM). Recent advances in the field underscore encouraging outcomes suggesting the consumption of synbiotics leads to favorable changes in the gut microbiota. These changes result in the production of bioactive metabolites such as short-chain fatty acids (crucial for lowering blood sugar levels), reducing inflammation, preventing insulin resistance, and encouraging the release of glucagon-like peptide-1 in the host. Notably, novel strategies supplementing synbiotics to support gut microbiota are gaining attraction as pivotal interventions in mitigating T2DM-induced health complications. Thus, by nurturing a symbiotic relationship between prebiotics and probiotics i.e. synbiotics, these interventions hold promise in reshaping the microbial landscape of the gut thereby offering a multifaceted approach to managing T2DM and its associated morbidities. Supporting the potential of synbiotics underscores a paradigm shift toward holistic and targeted interventions in diabetes management, offering prospects for improved outcomes and enhanced quality of life for affected individuals. Nevertheless, more research needs to be done to better understand the single and multispecies pre/pro and synbiotics in the prevention and management of T2DM-induced health complications.

Diabetes is a chronic metabolic disease affecting millions worldwide. It is characterized by a lack of insulin production or impaired insulin function, leading to elevated blood glucose levels. Conventional treatment methods for diabetes management typically include lifestyle changes and medications. However, alternative therapies have gained attention in recent years, including traditional medicine containing bioactive compounds, supplements like vitamin D and Omega-3 fatty acids, aromatherapy, and homeopathy. Diabetic complications are common in patients with uncontrolled diabetes and can lead to serious health problems, including diabetic retinopathy, impaired wound healing, kidney disease, nerve damage, and cardiovascular disease. Alternative remedies, such as traditional medicine containing bioactive compounds, supplements, and aromatherapy, have been studied for their potential benefits in managing these complications. Traditional medicines like bitter melon, cinnamon, and fenugreek have been shown to have anti-diabetic effects due to their bioactive compounds. Similarly, supplements like vitamin D and Omega-3 fatty acids have been found to improve glycemic control in patients with diabetes. Aromatherapy, which involves the use of essential oils, has also been explored for its potential benefits in diabetes management. Homeopathy, which uses highly diluted substances to stimulate the body's natural healing abilities, has been used to treat diabetes-related symptoms like neuropathy and wounds. Personalized care is essential in natural diabetes management because each person's body and health needs are unique. A holistic approach that addresses the individual's physical, emotional, and spiritual well-being is essential. As research in this field continues to expand, a more comprehensive understanding of diabetes management will lead to improved outcomes for those living with this condition., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by high blood glucose and is associated with high morbidity and mortality among the diabetic population. Uncontrolled chronic hyperglycaemia causes increased formation and accumulation of different oxidative and nitrosative stress markers, resulting in microvascular and macrovascular complications, which might seriously affect the quality of a patient's life. Conventional treatment strategies are confined to controlling blood glucose by regulating the insulin level and are not involved in attenuating the life-threatening complications of diabetes mellitus. Thus, there is an unmet need to develop a viable treatment strategy that could target the multi-etiological factors involved in the pathogenesis of diabetic complications. Stem cell therapy, a regenerative medicine approach, has been investigated in diabetic complications owing to their unique characteristic features of self-renewal, multilineage differentiation and regeneration potential. The present review is focused on potential therapeutic applications of stem cells in the treatment of microvascular diabetic complications such as nephropathy, retinopathy, and polyneuropathy., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Renal tubulointerstitial fibrosis (TIF) is considered as the final convergent pathway of diabetic nephropathy (DN) without effective therapies currently. MiRNAs play a key role in fibrotic diseases and become promising therapeutic targets for kidney diseases, while miRNA clusters, formed by the cluster arrangement of miRNAs on chromosomes, can regulate diverse biological functions alone or synergistically. In this study, we developed clustered miR-23a/27a/26a-loaded skeletal muscle satellite cells-derived exosomes (Exos) engineered with RVG peptide, and investigated their therapeutic efficacy in a murine model of DN. Firstly, we showed that miR-23a-3p, miR-26a-5p and miR-27a-3p were markedly decreased in serum samples of DN patients using miRNA sequencing. Meanwhile, we confirmed that miR-23a-3p, miR-26a-5p and miR-27a-3p were primarily located in proximal renal tubules and highly negatively correlated with TIF in db/db mice at 20 weeks of age. We then engineered RVG-miR-23a/27a/26a cluster loaded Exos derived from muscle satellite cells, which not only enhanced the stability of miR-23a/27a/26a cluster, but also efficiently delivered more miR-23a/27a/26a cluster homing to the injured kidney. More importantly, administration of RVG-miR-23a/27a/26a-Exos (100 μg, i.v., once a week for 8 weeks) significantly ameliorated tubular injury and TIF in db/db mice at 20 weeks of age. We revealed that miR-23a/27a/26a-Exos enhanced antifibrotic effects by repressing miRNA cluster-targeting Lpp simultaneously, as well as miR-27a-3p-targeting Zbtb20 and miR-26a-5p-targeting Klhl42, respectively. Knockdown of Lpp by injection of AAV-Lpp-RNAi effectively ameliorated the progression of TIF in DN mice. Taken together, we established a novel kidney-targeting Exo-based delivery system by manipulating the miRNA-23a/27a/26a cluster to ameliorate TIF in DN, thus providing a promising therapeutic strategy for DN., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Diabetic chronic wounds cause massive levels of patient suffering and economic problems worldwide. The state of chronic inflammation arises in response to a complex combination of diabetes mellitus-related pathophysiologies. Advanced treatment options are available; however, many wounds still fail to heal, exacerbating morbidity and mortality. This review describes the chronic inflammation pathophysiologies in diabetic ulcers and treatment options that may help address this dysfunction either directly or indirectly. We suggest that treatments to reduce inflammation within these complex wounds may help trigger healing., (© 2022 The Authors. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.)

The number of diabetic patients visiting stomatology for periodontal disease is increasing, and the symptoms are relatively severe, and often complications increase the complexity of periodontal treatment. This article briefly describes the research progress and clinical manifestations of the epidemiology and related pathological mechanisms of periodontitis with diabetes, focusing on the treatment and providing reference for stomatologists in the clinical diagnosis and treatment of patients with diabetic periodontitis.

Aims: Oxidative stress also plays an important role in the pathogenesis of diabetic neuropathy (DN). Both resveratrol (RES) and exercise (EX) have potent anti-oxidative benefits. Low levels of nerve growth factor (NGF) and SIRT1 (a member of sirtuin family) have been reported in patients with DN. The current study has been designed to investigate the role of serum NGF and SIRT1 on DN-induced hyperalgesia and motor incoordination and to evaluate the possible protective role of RES and/or EX., Main Methods: A total of 40 male adult albino rats divided into five groups; control, DN, DN + RES, DN + EX, and DN + RES and EX. DN was confirmed by sensorimotor disturbance and diminished nerve conduction velocity (NCV). NGF and SIRT1 levels were measured by western blot. Calcitonin gene-related peptide (CGRP) was measured by PCR. Myofibrillar degeneration and inflammation scores were revealed via H&E microscopic analysis of the gastrocnemius muscle. Immunohistochemical evaluation of caspase3 and TNF-α was performed in the lumber segment of spinal cord and gastrocnemius muscle sections. Ultrastructural evaluation of sciatic nerve axonal degeneration has also been assessed., Key Findings: DN group showed decreased SIRT1 level, decreased NGF level and correlated with CGRP level and Na+/K+ ATPase. Treatment with RES and/or EX resulted in improvement of sensorimotor disturbance. DN characterized by reduced SOD level, whereas RES and/or EX could limit oxidative damage by up-regulation Bcl2, Akt and GAP-43 and down-regulation of caspase3 and TNF-α. In conclusion, increased level of SIRT1and NGF by incorporation of RES (natural supplementation) and EX (life style modification) could improve the neuroinflammatory state in DN., Competing Interests: Conflict of Interests The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Patients with concurrent atrial fibrillation (AF) and diabetes mellitus (DM) [AF-DM] have a high risk of cardiovascular and diabetes-related complications, but are less engaged in a comprehensive treatment approach. We evaluated the association of early rhythm control (ERC), lifestyle modification (LSM), and a combination of ERC and LSM with cardiovascular or diabetes-related complication risk in patients with AF-DM (type 2)., Methods: From the National Health Information Database, 47,940 patients diagnosed with AF-DM in 2009-2016 were included. We defined ERC as rhythm control therapy within two years of AF diagnosis and LSM as adherence to ≥ 2 of the healthy behaviors among non-current smoking, non-drinking, and regular exercise. We compared the primary (ischemic stroke) and secondary (macro- and microvascular complications, glycemic emergency, and all-cause death) outcomes in four groups: non-ERC and non-LSM (group 1), LSM only (group 2), ERC only (group 3), and both ERC and LSM (group 4)., Results: Of total, 10,617 (22%), 26,730 (55.8%), 2,903 (6.1%), and 7,690 (16.0%) were classified into groups 1 to 4, in sequence. The mean duration from AF diagnosis to ERC was 25.6 ± 75.5 days. During 4.0 (interquartile range: 2.5-6.2) years' follow-up, groups 2 and 3 were associated with 23% and 33% lower risks of stroke than group 1, respectively. Group 4 was associated with the lowest risk of stroke: hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.51-0.67, p < 0.001. Regarding secondary outcomes, the lowest risks were also observed in group 4; macro- and microvascular complications, glycemic emergency, and all-cause death had HRs (95% CIs) of 0.63 (0.56-0.70), 0.88 (0.82-0.94), 0.72 (0.62-0.84), and 0.80 (0.73-0.87), respectively, all p < 0.001., Conclusions: For AF-DM patients, ERC and LSM exert a synergistic effect in preventing cardiovascular and diabetes-related complications with the greatest lowered risk of stroke. A comprehensive treatment approach should be pursued in AF-DM patients., (© 2023. The Author(s).)

Objective: To estimate medical costs associated with 17 diabetes complications and treatment procedures among Medicare beneficiaries aged ≥65 years with type 1 diabetes., Research Design and Methods: With use of the 2006-2017 100% Medicare claims database for beneficiaries enrolled in fee-for-service plans and Part D, we estimated the annual cost of 17 diabetes complications and treatment procedures. Type 1 diabetes and its complications and procedures were identified using ICD-9/ICD-10, procedure, and diagnosis-related group codes. Individuals with type 1 diabetes were followed from the year when their diabetes was initially identified in Medicare (2006-2015) until death, discontinuing plan coverage, or 31 December 2017. Fixed-effects regression was used to estimate costs in the complication occurrence year and subsequent years. The cost proportion of a complication was equal to the total cost of the complication, calculated by multiplying prevalence by the per-person cost divided by the total cost for all complications. All costs were standardized to 2017 U.S. dollars., Results: Our study included 114,879 people with type 1 diabetes with lengths of follow-up from 3 to 10 years. The costliest complications per person were kidney failure treated by transplant ($77,809 in the occurrence year and $13,556 in subsequent years), kidney failure treated by dialysis ($56,469 and $41,429), and neuropathy treated by lower-extremity amputation ($40,698 and $7,380). Sixteen percent of the total medical cost for diabetes complications was for treating congestive heart failure., Conclusions: Costs of diabetes complications were large and varied by complications. Our results can assist in cost-effectiveness analysis of treatments and interventions for preventing or delaying diabetes complications in Medicare beneficiaries aged ≥65 years with type 1 diabetes., (© 2022 by the American Diabetes Association.)

Objective: To investigate the efficacy of a paeoniflorin-sodium alginate (SA)-gelatin skin scaffold for treating diabetic wound in a rat model., Methods: Bioinks were prepared using various percentages of paeoniflorin in the total weight of a solution containing SA and gelatin. Skin scaffolds containing 0%, 1%, 3%, 5%, and 10% paeoniflorin were printed using 3D bioprinting technology, and scaffold microstructure was observed with scanning electron microscopy. Skin scaffolds were then used in rats with diabetic wounds. H&E staining, Masson staining, and immunohistochemical staining for IL-1β and CD31 were performed on days 7 and 14., Results: All skin scaffolds had a mesh-like structure with uniform pore distribution. Wounds healed well in each group, with the 1% and 3% groups demonstrating the most complete healing. H&E staining showed that skin accessory organs had appeared in each group. On day 7, collagen deposition in the 3% group was higher than in the other groups (P＜0.05), and IL-1β infiltration was lower in the 10% group than in the 3% group (P = 0.002). On day 14, IL-1β infiltration was not significantly different between the 10% and 3% groups (P = 0.078). The CD31 level was higher in the 3% group than in the other groups on days 7 and 14 (P＜0.05)., Conclusion: A 3% paeoniflorin-SA-gelatin skin scaffold promoted the healing of diabetic wounds in rats. This scaffold promoted collagen deposition and microvascular regeneration and demonstrated anti-inflammatory properties, suggesting that this scaffold type could be used to treat diabetic wounds., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Diabetes is a chronic disorder characterized by dysregulated glycemic conditions. Diabetic complications include microvascular and macrovascular abnormalities and account for high morbidity and mortality rates in patients. Current clinical approaches for diabetic complications are limited to symptomatic treatments and tight control of blood sugar levels. Extracellular vesicles (EVs) released by somatic and stem cells have recently emerged as a new class of potent cell-free therapeutic delivery packets with a great potential to treat diabetic complications. EVs contain a mixture of bioactive molecules and can affect underlying pathological processes in favor of tissue healing. In addition, EVs have low immunogenicity and high storage capacity while maintaining nearly the same regenerative and immunomodulatory effects compared to current cell-based therapies. Therefore, EVs have received increasing attention for diabetes-related complications in recent years. In this review, we provide an outlook on diabetic complications and summarizes new knowledge and advances in EV applications. Moreover, we highlight recommendations for future EV-related research., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Type 2 diabetes is a major factor contributing to cognitive decline and Alzheimer's disease (AD). Treadmill running is considered to be a critical approach for mice and rats to lower blood sugar and improve learning and memory capacity. The growth factor receptor-bound protein 10 (Grb10) has been proposed to inhibit insulin signaling and defective brain insulin signaling resulted in the cognitive deficits in patients with AD. However, the positive roles of treadmill training on diabetic- related impaired cognitive function and their molecular mechanisms remain unclear. Here, to investigate whether there was neuroprotective effects of treadmill training on impaired cognitive function caused by diabetes, the rats were injected intraperitoneally with streptozotocin at a dose of 30 mg/kg to establish diabetic model (DM). We found that higher Grb10, BACE1 and PHF10 protein levels in the hippocampus of DM rats, lower phosphorylation IGF-1Rβ and IRS-1( ser307 ). However, 8 weeks treadmill training effectively reduced abnormal Grb10, enhanced postsynaptic density protein PSD-93, PSD-95, SYN expressions of hippocampus, restored PI3K/Akt/ERK and mTOR/AMPK signaling, thus alleviated spatial learning and memory deficit, compared with DM group. Additionally, treadmill training also increased GLUT4 transportation. Overall, our findings suggest that treadmill intervention improved cognitive impairments caused by diabetes disease partly through modulating Grb10/ PI3K/Akt/ERK as well as mTOR/AMPK signaling., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: To estimate the direct medical cost of type 2 diabetes mellitus (T2DM) and its complications in the Indonesian population from a payer perspective using a prevalence-based approach., Methods: The direct medical costs in 2016 were estimated using the database of Indonesia's National Health Insurance, known as Jaminan Kesehatan Nasional, which included diagnosis-related group costs and unbundled costs for patients accessing advanced care. The study population included people aged 30 years or older having a diagnosis of T2DM. T2DM and its related complications were identified using the International Classification of Diseases, 10th Revision, code. Hypoglycemia and all complications listed in the Diabetes Severity Complications Index were included. Descriptive analysis was conducted. Costs were converted to 2016 US dollar equivalent., Results: Of the 18.9 million Jaminan Kesehatan Nasional members who accessed secondary and tertiary care, 812 204 (4%) were identified with T2DM, of which 57% had complications. The most common complication was cardiovascular diseases (24%). The total direct medical cost was US $576 million, with 56% spent on hospitalization, 38% on specialist visits, 4% on unbundled non-diabetes-related medication, and 2% on unbundled anti-hyperglycemic medications. Approximately 74% of the total costs was used for the management of people with complications. People with complications (US $930/person/year ± US $1480/person/year) incurred twice the cost of those without complications (US $421/person/year ± US $745/person/year)., Conclusion: The direct medical cost for management of people with T2DM in Indonesia was high. Early diagnosis and optimal management of T2DM to prevent complications may reduce the costly sequelae and have a possibility of cost savings., (Copyright © 2021. Published by Elsevier Inc.)

Diabetes is an ambulatory care sensitive condition that quality of care can prevent complications development and hospitalization needs. However, diabetes patients with disability face greater challenges with receiving quality diabetes care than those without disabilities. This study examined diabetes-related avoidable hospitalizations (DRAH) focusing on the association with disability. We used nationally representative health insurance cohort data from 2002 to 2013. The study population is people who were newly diagnosed with type 2 diabetes. We measured the cumulated number of DRAH using the Prevention Quality Indicators (PQIs). The variables of interest were disability severity and type. We performed a recurrent events analysis using Cox proportional hazard regression model. Among 49,410 type 2 diabetes patients, 12,231 (24.8%) experienced DRAHs at least once during the follow-up period. Among the total population, 5924 (12.0%) diabetes patients were registered as disabled. The findings report that disability severity was significantly associated with higher risks for DRAH, where severely disabled diabetes patients showed the highest hazard ratio of 2.24 (95% CI 1.80-2.79). Among three DRAH indicators, severely disabled diabetes patients showed increased risks for long-term (AHR 2.21, 95% CI 1.89-2.60) and uncontrolled (AHR 2.28, 95% CI 1.80-2.88) DRAH. In addition, intellectual (AHR 5.52, 95% CI 3.78-8.05) and mental (AHR 3.97, 95% CI 2.29-6.89) disability showed higher risks than other types of disability. In conclusion, diabetes patients with disability are at higher risk for DRAH compared to those without disabilities, and those with intellectual and mental disabilities were more likely to experience DRAH compared to those with physical or other types of disability. These findings call for action to find the more appropriate interventions to improve targeted diabetes primary care for patients with disability. Further research is needed to better understand determinants of increasing risks of DRAH., (© 2022. The Author(s).)

Diabetes mellitus (DM) is considered as a main challenge in both developing and developed countries, as lifestyle has changed and its management seems to be vital. Type I and type II diabetes are the main kinds and they result in hyperglycemia in patients and related complications. The gene expression alteration can lead to development of DM and related complications. The AMP-activated protein kinase (AMPK) is an energy sensor with aberrant expression in various diseases including cancer, cardiovascular diseases and DM. The present review focuses on understanding AMPK role in DM. Inducing AMPK signaling promotes glucose in DM that is of importance for ameliorating hyperglycemia. Further investigation reveals the role of AMPK signaling in enhancing insulin sensitivity for treatment of diabetic patients. Furthermore, AMPK upregulation inhibits stress and cell death in β cells that is of importance for preventing type I diabetes development. The clinical studies on diabetic patients have shown the role of AMPK signaling in improving diabetic complications such as brain disorders. Furthermore, AMPK can improve neuropathy, nephropathy, liver diseases and reproductive alterations occurring during DM. For exerting such protective impacts, AMPK signaling interacts with other molecular pathways such as PGC-1α, PI3K/Akt, NOX4 and NF-κB among others. Therefore, providing therapeutics based on AMPK targeting can be beneficial for amelioration of DM., (Copyright © 2021. Published by Elsevier Masson SAS.)

Diabetes mellitus (DM), a chronic metabolic disease characterised by elevated levels of blood glucose, is among the most common chronic diseases. The incidence and prevalence of DM have been increasing over the years. The complications of DM represent a serious health problem. The long-term complications include macroangiopathy, microangiopathy and neuropathy as well as sexual dysfunction (SD) in both men and women. Erectile dysfunction (ED) has been considered the most important SD in men with DM. The prevalence of ED is approximately 3.5-fold higher in men with DM than in those without DM. Common risk factors for the development of DM and its complications include sedentary lifestyle, overweight/obesity and increased caloric consumption. Although lifestyle changes may help improve sexual function, specific treatments are often needed. This study aims to review the definition and prevalence of ED in DM, the impact of DM complications and DM treatment on ED and, finally, the current and emerging therapies for ED in patients with DM., (© 2021 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Although some studies have shown that some static magnetic fields (SMFs) can promote wound healing in diabetic mice, it is not clear whether the other diabetes complications, such as liver disease and diabetic nephropathy, can also be alleviated. Here, we constructed two simple magnetic plates using neodymium permanent magnets to examine the comprehensive effects of moderate SMFs on genetically obese leptin receptor-deficient db/db diabetic mice. We found that although the blood glucose was not obviously reduced by these two SMF settings, both of the glycated serum protein (GSP) and malondialdehyde (MDA) levels were significantly decreased (Cohen's d = 2.57-3.04). Moreover, the wound healing, liver lipid accumulation, and renal defects were all significantly improved by SMF treatment (Cohen's d = 0.91-2.05). Wound tissue examination showed obvious nuclear factor erythroid 2-related factor 2 (NRF2) level decrease (Cohen's d = 2.49-5.40) and Ki-67 level increase (Cohen's d = 2.30-3.40), indicating decreased oxidative stress and increased cell proliferation. In vitro cellular studies with fibroblast NIH3T3 cells showed that SMFs could reduce high glucose-induced NRF2 nucleus translocation (Cohen's d = 0.87-1.15) and cellular reactive oxygen species (ROS) elevation (Cohen's d = 0.92), indicating decreased oxidative stress. Consequently, high glucose-induced impairments in cell vitality, proliferation, and migration were all improved by SMF treatment. Therefore, our results demonstrate that these simple SMF devices could effectively reduce oxidative stress in diabetic mice and may provide a cost-effective physical therapy strategy to alleviate multiple diabetic complications in the future.

Of increasing prevalence, diabetes is characterised by elevated blood glucose and chronic inflammation that precedes the onset of multiple secondary complications, including those of the kidney and the eye. As the leading cause of end stage renal disease and blindness in the working population, more than ever is there a demand to develop clinical interventions which can both delay and prevent disease progression. Connexins are membrane bound proteins that can form pores (hemichannels) in the cell membrane. Gated by cellular stress and injury, they open under pathophysiological conditions and in doing so release 'danger signals' including adenosine triphosphate into the extracellular environment. Linked to sterile inflammation via activation of the nod-like receptor protein 3 inflammasome, targeting aberrant hemichannel activity and the release of these danger signals has met with favourable outcomes in multiple models of disease, including secondary complications of diabetes. In this review, we provide a comprehensive update on those studies which document a role for aberrant connexin hemichannel activity in the pathogenesis of both diabetic eye and kidney disease, ahead of evaluating the efficacy of blocking connexin-43 specific hemichannels in these target tissues on tissue health and function.

Background: Chronic kidney disease is often asymptomatic in its early stages but constitutes a severe burden for patients and causes major healthcare systems costs worldwide. While models for assessing the cost-effectiveness of screening were proposed in the past, they often presented only a limited view. This study aimed to develop a simulation-based German Albuminuria Screening Model (S-GASM) and present some initial applications., Methods: The model consists of an individual-based simulation of disease progression, considering age, gender, body mass index, systolic blood pressure, diabetes, albuminuria, glomerular filtration rate, and quality of life, furthermore, costs of testing, therapy, and renal replacement therapy with parameters based on published evidence. Selected screening scenarios were compared in a cost-effectiveness analysis., Results: Compared to no testing, a simulation of 10 million individuals with a current age distribution of the adult German population and a follow-up until death or the age of 90 shows that a testing of all individuals with diabetes every two years leads to a reduction of the lifetime prevalence of renal replacement therapy from 2.5% to 2.3%. The undiscounted costs of this intervention would be 1164.10 € / QALY (quality-adjusted life year). Considering saved costs for renal replacement therapy, the overall undiscounted costs would be-12581.95 € / QALY. Testing all individuals with diabetes or hypertension and screening the general population reduced the lifetime prevalence even further (to 2.2% and 1.8%, respectively). Both scenarios were cost-saving (undiscounted, - 7127.10 €/QALY and-5439.23 €/QALY)., Conclusions: The S-GASM can be used for the comparison of various albuminuria testing strategies. The exemplary analysis demonstrates cost savings through albuminuria testing for individuals with diabetes, diabetes or hypertension, and for population-wide screening., Competing Interests: The authors have declared that no competing interests exist.

Diabetes is a common condition that is increasing in incidence worldwide. Although the skin manifestations of this condition are well described, there is scant literature on the associated nail changes. In this review, we describe the various clinical features of nail changes associated with diabetes, which can be broadly divided into infections, vascular changes, neuropathic manifestations and miscellaneous changes, although there is overlap between them. There is no pathognomonic nail alteration, but it is important for clinicians to be aware of the potential nail manifestations in diabetes as they can facilitate investigations and thereby early diagnosis of diabetes, resulting in holistic management of the patient., (© 2021 British Association of Dermatologists.)

Objective: MiRNAs are important regulators of inflammation and wound healing. However, the mechanisms through which miRNAs regulate wound healing under normal and diabetic conditions are poorly understood. We aimed to determine the effects of miR-146a on the pathogenesis of wound healing in normal and streptozotocin (STZ)-induced diabetic mice. Approach: Wild-type (WT) and miR-146a knockout (KO) mice were induced to develop diabetes with STZ. Next, skin and corneal wounds were produced and measured. Percent wound closure and histology were evaluated. Inflammation at wound sites was analyzed using flow cytometry, reverse-transcription PCR, and western blot. Results: Healing of wounded skin was significantly delayed in miR-146a KO compared with WT mice. However, corneal epithelial wound healing did not differ significantly in the mice with normal blood glucose, whereas corneal and skin wound healing was significantly delayed in KO mice with diabetes. Neutrophil infiltration increased in skin wounds of KO compared with normal mice. The potential mechanisms were associated with dysregulated interleukin 1β, tumor necrosis factor alpha (TNF-α), IRAK1 (interleukin-1 receptor-associated kinase 1), TRAF6 (TNF receptor-associated factor 6), and nuclear factor kappa B (NF-κB) signaling induced by miR-146a KO. Innovation: Skin wound healing was delayed in miR-146a KO mice and enhanced inflammatory responses were mediated by the NF-κB signaling pathway. Conclusions: Deficiency in miR-146a delayed skin wound healing by enhancing inflammatory responses in normal and diabetic mice. Therefore, miR-146a may be a potential target for modulation to accelerate skin wound healing.

Autonomic neuropathy in patients with diabetes mellitus, and especially complications related to gastrointestinal neuropathy, are often overlooked in the clinic. Diabetic gastroenteropathy affects every segment of the gastrointestinal tract and generates symptoms that may include nausea, early satiety, vomiting, abdominal pain, constipation, and diarrhea. Severe cases can be complicated by weight loss, dehydration, and electrolyte disturbances. The pathophysiology is complex, the diagnostics and treatment options are multidisciplinary, and there is generally a lack of evidence for the treatment options. The aims for this review are first to summarize the pathophysiology and describe possible and expected symptoms and complications.Further, we will try to supply the clinician with a straightforward tool for diagnostics, and then, we shall summarize established treatment options, including diet recommendations, pharmacological and non-pharmacological options. Finally, we will explore the multiple possibilities of novel treatment, looking at medications related to the pathophysiology of neuropathy, other manifestations of autonomic neuropathies, and symptomatic treatment for other gastrointestinal disorders, also including new knowledge of endosurgical and neuromodulatory treatment. The overall goal is to increase awareness and knowledge on this frequent diabetic complication and to provide better tools for diagnosis and treatment. Ultimately, we hope to encourage further research in this field, as there are clear shortcomings in terms of biomarkers, pathophysiology, as well as treatment possibilities. In conclusion, diagnosis and management of diabetic gastroenteropathy are challenging and often require multidisciplinary teams and multimodal therapies. Treatment options are sparse, but new pharmacological, endoscopic, and neuromodulatory techniques have shown promising results in initial studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Mesenchymal stromal cells (MSCs) are applied in regenerative medicine of several tissues and organs nowadays by virtue of their self-renewal capabilities, multiple differentiation capacity, potent immunomodulatory properties, and their ability to be favourably cultured and manipulated. With the continuous development of "cell-free therapy" research, MSC-derived small extracellular vesicles (MSC-sEVs) have increasingly become a research hotspot in the treatment of various diseases. Small extracellular vesicles (SEVs) are membrane vesicles with diameters of 30 to 150 nm that mediate signal transduction between adjacent or distal cells or organs by delivering non-coding RNA, protein, and DNA. The contents and effects of sEVs vary depending on the properties of the originating cell. In recent years, MSC-sEVs have been found to play an important role in the occurrence and development of diabetes mellitus as a new way of communication between cells. Diabetes mellitus is a common metabolic disease in clinic. Its complications of the heart, brain, kidney, eyes, and peripheral nerves are a serious threat to human health and has been a hot issue for clinicians. MSC-sEVs could be applied to repair or prevent damage from the complications of diabetes mellitus through anti-inflammatory effects, reduction of endoplasmic reticulum-related protein stress, polarization of M2 macrophages, and increasing autophagy. Therefore, we highly recommend that MSC-sEVs-based therapies to treat diabetes mellitus and its chronic complication be further explored. The analysis of the role and molecular mechanisms of MSC-sEVs in diabetes and its related complications will provide new idea and insights for the prevention and treatment of diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Lin, Xu, Shan, Guo, Lei, Zheng, Wang, Xu and Yuan.)

Objectives: To assess the quality of diabetic eye disease clinical practice guidelines., Study Design and Setting: A systematic search of diabetic eye disease guidelines was conducted on six online databases and guideline repositories. Four reviewers independently rated quality using the Appraisal of Guidelines, Research, and Evaluation (AGREE II) instrument. Aggregate scores (%) for six domains and overall quality assessment were calculated. A "good quality" guideline was one with ≥60% score for "rigor of development" and in at least two other domains., Results: Eighteen guidelines met the inclusion criteria, of which 13 were evidence-based guidelines (involved systematic search and grading of evidence). The median scores (interquartile range (IQR)) for "scope and purpose," "stakeholder involvement," "rigor of development," "clarity of presentation," "applicability" and "editorial independence" were 73.6% (54.2%-80.6%), 48.6% (29.2%-71.5%), 60.2% (30.9%-78.1%), 86.6% (76.7%-94.4%), 28.6% (18.0%-37.8%) and 60.2% (30.9%-78.1%), respectively. The median overall score (out of 7) of all guidelines was 5.1 (IQR: 3.7-5.8). Evidence-based guidelines scored significantly higher compared to expert-consensus guidelines. Half (n = 9) of the guidelines (all evidence-based) were of "good quality.", Conclusion: A wide variation in methodological quality exists among diabetic eyecare guidelines, with nine demonstrating "good quality." Future iterations of guidelines could improve by appropriately engaging stakeholders, following a rigorous development process, including support for application in clinical practice and ensuring editorial transparency., (Copyright © 2021. Published by Elsevier Inc.)

To relieve the severe economic and social burdens and patient suffering caused by the increasing incidence of chronic wounds, more effective treatments are urgently needed. In this study, we focused on developing a novel sprayable wound dressing with the active ingredient β-1,3/1,6-glucan (βG). Since βG is already available as the active ingredient in a commercial wound healing product provided as a hydrogel in a tube (βG-Gel), the sprayable format should bring clinical benefit by being easily sprayed onto wounds; whilst retaining βG-Gel's physical stability, biological safety and wound healing efficacy. Potentially sprayable βG hydrogels were therefore formulated, based on an experimental design setup. One spray formulation, named βG-Spray, was selected for further investigation, as it showed favorable rheological and spraying properties. The βG-Spray was furthermore found to be stable at room temperature for more than a year, retaining its rheological properties and sprayability. The cytotoxicity of βG-Spray in keratinocytes in vitro, was shown to be promising even at the highest tested concentration of 100 μg/ml. The βG-Spray also displayed favorable fluid affinity characteristics, with a capacity to both donate and absorb close to 10% fluid relative to its own weight. Finally, the βG-Spray was proven comparably effective to the commercial product, βG-Gel, and superior to both the water and the carrier controls (NoβG-Spray), in terms of its ability to promote wound healing in healing-impaired animals. Contraction was found to be the main wound closure mechanism responsible for the improvement seen in the βG-treatment groups (βG-Spray and βG-Gel). In conclusion, the novel sprayable βG formulation, confirmed its potential to expand the clinical use of βG as wound dressing., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Diabetic gastroparesis (DGP) is one of the most common complication of diabetes. At present, despite the increasing number of clinical researches of treatment with Tuina have been reported, there are no systematic reviews of Tuina therapy for DGP. Therefore, it is of great significance to evaluate its safety and efficacy as a complementary and alternative therapy., Methods and Analysis: Randomized controlled trials (RCTs) of Tuina therapy in the treatment of DGP will be retrieved from PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang Database (Wan Fang), Chinese Biomedical Literature Database (CBM), VIP Database for Chinese Technical Periodicals (VIP), Medline, and Clinical Trial Register (CTR). We will consider articles published in English or Chinese between database initiation and October 2021. Research selection, data extraction, risk of bias assessment, and meta-analyses will be independently completed by 2 researchers. Our researchers will use Revman 5.3 software, provided by the Cochrane Collaborative Network for conducting systematic reviews and meta-analysis., Results: This systematic review provides a high-quality synthesis to assess the effectiveness and safety of Tuina therapy for treating DGP., Conclusion: The conclusions of our study will provide evidence to determine whether Tuina therapy is an effective and safe intervention for patients with DGP., Systematic Review Registration: : INPLASY2021110019., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Physical exercise has acute and chronic effects on inflammatory balance, metabolic regulation, and redox status. Exercise-induced adaptations are mediated by enhanced 70-kDa heat shock protein (HSP70) levels and an improved heat shock response (HSR). Therefore, exercise could be useful against disease conditions [obesity, diabetes mellitus (DM), and exposure to atmospheric pollutants] marked by an impaired HSR. However, exercise performed by obese or diabetic subjects under pollution conditions might also be dangerous at certain intensities. Intensity correlates with an increase in HSP70 levels during physical exercise until a critical point at which the effort becomes harmful and impairs the HSR. Establishing a unique biomarker able to indicate the exercise intensity on metabolism and cellular fatigue is essential to ensure adequate and safe exercise recommendations for individuals with obesity or DM who require exercise to improve their metabolic status and live in polluted regions. In this review, we examined the available evidence supporting our hypothesis that HSP70 could serve as a biomarker for determining the optimal exercise intensity for subjects with obesity or diabetes when exposed to air pollution and establishing the fine threshold between anti-inflammatory and pro-inflammatory exercise effects., (© 2021. Cell Stress Society International.)

Diabetes-related cardiovascular disease (CVD) is a global health issue that causes thousands of people's death around the world annually. Diabetes-related CVD is still prevailing despite the progression being made in its diagnosis and treatment. Therefore it is urgent to find therapeutic strategies.to prevent it. MicroRNA (miRNA) is a single-stranded non-coding RNA involved in the process of post-transcriptional control of gene expression in eukaryotes. A large number of literatures reveal that miRNAs are implicated in diabetes-related CVD. The increase of miRNAs in exosomes may promote the occurrence and development of diabetes-related cardiovascular complication. However, some other studies identify that miRNAs in exosomes are supposed to be involved in cardiac regeneration and confer cardiac protection effect. Therefore, targeting the miRNA in exosome is regarded as a potent therapeutic measure to alleviate diabetes-related CVD. In this article, we review current knowledge about the role of exosomal miRNAs in diabetes-related cardiovascular complication, such as coronary heart disease, Peripheral artery disease, stroke, diabetic cardiomyopathy, diabetic nephropathy and diabetic retinopathy. Exosomal miRNAs are considered to be central regulators of diabetes-Related CVD and provide a therapeutic tool for diagnosis and treatment of diabetes-related cardiovascular complication., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Given the increasing prevalence of diabetes in low-income and middle-income countries (LMICs), we aimed to estimate the health and cost implications of achieving different targets for diagnosis, treatment, and control of diabetes and its associated cardiovascular risk factors among LMICs., Methods: We constructed a microsimulation model to estimate disability-adjusted life-years (DALYs) lost and health-care costs of diagnosis, treatment, and control of blood pressure, dyslipidaemia, and glycaemia among people with diabetes in LMICs. We used individual participant data-specifically from the subset of people who were defined as having any type of diabetes by WHO standards-from nationally representative, cross-sectional surveys (2006-18) spanning 15 world regions to estimate the baseline 10-year risk of atherosclerotic cardiovascular disease (defined as fatal and non-fatal myocardial infarction and stroke), heart failure (ejection fraction of <40%, with New York Heart Association class III or IV functional limitations), end-stage renal disease (defined as an estimated glomerular filtration rate <15 mL/min per 1·73 m 2 or needing dialysis or transplant), retinopathy with severe vision loss (<20/200 visual acuity as measured by the Snellen chart), and neuropathy with pressure sensation loss (assessed by the Semmes-Weinstein 5·07/10 g monofilament exam). We then used data from meta-analyses of randomised controlled trials to estimate the reduction in risk and the WHO OneHealth tool to estimate costs in reaching either 60% or 80% of diagnosis, treatment initiation, and control targets for blood pressure, dyslipidaemia, and glycaemia recommended by WHO guidelines. Costs were updated to 2020 International Dollars, and both costs and DALYs were computed over a 10-year policy planning time horizon at a 3% annual discount rate., Findings: We obtained data from 23 678 people with diabetes from 67 countries. The median estimated 10-year risk was 10·0% (IQR 4·0-18·0) for cardiovascular events, 7·8% (5·1-11·8) for neuropathy with pressure sensation loss, 7·2% (5·6-9·4) for end-stage renal disease, 6·0% (4·2-8·6) for retinopathy with severe vision loss, and 2·6% (1·2-5·3) for congestive heart failure. A target of 80% diagnosis, 80% treatment, and 80% control would be expected to reduce DALYs lost from diabetes complications from a median population-weighted loss to 1097 DALYs per 1000 population over 10 years (IQR 1051-1155), relative to a baseline of 1161 DALYs, primarily from reduced cardiovascular events (down from a median of 143 to 117 DALYs per 1000 population) due to blood pressure and statin treatment, with comparatively little effect from glycaemic control. The target of 80% diagnosis, 80% treatment, and 80% control would be expected to produce an overall incremental cost-effectiveness ratio of US$1362 per DALY averted (IQR 1304-1409), with the majority of decreased costs from reduced cardiovascular event management, counterbalanced by increased costs for blood pressure and statin treatment, producing an overall incremental cost-effectiveness ratio of $1362 per DALY averted (IQR 1304-1409)., Interpretation: Reducing complications from diabetes in LMICs is likely to require a focus on scaling up blood pressure and statin medication treatment initiation and blood pressure medication titration rather than focusing on increasing screening to increase diabetes diagnosis, or a glycaemic treatment and control among people with diabetes., Funding: None., Competing Interests: Declaration of interests SB reports grants from the US National Institutes of Health (NIH) and US Centers for Disease Control and Prevention; consulting fees from the Clinton Health Access Initiative and University of California San Francisco; patents pending for a multi-model patient outreach system; unpaid leadership roles at La Scuola International School and Columbia University Global Research Analytics for Population Health; and stock options at Collective Health, outside the submitted work. DF reports volunteer affiliations with Wuqu' Kawoq and GlucoSalud, outside the submitted work. RA reports contracts with Novo Nordisk, outside the submitted work. TB reports grants from the NIH–National Institute of Allergy and Infectious Diseases, NIH–National Institute on Aging, NIH, National Institute of Child Health and Human Development, Wellcome, Alexander von Humboldt Foundation, UNAIDS, German Research Foundation, European Union, German Federal Ministry of Education and Research, German Federal Ministry of Environment, Nature Conservation and Nuclear Safety, German Federal Ministry of Health, KfW, Else Kröner Foundation, African Academy of Science, European and Developing Countries Clinical Trials Partnership, and the Bill & Melinda Gates Foundation. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Diabetes mellitus and the associated complications are metabolic diseases with high morbidity that result in poor quality of health and life. The lack of diagnostic methods for early detection results in patients losing the best treatment opportunity. Oral hypoglycemics and exogenous insulin replenishment are currently the most common therapeutic strategies, which only yield temporary glycemic control rather than curing the disease and its complications. Exosomes are nanoparticles containing bioactive molecules reflecting individual physiological status, regulating metabolism, and repairing damaged tissues. They function as biomarkers of diabetes mellitus and diabetic complications. Considering that exosomes are bioactive molecules, can be obtained from body fluid, and have cell-type specificity, in this review, we highlight the multifold effects of exosomes in the pathology and therapy of diabetes mellitus and diabetic complications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sun, Tao, Wu, Zhang, Liu and Wang.)

Context: Type 2 diabetes (T2D) shows a high mortality rate, partly mediated by atherosclerotic plaque instability. Discovering novel biomarkers may help identify high-risk patients who would benefit from more aggressive and specific managements. We recently described a serum resistin and multicytokine inflammatory pathway (REMAP), including resistin, interleukin (IL)-1β, IL-6, IL-8, and TNF-α, that is associated with cardiovascular disease., Objective: We investigated whether REMAP is associated with and improves the prediction of mortality in T2D., Methods: A REMAP score was investigated in 3 cohorts comprising 1528 patients with T2D (409 incident deaths) and in 59 patients who underwent carotid endarterectomy (CEA; 24 deaths). Plaques were classified as unstable/stable according to the modified American Heart Association atherosclerosis classification., Results: REMAP was associated with all-cause mortality in each cohort and in all 1528 individuals (fully adjusted hazard ratio [HR] for 1 SD increase = 1.34, P < .001). In CEA patients, REMAP was associated with mortality (HR = 1.64, P = .04) and a modest change was observed when plaque stability was taken into account (HR = 1.58; P = .07). REMAP improved discrimination and reclassification measures of both Estimation of Mortality Risk in Type 2 Diabetic Patients and Risk Equations for Complications of Type 2 Diabetes, well-established prediction models of mortality in T2D (P < .05-< .001)., Conclusion: REMAP is independently associated with and improves predict all-cause mortality in T2D; it can therefore be used to identify high-risk individuals to be targeted with more aggressive management. Whether REMAP can also identify patients who are more responsive to IL-6 and IL-1β monoclonal antibodies that reduce cardiovascular burden and total mortality is an intriguing possibility to be tested., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Individuals with diabetes/stress hyperglycemia carry an increased risk for adverse clinical outcome in case of SARS-CoV-2 infection. The purpose of this study was to evaluate whether this risk is, at least in part, modulated by an increase of thromboembolic complications., Methods: We prospectively followed 180 hospitalized patients with confirmed COVID-19 pneumonia admitted to the Internal Medicine Units of San Raffaele Hospital. Data from 11 out of 180 patients were considered incomplete and excluded from the analysis. We analysed inflammation, tissue damage biomarkers, hemostatic parameters, thrombotic events (TEs) and clinical outcome according to the presence of diabetes/stress hyperglycemia., Results: Among 169 patients, 51 (30.2%) had diabetes/stress hyperglycemia. Diabetes/stress hyperglycemia and fasting blood glucose (FBG) were associated with increased inflammation and tissue damage circulating markers, higher D-dimer levels, increased prothrombin time and lower antithrombin III activity. Forty-eight venous and 10 arterial TEs were identified in 49 (29%) patients. Diabetes/stress hyperglycemia (HR 2.71, p = 0.001), fasting blood glucose (HR 4.32, p < 0.001) and glucose variability (HR 1.6, p < 0.009) were all associated with an increased risk of thromboembolic complication. TEs significantly increased the risk for an adverse clinical outcome only in the presence of diabetes/stress hyperglycemia (HR 3.05, p = 0.010) or fasting blood glucose ≥7 mmol/L (HR 3.07, p = 0.015)., Conclusions: Thromboembolism risk is higher among patients with diabetes/stress hyperglycemia and COVID-19 pneumonia and is associated to poor clinical outcome. In case of SARS-Cov-2 infection patients with diabetes/stress hyperglycemia could be considered for a more intensive prophylactic anticoagulation regimen., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose in relation to the topic of this manuscript. The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. This work was funded by Program Project COVID-19 OSR-UniSR and COVID-2020-12371617Ministero della Salute., (Copyright © 2021 Elsevier Inc. All rights reserved.)