Search

Introduction: Aldose reductase (AKR1B1, EC: 1.1.1.21) is a recognized target for the treatment of long-term diabetic complications since its activation in hyperglycemia and role in the polyol pathway. In particular, the tissue-specificity of AKR1B1 expression makes the design of the traditional Aldose Reductase Inhibitors (ARIs) and the more recent Aldose Reductase Differential Inhibitors (ARDIs) exploitable strategies to treat pathologies resulting from diabetic conditions., Areas Covered: A brief overview of the roles and functions of AKR1B1 along with known ARIs and ARDIs was provided. Then, the design of the latest inhibitors in the scientific scenario was discussed, aiming at introducing the research achievement in the field of intellectual properties. Patents dealing with AKR1B1 and diabetes filed in the 2019-2023 period were collected and analyzed. Reaxys, Espacenet, SciFinder n , and Google Patents were surveyed, using 'aldose reductase' and 'inhibitor' as the reference keywords. The search results were then filtered by PRISMA protocol, thus obtaining 16 records to review., Expert Opinion: Although fewer in number than in the early 2000s, patent applications are still being filed in the field of ARIs, with a large number of Chinese inventors reporting new synthetic ARIs in favor of the repositioning approach.

Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, with its prevalence linked to both genetic predisposition and environmental factors. Epigenetic modifications, particularly through histone deacetylases (HDACs), have been recognized for their significant influence on DM pathogenesis. This review focuses on the classification of HDACs, their role in DM and its complications, and the potential therapeutic applications of HDAC inhibitors. HDACs, which modulate gene expression without altering DNA sequences, are categorized into four classes with distinct functions and tissue specificity. HDAC inhibitors (HDACi) have shown efficacy in various diseases, including DM, by targeting these enzymes. The review highlights how HDACs regulate β-cell function, insulin sensitivity, and hepatic gluconeogenesis in DM, as well as their impact on diabetic cardiomyopathy, nephropathy, and retinopathy. Finally, we suggest that targeted histone modification is expected to become a key method for the treatment of diabetes and its complications. The study of HDACi offers insights into new treatment strategies for DM and its associated 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. Published by Elsevier Masson SAS.)

A four-step synthetic process has been developed to prepare 1,3,5,8-tetrahydroxyxanthone (2a) and its isomer 1,3,7,8-tetrahydroxyxanthone (2b). 25 more xanthones were also synthesized by a modified scheme. Xanthone 2a was identified as the most active inhibitor against both α-glucosidase and aldose reductase (ALR2), with IC 50 values of 7.8 ± 0.5 μM and 63.2 ± 0.6 nM, respectively, which was far active than acarbose (35.0 ± 0.1 μM), and a little more active than epalrestat (67.0 ± 3.0 nM). 2a was also confirmed as the most active antioxidant in vitro with EC 50 value of 8.9 ± 0.1 μM. Any structural modification including methylation, deletion, and position change of hydroxyl group in 2a will cause an activity loss in inhibitory and antioxidation. By applying a H 2 O 2 -induced oxidative stress nematode model, it was confirmed that xanthone 2a can be absorbed by Caenorhabditis elegans and is bioavailable to attenuate in vivo oxidative stress, including the effects on lifespan, superoxide dismutase, Catalase, and malondialdehyde. 2a was verified with in vivo hypoglycemic effect and mitigation of embryo malformations in high glucose. All our data support that xanthone 2a behaves triple roles and is a potential agent to treat diabetic mellitus, gestational diabetes mellitus, and diabetic complications., (© 2024 Wiley Periodicals LLC.)

Importance: The association of value-based medication benefits with diabetes health outcomes is uncertain., Objective: To assess the association of a preventive drug list (PDL) value-based medication benefit with acute, preventable diabetes complications., Design, Setting, and Participants: This cohort study used a controlled interrupted time series design and analyzed data from a large, national, commercial health plan from January 1, 2004, through June 30, 2017, for patients with diabetes aged 12 to 64 years enrolled through employers that adopted PDLs (intervention group) and matched and weighted members with diabetes whose employers did not adopt PDLs (control group). All participants were continuously enrolled and analyzed for 1 year before and after the index date. Subgroup analysis assessed patients with diabetes living in lower-income and higher-income neighborhoods. Data analysis was performed between August 19, 2020, and December 1, 2023., Exposure: At the index date, intervention group members experienced employer-mandated enrollment in a PDL benefit that was added to their follow-up year health plan. This benefit reduced out-of-pocket costs for common cardiometabolic drugs, including noninsulin antidiabetic agents and insulin. Matched control group members continued to have cardiometabolic medications subject to deductibles or co-payments at follow-up., Main Outcomes and Measures: The primary outcome was acute, preventable diabetes complications (eg, bacterial infections, neurovascular events, acute coronary disease, and diabetic ketoacidosis) measured as complication days per 1000 members per year. Intermediate measures included the proportion of days covered by and higher use (mean of 1 or more 30-day fills per month) of antidiabetic agents., Results: The study 10 588 patients in the intervention group (55.2% male; mean [SD] age, 51.1 [10.1] years) and 690 075 patients in the control group (55.2% male; mean [SD] age, 51.1 [10.1] years) after matching and weighting. From baseline to follow-up, the proportion of days covered by noninsulin antidiabetic agents increased by 4.7% (95% CI, 3.2%-6.2%) in the PDL group and by 7.3% (95% CI, 5.1%-9.5%) among PDL members from lower-income areas compared with controls. Higher use of noninsulin antidiabetic agents increased by 11.3% (95% CI, 8.2%-14.5%) in the PDL group and by 15.2% (95% CI, 10.6%-19.8%) among members of the PDL group from lower-income areas compared with controls. The PDL group experienced an 8.4% relative reduction in complication days (95% CI, -13.9% to -2.8%; absolute reduction, -20.2 [95% CI, -34.3 to -6.2] per 1000 members per year) compared with controls from baseline to follow-up, while PDL members residing in lower-income areas had a 10.2% relative reduction (95% CI, -17.4% to -3.0%; absolute, -26.1 [95% CI, -45.8 to -6.5] per 1000 members per year)., Conclusions and Relevance: In this cohort study, acute, preventable diabetes complication days decreased by 8.4% in the overall PDL group and by 10.2% among PDL members from lower-income areas compared with the control group. The results may support a strategy of incentivizing adoption of targeted cost-sharing reductions among commercially insured patients with diabetes and lower income to enhance health outcomes.

Diabetes, characterized as a well-known chronic metabolic syndrome, with its associated complications pose a substantial and escalating health and healthcare challenge on a global scale. Current strategies addressing diabetes are mainly symptomatic and there are fewer available curative pharmaceuticals for diabetic complications. Thus, there is an urgent need to identify novel pharmacological targets and agents. The impaired mitochondria have been associated with the etiology of diabetes and its complications, and the intervention of mitochondrial dysfunction represents an attractive breakthrough point for the treatments of diabetes and its complications. Natural products (NPs), with multicenter characteristics, multi-pharmacological activities and lower toxicity, have been caught attentions as the modulators of mitochondrial functions in the therapeutical filed of diabetes and its complications. This review mainly summarizes the recent progresses on the potential of 39 NPs and 2 plant-extracted mixtures to improve mitochondrial dysfunction against diabetes and its complications. It is expected that this work may be useful to accelerate the development of innovative drugs originated from NPs and improve upcoming therapeutics in 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Flavonoids have been reported to be vital in treating various chronic disorders. Luteolin (3',4',5,7-tetrahydroxyflavone) is a flavonoid present in a variety of plant sources such as celery, green pepper, olive oil, peppermint, thyme, rosemary, oregano, etc. It has been reported to have various pharmacological activities such as antioxidant, anti-inflammatory, anticancer, antidiabetic, anti-Alzheimer, antimicrobial, etc. Many scientific studies have been carried out on luteolin for its possible effects on diabetes and its associated complications. The present review focuses on the role of luteolin in diabetes mellitus and the associated complications. The antidiabetic impact of luteolin is linked with the increased expression of PPARγ and GLUT. Various in vitro and in vivo studies have been performed to explore the effects of luteolin on diabetic complications, and it has shown a significant impact in the management of the same., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Diabetes mellitus (DM) is an endocrinological disorder in which blood sugar levels get elevated and if unmanaged, it leads to several critical complications. Existing therapies or drugs are not able to attain absolute control of DM. Moreover, associated side/adverse effects associated with pharmacotherapy further worsen the Quality of life of patients. Present review is focused on therapeutical potential of flavonoids in management of diabetes and diabetic complications. Plenteous literature has established significant potential of flavonoids in the treatment of diabetes and diabetic complications. A number of flavonoids are found to be effective in treatment of not only diabetes but progression of diabetic complication was also found to be attenuated with the use of flavonoids. Moreover, SAR studies of some flavonoids also indicated the that efficacy of flavonoids is increased with a change in functional group of flavonoids in the treatment of diabetes and diabetic complications. A number of clinical trials are into action to investigate the therapeutic potential of flavonoids as first-line drugs or as adjuvants for treatment of diabetes and diabetic complications.. Owing to their diverse mechanism of action, efficacy and safety, flavonoids may be conscripted as potential candidate for treatment of diabetic complications.

Diabetes is a metabolic illness marked by elevated levels of glucose in the bloodstream due to the inadequate production or use of insulin in the body. Diabetes can result in a range of consequences, with the most prevalent being cardiovascular disease, renal failure, vision loss, and limb removal. Natural compounds isolated from different sources, like colostrum, are the most important compounds for the treatment of diabetes. Colostrum is a form of lactation produced by mammals in the first days after giving birth to their offspring, having a rich source of constituents and showing multipharmacological properties. This review was prepared on the basis of a variety of authoritative search databases, including Google Scholar, Scopus, and PubMed. In addition, the publications and other online sources were also included. In the literature search, the terms "colostrum," "diabetes," "uses," "management," "constituent," "composition," "alternative sources," "mechanism of action," "preclinical," "clinical," "marketed formulations," and "patents" were utilized as keywords and collected from last two decades. Colostrum has been utilized as a treatment for a wide variety of illnesses due to its active constituents. A variety of colostrums are available in the market, like goat colostrum, porcine colostrum, sheep colostrum, human colostrum and many more. They have the full potential of nutrients like minerals, vitamins, lactose, essential enzymes, proteins and high concentrations of immunoproteins. Mostly, the colostrums are used for treating diabetes and its complications. Preclinical and clinical studies of metabolic syndrome, especially on diabetes and its complications, were also reported at the National and International levels, which evidently prove that the use of colostrums in the long term can be beneficial for various ailments associated with diabetes. In general, the findings of this review indicate that supplementation with colostrum may hold promise as a novel therapeutic intervention for people who have diabetes and its complications; however, additional research is required to fully understand its mechanisms of action and determine the best possible dosage as well as the time period of supplementation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Diabetes Mellitus is an endocrine disorder that will affect, about 693 million adults by 2045 worldwide, (>50% increase from 2017). The conventional treatment of the disease, include the oral hypoglycemic drugs which are given in combination with other drugs and are known to possess various adverse effects like gastrointestinal disturbance, nausea, water retention etc. PURPOSE: Due to the urgent need of combating this disorder without side effects, the alternative and complementary therapies should be explored due to their natural origins and comparable safety. Herbal sources serve as new leads, due to the presence of phytoconstituents with potential therapeutic properties, efficacy and safety. In this review, we tried to summarise the polyphenolic phytoconstituents effective in the treatment of diabetic complications., Methods: A systematic literature search was conducted using 4 databases (Google scholar, Pubmed, Scopus, Embase) for the identification of relevant data. Search was performed using various key words such as "diabetes", "polyphenols", "marine sources","anti-diabetic polyphenols". The in vitro studies involving the cell lines used in diabetes and animal models were also considered for inclusion. Additional research papers were identified by reviewing abstracts, scrutinizing reference lists, and reviewing previously published review articles., Results: Polyphenols, a group of phytoconstituents are known worldwide for their tremendous antioxidant potential. So, various research groups have explored their mechanism and therapeutic value in diabetic complications, to improve the insulin sensitivity and glucose metabolism, in controlling the glycemic conditions., Conclusion: Polyphenols exhibit effective therapeutic potential in managing diabetic complications through their multifaceted mechanism of action. They exhibit antioxidative, anti-inflammatory, and anti-glycemic properties, which collectively contribute to their beneficial effects in mitigating diabetic complications. Thus, the inclusion of polyphenols into the diet, may be cosidered as an approach of managing diabetes on long term basis. In this review, we have tried to identify polyphenols effective in diabetes and summarize their mechanism of action along with their potential, for the treatment of diabetic 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 © 2023 Elsevier GmbH. All rights reserved.)

MiRNAs are a large group of non-coding RNAs which participate in different cellular pathways like inflammation and oxidation through transcriptional, post-transcriptional, and epigenetic regulation. In the post-transcriptional regulation, miRNA interacts with the 3'-UTR of mRNAs and prevents their translation. This prevention or dysregulation can be a cause of pathological conditions like diabetic complications. A huge number of studies have revealed the association between miRNAs and diabetic complications, including diabetic nephropathy, cardiomyopathy, neuropathy, retinopathy, and delayed wound healing. To address this issue, recent studies have focused on the use of polyphenols as selective and safe drugs in the treatment of diabetes complications. In this article, we will review the involvement of miRNAs in diabetic complications' occurrence or development. Finally, we will review the latest findings on targeting miRNAs by polyphenols like curcumin, resveratrol, and quercetin for diabetic complications therapy.

Diabetes mellitus is one of the major non-communicable diseases accounting for millions of death annually and increasing economic burden. Hyperglycemic condition in diabetes creates oxidative stress that plays a pivotal role in developing diabetes complications affecting multiple organs such as the heart, liver, kidney, retina, and brain. Green tea from the plant Camellia sinensis is a common beverage popular in many countries for its health benefits. Green tea extract (GTE) is rich in many biologically active compounds, e.g., epigallocatechin-3- O -gallate (EGCG), which acts as a potent antioxidant. Recently, several lines of evidence have shown the promising results of GTE and EGCG for diabetes management. Here, we have critically reviewed the effects of GTE and EGCC on diabetes in animal models and clinical studies. The concerns and challenges regarding the clinical use of GTE and EGCG against diabetes are also briefly discussed. Numerous beneficial effects of green tea and its catechins, particularly EGCG, make this natural product an attractive pharmacological agent that can be further developed to treat diabetes and its complications.

Cardiovascular disease (CVD) complications have remained a major cause of death among patients with diabetes. Hence, there is a need for effective therapeutics against diabetes-induced CVD complications. Since its discovery, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been reported to be involved in the pathology of various CVDs, with studies showing a positive association between plasma levels of PCSK9, hyperglycemia, and dyslipidemia. PCSK9 regulates lipid homeostasis by interacting with low-density lipoprotein receptors (LDLRs) present in hepatocytes and subsequently induces LDLR degradation via receptor-mediated endocytosis, thereby reducing LDL uptake from circulation. In addition, PCSK9 also induces pro-inflammatory cytokine expression and apoptotic cell death in diabetic-CVD. Furthermore, therapies designed to inhibit PCSK9 effectively reduces diabetic dyslipidemia with clinical studies reporting reduced cardiovascular events in patients with diabetes and no significant adverse effect on glycemic controls. In this review, we discuss the role of PCSK9 in the pathogenesis of diabetes-induced CVD and the potential mechanisms by which PCSK9 inhibition reduces cardiovascular events in diabetic patients., Competing Interests: The authors declare no competing interests.

Diabetes mellitus (DM) is a global health issue in the twenty-first century, and there are numerous challenges in preventing and alleviating its chronic complications. The herb Epimedium has beneficial therapeutic effects on various human diseases, including DM. Its major flavonoid component, icariin, has significant anti-DM activity and may help improve pancreatic β-cell dysfunction and insulin resistance. Furthermore, preclinical evidence has shown that icariin and its in vivo bioactive form, icariside II, have preventive and therapeutic effects on several diabetic complications, including diabetic cardiomyopathy, diabetic vascular endothelial disorder, diabetic nephropathy, and diabetic erectile dysfunction. In this review, we present the general and toxicological information concerning icariin and icariside II and review the anti-DM effects of icariin from a molecular perspective. Additionally, we discuss the potential benefits of icariin and icariside II on the important pathological mechanisms of various diabetic complications. Despite positive preclinical evidence, additional investigations are needed before relevant clinical studies can be conducted. Therefore, we conclude with suggestions for future research. Hopefully, this review will provide a comprehensive molecular perspective for future research and product development related to icariin and icariside II in treating DM and diabetic complications.

Copper is an essential trace metal for normal cellular functions; a lack of copper is reported to impair the function of important copper-binding enzymes, while excess copper could lead to cell death. Numerous studies have shown an association between dietary copper consumption or plasma copper levels and the incidence of diabetes/diabetes complications. And experimental studies have revealed multiple signaling pathways that are triggered by copper shortages or copper overload in diabetic conditions. Moreover, studies show that treated with copper chelators improve vascular function, maintain copper homeostasis, inhibit cuproptosis, and reduce cell toxicity, thereby alleviating diabetic neuropathy, retinopathy, nephropathy, and cardiomyopathy. However, the mechanisms reported in these studies are inconsistent or even contradictory. This review summarizes the precise and tight regulation of copper homeostasis processes, and discusses the latest progress in the association of diabetes and dietary copper/plasma copper. Further, the study pays close attention to the therapeutic potential of copper chelators and copper in diabetes and its complications, and hopes to provide new insight for the treatment of diabetes., (© 2023 Wiley-VCH GmbH.)

Mucormycosis, an extremely fatal fungal infection, is a major hurdle in the treatment of diabetes consequences. The increasing prevalence and restricted treatment choices urge the investigation of novel therapeutic techniques. Because of their effective antimicrobial characteristics and varied modes of action, fish-derived peptides have lately emerged as viable options in the fight against mucormycosis. This review examines the potential further application of fish-derived peptides in diagnosing and managing mucormycosis in relation to diabetic complications. First, we examine the pathophysiology of mucormycosis and the difficulties in treating it in diabetics. We emphasize the critical need for alternative therapeutic methods for tackling the limitations of currently available antifungal medicines. The possibility of fish-derived peptides as an innovative approach to combat mucormycosis is then investigated. These peptides, derived from several fish species, provide wide antimicrobial properties against a variety of diseases. They also have distinct modes of action, such as rupture of cell membranes, suppression of development, and modification of the host immunological response. Furthermore, we investigate the problems and prospects connected with the clinical application of fish-derived peptides. Ultimately, future advances in fish-derived peptides, offer interesting avenues for the management of mucormycosis in the context of diabetic comorbidities. More research and clinical trials are needed to properly investigate these peptide's therapeutic potential and pave the way for their adoption into future antifungal therapies., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: Whereas some guidelines recommend statin use to achieve low-density lipoprotein cholesterol (LDL-C) goal < 70 mg/dL for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in patients at higher risk, others recommend against a target LDL-C level. Achieving a target level < 70 mg/dL commonly requires the use of high intensity statins, which has been associated with higher risk of diabetes progression. The objective of this study is to assess the association of strict (≤ 70 mg/dL) versus lenient (> 70 to100 mg/dL) LDL-C lowering on major adverse cardiovascular events (MACE), diabetes progression, diabetes microvascular complications, and total mortality in patients with diabetes., Methods: This was a retrospective propensity score (PS)-matched study from a national cohort of, predominantly male, veterans diagnosed with diabetes without prior cardiovascular disease (from fiscal years 2003-2015), who were initiated on a statin. We created PS to match strict (mean LDL-C during follow-up ≤ 70 mg/dL) versus lenient (mean LDL-C during follow up > 70-100 mg/dL) using 65 baseline characteristics including comorbidities, risk scores, medication classes usage, vital signs, and laboratory data. Outcomes included MACE, diabetes progression, microvascular diabetes complications, and total mortality., Results: From 80,110 eligible patients, we PS-matched 21,294 pairs of statin initiators with strict or lenient LDL-C lowering. The mean (SD) age was 64 (9.5) years and mean (SD) duration of follow-up was 6 (3) years. MACE was similar in the PS-matched groups [6.1% in strict versus 5.8% in lenient; odds ratio (OR): 1.06; 95% confidence interval (95% CI) 0.98-1.15, P = 0.17]. Diabetes progression was higher among the strict vs lenient group (66.7% in strict versus 64.1% in lenient; OR 1.12; 95% CI 1.08-1.17, P < 0.001). There was no difference in microvascular diabetes complications (22.3% in strict versus 21.9% in lenient; OR 1.02; 95% CI 0.98-1.07, P = 0.31) and no difference in total mortality (14.6% in strict versus 15% in lenient; OR 0.97; 95% CI 0.92-1.02, P = 0.20)., Conclusion: Strict compared with lenient lowering of LDL-C with statins in men with diabetes without preexisting ASCVD did not decrease the risk of MACE but was associated with an increased diabetes progression. Clinicians should monitor their patients for diabetes progression upon escalating statins to achieve LDL-C levels ≤ 70 mg/dL., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Diabetes mellitus is a metabolic disease that is characterized by chronic hyperglycemia due to a variety of etiological factors. Long-term metabolic stress induces harmful inflammation leading to chronic complications, mainly diabetic ophthalmopathy, diabetic cardiovascular complications and diabetic nephropathy. With diabetes complications being one of the leading causes of disability and death, the use of anti-inflammatories in combination therapy for diabetes is increasing. There has been increasing interest in targeting significant regulators of the inflammatory pathway, notably receptor-interacting serine/threonine-kinase-1 (RIPK1) and receptor-interacting serine/threonine-kinase-3 (RIPK3), as drug targets for managing inflammation in treating diabetes complications. In this review, we aim to provide an up-to-date summary of current research on the mechanism of action and drug development of RIPK1 and RIPK3, which are pivotal in chronic inflammation and immunity, in relation to diabetic complications which may be benefit for explicating the potential of selective RIPK1 and RIPK3 inhibitors as anti-inflammatory therapeutic agents for 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 © 2023 Ke, Zhang, Liu, Chen, Dai, Sun, Chu and Li.)

Worldwide, diabetes and its complications have seriously affected people's quality of life and become a serious public health problem. C-peptide is not only an indicator of pancreatic β-cell function, but also a biologically active peptide that can bind to cell membrane surface signaling molecules and activate downstream signaling pathways to play antioxidant, anti-apoptotic and inflammatory roles, or regulate cellular transcription through internalization. It is complex how C-peptide is related to diabetic complications. Both deficiencies and overproduction can lead to complications, but their mechanisms of action may be different. C-peptide replacement therapy has shown beneficial effects on diabetic complications in animal models when C-peptide is deficient, but results from clinical trials have been unsatisfactory. The complex pattern of the relationship between C-peptide and diabetic chronic complications has not yet been fully understood. Future basic and clinical studies of C-peptide replacement therapies will need to focus on baseline levels of C-peptide in addition to more attention also needs to be paid to post-treatment C-peptide levels to explore the optimal range of fasting C-peptide and postprandial C-peptide maintenance., 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 © 2023 Chen, Huang, Liu, Chi, Wang and Xu.)

Constipation is a major complications of diabetes mellitus. With the accelerating prevalence of diabetes worldwide and an aging population, there is considerable research interest regarding the altered function and structure of the gastrointestinal tract in diabetic patients. Despite current advances in hyperglycemic treatment strategies, the specific pathogenesis of diabetic constipation remains unknown. Patients with constipation, may be reluctant to eat regularly, which may worsen glycemic control and thus worsen symptoms associated with underlying diabetic bowel disease. This paper presents a review of the complex relationship between diabetes and constipation, exploring the morphological alterations and biomechanical remodeling associated with intestinal motility dysfunction, as well as alterations in intestinal neurons, cellular signaling pathways, and oxidative stress. Further studies focusing on new targets that may play a role in the pathogenesis of diabetic constipation may, provide new ideas for the development of novel therapies to treat or even prevent diabetic constipation., Competing Interests: Declaration of Competing Interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Diabetes mellitus causes a wide range of metabolic derangements with multiple organ damage. The microvascular and macrovascular complications of diabetes result partly from the damage to the glycosaminoglycans (GAG) in the basement membrane. GAGs are negatively charged polysaccharides with repeating disaccharide units. They play a significant role in cellular proliferation and signal transduction. Destruction of extracellular matrix results in diseases in various organs including myocardial fibrosis, retinal damage and nephropathy. To substitute the natural GAGs pharmacotherapeutically, they have been synthesized by using basic disaccharide units. Among the four classes of GAGs, heparin is the most widely studied. Recent studies have revealed multiple significant GAG-protein interactions suggesting their use for the management of diabetic complications. Moreover, they can act as biomarkers for assessing the disease progression. A number of GAG-based therapeutic agents are being evaluated for managing diabetic complications. The current review provides an outline of the role of GAGs in diabetes while covering their interaction with different molecular players that can serve as targets for the diagnosis, management and prevention of diabetes and its complications. The medicinal chemistry and clinical pharmacotherapeutics aspects have are covered to aid in the establishment of GAG-based therapies as a possible avenue for diabetes., 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 © 2023 Elsevier B.V. All rights reserved.)

Background: Around 6.5% of the population in the United Kingdom has been diagnosed with diabetes. It is associated with several long-term consequences and higher hospitalization rates., Aim: To examine the profile of hospital admissions related to diabetes mellitus and the prescription rates of antidiabetic medications in England and Wales., Method: This is an ecological study that was conducted for the period between April 1999 and April 2020 using publicly available hospitalisation data in England and Wales. Hospital admission data for patients of all ages was extracted from Hospital Episode Statistics in England and the Patient Episode Database for Wales. The difference between admission rates in 1999 and 2020, as well as the difference between diabetes mellitus medication prescription rates in 2004 and 2020, were assessed using the Pearson Chi-squared test. A Poisson regression model with robust variance estimation was used to examine the trend in hospital admissions., Results: A total of 1,757,892 diabetes mellitus hospital admissions were recorded in England and Wales during the duration of the study. The hospital admission rate for diabetes mellitus increased by 15.2%. This increase was concomitant with an increase in the antidiabetic medication prescribing rate of 105.9% between 2004 and 2020. Males and those in the age group of 15-59 years had a higher rate of hospital admission. The most common causes of admissions were type 1 diabetes mellitus related complications, which accounted for 47.1% of all admissions., Conclusion: This research gives an in-depth overview of the hospitalization profile in England and Wales during the previous two decades. In England and Wales, people with all types of diabetes and related problems have been hospitalized at a high rate over the past 20 years. Male gender and middle age were significant determinants in influencing admission rates. Diabetes mellitus type 1 complications were the leading cause of hospitalizations. We advocate establishing preventative and educational campaigns to promote the best standards of care for individuals with diabetes in order to lower the risk of diabetes-related complications., (© 2023. The Author(s).)

Diabetic ulcer(DU) is a chronic and refractory ulcer which often occurs in the foot or lower limbs. It is a diabetic complication with high morbidity and mortality. The pathogenesis of DU is complex, and the therapies(such as debridement, flap transplantation, and application of antibiotics) are also complex and have long cycles. DU patients suffer from great economic and psychological pressure while enduring pain. Therefore, it is particularly important to promote rapid wound healing, reduce disability and mortality, protect limb function, and improve the quality of life of DU patients. By reviewing the relevant literatures, we have found that autophagy can remove DU wound pathogens, reduce wound inflammation, and accelerate ulcer wound healing and tissue repair. The main autophagy-related factors microtubule-binding light chain protein 3(LC3), autophagy-specific gene Beclin-1, and ubiquitin-binding protein p62 mediate autophagy. The traditional Chinese medicine(TCM) treatment of DU mitigates clinical symptoms, accelerates ulcer wound healing, reduces ulcer recurrence, and delays further deterioration of DU. Furthermore, under the guidance of syndrome differentiation and treatment and the overall concept, TCM treatment harmonizes yin and yang, ameliorates TCM syndrome, and treats underlying diseases, thereby curing DU from the root. Therefore, this article reviews the role of autophagy and major related factors LC3, Beclin-1, and p62 in the healing of DU wounds and the intervention of TCM, aiming to provide reference for the clinical treatment of DU wounds and subsequent in-depth studies.

Ethnopharmacological Relevance: Ginseng is one of the most widely used herbs in the world for the treatment of various diseases, and ginsenoside is the representative bioactive component in ginseng. There have been many in vivo studies on ginsenoside for the treatment of diabetic nephropathy (DN), the most common diabetic microvascular complication and the main cause of diabetic morbidity and mortality., Aim of the Study: The purpose of this study is to evaluate the efficacy of ginsenosides on DN by preclinical evidence and meta-analysis. Meanwhile, the main possible action mechanisms of ginsenosides against DN were also summarized., Materials and Methods: We systematically searched PubMed, WOS, Embase, Cochrane, WanFang, Cqvip, CNKI and CBM databases from January 1, 2000, to November 15, 2021, to evaluate the animal experiments of ginsenosides for the treatment of DN. Finally, 30 animal experiments were included. Twelve outcome measures, including renal function indicators (24-h urine protein, serum creatinine, urea nitrogen, creatinine clearance, uric acid, urinary albumin to creatinine ratio), oxidative stress biomarkers (GPX, MDA, SOD), inflammatory factors (IL-1, IL-6, TNF-α) were obtained by using RevMan 5.4 software for meta-analysis., Results: The results showed that except for no significant difference in CCr, other indicators such as 24h UP, SCr, blood urea nitrogen, uric acid and UACR were significantly decreased. It showed that ginsenoside could improve renal function in diabetes. Meanwhile ginsenoside significantly up-regulated antioxidant enzymes SOD and GPX, down-regulated MDA and inflammatory factors IL-1, IL-6 and TNF-α, indicating that ginsenoside may have antioxidant and anti-inflammatory effects., Conclusion: Ginsenoside can protect against the renal failure in diabetes through anti-inflammation, anti-oxidation, anti-renal fibrosis, anti-apoptosis/pyroptosis, regulation of blood glucose/lipid metabolism, etc. Which provides preclinical evidence for the application of ginsenoside in the treatment of DN., 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 © 2022 Elsevier B.V. All rights reserved.)

Significance: Diabetes and its related complications are becoming an increasing public health problem that affects hundreds of millions of people globally. Increased disability and mortality rate of diabetic individuals are closely associated with various life-threatening complications, such as atherosclerosis, nephropathy, retinopathy, and cardiomyopathy. Recent Advances: Conventional treatments for diabetes are still limited because of undesirable side effects, including obesity, hypoglycemia, and hepatic and renal toxicity. Studies have shown that hydrogen sulfide (H 2 S) plays a critical role in the modulation of glycolipid metabolism, pancreatic β cell functions, and diabetic complications. Critical Issues: Preservation of endogenous H 2 S systems and supplementation of H 2 S donors are effective in attenuating diabetes-induced complications, thus representing a new avenue to treat diabetes and its associated complications. Future Directions: This review systematically recapitulates and discusses the most recent updates regarding the therapeutic effects of H 2 S on diabetes and its various complications, with an emphasis on the molecular mechanisms that underlie H 2 S-mediated protection against diabetic complications. Furthermore, current clinical trials of H 2 S in diabetic populations are highlighted, and the challenges and solutions to the clinical transformation of H 2 S-derived therapies in diabetes are proposed. Finally, future research directions of the pharmacological actions of H 2 S in diabetes and its related complications are summarized. Antioxid. Redox Signal. 38, 18-44.

Diabetes mellitus is a metabolic syndrome of excess glucose levels in the blood. It may be due to glucose intolerance by the tissues and inadequate insulin production from pancreatic β- cells. However, diabetic complication includes cardiovascular and kidney diseases, eye, skin, and foot complications, and neuropathy. The intention behind writing this article was to gather recent information regarding the use of ancient traditional medicinal plants having recent importance in treating diabetes. Several therapies are available for curing the condition based on severity and type of diabetes. Although pharmacological treatments are effective and economical, drugs are associated with unwanted side effects and physiological complications on long-term use. Interestingly, herbs and herbal plants have been used since ancient times against diabetes worldwide. Its importance still exists due to medicinal plants' effectiveness and safety profile in treating various diseases. In this article, we searched online databases, including PUBMED, SCOPUS, MEDLINE, and traditional resources, for collecting information regarding the use of plants against diabetes. We described the pathophysiology of the disease and incorporated plant sources and their chemical constituents responsible for antidiabetic activity with their mechanism in reducing blood glucose levels. The present article may be very helpful for researchers and professionals whose work is inclined towards diabetes and in search of lead compounds for the development of a suitable drug., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: A number of complexities in compliance with long-term diabetes have been elicited. It has become a global concern without any convincing medicinal, therapeutical methodology. Both hyperglycaemia and oxidative pressure are major notable parts that play a significant role in the initialization of diabetic inconvenience. Natural medications have gained a lot of attention in recent years as expected restorative specialists in the prevention and treatment of diabetic complications due to their many objectives and less poisonous outcomes. This survey means to evaluate the accessible information on therapeutic spices for constriction and the executives of diabetic complications., Materials and Methods: Bibliographic investigation was accomplished by checking old-style course books and papers, directing overall bases of logical information (SCOPUS, PUBMED, SCIELO, Google Scholar, NISCAIR,) to recapture accessible distributed writing. For the assessment of plants with the potential in calming diabetic complications, several inclusion models rely on the numerous medicinal spices as well as their crucial mixes. Furthermore, several models, including plants, have been considered, each of which has a suitable impact on increasing oxidative pressure in diabetes., Results: Different therapeutic plants/plant withdrawals containing alkaloids, terpenoids, phenolic compounds, flavonoids, saponins, and phytosterol-type synthetic constituents were uncovered that are profitable in the administration of diabetic complexities. Results may be attributed to the improvement of oxidative pressure, constant hyperglycemia, and twitch of different metabolic pathways related to the pathogenesis of diabetic confusions., Conclusion: An optimistic approach for new medication terminology to treat diabetic confusion is screening compound competitors from homegrown medication. Investigation of the activity of different plant extracts as well as their potency profile and to determine their job in the treatment of diabetic inconveniences must be there. In addition, an ideal rat model which imitates human diabetic complications ought to be created., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The lack of currently available drugs for treating diabetes complications has stimulated our interest in finding new Aldose Reductase inhibitors (ARIs) with more beneficial biological properties. One metabolic method uses aldose reductase inhibitors in the first step of the polyol pathway to control excess glucose flux in diabetic tissues. Computer-aided drug discovery (CADD) is key in finding and optimizing potential lead substances. AR inhibitors (ARI) have been widely discussed in the literature. For example, Epalrestat is currently the only ARI used to treat patients with diabetic neuropathy in Japan, India, and China. Inhibiting R in patients with severe to moderate diabetic autonomic neuropathy benefits heart rate variability. AT-001, an AR inhibitor, is now being tested in COVID-19 to see how safe and effective it reduces inflammation and cardiac damage. In summary, these results from animal and human studies strongly indicate that AR can cause cardiovascular complications in diabetes. The current multi-center, large-scale randomized human study of the newly developed powerful ARI may prove its role in diabetic cardiovascular disease to establish therapeutic potential. During the recent coronavirus disease (COVID-19) outbreak in 2019, diabetes and cardiovascular disease were risk factors for severely negative clinical outcomes in patients with COVID19. New data shows that diabetes and obesity are among the strongest predictors of COVID-19 hospitalization. Patients and risk factors for severe morbidity and mortality of COVID- 19., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Diabetes is a chronic metabolic disease characterized by an excess of glucose in the blood. If the constant sugar level is not managed correctly in diabetic patients, it may lead to microvascular complications such as diabetic retinopathy, neuropathy, and nephropathy. There are several synthetic drugs for the management of diabetes; however, these drugs produce immense adverse effects in long-term use. Flavonoids are naturally occurring substances categorized in various classes. They are known for their diverse pharmacological actions, and one of them is prominent antihyperglycemic action and their activities in diabetic complications. In the last few decades, many research studies emphasized the potential of flavonoids in diabetes management. Nevertheless, most flavonoids are insoluble in water and cannot produce desired therapeutic action when administered in conventional dosage forms. To overcome this issue, flavonoids were formulated into different nanoformulations to enhance solubility, absorption, and therapeutic efficacy. This review article focuses on flavonoid nanoformulations and in vitro and in vivo studies reported to overcome diabetes mellitus and its complications., (© 2022. Controlled Release Society.)

Diabetes is a group of metabolic diseases characterised by chronic hyperglycaemia caused by multiple causes, which is caused by insulin secretion and/or utilisation defects. It is characterised by increased fasting and postprandial blood glucose levels due to insulin deficiency or insulin resistance. It is reported that the harm of diabetes mainly comes from its complications, and the cardiovascular disease caused by diabetes is the primary cause of its harm. China has the largest number of diabetic patients in the world, and the prevention and control of diabetes are facing great challenges. In recent years, many kinds of literature have been published abroad, which have proved that coumarin and its derivatives are effective in the treatment of diabetic complications such as nephropathy and cardiovascular disease. In this paper, the types of antidiabetic drugs and the anti-diabetic mechanism of coumarins were reviewed.

3-N-butylphthalide (NBP) is a component isolated from seeds of Chinese celery, and it was firstly approved for the treatment of ischemic stroke. With the gradual in-depth understanding of its pharmacological action, it was found that it may have potential effects on treating diabetes and its complications. This review aims to illustrate the researches on the properties of NBP and its therapeutic efficacy in diabetic related diseases. This review will discuss the results of experiments in vitro and in vivo to make progress in understanding the beneficial effects of NBP and its derivatives on diabetic complications including diabetic vascular diseases, diabetic peripheral neuropathy, diabetic brain related diseases and diabetic cataract. We will also demonstrate NBP's numerous molecular targets and interactions with multiple cellular signaling pathways such as oxidative stress, inflammatory responses, apoptosis and autophagy. NBP is proved to be a potential therapeutic approach for treating diabetic complications., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Postprandial hyperglycaemia (PPH) may sometimes be relegated to the background in the treatment of diabetic patients, while its control seems important if not essential to reach an adequate overall glycaemic control. PPH is correlated with glycated haemoglobin and diabetic complications. It is also identified as a cardiovascular risk factor. PPH's monitoring and adequate control are not only a therapeutic goal for diabetes itself but also for reducing associated adverse outcomes other than diabetic complications. PPH is related to the quality of life of patients. Continuous glucose monitoring allows a better appraisal of PPH. The use of new insulin formulations as ultra-fast insulins seems to be the better way to manage post-prandial blood glucose peaks., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Background: Statins increase insulin resistance, which may increase risk of diabetic microvascular complications. Little is known about the impact of statins on renal, ophthalmologic, and neurologic complications of diabetes in practice. The objective of this study was to examine the association of statins with renal disease progression, ophthalmic manifestations, and neurological manifestations in diabetes., Methods: This is a retrospective cohort study, new-user active comparator design, that included a national Veterans Health Administration (VA) patients with diabetes from 2003 to 2015. Patients were age 30 years or older and were regular users of the VA with data encompassing clinical encounters, demographics, vital signs, laboratory tests, and medications. Patients were divided into statin users or nonusers (active comparators). Statin users initiated statins and nonusers initiated H2-blockers or proton pump-inhibitors (H2-PPI) as an active comparator. Study outcomes were: 1) Composite renal disease progression outcome; 2) Incident diabetes with ophthalmic manifestations; and 3) Incident diabetes with neurological manifestations., Results: Out of 705,774 eligible patients, we propensity score matched 81,146 pairs of statin users and active comparators. Over a mean (standard deviation) of follow up duration of 4.8 (3) years, renal disease progression occurred in 9.5% of statin users vs 8.3% of nonusers (odds ratio [OR]: 1.16; 95% confidence interval [95%CI]: 1.12-1.20), incident ophthalmic manifestations in 2.7% of statin users vs 2.0% of nonusers (OR: 1.35, 95%CI:1.27-1.44), and incident neurological manifestations in 6.7% of statin users vs 5.7% of nonusers (OR: 1.19, 95%CI:1.15-1.25). Secondary, sensitivity, and post-hoc analyses were consistent and demonstrated highest risks among the healthier subgroup and those with intensive lowering of LDL-cholesterol., Conclusions: Statin use in patients with diabetes was associated with modestly higher risk of renal disease progression, incident ophthalmic, and neurological manifestations. More research is needed to assess the overall harm/benefit balance for statins in the lower risk populations with diabetes and those who receive intensive statin therapy., Competing Interests: NO authors have competing interests.

Diabetic dermopathy (DD) is a common complication of long-standing diabetes, and is often seen in association with chronic micro- and macro-vascular dysfunction. Hence, it can be considered an equivalent of vascular complications of diabetes. Our article focuses on a proactive approach to its management, involving both dermo-cosmetic and metabolic targeted therapies. A combination of occlusive and humectant moisturisers, with anti-inflammatory and pro-regenerative topical treatments, can help manage and minimize DD, while preventing its complications. We term such topical preparations as 'healing moisturisers' or 'regenerative moisturisers.

Significance: Modulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated antioxidant response is a key aspect in the onset of diabetes-related cardiovascular complications. With this review, we provide an overview of the recent advances made in the development of Nrf2-targeting strategies for the treatment of diabetes, with particular attention toward the activation of Nrf2 by natural antioxidant compounds, nanoparticles, and oxidative stress-modulating biocompatible scaffolds. Recent Advances: In the past 30 years, studies addressing the use of antioxidant therapies to treat diabetes have grown exponentially, showing promising but yet inconclusive results. Animal studies and clinical trials on the Nrf2 pathway have shown promising results, suggesting that its activation can delay or reverse some of the cardiovascular impairments in diabetes. Critical Issues: Hyperglycemia- and oscillating glucose levels-induced reactive oxygen species (ROS) accumulation is progressively emerging as a central factor in the onset and progression of diabetes-related cardiovascular complications, including endothelial dysfunction, retinopathy, heart failure, stroke, critical limb ischemia, ulcers, and delayed wound healing. In this context, accumulating evidence suggests a central role for Nrf2-mediated antioxidant response, one of the most studied cellular defensive mechanisms against ROS accumulation. Future Directions: Innovative approaches such as tissue engineering and nanotechnology are converging toward targeting oxidative stress in diabetes. Antioxid. Redox Signal. 36, 707-728.

The global diabetes epidemic and its complications are increasing, thereby posing a major threat to public health. A comprehensive understanding of diabetes mellitus (DM) and its complications is necessary for the development of effective treatments. Ferroptosis is a newly identified form of programmed cell death caused by the production of reactive oxygen species and an imbalance in iron homeostasis. Increasing evidence suggests that ferroptosis plays a pivotal role in the pathogenesis of diabetes and diabetes-related complications. In this review, we summarize the potential impact and regulatory mechanisms of ferroptosis on diabetes and its complications, as well as inhibitors of ferroptosis in diabetes and diabetic complications. Therefore, understanding the regulatory mechanisms of ferroptosis and developing drugs or agents that target ferroptosis may provide new treatment strategies for patients with 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 © 2022 Yang and Yang.)

(1) Background: Orthosiphon stamineus Benth. is a traditional medicine used in the treatment of diabetes and chronic renal failure in southern China, Malaysia, and Thailand. Diabetes is a chronic metabolic disease and the number of diabetic patients in the world is increasing. This review aimed to systematically review the effects of O. stamineus in the treatment of diabetes and its complications and the pharmacodynamic material basis. (2) Methods: This systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), using the databases ScienceDirect, PubMed, and Web of Science. (3) Results: Thirty-one articles related to O. stamineus and diabetes were included. The mechanisms of O. stamineus in the treatment of diabetes and its complications mainly included inhibiting α-amylase and α-glucosidase activities, antioxidant and anti-inflammatory activities, regulating lipid metabolism, promoting insulin secretion, ameliorating insulin resistance, increasing glucose uptake, promoting glycolysis, inhibiting gluconeogenesis, promoting glucagon-likepeptide-1 (GLP-1) secretion and antiglycation activity. Phenolic acids, flavonoids and triterpenoids might be the main components for hypoglycemia effects in O. stamineus . (4) Conclusion: O. stamineus could be an antidiabetic agent to treat diabetes and its complications. However, it needs further study on a pharmacodynamic substance basis and the mechanisms of effective constituents., Competing Interests: The authors declare no conflict of interest.

Background: Increasing academic efforts have been made to explore the correlation of long noncoding RNAs (lncRNAs) with human diseases, particularly metabolic diseases like diabetes mellitus. Taking lncRNA H19 as an example, this review intends to reveal the functions and mechanism of lncRNA H19 in diabetes mellitus and diabetic complications., Methods: The research results associated with lncRNA H19 and diabetes mellitus are collected and summarized on PubMed., Conclusion: LncRNA H19 is a potential instructive marker for the treatment of diabetes mellitus and diabetic complications., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Diabetes mellitus (DM) and DM-induced vascular complications are significant global healthcare problems, causing a decrease in patient quality of life. The main reason for the disability and mortality of patients is rapidly progressing micro-and macroangiopathies. Currently, free radical oxidation is recognized as one of the main mechanisms in the development of DM and associated complications. Under normal physiological conditions, the level of free radicals and antioxidant defense capabilities is balanced. However, imbalance occurs between the antioxidant defense system and pro-oxidants during chronic hyperglycemia and may invoke the formation of excess free radicals, leading to activation of lipid peroxidation and accumulation of highly toxic products of free radical oxidation. This is accompanied by varying degrees of insulin deficiency and insulin resistance in DM patients. Simultaneously with the activation of free radical generation, a decrease in the activity of antioxidant defense factors (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, vitamins C and E) and an acceleration of diabetic complications are seen. Therefore, we hypothesize that antioxidants may play a positive role in the treatment of DM patients to prevent DM-induced vascular complications. However, this has not been sufficiently studied. In this review, we discuss recent insights into the potential underlying mechanisms of oxidative stress-induced diabetic complications and the implications of antioxidants in mitigation of DM-induced vascular complications., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The pathobiology of diabetes and associated complications has been widely researched in various countries, but effective prevention and treatment methods are still insufficient. Diabetes is a metabolic disorder of carbohydrates, fats, and proteins caused by an absence of insulin or insulin resistance, which mediates an increase of oxidative stress, release of inflammatory factors, and macro- or micro-circulation dysfunctions, ultimately developing into diverse complications., Summary: In the last decade through pathogenesis research, epigenetics has been found to affect metabolic diseases. Particularly, DNA methylation, histone acetylation, and miRNAs promote or inhibit diabetes and complications by regulating the expression of related factors. Curcumin has a wide range of beneficial pharmacological activities, including anti-inflammatory, anti-oxidation, anticancer, anti-diabetes, anti-rheumatism, and increased immunity. Key Messages: In this review, we discuss the effects of curcumin and analogs on diabetes and associated complications through epigenetics, and we summarize the preclinical and clinical researches for curcumin and its analogs in terms of management of diabetes and associated complications, which may provide an insight into the development of targeted therapy of endocrine diseases., (© 2021 S. Karger AG, Basel.)

The alterations in vascular homeostasis are deeply involved in the development of numerous diseases, such as coronary heart disease, stroke, and diabetic complications. Changes in blood flow and endothelial permeability caused by vascular dysfunction are the common mechanisms for these three types of diseases. The disorders of glucose and lipid metabolism can bring changes in the energy production patterns in endothelium and surrounding cells which may consequently cause energy metabolic disorders, oxidative stress, and inflammatory responses. Traditional Chinese medicine (TCM) follows the principle of the "treatment by the syndrome differentiation." TCM considers coronary heart disease, stroke, and diabetes complications all as the type of Qi-deficiency and blood stasis syndrome, which mainly occurs in the vascular system. Therefore, the common pathogenesis of these three types of diseases suggests that the treatment strategy by TCM should be in a close manner and referred to as "treating different diseases by the same treatment." Qishen Yiqi dripping pill is a modern Chinese herbal medicine that has been widely used for the treatment of patients with coronary heart disease characterized as Qi-deficiency and blood stasis in China. Recently, many clinical reports have demonstrated the potential therapeutic effects of Qishen Yiqi dripping pills on ischemic stroke and diabetic nephropathy. Based on these reports, we will summarize the clinical applications of Qishen Yiqi dripping pills on coronary heart disease, ischemic stroke, and diabetic nephropathy, including the involved mechanisms discussed in various research works., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Impaired wound healing is of the most conspicuous characteristics of diabetic mellitus. Reduced blood flow, chronic inflammatory reactions, infection, endothelial dysfunction, elevated levels of reactive oxygen species, and metabolic disorders cause wounds to heal more slowly in these patients. Previous studies have reported useful impacts of growth factors in management of such wounds. However, due to their short half-life and low stability, a suitable delivery platform with sustained release profile may boost their healing potential. Controlled and localized delivery of growth factors via electrospun fibers have been extensively explored in previous studies. The electrospinning method; although not new, has turned out to be extremely effective for the preparation of delivery carriers for growth factors. Due to their structural resemblance to native tissues' extracellular matrix, high encapsulation efficacy, tunability, and high surface to volume ratio, electrospun scaffolds have gained significant attention in drug delivery and tissue engineering. In the current review, careful integration of current research regarding the applications of growth factors' delivery through electrospun fibers in diabetic wounds healing has been done. This review will not only give an insight into the current updates, but will also highlights the future perspectives and challenges., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The potential relationship between diabetes and COVID-19 has been evaluated. However, new knowledge is rapidly emerging. In this study, we systematically reviewed the relationship between viral cell surface receptors (ACE2, AXL, CD147, DC-SIGN, L-SIGN and DPP4) and SARS-CoV-2 infection risk, and emphasized the implications of ACE2 on SARS-CoV-2 infection and COVID-19 pathogenesis. Besides, we updated on the two-way interactions between diabetes and COVID-19, as well as the treatment options for COVID-19 comorbid patients from the perspective of ACE2. The efficacies of various clinical chemotherapeutic options, including anti-diabetic drugs, renin-angiotensin-aldosterone system inhibitors, lipid-lowering drugs, anticoagulants, and glucocorticoids for COVID-19 positive diabetic patients were discussed. Moreover, we reviewed the significance of two different forms of ACE2 (mACE2 and sACE2) and gender on COVID-19 susceptibility and severity. This review summarizes COVID-19 pathophysiology and the best strategies for clinical management of diabetes patients with COVID-19., 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 Xie, Zhang, Wang, Chen, Lu and Wu.)

The first reports of a link between thiamine and diabetes date back to the 1940s. Some years later, a role for thiamine deficiency in diabetic neuropathy became evident, and some pilot studies evaluated the putative effects of thiamine supplementation. However, the administration of thiamine and its lipophilic derivative benfotiamine for the treatment of this complication gained consensus only at the end of the '90 s. The first evidence of the beneficial effects of thiamine on microvascular cells involved in diabetic complications dates to 1996: from then on, several papers based on in vitro and animal models have addressed the potential use of this vitamin in counteracting diabetic microangiopathy. A few pilot studies in humans reported beneficial effects of thiamine administration on diabetic nephropathy, but, despite all promising proofs-of-concept, the possible role of thiamine in counteracting development or progression of retinopathy has not been addressed until now. Thiamine is a water-soluble vitamin, rapidly expelled from the body, with no issues of over-dosage or accumulation; unfortunately, it is non-patentable, and neither industry nor independent donors are interested in investing in large-scale randomized controlled clinical trials to investigate its potential in diabetes and its complications. Consequently, science will not be able to disprove a promising hypothesis and, more importantly, diabetic people remain deprived of a possible way to ameliorate their condition., (© 2021. The Author(s).)

Angiotensin-converting enzyme (ACE) inhibitors are antihypertensive medications often used in the treatment of diabetes-related complications. Synthetic ACE inhibitors are known to cause serious side effects like hypotension, renal insufficiency, and hyperkalaemia. Therefore, there has been an intensifying search for natural ACE inhibitors. Many plants or plant-based extracts are known to possess ACE-inhibitory activity. In this review, articles focusing on the natural ACE inhibitors extracted from plants were retrieved from databases like Google Scholar, PubMed, Scopus, and Web of Science. We have found more than 50 plant species with ACE-inhibitory activity. Among them, Angelica keiskei, Momordica charantia, Muntingia calabura, Prunus domestica, and Peperomia pellucida were the most potent, showing comparatively lower half-maximal inhibitory concentration values. Among the bioactive metabolites, peptides (e.g., Tyr-Glu-Pro, Met-Arg-Trp, and Gln-Phe-Tyr-Ala-Val), phenolics (e.g., cyanidin-3-O-sambubioside and delphinidin-3-O-sambubioside), flavonoids ([-]-epicatechin, astilbin, and eupatorin), terpenoids (ursolic acid and oleanolic acid) and alkaloids (berberine and harmaline) isolated from several plant and fungus species were found to possess significant ACE-inhibitory activity. These were also known to possess promising antioxidant, antidiabetic, antihyperlipidemic and anti-inflammatory activities. Considering the minimal side effects and lower toxicity of herbal compounds, development of antihypertensive drugs from these plant extracts or phytocompounds for the treatment of diabetes-associated complications is an important endeavour. This review, therefore, focuses on the ACE inhibitors extracted from different plant sources, their possible mechanisms of action, present status, and any safety concerns., 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 © 2021 Shanghai Changhai Hospital. Published by Elsevier B.V. All rights reserved.)

The COVID-19 pandemic has escalated the occurrence of hypoxia including thrombotic stroke worldwide, for which nitric oxide (NO) therapy seems very promising and translatable. Therefore, various modes/routes of NO-delivery are now being tested in different clinical trials for safer, faster, and more effective interventions against ischemic insults. Intravenous (IV) infusion of S-Nitrosoglutathione (GSNO), the major endogenous molecular pool of NO, has been reported to protect against mechanical cerebral ischemia-reperfusion (IR); however, it has been never tested in any kind of "clinically" relevant thromboembolic stroke models with or without comorbidities and in combination with the thrombolytic reperfusion therapy. Moreover, "IV-effects" of higher dose of GSNO following IR-injury have been contradicted to augment stroke injury. Herein, we tested the hypothesis that nebulization of low-dose GSNO will not alter blood pressure (BP) and will mitigate stroke injury in diabetic mice via enhanced cerebral blood flow (CBF) and brain tissue oxygenation (PbtO2). GSNO-nebulization (200 μg/kgbwt) did not alter BP, but augmented the restoration of CBF, improved behavioral outcomes and reduced stroke injury. Moreover, GSNO-nebulization increased early reoxygenation of brain tissue/PbtO2 as measured at 6.5 h post-stroke following thrombolytic reperfusion, and enervated unwanted effects of late thrombolysis in diabetic stroke. We conclude that the GSNO-nebulization is safe and effective for enhancing collateral microvascular perfusion in the early hours following stroke. Hence, nebulized-GSNO therapy has the potential to be developed and translated into an affordable field therapy against ischemic events including strokes, particularly in developing countries with limited healthcare infrastructure.

Diabetes mellitus (DM), characterized by abnormal carbohydrate, lipid, and protein metabolism, is a metabolic disorder caused by a shortage of insulin secretion or decreased sensitivity of target cells to insulin. In addition to changes in lifestyle, a low-calorie diet is recommended to reduce the development of DM. Steviol glycosides (SGs), as natural sweeteners, have gained attention as sucrose alternatives because of their advantages of high sweetness and being low calorie. Most SGs with multiple bioactivities are beneficial to regulate physiological functions. Though SGs have been widely applied in food industry, there is little data on their glucosylated derivatives that are glucosylated steviol glycosides (GSGs). In this review, we have discussed the metabolic fate of GSGs in contrast to SGs, and the molecular mechanisms of glycoside metabolites against diabetes-related metabolic disorders are also summarized. SGs are generally extracted from the Stevia leaf, while GSGs are mainly manufactured using enzymes that transfer glucose units from a starch source to SGs. Results from this study suggest that SGs and GSGs share same bioactive metabolites, steviol and steviol glucuronide (SVG), which exhibit anti-hyperglycemic effects by activating glucose-induced insulin secretion to enhance pancreatic β-cell function. In addition, steviol and SVG have been found to ameliorate the inflammatory response, lipid imbalance, myocardial fibrosis and renal functions to modulate diabetes-related metabolic disorders. Therefore, both SGs and GSGs may be used as potential sucrose alternatives and/or pharmacological alternatives for preventing and treating metabolic disorders.

Aim: To investigate the epidemiology of S. aureus and MRSA nasal carriage among people with diabetes at the Korle Bu Teaching Hospital in Accra, including the prevalence, predictors of carriage, and antibiotic resistance., Methodology: This study was cross-sectional, involving 300 diabetes patients and 106 non-diabetic individuals. Swab specimens of the nares were obtained from the participants and bacteriologically-cultured. Identification and characterization of S. aureus and MRSA were based on standard bacteriological methods; antimicrobial susceptibility testing was by the Kirby-Bauer method., Results: The prevalence of staphylococcal carriage, the diabetes group relative to the non-diabetes group, were 31.0% and 10.4% (S. aureus), and 3.3% and 0.0% (MRSA). Presence of diabetes predisposed to S. aureus carriage, but not MRSA nor coagulase-negative staphylococci (CoNS) carriage (OR = 3.88; p < 0.0001). Colonization with CoNS was protective of S. aureus (OR = 0.039, p < 0.001) and MRSA (OR = 0.115, p = 0.043) colonization among the diabetics. The antimicrobial resistance patterns recorded among the S. aureus isolated from the diabetic individuals relative to the non-diabetics were as follows: penicillin (95% vs. 91%), tetracycline (37% vs. 27%), cotrimoxazole (30% vs. 36%), erythromycin (17% vs. 0%), norfloxacin (13% vs. 0%), clindamycin (12% vs. 0%), gentamicin (9% vs. 0%), fusidic acid (10% vs. 9%), linezolid (4% vs. 0%), and rifampicin (5% vs. 0%). The proportion of multidrug resistant S. aureus was 41% (n = 38) in the diabetes group and 0% in the non-diabetes group; this difference was statistically significant (p = 0.01)., Conclusions: The presence of diabetes predisposed the participants to S. aureus carriage by almost four folds, but not MRSA carriage. Colonization with CoNS was protective of S. aureus and MRSA carriage in the diabetes group. Finally, linezolid remains a good therapeutic agent for anti-MRSA therapy., Competing Interests: FCNK and M-MO are affiliated with FleRhoLife Research Consult, but this firm didnot provide financial support nor play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The development of a closed-loop artificial pancreas (AP) in the Western countries and Japan is different. In Western countries, wearable AP with a closed-loop glycemic control system has been developed as a treatment for patients with type 1 and type 2 diabetes. On the contrary, in Japan, bedside closed-loop AP explored by a Japanese company (Nikkiso, Tokyo, Japan) has developed as perioperative glycemic control device in surgical patients and acute care patients with emergency. In this article, we reviewed the scientific evidence in the past and present and future prospects of perioperative glycemic control using bedside AP with a closed-loop system in Japan. Conventional perioperative strict glycemic controls have three major problems: hyperglycemia, hypoglycemia, and variability in blood glucose concentrations. In Japan, perioperative strict glycemic control using the current bedside AP STG-55 (Nikkiso, Tokyo, Japan) has been developed since 2010. This novel glycemic control method achieved not only stable glycemic control without hyperglycemia, hypoglycemia, and less variability of blood glucose concentrations but also reduced postoperative infectious complications in patients undergoing major surgeries. Among the rapidly increasing number of surgical or emergency patients with diabetes, frailty, and sarcopenia of intrinsic glucose intolerance, more sophisticated and smaller AP available easily in operating rooms and intensive care units will be warranted to promote improved therapeutic outcomes in such critically ill patients., (© 2021 International Center for Artificial Organs and Transplantation and Wiley Periodicals LLC.)

Diabetic retinal disease remains one of the most common complications of diabetes mellitus (DM) and a leading cause of preventable blindness. The mainstay of management involves glycemic control, intravitreal, and laser therapy. However, intravitreal therapy commonly requires frequent hospital visits and some patients fail to achieve a significant improvement in vision. Novel and long-acting therapies targeting a range of pathways are warranted, while evidence to support optimal combinations of treatments is currently insufficient. Improved understanding of the molecular pathways involved in pathogenesis is driving the development of therapeutic agents not only targeting visible microvascular disease and metabolic derangements, but also inflammation and accelerated retinal neurodegeneration. This review summarizes the current and emerging treatments of diabetic retinal diseases and provides an insight into the future of managing this important condition.