Advancements in culture technology of adipose-derived stromal/stem cells: implications for diabetes and its complications.

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.

RNA therapeutics for treatment of diabetes.

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.

MiR-17-5p-engineered sEVs Encapsulated in GelMA Hydrogel Facilitated Diabetic Wound Healing by Targeting PTEN and p21.

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 (sEVs17-OE) and encapsulated them in gelatin methacryloyl (GelMA) hydrogel for diabetic wounds treatment are fabricated. SEVs17-OE are successfully fabricated with a 16-fold increase in miR-17-5p expression. SEVs17-OE inhibited senescence and promoted the proliferation, migration, and tube formation of high glucose-induced human umbilical vein endothelial cells (HG-HUVECs). Additionally, sEVs17-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 sEVs17-OE. Accordingly, the downstream genes and pathways of p21 and PTEN, are activated. Next, sEVs17-OE are loaded in GelMA hydrogel to fabricate a novel bioactive wound dressing and to evaluate their effects on diabetic wound healing. Gel-sEVs17-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 sEVs17-OE in GelMA hydrogel, offering an option for chronic wound management is successfully fabricated.

The Fusion Clinic: Integrating the care of people with severe mental illness and diabetes.

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 HbA1c and lipid profile improved after referral to the clinic. HbA1c 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.

Comparative efficacy and safety of Faricimab and other anti-VEGF therapy for age-related macular degeneration and diabetic macular edema: A systematic review and meta-analysis of randomized clinical trials.

INTRODUCTION: A systematic review and meta-analysis were conducted to evaluate the efficacy and the overall safety of Faricimab compared with other anti-vascular endothelial growth factors (VEGF) therapy for neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME). MATERIALS AND METHODS: A systematic literature search of a comprehensive electronic database was performed to identify randomized clinical trials published from January 2013 to January 2023 for Faricimab in AMD and DME. Weighted mean differences and risk ratios were used to integrate the different studies. RESULTS: A total of 4 randomized controlled trials (RCTs) with 1678 AMD patients and 3 RCTs with 20 DME patients were included in the meta-analysis.In patients with AMD, a significant difference was found in the number of injections between Faricimab and other anti-VEGF therapy (MD = -2.42, 95% CI [-3.93 to -0.90], P = .002).No significant difference was found for the change in best corrected visual acuity (BVCA), central subfoveal thickness (CST), and gaining 15 or more letters. Similarly, no significant difference was found for adverse events.In patients with DME, a significant difference was observed for CST (MD = -22.41, 95% CI [-29.95 to -14.86], P < .00001) and the number of injections(MD = -0.93, 95% CI [-1.33 to -0.54], P < .00001). No significant difference was found for BVCA and gaining 15 or more letters, and no significant difference was found for adverse events. CONCLUSIONS: Comprehensive evidence confirms that Faricimab achieves non-inferior or even better CST improvement than other anti-VEGF therapies with extended dosing intervals, but more long-term follow-up studies are needed to support our conclusions.

Stem cells as a regenerative medicine approach in treatment of microvascular diabetic complications.

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.

Satellite cell-derived exosome-mediated delivery of microRNA-23a/27a/26a cluster ameliorates the renal tubulointerstitial fibrosis in mouse diabetic nephropathy.

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.

[Diagnosis and treatment strategy of periodontitis with diabetes].

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.

Synergistic role of resveratrol and exercise training in management of diabetic neuropathy and myopathy via SIRT1/NGF/GAP43 linkage.

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.

Improved prognosis with integrated care management including early rhythm control and healthy lifestyle modification in patients with concurrent atrial fibrillation and diabetes mellitus: a nationwide cohort study.

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.

Medical Costs Associated With Diabetes Complications in Medicare Beneficiaries Aged 65 Years or Older With Type 1 Diabetes.

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.

The importance of inflammation control for the treatment of chronic diabetic wounds.

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.

The efficacy of a paeoniflorin-sodium alginate-gelatin skin scaffold for the treatment of diabetic wound: An in vivo study in a rat model.

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-1ß 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-1ß infiltration was lower in the 10% group than in the 3% group (P = 0.002). On day 14, IL-1ß 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.

Static Magnetic Fields Reduce Oxidative Stress to Improve Wound Healing and Alleviate Diabetic Complications.

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.

Disparities in diabetes-related avoidable hospitalization among diabetes patients with disability using a nationwide cohort study.

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.

Connexin 43: A Target for the Treatment of Inflammation in Secondary Complications of the Kidney and Eye in Diabetes.

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.

AMPK signaling in diabetes mellitus, insulin resistance and diabetic complications: A pre-clinical and clinical investigation.

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 ß 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.