Diabetic Model Research Articles

Precisely Engineering a ROS‐Regulatable Decellularized Matrix to Rejuvenate Endogenous Repair for Heart Valve Remodeling in Diabetic Cohort

AbstractThe reconstruction of a heart valve through in situ tissue engineering remains a formidable challenge, particularly for patients with diabetes mellitus, because the pathophysiological alterations associated with diabetes substantially impair the cardiovascular system's intrinsic repair capacity. In this study, reactive oxygen species (ROS) regulation are integrated into the fabrication of pro‐endothelialization interfaces to counteract the adverse repair environment. Specifically, a heparin‐mimicking alginate‐derived glycopeptide and the natural ROS scavenger melanin are modified onto the surface of a decellularized extracellular matrix (dECM). This tailored interface significantly enhances endothelial cell (EC) adhesion while reducing platelet adhesion. The incorporation of melanin effectively suppresses ROS elevation in ECs and macrophages under hyperglycemic conditions. Consequently, this intervention promotes EC rejuvenation by enhancing proliferation, migration, and anti‐apoptotic capabilities, while concurrently attenuating the release of inflammatory and pro‐fibrotic factors by macrophages. The dECM is intravascularly implanted in a diabetic rabbit model after being fabricated into a covered stent, demonstrating favorable remodeling characteristics such as enhanced endothelialization and reduced fibrotic deposition. This scaffold design, specifically tailored to the pathological conditions of diabetes, offers a precise biomaterial strategy for in situ heart valve tissue engineering.

Effect of cuproptosis on acute kidney injury after cardiopulmonary bypass in diabetic patients

BACKGROUND Cardiopulmonary bypass (CPB) is a common procedure in cardiac surgery. CPB is a high-risk factor for acute kidney injury (AKI), and diabetes is also such a factor. Diabetes can lead to copper overload. It is currently unclear whether AKI after CPB in diabetic patients is related to copper overload. AIM To explore whether the occurrence of CPB-AKI in diabetic patients is associated with cuproptosis. METHODS Blood and urine were collected from clinical diabetic and non-diabetic patients before and after CPB. Levels of copper ion, lactate, glucose, heat shock protein-70 (HSP-70), and dihydrolipoamide dehydrogenase (DLAT) were determined. A diabetic rat model was established and CPB was performed. The rats were assessed for the development of CPB-AKI, and for the association of AKI with cuproptosis by detecting copper levels, iron-sulfur cluster proteins and observation of mitochondrial structure by electron microscopy. RESULTS CPB resulted in elevations of copper, lactate, HSP-70 and DLAT in blood and urine in both diabetic and non-diabetic patients. CPB was associated with pathologic and mitochondrial damage in the kidneys of diabetic rats. Cuproptosis-related proteins also appeared to be significantly reduced. CONCLUSION CPB-AKI is associated with cuproptosis. Diabetes mellitus is an important factor aggravating CPB-AKI and cuproptosis.

Effects of Okinawan wild yam and its component diosgenin on glucose and lipid metabolism in type 2 diabetes model KK-Ay mice

Effects of Okinawan wild yam and its component diosgenin on glucose and lipid metabolism in type 2 diabetes model KK-Ay mice

Don´t give up on mitochondria as a target for the treatment of diabetes and its complications

In this editorial, we discuss an article by Wang et al , focusing on the role of mitochondria in peripheral insulin resistance and insulin secretion. Despite numerous in vitro and pre-clinical studies supporting the involvement of mitochondrial dysfunction and oxidative stress in the pathogenesis of diabetes and its complications, efforts to target mitochondria for glycemic control in diabetes using mitochondria-targeted antioxidants have produced inconsistent results. The intricate functionality of mitochondria is summarized to underscore the challenges it poses as a therapeutic target. While mitochondria-targeted antioxidants have demonstrated improvement in mitochondrial function and oxidative stress in pre-clinical diabetes models, the results regarding glycemic control have been mixed, and no studies have evaluated their hypoglycemic effects in diabetic patients. Nonetheless, pre-clinical trials have shown promising outcomes in ameliorating diabetes-related complications. Here, we review some reasons why mitochondria-targeted antioxidants may not function effectively in the context of mitochondrial dysfunction. We also highlight several alternative approaches under development that may enhance the targeting of mitochondria for diabetes treatment.

TGF-β-mediated crosstalk between TIGIT+ Tregs and CD226+CD8+ T cells in the progression and remission of type 1 diabetes

Type 1 diabetes (T1D) is a chronic autoimmune condition characterized by hyperglycemia resulting from the destruction of insulin-producing β-cells that is traditionally deemed irreversible, but partial remission (PR) with temporary reversal of hyperglycemia is sometimes observed. Here we use single-cell RNA sequencing to delineate the immune cell landscape across patients in different T1D stages. Together with cohort validation and functional assays, we observe dynamic changes in TIGIT+CCR7− Tregs and CD226+CCR7−CD8+ cytotoxic T cells during the peri-remission phase. Machine learning algorithms further identify TIGIT+CCR7− Tregs and CD226+CD8+ T cells as biomarkers for β-cell function decline in a predictive model, while cell communication analysis and in vitro assays suggest that TIGIT+CCR7− Tregs may inhibit CD226+CCR7−CD8+ T cells via TGF-β signaling. Lastly, in both cyclophosphamide-induced and streptozotocin (STZ)-induced mouse diabetes models, CD226 inhibition postpones insulitis onset and reduces hyperglycemia severity. Our results thus identify two interrelated immune cell subsets that may serve as biomarkers for monitoring disease progression and targets for therapeutic intervention of T1D.

MiR-210 as a therapeutic target in diabetes-associated endothelial dysfunction.

MicroRNA (miR)-210 function in endothelial cells and its role in diabetes-associated endothelial dysfunction are not fully understood. We aimed to characterize the miR-210 function in endothelial cells and study its therapeutic potential in diabetes. Two different diabetic mouse models (db/db and Western diet-induced), miR-210 knockout and transgenic mice, isolated vessels and human endothelial cells were used. miR-210 levels were lower in aortas isolated from db/db than in control mice. Endothelium-dependent relaxation (EDR) was impaired in aortas from miR-210 knockout mice, and this was restored by inhibiting miR-210 downstream protein tyrosine phosphatase 1B (PTP1B), mitochondrial glycerol-3-phosphate dehydrogenase 2 (GPD2), and mitochondrial oxidative stress. Inhibition of these pathways also improved EDR in both diabetic mouse models. High glucose reduced miR-210 levels in endothelial cells and impaired EDR in mouse aortas, effects that were reversed by overexpressing miR-210. However, plasma miR-210 levels were not affected in individuals with type 2 diabetes (T2D) following improved glycaemic status. Of note, genetic overexpression using miR-210 transgenic mice and pharmacological overexpression using miR-210 mimic in vivo ameliorated endothelial dysfunction in both diabetic mouse models by decreasing PTP1B, GPD2 and oxidative stress. Genetic overexpression of miR-210 altered the aortic transcriptome, decreasing genes in pathways involved in oxidative stress. miR-210 mimic restored decreased nitric oxide production by high glucose in endothelial cells. This study unravels the mechanisms by which down-regulated miR-210 by high glucose induces endothelial dysfunction in T2D and demonstrates that miR-210 serves as a novel therapeutic target.

Ischemia-induced endogenous Nrf2/HO-1 axis activation modulates microglial polarization and restrains ischemic brain injury.

Cerebral ischemic stroke accounts for more than 80% of all stroke cases. During cerebral ischemia, reactive oxygen species produced in the ischemic brain induce oxidative stress and inflammatory responses. Nrf2 is a transcription factor responsible for regulating cellular redox balance through the induction of protective antioxidant and phase II detoxification responses. Although the induction of endogenous Nrf2/HO-1 axis activation has been observed in the ischemic brain, whether ischemia-induced endogenous Nrf2/HO-1 axis activation plays a role in modulating microglia (MG) phenotypes and restraining ischemic brain injury is not characterized and requires further exploration. To investigate that, we generated mice with Nrf2 knockdown specifically in MG to rigorously assess the role of endogenous Nrf2 activation in ischemic brain injury after stroke. Our results showed that MG-specific Nrf2 knockdown exacerbated ischemic brain injury after stroke. We found that Nrf2 knockdown altered MG phenotypes after stroke, in which increased frequency of inflammatory MG and decreased frequency of anti-inflammatory MG were detected in the ischemic brain. Moreover, we identified attenuated Nrf2/HO-1 axis activation led to increased CD68/IL-1β and suppressed CD206 expression in MG, resulting in aggravated inflammatory MG in MG-specific Nrf2 knockdown mice after stroke. Intriguingly, using type II diabetic preclinical models, we revealed that diabetic mice exhibited attenuated Nrf2/HO-1 axis activation in MG and exacerbated ischemic brain injury after stroke that phenocopy mice with MG-specific Nrf2 knockdown. Finally, the induction of exogenous Nrf2/HO-1 axis activation in MG through pharmacological approaches ameliorated ischemic brain injury in diabetic mice. In conclusion, our findings provide cellular and molecular insights demonstrating ischemia-induced endogenous Nrf2/HO-1 axis activation modulates MG phenotypes and restrains ischemic brain injury. These results further strengthen the therapeutic potential of targeting Nrf2/HO-1 axis in MG for the treatment of ischemic stroke and diabetic stroke.

Wireless, Programmable, and Refillable Hydrogel Bioelectronics for Enhanced Diabetic Wound Healing.

Diabetic wounds, characterized by complex pathogenesis and high infection rates, pose significant challenges in treatment due to prolonged recovery times and high recurrence rates, often leading to severe complications such as amputation and death. Traditional dry dressing treatments fail to address the unique microenvironment of diabetic wounds and tend to cause secondary damage due to frequent replacement. In this study, an electronic-embedding, drug-loading hydrogel bioelectronics is reported for accelerating diabetic wound healing using a combination of programmable pharmaceutical and electrostimulative approaches. Encapsulated in stretchable and biocompatible materials, this device is capable of multiple drug refilling and accelerated drug release modulated by on-board electronics. In vivo experiments on diabetic model rats confirm the device's effectiveness in promoting wound healing. This innovative approach implies the potential for improving diabetic wound management using a combination of physical, material, and pharmaceutical interventions.

Artificial Intelligence in Diabetes Mellitus Prediction: Advancements and Challenges - A Review

Abstract: Poor dietary habits and a lack of understanding are contributing to the rapid global increase in the number of diabetic people. Therefore, a framework that can accurately forecast a large number of patients based on clinical details is needed. Artificial intelligence (AI) is a rapidly evolving field, and its implementations to diabetes, a worldwide pandemic, have the potential to revolutionize the strategy of diagnosing and forecasting this chronic condition. Algorithms based on artificial intelligence fundamentals have been developed to support predictive models for the risk of developing diabetes or its complications. In this review, we will discuss AI-based diabetes prediction. Thus, AI-based new-onset diabetes prediction has not beaten the statistically based risk stratification models, in traditional risk stratification models. Despite this, it is anticipated that in the near future, a vast quantity of well-organized data and an abundance of processing power will optimize AI's predictive capabilities, greatly enhancing the accuracy of diabetic illness prediction models.

Ferric Iron/Shikonin Nanoparticle-Embedded Hydrogels with Robust Adhesion and Healing Functions for Treating Oral Ulcers in Diabetes.

Oral ulcers can be addressed using various biomaterials designed to deliver medications or cytokines. Nevertheless, the effectiveness of these substances is frequently limited in many patients due to poor adherence, short retention time in the mouth, and less-than-optimal drug efficacy. In this study, a new hydrogel patch (FSH3) made of a silk fibroin/hyaluronic acid matrix with light-sensitive adhesive qualities infused with ferric iron/shikonin nanoparticles to enhance healing effects is presented. Initially, this hydrogel forms an adhesive barrier over mucosal lesions through a straightforward local injection, solidifying when exposed to UV light. Subsequently, FSH3 demonstrates superior reactive oxygen species elimination and near-infrared photothermal bactericidal activity. These characteristics support bacterial elimination and regulate oxidative levels, promoting a wound's progression from inflammation to tissue regeneration. In a diabetic rat model mimicking oral ulcers, FSH3 significantly speeds up healing by adjusting the inflammatory environment of the injured tissue, maintaining balance in oral microbiota, and promoting faster re-epithelialization. Overall, the light-sensitive FSH3 hydrogel shows potential for rapid wound recovery and may transform therapeutic methods for managing oral ulcers in diabetes.

Ferroptosis-associated alterations in diabetes following ischemic stroke: Insights from RNA sequencing

ObjectiveFerroptosis is an iron-dependent form of programmed cell death associated with lipid peroxidation. Though diabetes worsens cerebral injury and clinical outcomes in stroke, it is poorly understood whether ferroptosis contributes to diabetes-exacerbated stroke. This study aimed to identify ferroptosis-associated differentially expressed genes in ischemic stroke under diabetic condition and then explore their roles using comprehensive bioinformatics analyses. MethodsType 1 diabetes (T1D) model was established in male mice at 8–10 weeks of age by one intraperitoneal injection of streptozotocin (110 mg/kg). Ischemic stroke was induced by a transient 45-minute middle cerebral artery occlusion and evaluated three days thereafter. Ischemic brain cortex was dissected 24 h after the reperfusion and subjected to bulk tissue RNA sequencing followed by bioinformatics analysis and verification of key findings via quantitative real-time PCR. ResultsEnlarged infarct size was seen in diabetic, as compared with non-diabetic mice, in conjunction with worsened neurological behaviors. Both body and spleen weights were reduced in diabetic as compared with non-diabetic mice. There was a trend for reduced survival rate in diabetic mice following the stroke. In RNA sequencing analysis, we identified 1299 differentially expressed genes in ischemic brain between diabetic and non-diabetic mice, with upregulation and downregulation for 732 and 567 genes, respectively. Among these genes, 27 genes were associated with ferroptosis. Further analysis reveals that solute carrier family 25 member 28(SLC25A28) and sterol carrier protein 2(SCP2) were the top genes associated with ferroptosis in diabetic mice following ischemic stroke. In several bioinformatics analyses, we found SLC25A28, one of the top ferroptosis-related genes, is involved in several metabolic and regulatory pathways as well as the regulatory complexity of microRNAs and circular RNAs, which demonstrates the potential role of SLC25A28 in diabetes-exacerbated stroke. Drug network analysis suggests SLC25A28 as a potential therapeutic target for ameliorating ischemic injury in diabetes. ConclusionsOur bulk RNA sequencing and bioinformatics analyses show that altered ferroptosis signaling pathway was associated with the exacerbation of experimental stroke injury under diabetic condition. Especially, additional investigation into the mechanisms of SLC25A28 and SCP2 in diabetes-exacerbated stroke will be explored in the future study.

Collaborative Enhancement of Diabetic Wound Healing and Skin Regeneration by Recombinant Human Collagen Hydrogel and hADSCs.

Stem cell-based therapies hold significant promise for chronic wound healing and skin appendages regeneration, but challenges such as limited stem cell lifespan and poor biocompatibility of delivery systems hinder clinical application. In this study, an in situ delivery system for human adipose-derived stem cells is developed (hADSCs) to enhance diabetic wound healing. The system utilizes a photo-crosslinking recombinant human type III collagen (rHCIII) hydrogel to encapsulate hADSCs, termed the hADSCs@rHCIII hydrogel. This hydrogel undergoes local crosslinking at the wound site, establishing a sturdy 3D niche suitable for stem cell function. Consequently, the encapsulated hADSCs exhibit strong attachment and spreading within the hydrogels, maintaining their proliferation, metabolic activity, and viability for up to three weeks in vitro. Importantly, in vivo studies demonstrate that the hADSCs@rHCIII hydrogel achieves significant in situ delivery of stem cells, prolonging their retention within the wound. This ultimately enhances their immunomodulatory capabilities, promotes neovascularization and granulation tissue formation, facilitates matrix remodeling, and accelerates healing in a diabetic mouse wound model. Collectively, these findings highlight the potential of the conveniently-prepared and user-friendly hADSCs@rHCIII hydrogel as a promising therapeutic approach for diabetic wound treatment and in situ skin regeneration.

Effect of Abelmoschus esculentus L. (Okra) on Dyslipidemia: Systematic Review and Meta-Analysis of Clinical Studies.

The global prevalence of cardiovascular diseases (CVDs), including dyslipidemia and atherosclerosis, is rising. While pharmacological treatments for dyslipidemia and associated CVDs exist, not all individuals can afford them, and those who do often experience adverse side effects. Preclinical studies have indicated the potential benefits of Abelmoschus esculentus and its active phytochemicals in addressing dyslipidemia in rodent models of diabetes. However, there is limited clinical evidence on lipid parameters. Thus, this study aimed to assess the potential impact of Abelmoschus esculentus on dyslipidemia. A literature search was performed on PubMed, Scopus, and Cochrane Library for relevant trials published from inception until 11 August 2024. Data analysis was performed using Jamovi software version 2.4.8 and Review Manager (version 5.4), with effect estimates reported as standardized mean differences (SMDs) and 95% confidence intervals (CI). The evidence from eight studies with nine treatment arms showed that Abelmoschus esculentus reduces total cholesterol (TC), SMD = -0.53 (95% CI: -1.00 to -0.07), p = 0.025), compared to placebo. Additionally, triglyceride (TG) was reduced in Abelmoschus esculentus compared to placebo, SMD = -0.24 (95% CI: -0.46 to -0.02), p = 0.035. Furthermore, low-density lipoprotein (LDL) was also reduced, SMD = -0.35 (95% CI: -0.59 to -0.11), p = 0.004 in Abelmoschus esculentus versus placebo. This remedy substantially increased high-density lipoprotein (HDL), SMD = 0.34 (95% CI: 0.07 to 0.61), p = 0.014). Abelmoschus esculentus substantially improved lipid profile in prediabetes, T2D, obesity, and diabetic nephropathy. While the evidence confirms the potential benefits of Abelmoschus esculentus in reducing dyslipidemia, it is important for future clinical studies to standardize the effective dosage for more reliable results. Therefore, future trials should focus on these markers in well-designed trials with sufficient sample sizes. Furthermore, Abelmoschus esculentus can be supplemented to the diet of the relevant populations to alleviate dyslipidemia.

Protective Potential of Cicerbita alpina Leaf Extract on Metabolic Disorders and Oxidative Stress in Model Animals.

Metabolic disorders (MDs) include disease states such as diabetes mellitus, obesity, dyslipidemia, hyperuricemia, etc., affecting about 30% of the planet's population. The purpose of the present study was to investigate the protective potential of Cicerbita alpina leaf extract (ECA) against chemically induced type 2 diabetes in Wistar rats. Additionally, some biochemical parameters in the blood serum and liver, as well as histopathological investigation, were also performed. Quantitative analysis of the major compounds in the used extract was performed using ultrahigh-performance liquid chromatography-diode array detection (UHPLC-DAD) analyses using the external standard method. C. alpina extract revealed a beneficial effect on MDs, lowering blood sugar levels and MDA quantity in the liver, increasing the reduced glutathione level, and increasing antioxidant enzyme activity. Cichoric acid (CA) (91.93 mg/g dry extract (de) ± 4.64 mg/g de) was found to be the dominant compound in the extract, followed by caftaric (11.36 ± 2.10 mg/g de), and chlorogenic acid (CGA) (9.25 ± 0.05 mg/g de). In conclusion, C. alpina leaf extract (ECA) is rich in caffeoyltartaric and caffeoylquinic acids and provides beneficial effects on the diabetic animal model.

Zinc-based Polyoxometalate Nanozyme Functionalized Hydrogels for optimizing the Hyperglycemic-Immune Microenvironment to Promote Diabetic Wound Regeneration.

In diabetic wounds, hyperglycemia-induced cytotoxicity and impaired immune microenvironment plasticity directly hinder the wound healing process. Regulation of the hyperglycemic microenvironment and remodeling of the immune microenvironment are crucial. Here, we developed a nanozymatic functionalized regenerative microenvironmental regulator (AHAMA/CS-GOx@Zn-POM) for the effective repair of diabetic wounds. This novel construct integrated an aldehyde and methacrylic anhydride-modified hyaluronic acid hydrogel (AHAMA) and chitosan nanoparticles (CS NPs) encapsulating zinc-based polymetallic oxonate nanozyme (Zn-POM) and glucose oxidase (GOx), facilitating a sustained release of release of both enzymes. The GOx catalyzed glucose to gluconic acid and (H₂O₂), thereby alleviating the effects of the hyperglycemic microenvironment on wound healing. Zn-POM exhibited catalase and superoxide dismutase activities to scavenge reactive oxygen species and H₂O₂, a by-product of glucose degradation. Additionally, Zn-POM induced M1 macrophage reprogramming to the M2 phenotype by inhibiting the MAPK/IL-17 signaling diminishing pro-inflammatory cytokines, and upregulating the expression of anti-inflammatory mediators, thus remodeling the immune microenvironment and enhancing angiogenesis and collagen regeneration within wounds. In a rat diabetic wound model, the application of AHAMA/CS-GOx@Zn-POM enhanced neovascularization and collagen deposition, accelerating the wound healing process. Therefore, the regenerative microenvironment regulator AHAMA/CS-GOx@Zn-POM can achieve the effective conversion of a pathological microenvironment to regenerative microenvironment through integrated control of the hyperglycemic-immune microenvironment, offering a novel strategy for the treatment of diabetic wounds.

Evaluating the World Health Organization's HEARTS Model for Hypertension and Diabetes Management: A Pilot Implementation Study in Guatemala.

The World Health Organization HEARTS Technical Package is a widely implemented global initiative to improve the primary care management of cardiovascular disease risk factors. The study's objective is to report outcomes from a pilot implementation trial of integrated hypertension and diabetes management based on the HEARTS model in Guatemala. We conducted a single-arm pilot implementation trial over 6 months from October 2023 to May 2024 in 11 Guatemalan Ministry of Health primary care facilities in two districts. The pilot evaluated a package of five HEARTS-aligned implementation strategies to improve the pharmacological treatment of hypertension and diabetes. The primary outcomes were feasibility and acceptability, measured through 20 structured interviews with Ministry of Health employees and by examining enrollment and retention. Secondary outcomes included a suite of implementation and clinical outcomes, including treatment rate. The study enrolled 964 patients, of whom 58.8% had hypertension only, 30.4% had diabetes only, and 10.8% had both conditions. Surveys on feasibility and acceptability among Ministry of Health staff had a median score of 5.0 (IQR: 5.0 to 5.0) and 5.0 (IQR range: 4.8 to 5.0), respectively, exceeding the prespecified benchmark of ≥3.5. Both districts achieved the prespecified benchmark of enrolling ≥25 hypertension patients and ≥25 diabetes patients. Only 36% of patients attended a follow-up visit within three months, lower than the prespecified benchmark of ≥75%. M treatment rates during the pilot increased by 22.3 (95% CI: 16.2 to 28.4; P<0.001) and 3.5 (95% CI: -1.6 to 8.7; P=0.17) patients per month for hypertension and diabetes, respectively. Implementation of an integrated hypertension and diabetes model based on HEARTS was generally feasible and acceptable in the Ministry of Health in Guatemala. Findings can refine national scale-up in Guatemala and inform HEARTS implementation projects in other settings.

SGLT2i and GLP1-RA exert additive cardiorenal protection with a RAS blocker in uninephrectomized db/db mice.

Diabetic Kidney Disease (DKD) is the main cause of end-stage renal disease in the developed world. The current treatment of the DKD with renin-angiotensin system (RAS) blockade does not totally halt the progression to end stage kidney disease. Currently, several drugs have shown to delay DKD progression such as sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like-1 receptor agonists (GLP-1RA). We hypothesized that by combining several drugs that prevent DKD progression on top of RAS blockade a synergistic effect would be achieved in terms of cardiorenal protection. In the present study, we analysed if the combination of a RAS blocker (ramipril) with a SGLT2i (empagliflozin) and/or GLP-1RA (semaglutide) in a type 2 diabetic mouse model could have add-on effects in kidney and heart protection. Male and female uninephrectomized type 2 diabetic db/db mice were treated with empagliflozin and/or semaglutide on top of ramipril during 8weeks. During the study body weight, water and food intake were weekly monitored, glycaemia biweekly and albuminuria and glomerular filtration rate (GFR) before and after the treatment. At the end of the experiment, kidney and heart were isolated for histological and gene expression studies as well as for intrarenal RAS state assessment. Semaglutide combined with ramipril and/or empagliflozin significantly decreased albuminuria but only when combined with both compounds, semaglutide further decreased blood glucose, glomerular hyperfiltration in male mice and glomerular mesangial matrix expansion. In kidney, only the triple treatment with empagliflozin, semaglutide and ramipril reduced the expression of the proinflammatory and profibrotic genes ccl2 and TGFß1. In addition, the combination of empagliflozin and semaglutide on top of RAS blockade was superior in decreasing cardiomyocyte hypertrophy and heart fibrosis in db/db mice. Our results suggest that the combination of SGLT2i with GLP-1RA is superior in cardiorenal protection in DKD than the drugs administered alone on top of RAS blockade.

O-GlcNAcylation of circadian clock protein Bmal1 impairs cognitive function in diabetic mice.

Neuronal damage in the hippocampus induced by high glucose has been shown to promote the onset and development of cognitive impairment in diabetes, but the underlying molecular mechanism remains unclear. Guided by single-cell RNA sequencing, we here report that high glucose increases O-GlcNAcylation of Bmal1 in hippocampal neurons. This glycosylation promotes the binding of Clock to Bmal1, resulting in the expression of transcription factor Bhlhe41 and its target Dnajb4. Upregulated Dnajb4 in turn leads to ubiquitination and degradation of the mitochondrial Na + /Ca2+ exchanger NCLX, thereby inducing mitochondrial calcium overload that causes neuronal damage and cognitive impairment in mice. Notably, Bhlhe41 downregulation or treatment with a short peptide that specifically blocks O-GlcNAcylation of Bmal1 on Ser424 mitigated these adverse effects in diabetic mouse models. These data highlight the crucial role of O-GlcNAcylation in circadian clock gene expression and may facilitate the design of targeted therapies for diabetes-associated cognitive impairment.

Chronic hyperglycemia alters retinal astrocyte microstructure and uptake of cholera toxin B in a murine model of diabetes.

Astrocytes are the principle glial cells of the central nervous system and play an active role in maintaining proper metabolism in surrounding neurons. Because of their involvement in metabolic control, it is likely that their physiology changes in response to metabolic diseases such as diabetes and associated diabetic retinopathy. Here, we investigated whether microstructural changes in astrocyte morphology occur during the early stages of chronic hyperglycemia that may be indicative of early pathogenic programs. We used MORF3 mice in conjunction with streptozotocin-induced hyperglycemia to investigate the morphology of single retinal astrocytes at an early timepoint in diabetic disease. We report that astrocytes initiate a morphological remodeling program, which depends on both the glycemic background and the presence of intravitreal injury, to alter the amount of the neuronal-associated pad and bristle microstructural motifs. Additionally, hyperglycemia increases astrocyte uptake of cholera toxin B, possibly reflecting changes in glycolipid and glycoprotein biosynthesis. Chronic hyperglycemia coupled with intravitreal injection of cholera toxin B also causes extensive leukocyte infiltration into the retina. Our results have important clinical relevance as current therapies for diabetic retinopathy involve intravitreal injection of pharmaceuticals in individuals with often poorly controlled blood glucose levels.

Ameliorative effects of Penthorum chinense Pursh on insulin resistance and oxidative stress in diabetic obesity db/db mice.

Penthorum chinense Pursh (PCP), a medicinal and edible plant, has been reported to protect against liver damage by suppressing oxidative stress. Type 2 diabetes mellitus (T2DM) is associated with liver dysfunction and oxidative stress. In the present study, we aim to investigate the hypoglycemic effect of PCP on db/db mice and further explore the underlying mechanisms. Thirty-two db/db mice were randomized into four groups, including a diabetic model control group (MC) and three diabetic groups treated with low (LPCP, 300 mg/kg/d), medium (MPLP, 600 mg/kg/d), and high doses of PCP (HPCP, 1200 mg/kg/d), and the normal control group (NC) of eight db/m mice were included. Mice in the NC and MC groups received the ultrapure water. After four weeks of intervention, parameters of fasting blood glucose (FBG), insulin resistance (IR), blood lipid levels, hepatic oxidative stress, and enzymes related to hepatic glucose metabolism were compared in the groups. PCP administration significantly reduced FBG and IR in diabetic db/db mice, and improved hepatic glucose metabolism by increasing glucose transporter 2 (GLUT2) and glucokinase (GCK) protein expression. Meanwhile, PCP supplementation ameliorated hepatic oxidative stress by decreasing malonaldehyde content and increasing the activities of superoxide dismutase and glutathione peroxidase in db/db mice. Furthermore, PCP treatment reduced obesity and food intake in db/db mice, and improved dyslipidemia demonstrated by increasing high-density lipoprotein cholesterol (HDL-C) while decreasing total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (HDL-C). All doses of PCP treatment decreased the values of LDL-C/HDL-C in a dose-response relationship. PCP significantly alleviated hyperglycemia, hyperinsulinemia, hyperlipidemia, and obesity, inhibited hepatic oxidative stress, and enhanced hepatic glucose transport in T2DM mice. Based on the above findings, the hypoglycemic effect of PCP may be attributed to the activation of the GLUT2/GCK expression in the liver and the reduction of hepatic oxidative stress.