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Diabetes mellitus (DM) and atrial fibrillation (AF) are major unsolved public health problems, and diabetes is an independent risk factor for AF. However, the mechanism(s) underlying this clinical association is unknown. ROS and protein O-GlcNAcylation (OGN) are increased in diabetic hearts, and calmodulin kinase II (CaMKII) is a proarrhythmic signal that may be activated by ROS (oxidized CaMKII, ox-CaMKII) and OGN (OGN-CaMKII). We induced type 1 (T1D) and type 2 DM (T2D) in a portfolio of genetic mouse models capable of dissecting the role of ROS and OGN at CaMKII and global OGN in diabetic AF. Here, we showed that T1D and T2D significantly increased AF, and this increase required CaMKII and OGN. T1D and T2D both required ox-CaMKII to increase AF; however, we did not detect OGN-CaMKII or a role for OGN-CaMKII in diabetic AF. Collectively, our data affirm CaMKII as a critical proarrhythmic signal in diabetic AF and suggest ROS primarily promotes AF by ox-CaMKII, while OGN promotes AF by a CaMKII-independent mechanism(s). These results provide insights into the mechanisms for increased AF in DM and suggest potential benefits for future CaMKII and OGN targeted therapies.

Background Diabetes mellitus (DM) is a key contributing factor to poor survival in lung transplantation recipients. Mitochondrial dysfunction is recognized as a critical mediator in the pathogenesis of diabetic lung ischemia–reperfusion (IR) injury. The protective effects of adiponectin have been demonstrated in our previous study, but the underlying mechanism remains unclear. Here we demonstrated an important role of mitophagy in the protective effect of adiponectin during diabetic lung IR injury. Methods High-fat diet-fed streptozotocin-induced type 2 diabetic rats were exposed to adiponectin with or without administration of the SIRT1 inhibitor EX527 following lung transplantation. To determine the mechanisms underlying the action of adiponectin, rat pulmonary microvascular endothelial cells were transfected with SIRT1 small-interfering RNA or PINK1 small-interfering RNA and then subjected to in vitro diabetic lung IR injury. Results Mitophagy was impaired in diabetic lungs subjected to IR injury, which was accompanied by increased oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction. Adiponectin induced mitophagy and attenuated subsequent diabetic lung IR injury by improving lung functional recovery, suppressing oxidative damage, diminishing inflammation, decreasing cell apoptosis, and preserving mitochondrial function. However, either administration of 3-methyladenine (3-MA), an autophagy antagonist or knockdown of PINK1 reduced the protective action of adiponectin. Furthermore, we demonstrated that APN affected PINK1 stabilization via the SIRT1 signaling pathway, and knockdown of SIRT1 suppressed PINK1 expression and compromised the protective effect of adiponectin. Conclusion These data demonstrated that adiponectin attenuated reperfusion-induced oxidative stress, inflammation, apoptosis and mitochondrial dysfunction via activation of SIRT1- PINK1 signaling-mediated mitophagy in diabetic lung IR injury.

Objective Increasing evidence highlights the critical role of Piezo1 in cardiovascular diseases, with its expression upregulated in diabetic heart. However, the involvement of Piezo1 in the pathogenesis of diabetic cardiomyopathy (DCM) remains unclear. This study aims to elucidate the regulatory role of Piezo1 in mitochondrial dynamics within the context of DCM and to investigate the underlying mechanisms. Methods We constructed cardiac-specific knockout of Piezo1 ( Piezo1 ∆Myh6 ) mice. Type 1 diabetes was induced using streptozotocin (STZ) injection while type 2 diabetes was established through a high-fat diet combined with STZ. Echocardiography assessed left ventricular function, histological evaluations used HE and Masson staining to examine cardiac pathology in Piezo1 fl/fl controls, Piezo1 ∆Myh6 controls, Piezo1 fl/fl diabetic and Piezo1 ∆Myh6 diabetic mice. Mitochondrial function including oxygen species level, mitochondrial morphology, and respiration rate were also assessed. Results Our findings revealed that Piezo1 expression was upregulated in the myocardium of diabetic mice and in high-glucose-treated cells. Cardiac-specific knockout of Piezo1 improved cardiac dysfunction and ameliorated cardiac fibrosis in diabetic mice. Moreover, Piezo1 deficiency also attenuated mitochondrial impairment. Piezo1 fl/fl diabetic mice exhibited increased calpain activity and excessive mitochondrial fission mediated by Drp1 and obvious reduced fusion; however, Piezo1 deficiency restored calpain levels and mitochondrial dysfunction. These observations were also corroborated in H9C2 cells and neonatal mouse cardiomyocytes. Cardiac-specific knockout of Piezo1 increased phosphorylation of Drp1 and ERK1/2 in vivo and in vitro. Piezo1 knockout or treatment with inhibitor improved mitochondrial function. Conclusions This study provides the first evidence that Piezo1 is elevated in DCM through the modulation of mitochondrial dynamics, which is reversed by Piezo1 deficiency. Thus, Piezo1 inhibition may provide a promising therapeutic strategy for the treatment of DCM. Graphic abstract In cardiomyocytes of Piezo1 fl / fl DCM mice, increased Ca 2+ entry upregulates calpain activity, and phosphorylated level of ERK1/2 and Drp1. Therefore, increased mitochondrial fission is shown in DCM hearts. Whereas, cardiomyocyte-specific knockout of Piezo1 alleviates mitochondrial dysfunction.

Integrin β1 and dipeptidyl peptidase (DPP)-4 play roles in endothelial cell biology. Vascular endothelial growth factor (VEGF)-A inhibits endothelial-to-mesenchymal transition (EndMT) through VEGF-R2, but through VEGF-R1 promotes EndMT by reducing the bioavailability of VEGF-A. Here we tested whether DPP-4-integrin β1 interactions have a role in EndMT in the renal fibrosis of diabetic nephropathy. In streptozotocin-induced fibrotic kidneys in diabetic CD-1 mice, levels of endothelial DPP-4, integrin β1, and phospho-integrin β1 were all higher and associated with plasma cystatin C elevation. The DPP-4 inhibitor linagliptin ameliorated kidney fibrosis, reduced plasma cystatin C levels, and suppressed endothelial levels of DPP-4, integrin β1, and phospho-integrin β1. In cultured endothelial cells, DPP-4 and integrin β1 physically interacted. Suppression of DPP-4 by siRNA was associated with suppression of integrin β1 and vice versa. Knockdown of either integrin β1 or DPP-4 resulted in the silencing of TGF-β2-induced TGF-β receptor heterodimer formation, smad3 phosphorylation, and EndMT. DPP-4 negatively regulated endothelial viability signaling by VEGF-R2 suppression and VEGF-R1 induction in endothelial cells. Thus, DPP-4 and integrin β1 interactions regulate key endothelial cell signal transduction in both physiological and pathological conditions including EndMT. Hence, inhibiting DPP-4 may be a therapeutic target for treating kidney fibrosis in diabetes.

Cardiovascular diseases such as myocardial ischaemia have a high fatality rate in patients with diabetes. This study was designed to expose the crosstalk between oxidative stress and AMPK, a vital molecule that controls biological energy metabolism, in myocardial ischaemia reperfusion injury (I/RI) in diabetic rats. Diabetes was stimulated in rats using streptozotocin injection. Rats were separated on random into control, control + I/R, Diabetes, Diabetes + I/R, Diabetes + I/R + N‐acetylcysteine and Diabetes + I/R + Vas2870 groups. Myocardial infarct size was determined, and the predominant Nox family isoforms were analysed. In vitro, the H9C2 cells were administered excess glucose and exposed to hypoxia/reoxygenation to mimic diabetes and I/R. The AMPK siRNA or AICAR was used to inhibit or activate AMPK expression in H9C2 cells, respectively. Then, myocardial oxidative stress and programmed cell death were measured. Diabetes or high glucose levels were found to aggravate myocardial I/RI or hypoxia/reoxygenation in H9C2 cells, as demonstrated by an increase in myocardial infarct size or lactate dehydrogenase levels, oxidative stress generation and induction of programmed cell death. In diabetic rat hearts, cardiac Nox1, Nox2 and Nox4 were all heightened. The suppression of Nox2 expression using Vas2870 or Nox2‐siRNA treatment in vivo or in vitro, respectively, protected diabetic rats from myocardial I/RI. AMPK gene knockout increased Nox2 protein expression while AMPK agonist decreased Nox2 expression. Therefore, diabetes aggravates myocardial I/RI by generating of Nox2‐associated oxidative stress in an AMPK‐dependent manner, which led to the induction of programmed cell death such as apoptosis, pyroptosis and ferroptosis.

Aims Diabetes is a leading cause of mortality worldwide, primarily due to cardiovascular diseases (CVD). Arterial stiffness is a CVD predictor and is associated with increased mortality in diabetic individuals. In diabetes, the formation and accumulation of methylglyoxal (MGO), a highly reactive glycolysis by product and a major precursor in advanced glycation endproducts (AGEs) formation, has been implicated in CVD. In this study, we investigated the role of endogenous MGO in arterial stiffening in a mouse model of type 1 diabetes (T1D) overexpressing the MGO-detoxifying enzyme glyoxalase-1 ( GLO1 ). Methods and results Diabetes was induced in C57BL/6 J mice through 5-day streptozotocin injections. 17-week-old control, diabetic, and GLO1 -overexpressing diabetic mice were used. Fasting glucose in diabetes and GLO1 /diabetes was higher than control. Plasma, urine, and aortic MGO, AGEs, and cross-links were determined using ultra-performance liquid chromatography tandem mass spectrophotometry. MGO was increased in plasma and urine in diabetic mice, while GLO1 decreased MGO in urine. The AGE cross-link pentosidine in aorta was increased in diabetes and ameliorated by GLO1 . Tail-cuff blood pressure and carotid-femoral pulse wave velocity were measured preceding euthanasia, and did not differ between groups. Descending thoracic aorta ex vivo passive biaxial arterial wall biomechanics were measured and diabetes showed elevated ex vivo PWV, which was attenuated by GLO1 overexpression. Material viscoelasticity was decreased in diabetes and normalised by GLO1 overexpression. Second harmonic generation imaging demonstrated a predominant axial orientation of diabetic collagen fibres, while GLO1 /diabetes led to a uniform orientation. When comparing GLO1/diabetes and diabetes, bulk RNA sequencing revealed 137 differentially expressed genes affecting extracellular matrix organisation, cell–cell and cell–matrix communication and interaction pathways. Conclusion In an animal model of T1D, GLO1 overexpression attenuates arterial stiffening at the underlying material levels, by modifying collagen ultrastructure and viscoelastic properties. Targeting MGO may provide a novel approach to prevent arterial T1D stiffening. Graphical abstract

Recent genome-wide association studies (GWAS) identified DUSP8, encoding a dual-specificity phosphatase targeting mitogen-activated protein kinases, as a type 2 diabetes (T2D) risk gene. Here, we reveal that Dusp8 is a gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male, but not female, Dusp8 loss-of-function mice, either with global or corticotropin-releasing hormone neuron-specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic-pituitary-adrenal axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of obese male Dusp8-KO mice, respectively. The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity, and systemic glucose tolerance was consistent with functional MRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. Further, expression of DUSP8 was increased in the infundibular nucleus of T2D humans. In summary, our findings suggest the GWAS-identified gene Dusp8 as a novel hypothalamic factor that plays a functional role in the etiology of T2D.

Withania frutescens L. is a wild perennial woody plant used by the local population for diverse therapeutic purposes. This work aims to study for the first time the potential inhibitory effect of this plant hydroethanolic extract on α-amylase and α-glucosidase activities using in vitro methods and its antidiabetic and antihyperglycemic activities using alloxan-induced diabetic mice as a model for experimental diabetes. Two doses were selected for the in vivo study (200 and 400 mg/kg) and glibenclamide, a well-known antidiabetic drug (positive control) in a subacute study (28 days) where the antihyperglycemic activity was also assessed over a period of 12 h on diabetic mice. The continuous treatment of diabetic mice with the extract of Withania frutescens for 4 weeks succeeded to slowly manage their high fasting blood glucose levels (after two weeks), while the antihyperglycemic test result revealed that the extract of this plant did not control hyperglycemia in the short term. No toxicity signs or death were noted for the groups treated with the plant extract, and it shows a protective effect on the liver and kidney. The in vitro assays demonstrated that the inhibition of alpha-amylase and alpha-glucosidase might be one of the mechanisms of action exhibited by the extract of this plant to control and prevent postprandial hyperglycemia. This work indicates that W. frutescens have an important long term antidiabetic effect that can be well established to treat diabetes.

Background Impaired Ca 2+ handling is involved in diabetic cardiomyopathy (DCM) progression. The activation of acid sphingomyelinase (ASMase) stimulated cardiomyocytes apoptosis and caused DCM. Here, we aimed to investigate whether ASMase regulates mitochondrial Ca 2+ homeostasis by acting on mitochondrial calcium uptake 1 (MICU1) and mitochondria-associated endoplasmic reticulum membranes (MAMs) formation to induce apoptosis during DCM. Methods and results We established a type 2 diabetes model by combining high-fat diet (HFD) with streptozotocin (STZ) injection in wild-type and cardiomyocyte-specific ASMase deletion (ASMase Myh6KO ) mice. ASMase deletion restored HFD/STZ-induced cardiac dysfunction, remodeling, myocardial lipid accumulation and apoptosis. Single cell sequencing and Gene ontology (GO) enrichment analysis pointed to “cardiac muscle contraction” and “positive regulation of mitochondrial calcium ion concentration”, which were confirmed by high glucose (HG, 30 mM) and palmitic acid (PA, 200 μM) induced mitochondrial Ca 2+ overload in H9c2 cell lines at time dependence, accompanied by the upregulation of ASMase and MICU1 protein expressions. The similar effects were noted in ASMase overexpressed cardiomyocytes. Interestingly, endoplasmic reticulum (ER) Ca 2+ level was decreased at the corresponding time, suggesting that increased mitochondrial Ca 2+ level may be derived from ER. Notably, enhanced MAMs formation was found in HG + PA treated H9c2 cells, accompanied by blocked autophagy, similar results were obtained in ASMase overexpressing cells or HFD/STZ hearts. Loss of ASMase prevented HFD/STZ or HG + PA incubation induced cardiac hypertrophy, mitochondrialCa 2+ overload, ROS production, autophagy blockage and MICU1 upregulation. Conclusions HFD/STZ-induced ASMase upregulation enhances MAMs formation, promoting mitochondrial Ca 2+ overload through MICU1 activation, leading to ROS generation, autophagy blockage and apoptosis in DCM. Therefore, targeting ASMase-MICU1 pathway emerges as a potential therapeutic approach for managing DCM. Graphical Abstract

The antidiabetic activity of two low doses of Moringa seed powder (50 and 100 mg/kg body weight, in the diet) on streptozotocin (STZ) induced diabetes male rats was investigated. Forty rats were divided into four groups. The diabetic positive control (STZ treated) group showed increased lipid peroxide, increased IL-6, and decreased antioxidant enzyme in the serum and kidney tissue homogenate compared with that of the negative control group. Immunoglobulins (IgA, IgG), fasting blood sugar, and glycosylated hemoglobin ( H b A 1 c ) were also increased as a result of diabetes in G2 rats. Moreover albumin was decreased, and liver enzymes and α-amylase were not affected. In addition, the renal functions and potassium and sodium levels in G2 were increased as a sign of diabetic nephropathy. Urine analysis showed also glucosuria and increased potassium, sodium, creatinine, uric acid, and albumin levels. Kidney and pancreas tissues showed also pathological alteration compared to the negative control group. Treating the diabetic rats with 50 or 100 mg Moringa seeds powder/kg body weight in G3 and G4, respectively, ameliorated the levels of all these parameters approaching the negative control values and restored the normal histology of both kidney and pancreas compared with that of the diabetic positive control group.