Bone-Differentiation-Associated Circ-Spen Regulates Death of Mouse Bone Marrow Mesenchymal Stem Cells by Inhibiting Apoptosis and Promoting Autophagy.

The role of estrogen receptor ß (ERß) in bone health is closely associated with its function in vivo, and ERß-/- mice have been widely utilized to explore the related influences. In this study, ERß-/- female mice were established to investigate the differential expression of circular RNAs (circRNAs) by RNA-Sequencing (RNA-Seq). Among these circRNAs, mmu_circ_0011379 (named Circ-Spen) exhibited high expression in ERß-/- female mice. However, the precise mechanism by which Circ-Spen regulates bone health remained unclear. This study identified Circ-Spen as a positive regulator of mouse bone marrow mesenchymal stem cell (mBMSC) viability. The expression of Circ-Spen was markedly increased in ERß-/- mice femurs tested by RT-qPCR. Moreover, Circ-Spen exhibited an enhanced expression during the bone formation process of mBMSCs. Qualitative experiments also demonstrated that Circ-Spen possessed a circular structure and was localized within the nucleus of mBMSCs. Functionally, it inhibited apoptosis via caspase-3, BCL-2, and BAX, while also promoting autophagy through BECN1 and P62 in mBMSCs tested by MTT assays, transmission electron microscopy (TEM), and Western blotting. These findings reveal the potential of targeting Circ-Spen as a promising therapeutic strategy for rejuvenating senescent mBMSCs and enhancing the efficiency of mBMSC transplantation, which lays the foundation for advancements in the field of bone therapy.

TGFBR3 supports anoikis through suppressing ATF4 signaling.

Epithelial morphogenesis and oncogenic transformation can cause loss of cell adhesion, and detached cells are eliminated by anoikis. Here, we reveal that transforming growth factor ß receptor 3 (TGFBR3) acts as an anoikis mediator through the coordination of activating transcription factor 4 (ATF4). In breast cancer tissues, TGFBR3 is progressively lost, but elevated TGFBR3 is associated with a histologic subtype characterized by cellular adhesion defects. Dissecting the impact of extracellular matrix (ECM) deprivation, we demonstrate that ECM loss promotes TGFBR3 expression, which in turn causes differentiation of cell aggregates, conferring a low-adhesion phenotype, and drives the intrinsic apoptotic pathway. We demonstrate that inhibition of TGFBR3 impairs epithelial anoikis by activating ATF4 signaling. These preclinical findings provide a rationale for therapeutic inhibition of ATF4 in the subgroup of breast cancer patients with low TGFBR3 expression.

Sex Differences in Type 2 Diabetes Mellitus-Related Left Ventricular Remodeling: A Cardiovascular Magnetic Resonance Study.

Background: The purpose of this study was to evaluate the sex differences in myocardial structure, tissue characteristics, and myocardial function in type 2 diabetes mellitus (T2DM) patients. Methods: A total of 62 T2DM patients and 40 controls were prospectively recruited for the study. All the participants were scanned using cardiovascular magnetic resonance (CMR) cine and underwent native and postcontrast T1 mapping to obtain left ventricular (LV) structure, function, and tissue characteristics. The differences between the control and T2DM patients were compared in males and females, respectively. Results: For myocardial structure, T2DM was associated with a larger ratio of myocardial mass to end-diastolic volume (MVR, T2DM: 0.87 ± 0.20 vs. controls: 0.73 ± 0.14, p = 0.008) and thicker wall thickness (WT, T2DM: 6.5 ± 1.1 mm vs. controls: 5.6 ± 1.0 mm, p = 0.002) in females. For tissue characteristics, T2DM was associated with a similar T1 value, elevated extracellular volume fraction (ECV, T2DM: 27.8 ± 3.6% vs. controls: 25.1 ± 2.5%, p = 0.002), and increased extracellular matrix volume index (ECMVi, T2DM: 15.8 ± 3.8 ml/m2 vs. controls: 13.4 ± 2.7 ml/m2, p = 0.008) in males. For myocardial function, in male, compared with control, T2DM was associated with decreased peak longitudinal diastolic strain rate (PLDSR, T2DM: 0.97 ± 0.19 1/s vs. control: 1.13 ± 0.29 1/s, p = 0.030). Conclusions: There might be sex differences in myocardial remodeling induced by T2DM, including LV structural concentric remodeling in female patients and extracellular matrix remodeling and subclinical diastolic dysfunction in male patients.

GSK3ß mediates the spatiotemporal dynamics of NLRP3 inflammasome activation.

Subcellular machinery of NLRP3 is essential for inflammasome assembly and activation. However, the stepwise process and mechanistic basis of NLRP3 engagement with organelles remain unclear. Herein, we demonstrated glycogen synthase kinase 3ß (GSK3ß) as a molecular determinant for the spatiotemporal dynamics of NLRP3 inflammasome activation. Using live cell multispectral time-lapse tracking acquisition, we observed that upon stimuli NLRP3 was transiently associated with mitochondria and subsequently recruited to the Golgi network (TGN) where it was retained for inflammasome assembly. This occurred in relation to the temporal contact of mitochondria to Golgi apparatus. NLRP3 stimuli initiate GSK3ß activation with subsequent binding to NLRP3, facilitating NLRP3 recruitment to mitochondria and transition to TGN. GSK3ß activation also phosphorylates phosphatidylinositol 4-kinase 2 Α (PI4k2A) in TGN to promote sustained NLRP3 oligomerization. Our study has identified the interplay between GSK3ß signaling and the organelles dynamics of NLRP3 required for inflammasome activation and opens new avenues for therapeutic intervention.

Assessment of right ventricular function using cardiovascular magnetic resonance in patients with type 2 diabetes mellitus.

BACKGROUND: Accurate evaluation of right ventricular (RV) function is always difficult due to its irregular shape and movement. Many indices have been proposed to assess RV function, but none have been universally accepted. This study evaluated RV function in type 2 diabetes mellitus (T2DM) patients using long-axis strain (LAS) and other traditional indices. METHODS: Fifty-seven patients with T2DM and 39 healthy controls were prospectively enrolled. Four-chamber cardiovascular magnetic resonance (CMR) and RV short-axis cine images were obtained from all participants to measure the tricuspid annular plane systolic excursion (TAPSE), RV ejection fraction (EF), peak longitudinal strain (PLS) and four LAS indices. The inter-and intraobserver variabilities were also calculated. RESULTS: Compared with healthy controls, T2DM was associated with a decreased LAS (apex/lateral wall) (-17.4%±4.2% vs. control, -19.7%±3.7%, P=0.008) and LAS (apex/middle point) (-17.5%±4.5% vs. control, -19.5%±3.9%, P=0.026), but both groups had a similar LAS (RV/lateral wall) and LAS (RV/middle point) (all P>0.05). After adjustments for age and body mass index, a significant difference was observed only for LAS (apex/lateral wall) (P=0.028). There were no significant differences in the TAPSE, RVEF and PLS (all P>0.05). LAS (apex/lateral wall) correlated with the TAPSE (r=-0.723, P<0.001), RVEF (r=-0.270, P=0.008) and PLS (r=0.210, P=0.040). The inter- and intraobserver variability of the LAS (apex/lateral wall) were lower than the other three LAS indices. CONCLUSIONS: Compared with traditional RV function indices, such as the TAPSE, RVEF and PLS, LAS is easy to obtain and shows high repeatability. LAS (apex/lateral wall) may provide a more sensitive T2DM-related RV dysfunction index.

The Combination of ß-Asarone and Icariin Inhibits Amyloid-ß and Reverses Cognitive Deficits by Promoting Mitophagy in Models of Alzheimer's Disease.

ß-Asarone is the main constituent of Acorus tatarinowii Schott and exhibits important effects in diseases such as neurodegenerative and neurovascular diseases. Icariin (ICA) is a major active ingredient of Epimedium that has attracted increasing attention because of its unique pharmacological effects in degenerative disease. In this paper, we primarily explored the effects of the combination of ß-asarone and ICA in clearing noxious proteins and reversing cognitive deficits. The accumulation of damaged mitochondria and mitophagy are hallmarks of aging and age-related neurodegeneration, including Alzheimer's disease (AD). Here, we provide evidence that autophagy/mitophagy is impaired in the hippocampus of APP/PS1 mice and in Aß1-42-induced PC12 cell models. Enhanced mitophagic activity has been reported to promote Aß and tau clearance in in vitro and in vivo models. Meanwhile, there is growing evidence that treatment of AD should be preceded by intervention before the formation of pathological products. The efficacy of the combination therapy was better than that of the individual therapies applied separately. Then, we found that the combination therapy also inhibited cell and mitochondrial damage by inducing autophagy/mitophagy. These findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis, and that combination treatment with mitophagy inducers represents a potential strategy for therapeutic intervention.

Corrigendum to "EOLA1 Inhibits Lipopolysaccharide-Induced Vascular Cell Adhesion Molecule-1 Expression by Association with MT2A in ECV304 Cells".

[This corrects the article DOI: 10.1155/2015/301562.].

Comparison of Allogeneic Platelet-rich Plasma With Autologous Platelet-rich Plasma for the Treatment of Diabetic Lower Extremity Ulcers.

REGISTRATION NUMBER OF CLINICAL TRIALS: ChiCTR1900021317.

The SGLT2 inhibitor dapagliflozin attenuates the activity of ROS-NLRP3 inflammasome axis in steatohepatitis with diabetes mellitus.

BACKGROUND: Diabetes mellitus (DM) is considered as a risk factor for the progress of liver diseases. After tissue damage, there is the highest amplitude of ubiquitously sterile inflammatory response in the liver, resulting in a major clinical consequence concerning a high prevalence of steatohepatitis in DM patients. This study aimed to investigate the inhibitory efficacy of dapagliflozin (DAPA), a sodium glucose cotransporter-2 (SGLT2) inhibitor, on experimental steatohepatitis with DM. METHODS: DM-steatohepatitis model was established by dual intraperitoneal injection of streptozotocin (STZ) and feeding with the high-fat diet (HFD) in apolipoprotein E-deficient (ApoE-/-) mice (n=40). The mice were concurrently treated with DAPA (1 mg/kg/d) by gavage for 12 weeks. RESULTS: In ApoE-/- mice, dual HFD/STZ dramatically induced hepatic damage and inflammation as compared with HFD alone. DAPA treatment was effective to protect from hepatic damage and inflammation in dual HFD/STZ treated ApoE-/- mice. DAPA also significantly the probability decreased the blood glucose, hepatic lipid accumulation, liver steatosis, and fibrotic response in dual HFD/STZ treated ApoE-/- mice. Further mechanistic investigations indicated that the protection of DAPA on diabetic liver injury was associated with the suppressed production of hepatic reactive oxygen species (ROS) and malondialdehyde (MDA) and the inhibited activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. CONCLUSIONS: These data demonstrate the efficacy of DAPA for protecting liver damage, inflammation and steatosis from experimental steatohepatitis with DM, and indicate a possible involvement of the inhibited activity of ROS-NLRP3 inflammasome.

Lower limb arterial intervention or autologous platelet-rich gel treatment of diabetic lower extremity arterial disease patients with foot ulcers.

BACKGROUND: To investigate whether lower limb vascular intervention or autologous platelet-rich gel (APG) treatment would benefit diabetic lower extremity arterial disease (LEAD) patients with foot ulcers. METHODS: A total of 82 diabetic LEAD patients with foot ulcers were recruited and divided into three groups: group A (30 patients received basal treatment), group B (21 patients received basal and APG treatment), and group C (31 patients received basal and lower limb vascular intervention treatment). All patients underwent routine follow-up visits for 6 months. The baseline characteristics and parameters were examined. After treatment, changes in all parameters from baseline were recorded. The differences between groups and the relationship among each parameter were determined. RESULTS: There were no differences in the ankle brachial index (ABI) or major amputation between groups A and B (P>0.05). Compared with groups A and B, the ABI and major amputation rate of group C were improved (P<0.05). There were no significant differences in transcutaneous oxygen partial pressure (TcPO2), the heal rate or minor amputation between groups A and C (P>0.05). Compared with groups A and C, TcPO2, the heal rate and minor amputation of group B were improved (P<0.05). The logistic regression analysis indicated that major amputation was mainly associated with the ABI, and minor amputation was mainly associated with TcPO2. Lower limb vascular intervention improves the ABI and reduces major amputation, and APG improves TcPO2 and reduces minor amputation. CONCLUSIONS: In diabetic LEAD patients with foot ulcers, major amputation was mainly associated with the ABI, while minor amputation was mainly associated with TcPO2. Interventional surgery (angioplasty) mainly improves the ABI, reduces the incidence of major amputation and improves the macrovasculature, and APG mainly improves local TcPO2, reduces the incidence of minor amputation and improves the microcirculation.

Exenatide reduces cardiomyocyte apoptosis by stimulating adiponectin secretion and activating APPL1-AMPK-PPARα axis.

BACKGROUND: To explore the mechanism that exenatide reduces cardiomyocyte apoptosis via the adiponectin pathway in vitro. METHODS: Cardiomyocytes were randomly divided into the control group (group C), diabetic group (group D), diabetic + exenatide treatment group (group DE), diabetic + exenatide treatment + APPL1 overexpression group (group OE), and diabetic + exenatide treatment + APPL1 knock-down group (group KD). After 48 h culture, the apoptosis rate, the adiponectin level in the cell culture fluid, and the expression levels of APPL1, p-AMPK, PPARα and NF-κB were detected by TUNEL, ELISA, and Western blotting, respectively. RESULTS: Compared to group C, the apoptosis rate was markedly increased, the adiponectin level was decreased, the expression of APPL1, p-AMPK and PPARα was down-regulated and that of NF-κB was up-regulated in group D (P<0.05); in group DE, the apoptosis rate was significantly decreased, the expression of APPL1, p-AMPK and PPARα was up-regulated and that of NF-κB was down-regulated, as compared with group D (P<0.05). The apoptosis rate in group OE was lower than that in group DE, the expression of APPL1, p-AMPK and PPARα was up-regulated and that of NF-κB was down-regulated (P<0.05). In group KD, the adiponectin level was elevated and the cardiomyocyte apoptosis rate was increased, as compared to group D (P<0.05). Furthermore, the expression of APPL1, p-AMPK and PPARα was down-regulated and that of NF-κB was up-regulated compared with group DE (P<0.05). CONCLUSIONS: Exenatide can activate the "APPL1-AMPK-PPARα" anti-apoptosis signaling axis by promoting adiponectin expression in cardiomyocytes and reducing the apoptosis of diabetic cardiomyocytes, thus protecting cardiomyocytes.

The Reduced Expression of EOLA1 May Be Related to Refractory Diabetic Foot Ulcer.

BACKGROUND: Chronic diabetic foot ulcer (DFU) is one of the most intractable complications of diabetes mellitus (DM). Its pathogenesis is complex, and uncontrolled chronic inflammation is an important factor. Endothelial overexpressed lipopolysaccharide-associated factor 1 (EOLA1) discovered in our laboratory is an intracellular protein with the function of inflammatory regulation. This study was aimed at observing the expression of EOLA1 in DFU skin tissues and its relationship with inflammation and at exploring the possible role of EOLA1 in DFU and its mechanism. METHODS: The patients with DFU were divided into 2 groups based on the formation time of ulcer: the acute wound (AW) group with the course of disease ≤ 4 weeks and the chronic wound (CW) group with the course of disease > 4 weeks. The relevant clinical data of patients were collected, and the skin tissues around the ulcer were used for immunofluorescence detection and immunohistochemical staining to observe inflammation. The expression levels of EOLA1, metallothionein 2A (MT2A), nuclear factor-κB (NF-κB), and interleukin-6 (IL-6) were detected by western blot. RESULTS: A total of 79 patients were enrolled in the study. The results of immunofluorescence and immunohistochemistry showed that EOLA1 was expressed in the epithelial tissues of DFU. However, the expression of EOLA1 in the CW group was significantly lower than that in the AW group (P < 0.05), and the expression of NF-κB and IL-6 was obviously increased (P < 0.05). CONCLUSION: The refractory wounds in patients with DFU may be closely related to the uncontrolled activation of inflammatory pathways in cells caused by the reduced expression of negative regulators of inflammation (e.g., EOLA1), and such decreased expression may be also strongly linked to the persistent state of inflammation.

Long-Term Outcomes of BMMSC Compared with BMMNC for Treatment of Critical Limb Ischemia and Foot Ulcer in Patients with Diabetes.

We first compared long-term clinical outcomes in treating critical limb ischemia (CLI) and foot ulcer in patients with diabetes between autologous bone marrow mesenchymal stem cell (BMMSC) and bone-marrow-derived mononuclear cell (BMMNC) transplants. Forty-one patients were enrolled and followed up for 3 years. They received an 18-day standard treatment before stem cell transplantation. Patients with bilateral CLI and foot ulcer were injected intramuscularly or basally with BMMSC, BMMNC, or normal saline (NS). Cox model analysis showed significant differences in the hazard ratio (HR) for amputation with treatment by BMMSC (HR 0.21 [95% CI (0.05, 0.95)], P = 0.043), infection of foot (HR 5.30 [95% CI (1.89, 14.92)], P = 0.002), and age ≥64 (HR 3.01 [95% CI (1.11, 8.15)], P = 0.030), but no significant differences by BMMNC at 9 months after transplantation. Regarding ulcer healing and recurrence rate, the BMMSC group demonstrated a significant difference from the NS group during the 3-6 months after transplantation or healing, but the BMMNC group did not. This trial suggests that, compared with BMMNC treatment, BMMSC treatment leads to a longer time of limb salvage and blood flow improvement, and, when compared with conventional therapy, it can promote limb blood flow and ulcerative healing, and reduce ulcer recurrence and amputation within 9 months.

Increased fractal dimension of left ventricular trabeculations is associated with subclinical diastolic dysfunction in patients with type-2 diabetes mellitus.

The aim of this study was to investigate the relationship among left ventricular (LV) concentric hypertrophy, endocardial remodeling, and myocardial deformation in type-2 diabetes mellitus (T2DM). Fifty-three T2DM patients with normotension and 36 healthy controls underwent cardiovascular magnetic resonance imaging to assess for LV concentric hypertrophy (LV myocardial mass index, LVMMi; LVMMi-to-LV end-diastolic volume index ratio, MVR), endocardial remodeling (fractal dimension of trabeculations, FD), and myocardial deformation (global longitudinal, radial and circumferential strain, systolic and diastolic strain rate). When compared with healthy controls, T2DM was associated with LV concentric hypertrophy (LVMMi: T2DM, 52.7 ± 8.9 g/m2; controls, 48.7 ± 8.4 g/m2, p = 0.032; MVR: T2DM, 0.88 ± 0.19 g/mL; controls, 0.77 ± 0.16 g/mL, p = 0.007), endocardial remodeling (max. apical FD: T2DM, 1.265 ± 0.056; controls, 1.233 ± 0.055, p = 0.008; mean apical FD: T2DM, 1.198 ± 0.043; controls, 1.176 ± 0.043, p = 0.020), and subtle diastolic dysfunction (peak longitudinal diastolic strain rate, PDSRL: T2DM, 1.1 ± 0.2/s; controls, 1.2 ± 0.3/s, p = 0.031). In the stepwise multivariable regression model, the MVR was an independent determinant of the maximum apical FD (standardized ß, sß = 0.525, p < 0.001) and mean apical FD (sß = 0.568, p < 0.001). The mean apical FD was an independent determinant of the PDSRL (p = 0.004). LV concentric hypertrophy is an independent determinant of endocardial remodeling, a process that may contribute to subtle LV diastolic dysfunction in T2DM patients.

Autologous platelet-rich gel combined with in vitro amplification of bone marrow mesenchymal stem cell transplantation to treat the diabetic foot ulcer: a case report.

The diabetic foot ulcer (DFU) is the leading cause of the high mortality and morbidity rates of diabetes patients, and the DFU accounts for approximately 15% of all diagnosed diabetes cases in China. Traditional treatment is typically ineffective for DFUs. Here, we present a case of DFU that was successfully treated with an autologous platelet-rich gel (APG) and in vitro amplification of bone marrow mesenchymal stem cell (BMMSC) transplantation. A 54-year-old woman initially presented with a right foot diabetic ulcer at the hospital. A wound at the lateral malleolus of the right foot was observed with exudation and infection. The standard treatment included glucose reduction with insulin, blood lipid control with atorvastatin, circulation improvement with alprostadil, anti-infection treatment with sensitive antibiotics, debridement, dressing, and continuous negative pressure suction, and after the standard treatment, the APG combined with in vitro amplification of BMMSC transplantation was used to help the healing of the ulcer. All of the above interventions may have contributed to the healing of the ulcer, and an APG combined with in vitro amplification of BMMSCs may promote DFU healing. The difficulty of DFU treatment remains a challenge, particularly in diabetic patients who develop foot ulcers, due to the complexity of its multifaceted pathogenesis. This case represents an effective adjuvant treatment for such patients.

Distribution of Microbes and Drug Susceptibility in Patients with Diabetic Foot Infections in Southwest China.

OBJECTIVE: To investigate the microbial distribution and drug susceptibility among diabetic foot ulcers (DFUs) with different Wagner grades and between acute and chronic DFUs. Methods. We enrolled 428 DFU patients who were hospitalized and treated in the Southwest Hospital. We collected deep ulcer secretion for microbial culture and drug susceptibility tests and analyzed the results. We reexamined 67 patients with poor anti-infection efficacy and analyzed microbial species. Results: The 354 positive samples included 201 cases (56.8%) of single-pathogen infections and 153 cases (43.2%) of multiple-pathogen infections before antibiotic therapy. A total of 555 strains were cultivated, including 205 (36.9%) strains of gram-positive organisms (GPOs), 283 (51.0%) gram-negative bacilli (GNB), and 67 (12.1%) fungal strains. In terms of distribution, patients with different Wagner grades had different bacterial composition ratios (P < 0.01). Patients with Wagner grades 3-5 mainly had GNB. The specimens from chronic ulcer wounds were primarily GNB (54.2%), whereas fungi accounted for 14.4% of the infections; the distribution was significantly different from that of acute ulcers (P < 0.01). The susceptibility tests showed that the Staphylococcus genus was more susceptible to vancomycin, linezolid, and tigecycline. Tobramycin was the most effective drug (97%) for the treatment of Escherichia coli, followed by ertapenem (96.4%), imipenem (93.5%), and cefotetan (90%). Most of the remaining GNB were susceptible to antibiotics such as carbapenems, aminoglycosides, fluoroquinolones, ceftazidime, cefepime, and piperacillin-tazobactam (>63.2%). After antibiotic therapy, the positive rate of microbial culture was 52.2%, and the proportion of GNB and fungi increased to 68.9% and 20%. CONCLUSION: The distribution and types of bacteria in diabetic foot infection (DFI) patients varied with the different Wagner classification grades, courses of the ulcers, and antibiotic therapy. Multidrug resistance were increased, and the clinical treatment of DFIs should select the most suitable antibiotics based on the pathogen culture and drug susceptibility test results.

Efficacy and long-term longitudinal follow-up of bone marrow mesenchymal cell transplantation therapy in a diabetic patient with recurrent lower limb bullosis diabeticorum.

Bullosis diabeticorum is a rare presentation of cutaneous manifestation most commonly affecting the lower limbs in patients with diabetes. The appearance, often as insidious as its resolution, is characterized by tense blisters on the skin surfaces of the lower limbs and the feet. The cause still remains unclear, but it may relate to microangiopathy and neuropathy. In this report, we present a case of a 64-year-old male with multiple episodes of blistering in the left lateral lower limb after a traumatic fall who was subsequently diagnosed with type 2 diabetes mellitus. The patient had a history of poorly controlled blood glucose and subsequently developed vasculopathy and peripheral neuropathy. Despite appropriate glycemic control and antibiotics therapy, the patient developed recurrent bullosis diabeticorum on five separate occasions during a 2-year span from 2005 to 2007. Building on our success with ischemic diabetic foot, we used bone marrow mesenchymal stem cell (BMMSC) transplantation therapy for bullosis diabeticorum. After a 9-month treatment, this patient developed another episode of cellulitis in the same lower limb which was successfully treated with antibacterial therapy. It is interesting that the patient reported no recurrence in the next 10-year follow-up span. This study demonstrates that bullosis diabeticorum could appear even before the onset of diabetes, and vascular insufficiency predisposes to the occurrence of bullosis diabeticorum. Our findings suggest that autologous BMMSC transplantation therapy may be an effective measure for recurrent bullosis diabeticorum; however, this will require further investigation to be conclusive. Early identification of diabetes and its complications and appropriate treatment may improve clinical outcomes and prevent lower limb amputation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00955669 . Registered on August 10, 2009.

Left atrium passive ejection fraction is the most sensitive index of type 2 diabetes mellitus-related cardiac changes.

The aims of this study were to use cardiovascular magnetic resonance (CMR) cine to assess left atrium (LA) and left ventricle (LV) function and structure in normotensive type 2 diabetes mellitus (T2DM) patients and to identify the most sensitive index of those T2DM-related cardiac changes. Fifty T2DM patients with normotension (25 males, age 54.7 ± 8.7 years, duration of diabetes: 7.5 ± 5.1 years) and 35 controls (16 males, age: 52.2 ± 13.2 years) were prospectively enrolled. All patients were scanned using CMR four- and two-chamber long-axis cine to assess LA and LV structure and function. Normotensive T2DM patients were associated with decreased LA total ejection fraction (EF), passive EF and LV end diastolic volume, normal LA active EF and LV myocardial mass and increased LV mass/volume (M/V). LA total EF and passive EF correlated with body mass index, duration of diabetes and M/V. To differentiate between diabetic patients and healthy controls, area under the receiver operating characteristic (ROC) curve (AUC) values were calculated to be 0.763, 0.706, 0.647 and 0.649 for LA passive EF, total EF, LVEDV and M/V, respectively. The addition of LA total EF, LVEDV, M/V and the combination thereof did not significantly improve AUC values in a model containing LA passive EF. Normotensive T2DM patients were associated with LA decreased total ejection fraction, decreased passive EF and LV concentric remodeling. Among these indices, LA passive EF was the most sensitive to T2DM-related LA function changes.

Assessment of Diabetic Cardiomyopathy by Cardiovascular Magnetic Resonance T1 Mapping: Correlation with Left-Ventricular Diastolic Dysfunction and Diabetic Duration.

PURPOSE: To quantify extracellular matrix expansion with the cardiovascular magnetic resonance (CMR) T1 mapping technique and the derived extracellular volume fraction (ECV) in diabetic cardiomyopathy (DbCM) patients and to detect the relationship among ECV, duration of diabetes, and diastolic function. MATERIALS: Thirty-eight patients with diabetic cardiomyopathy (20 males, age 54.6 ± 8.6 years) and thirty-two matched normal controls (15 males, age 51.4 ± 13.6 years) were prospectively enrolled. All of them were scanned by T1 mapping to obtain the native and postcontrast T1 values of myocardium and blood, and ECV was calculated accordingly. All patients also underwent transthoracic echocardiographic tissue Doppler imaging to assess left-ventricular diastolic function. RESULTS: There was a significant difference in ECV between the two groups (DbCMs 30.4 ± 2.9% versus controls 27.1 ± 2.4%, P < 0.001). The duration of diabetes was positively and strongly associated with ECV (R = 0.539, P = 0.0005). There was also a significant difference in ECV (P ≤ 0.001) among four groups (A, controls; B, DbCM patients with duration of diabetes <5 years; C, 5-10 years; and D, >10 years). ECV was negatively associated with LV E'/A' (R = -0.403, P = 0.012). CONCLUSION: CMR T1 mapping can reflect myocardial extracellular matrix expansion in DbCM and can be a powerful technique for the early diagnosis of DbCM.

Dapper1 attenuates hepatic gluconeogenesis and lipogenesis by activating PI3K/Akt signaling.

Studies have shown that hepatic insulin resistance, a disorder of glucose and lipid metabolism, plays a vital role in type 2 diabetes (T2D). To clarify the function of Dapper1 in glucose and lipid metabolism in the liver, we investigated the relationships between Dapper1 and adenosine triphosphate (ATP)- and Ca2+-mediated activation of PI3K/Akt. We observed a reduction in hepatic Dapper1 in db/db (mice that are homozygous for a spontaneous diabetes mutation) and HFD-induced diabetic mice with T2D. Hepatic overexpression of Dapper1 improved hyperglycemia, insulin resistance, and fatty liver. It also increased Akt (pAkt) signaling and repressed both gluconeogenesis and lipogenesis. Conversely, Ad-shDapper1-induced knockdown of hepatic Dapper1 promoted gluconeogenesis and lipogenesis. Furthermore, Dapper1 activated PI3K p110α/Akt in an insulin-independent manner by inducing ATP production and secretion in vitro. Blockade of P2 ATP receptors, the downstream phospholipase C (PLC), or the inositol triphosphate receptor (IP3R all reduced the Dapper1-induced increase in cytosolic free calcium and Dapper1-mediated PI3K/Akt activation, as did removal of calcium in the medium. In conclusion, Dapper1 attenuates hepatic gluconeogenesis and lipogenesis in T2D.