No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
International Diabetes Federation World Diabetes Congress 2015 (IDF 2015)
Journal of Diabetes
... According to the International Diabetes Federation, in 2015, 415 million people suffer diabetes, and it has become one of the greatest health emergencies of the 21st century. 1 Type 2 diabetes mellitus (T2DM) is a chronic disease with significant implications on global society and economy that requires attention and commitment on the part of patients in order to reduce comorbidities. 2,3 North America and the Caribbean have the highest prevalence of individuals with diabetes in comparison with other regions. ...
... According to the International Diabetes Federation, the majority of individuals with T2DM are living in developing countries such as Mexico. 1 Tence, the relevance of studying the relationship between quality of life-Depression and Type 2 diabetes in our population. In order to get a better comprehension of factors that could influence over the quality of life of patients with T2DM, we addressed the role of concomitant depression. ...
Background
Diabetes mellitus is a chronic disease that requires attention and commitment on the part of patients; improving the quality of life of these patients reduces health costs, morbidity, and mortality. We focused on investigating the factors related with the quality of life and depression symptomatology in patients with type 2 diabetes.
Participants and methods
A total of 173 Mexican patients with type 2 diabetes were recruited. An interview face-to-face, a sociodemographic characteristics questionnaire, the Short Form 36 (SF-36), and the Clinical Epidemiological Studies of Depression were applied. The biochemical parameters measured were blood glucose, cholesterol, triacylglycerol levels, and glycated hemoglobin.
Results
In all SF-36 subscales, female patients had lower scores in comparison with male patients; individuals ≥65 years of age showed less physical function. We observed that married patients presented a better quality of life than people who were widowed or divorced (P<0.05). Those with high rates of lipids showed decreased scores all the subscales of SF-36. Finally, we observed that depression was the major factor that decreased quality of life in patients with diabetes.
Conclusion
Our results suggest that untreated and unrecognized depression can decrease the quality of life in patients with diabetes mellitus type 2. Therefore, health care professionals need to consider these findings when treating patients with diabetes. Due to the limited number of patients included in the present study, more studies are needed, studying larger samples in order to provide conclusive results.
... It is estimated that 347 million individuals worldwide experience diabetes [5]. According to the International Diabetes Federation (IDA), diabetes is an international health problem impacting over four hundred fifteen million people and is projected to escalate to a total of 642 million by the year 2040 [6]. A further investigation revealed that diabetes is the fourth biggest cause of death in a majority of developed nations [7]. ...
This study highlights the prevalence of diabetes and hypertension as well as the risk factors that are linked to them. Those with diabetes are as much as four times greater likely than non-diabetics to experience hypertension. In diabetics, hypertension is substantially correlated with both obesity and dyslipidemia. Because it rarely causes symptoms, hypertension is referred to as the "silent killer" and is a serious health risk. Stress, excessive sodium intake, alcohol consumption, and physiological variables are among the factors contributing to hypertension in diabetics; genetic susceptibility, obesity, and sedentary lifestyles are all significant factors. These elements have contributed to a rise in the prevalence of hypertension in Pakistani society. Severe consequences such as congestive heart failure, renal failure, strokes, and cardiovascular disorders might result from the condition. Genetic predisposition, obesity, sedentary lifestyles, stress, high in sodium consumption, drinking alcohol, and physical characteristics are some of the factors that cause hypertension in diabetics. In Pakistani society, the incidence of hypertension has increased as a result of several factors. The condition may have severe effects, including strokes, cardiovascular illnesses, congestive heart failure, and renal failure.
... Diabetic nephropathy (DN) is the changes in chronic kidney structure and dysfunction caused by diabetes, which has become the leading cause of chronic kidney disease and end-stage renal disease [1]. According to statistics from the International Diabetes Federation (IDF), the number of diabetes patients worldwide in 2015 was 415 million, and it is expected to increase to 552 million in 2035 [2]. Pathological changes related to DN include macrophage infiltration, glomerular sclerosis and atrophy, interstitial fibrosis, and loss of renal function [3]. ...
Background. Diabetic nephropathy (DN) is the leading cause of chronic kidney disease, and the activation and infiltration of phagocytes are critical steps of DN. This study aimed to explore the mechanism of exosomes in macrophages and diabetes nephropathy and the role of miRNA-34a, which might provide a new path for treating DN. Materials and Methods. The DN model was established, and the success of the model establishment was confirmed by detecting general indicators, HE staining, and immunohistochemistry. Electron microscopy and NanoSight Tracking Analysis (NTA) were used to see the morphology and size of exosomes. MiRNA-34a inhibitor, miRNA-34a mimics, pc-PPARGC1A, and controls were transfected in macrophages with or without kidney exosomal. A dual-luciferase reporter gene experiment verifies the targeting relationship between miRNA-34a and PPARGC1A. After exosomal culture, macrophages are co-cultured with normal renal tubular cells to detect renal tubular cell fibrosis. Q-PCR and western blot were undertaken to detect related RNA and proteins. Results. An animal model of diabetic nephropathy was successfully constructed. Macrophages could phagocytose exosomes. After ingesting model exosomes, M1 macrophages were activated, while M2 macrophages were weakened, indicating the model mice’s kidney exosomes caused the polarization. MiRNA-34a inhibitor increased PPARGC1A expression. MiRNA-34a expressed higher in diabetic nephropathy Model-Exo. MiRNA-34a negatively regulated PPARGC1A. PPARGC1A rescued macrophage polarization and renal tubular cell fibrosis. Conclusion. Exosomal miRNA-34a of tubular epithelial cells promoted M1 macrophage activation in diabetic nephropathy via negatively regulating PPARGC1A expression, which may provide a new direction for further exploration of DN treatment.
... GDM increases the risk of developing type 2 diabetes mellitus (T2DM) in both mother and child. According to the International Diabetes Federation (IDF), in 2014, GDM's prevalence reached 1 %− 14 % worldwide (depending on study samples and settings) and 1 %− 5 % in China in 2015 [11]. Screening for GDM can be done only at 24-28 weeks of gestation by an oral glucose tolerance test (OGTT) (see Fig. 1). ...
... According to the report of the International Diabetes Federation, approximately 400 million people have diabetes currently, and the prevalence rate of diabetes will be close to 600 million by 2035 (1,2). Among the microvascular complications of diabetes, diabetic retinopathy (DR) is reported to be the most common cause of visual impairment in adults of working age (3). ...
Background
Previous research has indicated a vital association between hypertension, intraocular pressure (IOP), and diabetic retinopathy (DR); however, the relationship has not been elucidated. In this study, we aim to investigate the causal association of hypertension, IOP, and DR.
Methods
The genome-wide association study (GWAS) IDs for DR, hypertension, and IOP were identified from the Integrative Epidemiology Unit (IEU) Open GWAS database. There were 33,519,037 single-nucleotide polymorphisms (SNPs) and a sample size of 1,030,836 for DR. There were 16,380,466 SNPs and 218,754 participants in the hypertension experiment. There were 9,851,867 SNPs and a sample size of 97,465 for IOP. Univariable, multivariable, and bidirectional Mendelian randomization (MR) studies were conducted to estimate the risk of hypertension and IOP in DR. Moreover, causality was examined using the inverse variance weighted method, and MR results were verified by numerous sensitivity analyses.
Results
A total of 62 SNPs at the genome-wide significance level were selected as instrumental variables (IVs) for hypertension-DR. The results of univariable MR analysis suggested a causal relationship between hypertension and DR and regarded hypertension as a risk factor for DR [p = 0.006, odds ratio (OR) = 1.080]. A total of 95 SNPs at the genome-wide significance level were selected as IVs for IOP-DR. Similarly, IOP was causally associated with DR and was a risk factor for DR (p = 0.029, OR = 1.090). The results of reverse MR analysis showed that DR was a risk factor for hypertension (p = 1.27×10⁻¹⁰, OR = 1.119), but there was no causal relationship between DR and IOP (p > 0.05). The results of multivariate MR analysis revealed that hypertension and IOP were risk factors for DR, which exhibited higher risk scores (p = 0.001, OR = 1.121 and p = 0.030, OR = 1.124, respectively) than those in univariable MR analysis. Therefore, hypertension remained a risk factor for DR after excluding the interference of IOP, and IOP was still a risk factor for DR after excluding the interference of hypertension.
Conclusion
This study validated the potential causal relationship between hypertension, IOP, and DR using MR analysis, providing a reference for the targeted prevention of DR.
... Specifically, T2D accounts for aloft 90% epithetical sufferers and is the first allele akin to diabetes, indicating that this type of disease is relatively the greatest peril to human verdure [4,5]. The main pathogenesis of beta-cell dysfunction, inadequate insulin production, and insulin resistance all contribute to T1D [6,7], with insulin resistance being characterized by a disorganized glucose metabolism-liaise glucose leeway [8][9][10]. Normal insulin-related biological processes are routinely perturbed throughout the onset of T2D by intracellular signals or auxiliary therapeutics. ...
Diabetes is a critical disease and is crucial to personage agility. Type 2 Diabetes (T2D) accounts for 92% of epithetical cases. This paper proposes an optimized type 2 diabetes detection model using mixed single-cell RNA sequencing (scRNA-seq) technology. Diabetes is a chronic metabolic disorder affecting millions of people worldwide. Early detection of the disease can greatly improve treatment outcomes, but current diagnostic methods have limitations. Our proposed model integrates scRNA-seq data from both human pancreatic beta cells to identify gene expression patterns associated with diabetes. Our study shows that the proposed model is highly accurate in identifying diabetes, achieving an area under the curve (AUC) of 0.98. We employed an optimized model to improve the detection of diabetes at an early stage, leading to better treatment outcomes and an improved quality of life for patients. We initially incorporated optimal features from the dataset using the Monte Carlo (MC) feature selection method. This method helped us to estimate the relative importance (RI) score of each gene or feature, which is then used to rank the features. Further, we proposed an optimized deep belief network (ODBN) as a classification model to classify T2D and non-diabetes. To improve the performance of ODBN, an adaptive chimp optimization algorithm (AChOA) is introduced to optimize the weight parameters and achieved a performance accuracy of 96.57%.
... According to the report of the International Diabetes Federation, around 400 million people have diabetes currently, and the prevalence rate of diabetes will be close to 600 million by 2035 [1,2]. Among the microvascular complications of diabetes, diabetic retinopathy (DR) is reported to be the most common cause of visual impairment in adults of working age [3]. ...
Background: Previous research has indicated a vital association between hypertension, intraocular pressure (IOP), and diabetic retinopathy (DR), however, the relationship has not been elucidated. In this study we aim to investigate the causal association of hypertension, intraocular pressure, and diabetic retinopathy.
Methods: The Genome-wide association study (GWAS) IDs for DR and hypertension and IOP were identified from the Integrative Epidemiology Unit (IEU) Open GWAS database. There were 33,519,037 SNPs and a sample size of 1,030,836 for DR. There were 16,380,466 single nucleotide polymorphisms (SNPs) and 218,754 participants in the hypertension experiment. There were 9,851,867 SNPs and a sample size of 97,465 for IOP. Univariable and multivariable Mendelian randomization (MR) study was conducted to estimate the risk of hypertension and IOP in DR. Moreover, causality was examined using the inverse variance weighted method, and MR results were verified by numerous sensitivity analyses.
Results: A total of 62 SNPs at the genome-wide significance level were selected as instrumental variables (IVs) for hypertension-DR. The results of univariable MR analysis suggested a causal relationship between hypertension and DR and regarded hypertension as a risk factor for DR (P=0.006, odds ratio (OR) =1.081). A total of 94 SNPs at the genome-wide significance level were selected as IVs for hypertension-DR. Similarly, IOP was causally associated with DR and was a risk factor for DR (P=0.0292, OR=1.0922). The results of multivariate MR analysis revealed that hypertension and IOP were risk factors for DR, which exhibited higher risk scores (P=0.001, OR=1.121 and P=0.030, OR=1.124, respectively) than those in univariable MR analysis. Therefore, hypertension remained a risk factor for DR after excluding the interference of IOP, and IOP was still a risk factor for DR after excluding the interference of hypertension.
Conclusion: This study validated the potential causal relationship between hypertension, IOP, and DR using MR analysis, providing a reference for the targeted prevention of DR.
... Type 2 diabetes mellitus (T2DM) with risk factors as listed: age, gender, obesity, dyslipidemia, genetic abnormalities, and pre-diabetes (such as IFG and IGT), takes about 90% of all diabetes. According to the International Diabetes Federation, 380 million people in the world will have diabetes by 2025 (5). Besides, diabetic complications are growingly common in T2DM patients and may have substantial influences on their lives (6). ...
Tongxie Yaofang (TXYF), a Traditional Chinese Medicine (TCM) with four components as follows: Rhizoma Atractylodis Macrocephalae (baizhu), Radix Paeoniae Alba (baishao), Pericarpium Citri Reticulatae (chenpi) and Radix Saposhnikovia Divaricata (fangfeng), benefits irritable bowel syndrome (IBS). Nonetheless, proofs of this formula ameliorating D-IBS and T2DM are required. This research aimed at investigating the efficacy of TXYF in treating inflammation in rats with D-IBS and T2DM using animal models. In this study, gavage with high-fat diet, fasciculation, and senna was given to develop rat models with target diseases. To determine intestinal inflammations, major inflammatory factors, and intestinal permeability proteins, H&E staining, ELISA, and immunohistochemistry methods were employed, respectively. This study also utilized Western blot to discover potential inflammatory targets. Results of this research illustrates that TXYF treatment reduced the level of TNF-α, IL-1β, and IL-6, and raised the IL-10 concentration in liver-depressed spleende ficient rats with D-IBS and T2DM, indicating controlled inflammatory reactions. Staining analysis also showed improved disease states of animal models. Furthermore, efficient rebounds of claudin-1, an intestinal permeability-associated protein, were detected. Moreover, TXYF may treat D-IBS and T2DM in rats via the rage pathway.
... Diabetic nephropathy (DN), as the principal microvascular complication of diabetes, has become the primary factor leading to ESRD [93]. The main pathological changes of DN in renal biopsy samples are the diffuse mesangial expansion in the early stage and Kimmelstiel-Wilson nodule formation with longer diabetic duration. ...
Digital imaging and advanced microscopy play a pivotal role in the diagnosis of kidney diseases. In recent years, great achievements have been made in digital imaging, providing novel approaches for precise quantitative assessments of nephropathology and relieving burdens of renal pathologists. Developing novel methods of artificial intelligence (AI)-assisted technology through multidisciplinary interaction among computer engineers, renal specialists, and nephropathologists could prove beneficial for renal pathology diagnoses. An increasing number of publications has demonstrated the rapid growth of AI-based technology in nephrology. In this review, we offer an overview of AI-assisted renal pathology, including AI concepts and the workflow of processing digital image data, focusing on the impressive advances of AI application in disease-specific backgrounds. In particular, this review describes the applied computer vision algorithms for the segmentation of kidney structures, diagnosis of specific pathological changes, and prognosis prediction based on images. Lastly, we discuss challenges and prospects to provide an objective view of this topic.
... Due to either lack of insulin or pathogenic insulin reactive responses, diabetes can be divided into three groups: type 1 DM with low insulin production, type 2 DM with insulin resistance, and gestational diabetes with high blood sugar levels induced by diabetes recurrence during pregnancy (American Diabetes Association, 2014). According to the epidemiologic statistics data in 2015, more than four hundred million people suffered from diabetes, and about five million people died from such disease all over the world (Gao et al., 2016;Disease and Injury Incidence and Prevalence Collaborators, 2017;Global Burden of Disease Cancer Collaboration et al., 2017). Particularly, type 2 diabetes (T2D) makes up about 90% of all cases (392 million) and is the primary subtype of diabetes (Disease and Injury Incidence and Prevalence Collaborators, 2017;Global Burden of Disease Cancer Collaboration et al., 2017), indicating such kind of disease is one of the major threats to human health. ...
Diabetes is the most common disease and a major threat to human health. Type 2 diabetes (T2D) makes up about 90% of all cases. With the development of high-throughput sequencing technologies, more and more fundamental pathogenesis of T2D at genetic and transcriptomic levels has been revealed. The recent single-cell sequencing can further reveal the cellular heterogenicity of complex diseases in an unprecedented way. With the expectation on the molecular essence of T2D across multiple cell types, we investigated the expression profiling of more than 1,600 single cells (949 cells from T2D patients and 651 cells from normal controls) and identified the differential expression profiling and characteristics at the transcriptomics level that can distinguish such two groups of cells at the single-cell level. The expression profile was analyzed by several machine learning algorithms, including Monte Carlo feature selection, support vector machine, and repeated incremental pruning to produce error reduction (RIPPER). On one hand, some T2D-associated genes (MTND4P24, MTND2P28, and LOC100128906) were discovered. On the other hand, we revealed novel potential pathogenic mechanisms in a rule manner. They are induced by newly recognized genes and neglected by traditional bulk sequencing techniques. Particularly, the newly identified T2D genes were shown to follow specific quantitative rules with diabetes prediction potentials, and such rules further indicated several potential functional crosstalks involved in T2D.
... According to the recent report of the International Diabetes Federation (IDF), about 400 million people live with diabetes mellitus (DM) worldwide; this prevalence is estimated to approach 600 million individuals by 2035. [1] One of the most common microvascular complications of DM is diabetic retinopathy (DR), which is reported to be the leading cause of visual impairment in the working-age population. [2,3] Diabetic retinopathy is classically categorized into two types: nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). ...
Diabetic retinopathy (DR) is the major cause of visual impairment and blindness in the working-age population. Conventional management for nonproliferative diabetic retinopathy (NPDR) without diabetic macular edema (DME) is derived from the findings of the Early Treatment Diabetic Retinopathy Study (ETDRS). Although the ETDRS protocol basically includes observation, selected cases of severe NPDR may undergo scatter laser photocoagulation. Post-hoc analysis of recent trials has shown that patients with NPDR receiving intravitreal anti-vascular endothelial growth factor (anti-VEGF) for DME would experience improvement in the DR severity scale (DRSS). In addition, recent randomized trials (PANORAMA and Protocol W) have revealed that early intervention with intravitreal aflibercept in eyes with moderately severe to severe NPDR is associated with significant improvement in DRSS and reduced vision-threatening complications of DR. Based on recent studies, it seems that the therapeutic approach to NPDR may undergo a substantial change and a paradigm shift toward considering early intervention with the administration of intravitreal anti-VEGF injections. However, the long-term results and the duration of adherence to anti-VEGF therapy for eyes with NPDR are not yet defined. It is also not apparent whether improvement in DRSS is a true disease modification. Studies showed that DRSS improvement is not associated with retinal reperfusion. In addition, DRCR.net Protocol W showed no visual acuity benefit with the early intravitreal aflibercept injection in moderate to severe NPDR as compared with performing observation plus intravitreal aflibercept applied only after progression to proliferative DR or vision-impairing DME. The cost-benefit ratio is also a challenge. Herein, we look at different aspects of early anti-VEGF application and discuss its pros and cons in the process of treating NPDR.
... The latest epidemiological studies show that the prevalence rate of DM in Chinese adults is 12.8%; however, this value is not considered to represent the actual prevalence as a large number of individuals are in the pre-DM stage or have not been diagnosed [1] . According to the Global Burden of Disease report published in 2015, the prevalence of DM increased from approximately 333 million to approximately 435 million in 10 years [2] , and it is expected to affect 642 million individuals by 2040 [3] . Since November 2019, coronavirus disease 2019 (COVID- 19) has severely affected the routine care of many patients with DM, hypertension, or coronary heart disease worldwide. ...
The coronavirus disease 2019 (COVID-19) outbreak that occurred in late 2019 has posed a huge threat to the health of all humans, especially for individuals who already have diabetes mellitus (DM). DM is one of the most serious diseases that affect human health, with high morbidity and rates of complications. Medical scientists worldwide have been working to control blood sugar levels and the complications associated with sugar level alterations, with an aim to reduce the adverse consequences of acute and chronic complications caused by DM. Patients with DM face great challenges during the pandemic owing to not only changes in the allocation of medical resources but also their abnormal autoimmune status, which reduces their resistance to infections. This increases the difficulty in treatment and the risk of mortality. This review presents, from an epidemiological viewpoint, information on the susceptibility of patients with DM to COVID-19 and the related treatment plans and strategies used in this population.
... It is known for us that natural medicines such as walnut have the advantages of low cost, good efficacy, and low toxicity (Mohd, John, Karunanidhi, Mussa, & Ramasamy, 2017;Ooi, Adamu, Imam, Ithnin, & Ismail, 2018;Tang et al., 2018). Considering the healthy diet recommendation has specified the consumption of polyphenolic compounds to prevent T2DM (Gao, Regier, & Close, 2016), WM might have the ability to treat T2DM as a medical supplement for its richness of polyphenols. Here, the purpose of this research is to evaluate the effect of WMP on the metabolism of the glycolipid and the gut bacteria in a high-fat diet combined with STZ-induced T2DM. ...
Pressed degreased walnut meal (WM) was prepared from walnut kernel by cold-press deoil. It was rich in polyphenols with high activities of lowering lipids, antioxidation, anti-inflammation, and others, but the hypoglycemic activity has scarcely been reported. The purpose of this research was to investigate the preventive effect of the extracts of WM (WMP) on T2DM rats and the regulation of WMP on intestinal flora. Some results showed that WMP significantly held FBG, FINS and GSP, OGTT, the serum and hepatic TG, TC, HDL-C, LDL-C, AST, ALT, LPS, TNF-α, IL-6, and the hepatic MDA, CAT, SOD, as well as, prevented the pathological damage of the liver and the pancreas. The results of 16SrDNA sequencing demonstrated that WMP impeded the changes of intestinal flora in feces, mainly including Firmicutes, Bacteroidetes, and Proteobacteria. These indicated that WMP had promising effects on T2DM, which could be associated with the modulation of gut bacteria.
... Diabetic patients have an earlier onset of cardiovascular disease (approximately 14.6 years) than nondiabetic patients [11,12], and the incidence is more diffuse. By accelerating the formation and progression of atherosclerotic lesions, the risk of cardiovascular disease is increased 2-to 4-fold [13,14]. ...
Background:
Advanced glycation end products play an important role in diabetic atherosclerosis. The effects of advanced glycation end products (AGEs) on vascular smooth muscle cell- (VSMC-) derived foam cell formation and phenotypic transformation are unknown.
Methods:
Serological and histological samples were obtained from diabetic amputation patients and accident amputation patients from the Affiliated Hospital of Jiangsu University. CD68/Actin Alpha 2 (ACTA2) coimmunofluorescence sections were used to quantify the number of VSMCs with macrophage-like phenotypes. Western blotting was used to detect the expression of the receptor of advanced glycation end products in vascular samples. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate the level of serum Nε-carboxymethyl-lysine (CML). In vitro oil red O staining was used to examine lipid accumulation in VSMCs stimulated by CML. The expression of VSMCs and macrophage markers was measured by western blotting and quantitative real-time PCR. Furthermore, changes in VSMC migration and secretion were detected by the Transwell assay and ELISA.
Results:
In the arterial plaque sections of diabetic patients, VSMCs transformed to a macrophage-like phenotype. The serum CML and RAGE levels in the plaques were significantly higher in the diabetes group than those in the healthy control group and were significantly related to the number of macrophage-like VSMCs. CML stimulation promoted intracellular lipid accumulation. However, CML stimulation decreased the expression of VSMC markers and increased the expression of macrophage phenotype markers. Finally, CML promoted smooth muscle cell migration and the secretion of proinflammatory-related factors.
Conclusions:
CML induces VSMC-derived foam cell formation, and VSMCs transdifferentiate to a macrophage-like state, which may be mediated by the activation of RAGE.
... The number of diabetes patients is expected to increase from 415 million in 2015 to 640 million by 2040 globally (Gao et al., 2016). Vascular complication of diabetes is one of the most serious manifestations of the disease (Rask-Madsen and King, 2013), and the leading cause for this condition is vascular dysfunction including impaired vascular endothelial vasodilation, reduced vascular compliance, and slowed blood flow (Shi and Vanhoutte, 2017). ...
Hyperglycemia induces vascular endothelial dysfunction, which contributes to the development of vascular complication of diabetes. A classic prescription of traditional medicine, HuangqiGuizhiWuwu Decoction (HGWWD) has been used for the treatment of various cardiovascular and cerebrovascular diseases, which all are related with vascular pathology. The present study investigated the effect of HGWWD treatment in streptozocin (STZ)-induced vascular dysfunction in mouse models. In vivo studies were performed using wild type mice as well as arginase 1 knockout specific in endothelial cells (EC-A1–/–) of control mice, diabetes mice and diabetes mice treated with HGWWD (60 g crude drugs/kg/d) for 2 weeks. For in vitro studies, aortic tissues were treated with mice serum containing HGWWD with or without adenoviral arginase 1 (Ad-A1) transduction in high glucose (HG) medium. We found that HGWWD treatment restored STZ-induced impaired mean velocity and pulsatility index of mouse left femoral arteries, aortic pulse wave velocity and vascular endothelial relaxation accompanied by elevated NO production in the aorta and plasma, as well as reduced endothelial arginase activity and aortic arginase 1 expression. The protective effect of HGWWD is reversed by an inhibitor of nitric oxide synthesis. Meanwhile, the preventive effect of serum containing HGWWD in endothelial vascular dysfunction is completely blocked by Ad-A1 transduction in HG incubated aortas. HGWWD treatment further improved endothelial vascular dysfunction in STZ induced EC-A1–/– mice. This study demonstrates that HGWWD improved STZ-induced vascular dysfunction through arginase 1 – NO signaling, specifically targeting endothelial arginase 1.
... Diabetes is one of the main public health problems, and its prevalence has been increasing significantly in recent years; in 2017, the International Diabetes Federation (IDF) reported 425 million adult patients with diabetes worldwide, and over 350 million people are at risk of diabetes [1]. Diabetic nephropathy (DN) is one of the main microvascular complications of diabetes and has become the most common cause of end-stage renal disease in developed countries [2]. However, the etiology and pathogenesis of DN are complex; numerous studies have shown that oxidative stress and inflammation play a central role in the pathological process in DN, which has also been confirmed in our previous experiments [3]. ...
Background:
Hyperglycemia plays a vital role in diabetic nephropathy (DN); autophagy and its potential upregulator receptor-interacting protein kinase 2 (RIPK2) are associated with ROS, which play a potential role in regulating NLRP3, and may be involved in inflammation in DN.
Aim:
In this study, we aimed to explore the mechanisms mediated by RIPK2 in autophagy and the relationship with ROS-NLRP3 of DN, by investigating the levels of RIPK2 and autophagy in glomerular mesangial cells (GMCs) stimulated with high glucose.
Material and methods:
GMCs were divided into the following groups: normal group (NC), high glucose group (HG), and RIPK2 siRNA group. RIPK2, LC3, caspase1, and IL-1β levels were measured by western blotting and RT-PCR. Autophagosomes were measured by GFP-RFP-LC3; ROS were detected by DCFH-DA.
Results:
High glucose upregulated RIPK2 and LC3 in GMCs during short periods (0-12 h) (p < 0.01), while RIPK2 and LC3 were significantly downregulated in the long term (12-72 h) (p < 0.01); these changes were positively correlated with glucose concentration (p < 0.01). In addition, levels of ROS, caspase1, and IL-1β increased in a time- and dose-dependent manner in the high glucose group, even with an increased expression of LC3 (p < 0.01). However, LC3 expression decreased in the siRIPK2 group, while levels of ROS, caspase1, and IL-1β increased (p < 0.01).
Conclusions:
Autophagy was activated by high glucose at short time periods but was inhibited in the long term, demonstrating a dual role for high glucose in autophagy of GMCs. RIPK2 regulates ROS-NLRP3 inflammasome signaling through autophagy and may be involved in the pathogenesis of DN.
... Macrovascular complication is the principal cause of disability and death in diabetes patients. It occurs in patients with type 2 diabetes 14.6 years earlier than in individuals without diabetes, with greater severity, and with a more diffuse atherosclerotic lesion distribution [1,2]. Atherosclerosis is the main diabetic macrovascular complication, and is a vascular inflammatory disease characterized by lipid deposition in the arterial intima. ...
Advanced glycation end products (AGEs) are closely associated with diabetic macrovascular complications. The present study aimed to investigate the effects of Nε-Carboxymethyl-Lysine (the key active component of AGEs) in diabetic atherosclerosis on foam cell apoptosis and to explore the underlying mechanisms. Tissue sections were collected from 12 Type 2 diabetic patients and 4 control patients who underwent amputation surgery following a car accident. Peritoneal injection of streptozotocin in ApoE-/- mice was used to generate a diabetic model in vivo, and Raw 264.7 cells treated with CML and 740Y-P (a PI3K/AKT signaling agonist) were used to explore the effect of PI3K/AKT signaling in CML-induced foam cell apoptosis in vitro. The anterior tibial section of diabetic amputees contained a thinner fiber cap, higher lipid content, and more apoptotic cells than were found in control patients. in vitro studies using Raw 264.7 cell-derived foam cells and in vivo studies using diabetic ApoE-/- mice showed that CML levels dose-dependently reduced cell vitality, induced foam cell apoptosis and regulated apoptosis related protein. Furthermore, CML significantly decreased the phosphorylation of PI3K/AKT signaling, and restoration of PI3K/AKT signaling by 740Y-P decreased the CML-induced foam cell apoptosis. In conclusion, our results showed CML induced foam cell apoptosis in diabetic atherosclerosis through inhibiting the PI3K/AKT pathway.
... To further discover its underlying mechanism, we analyzed several key enzymes from carbon metabolism in mRNA level including PEPCK, GLUT1, GLUT2, GLUT3, LDHA, LDHB, GP, G6Pase, GYS1 and PFKFB3. The result indicated that CA dramatically downregulated the expression of pepck ( In addition, it's reported that high stimulation of glucose induced by cAMP and DEX in cell can lead to glucose toxicity and further inhibit the secretion of β cells, the latter of which may induce β cells apoptosis and hyperinsulinemia, and stimulate insulin resistance by reducing the amount of insulin receptor 33 . In our study, we also analyzed the expression of INSα and two of its receptor INSRα and INSRβ. ...
Type 2 diabetes (T2D) with high morbidity and mortality is characterized by abnormal glucose and lipid metabolism due in part to insulin resistance in liver, which lead to elevated hyperglycemia and hyperlipidemia. This study sough to explore the effects of corosolic acid (CA) in different T2D models and explored the underlying mechanism. Separated from Eriobotrya japonica leaves, CA purity was above 95% measured by a HPLC method. Compared with cAMP and DEX induced T2D HepG2 model, CA significantly stimulated glucose consumption and improved glycogen accumulation by inhibiting PEPCK mRNA expression. And in cAMP and DEX induced T2D zebrafish model, CA reduced glycogen degradation and increased glucose consumption by regulating some key enzymes in carbon metabolism including GLUT1, GLUT2, GLUT3, LDHA, LDHB, GP, G6Pase, GYS1, and PFKFB3. In addition, insulin receptor signals were also involved in CA-regulated hypoglycemic action. Furthermore, in STZ-induced T2D rat model, compared with diabetic control groups, CA remarkably downregulated the levels of serum lipid, blood glucose, ICAM-1, malonaldehyde and insulin resistance index, while upregulated SOD activity and impaired glucose tolerance. In a conclusion, CA can regulate glucose and lipid metabolic adaptation in T2D like HepG2, zebrafish and rat models partly through reducing inflammation and oxidative stress and suppressing PEPCK.
... Diabetes mellitus (DM) has become a global emergency due to its rapidly rising morbidity and chronic micro-and macrovascular complications [1,2]. Despite efforts to improve treatment, the risk of cardiovascular mortality of diabetic patients is approximately threefold higher than the general population [3]. ...
Platelet microparticles (PMPs) are closely associated with diabetic macrovascular complications. The present study aimed to investigate the effects of PMPs in diabetes on aortic vascular endothelial injury and to explore the underlying mechanisms. Peritoneal injection of streptozotocin was used to generate a diabetic rat model in vivo, and human umbilical vein endothelial cells (HUVECs) treated with PMPs were used in vitro. PMP levels in the circulation and aorta tissues were time-dependently increased in streptozotocin-induced diabetic rats at weeks 4, 8, and 12 (P < 0.05). Aspirin significantly inhibited the PMP levels at each time point (P < 0.05). In diabetic rats, the endothelial nitric oxide levels were decreased significantly combined with increased endothelial permeability. PMPs were internalized by HUVECs and primarily accumulated around the nuclei. PMPs inhibited endothelial nitric oxide levels to about 50% and caused approximately twofold increase in reactive oxygen species production. Furthermore, PMPs significantly decreased the endothelial glycocalyx area and expression levels of glypican-1 and occludin (P < 0.05). Interestingly, the PMP-induced endothelial injuries were prevented by raptor siRNA and rapamycin. In conclusion, increased PMPs levels contribute to aortic vascular endothelial injuries in diabetes through activating the mTORC1 pathway.
... Arch Med Sci Atheroscler Dis 2018 its prevalence is predicted to exceed 550 million patients by 2030 [7][8][9]. From a pathophysiological view, T2DM is multifactorial. Prolonged hyperglycemia / hyperlipemia (glucolipotoxicity) induces progressive β-cell dysfunction and finally β-cell apoptosis, leading to impaired insulin production [10,11]. ...
miRNAs are small, non-coding RNAs, functioning as negative suppressors of target gene expression. A significant proportion of the transcriptome is subject to miRNA modulation. A single miRNA determines the expression of hundreds of genes, while miRNAs are relatively stable in biological fluids. Thus, they have attracted scientific interest regarding their use as biomarkers for several diseases. miRNA-375 mainly influences β-cell function and insulin secretion. Several studies, primarily experimental, have assessed its role as a biomarker in type 2 diabetes, while recently retrieved human evidence supports this potential role. Besides its diagnostic potential, miRNA-375 may also have therapeutic implications. Based upon the growing epidemic of type 2 diabetes, there is an unmet need for the identification of biomarkers for the early recognition and monitoring of those patients. Long-term, prospective human studies are required to elucidate whether miRNA-375 can evolve as a key player in diagnosis and prognosis of type 2 diabetes.
... Among them, 2.5% will develop one of the most dangerous complications of diabetic foot, which is the Charcot arthropathy. 1 Osteoarticular lesions that result from disturbances of innervation, referred to as neuropathic arthropathy, were described in 1868 by Jean-Martin Charcot. 2 Complicated form of diabetes is the most common cause of neuropathic arthropathy in developed countries. Any peripheral neuropathy may lead to articular lesions. ...
Diabetes is the most common endocrine disorder of carbohydrate metabolism. If left untreated, or improperly treated for many years, diabetes leads to multiple organ complications. One of the serious consequences of the disease is damage to the peripheral and autonomic nerves known as diabetic neuropathy. The most advanced form of neuropathy, leading to damage to the structures of the forefoot, midfoot and hindfoot, is the so called Charcot foot, or neuropathic osteoarthropathy. Irreversible damage to the structures of the foot affects between 0,1% and 7.5% of patients with diabetes.
The optimal care for that form of foot damage is still a subject to debate. Available methods of caring for Charcot foot include invasive orthopedic treatment and conservative treatment. The use of negative pressure woudn therapy may be an effective, as well as transitional, way of managing Charcot foot.
... Based on a recent systematic review, it has been estimated that the direct annual cost of diabetes to the world is more than US$ 827 billion [1] . The International Diabetes Federation (IDF) estimates that total global health-care spending on diabetes more than tripled over the period 2003 to 2013 -the result of increases in the number of people with diabetes and increases in per capita diabetes spending [2] . ...
... Phytochemical investigations have been made resulting in substances like sesquiterpene lactones [5], polyacetylenes [6,7] and polyacetylene glucosides [8]. During the last decades, there is a surprising increase in prevalence of diabetes mellitus in populations of various regions of the world [9]. Since the polyacetylene glucosides M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT previously found in V. scorpioides showed little to none cytotoxicity, and the aforementioned analogous polyacetylene compounds were successful in reducing the glycemic index in mice, in this study the antihyperglycemic potential of V. scorpioides new polyacetylene glucoside has been accessed in order to shine a new light on the biological activity of this unique scaffold. ...
Natural polyacetylene compounds have been found mainly in seven botanical families and remain underexplored and understudied, despite its inherent chemical and biological reactivity, due to the presence of conjugated triple bonds. Some polyacetylene glucosides have been found to stimulate glucose uptake in C5BL/ks-db/db obese diabetic mice, and since polyacetylene glucosides previously found in Vernonia scorpioides showed little to none cytotoxicity, in this study the antihyperglycemic potential of a new V. scorpioides polyacetylene glucoside has been accessed in order to shine a new light on the biological activity of this unique scaffold. For the isolation of this new compound an optimized method of Centrifugal Partition Chromatography (CPC) is for the first time described together with its X-ray data. The results demonstrate that 3,4-dihydrovernoniyne-4-O-β-glucoside has significant effect on glycaemia at low dose 0.5 mg/kg, and pointing that the anti-hyperglycemic effect may be due in part to the inhibition of intestinal disaccharidases.
... Diabetes mellitus (DM) represents a major public health burden and a growing prevalent chronic disease. It is known that more than 400 million have diabetes, and it is estimated that the number of diabetic patients is expected to rise to over 640 million by 2040 [1]. Alzheimer's disease (AD) is the main cause of dementia, affecting over 26 million people worldwide [2], and its prevalence continues to increase [3]. ...
Diabetes mellitus (DM) and Alzheimer’s disease (AD) are two highly prevalent conditions in the elderly population and major public health burden. In the past decades, a pathophysiological link between DM and AD has emerged and central nervous system insulin resistance might play a significant role as a common mechanism; however, other factors such as inflammation and oxidative stress seem to contribute to the shared pathophysiological link. Both preclinical and clinical studies have evaluated the possible neuroprotective mechanisms of different classes of antidiabetic medications in AD, with some promising results. Here, we review the evidence on the mechanisms of action of antidiabetic drugs and their potential use in AD.
Metabolic syndrome (MetS) is common among schizophrenia patients, and one of MetS’s causes may be an imbalance in nitric oxide regulation. In this study, we examined associations of three polymorphic variants of the nitric oxide synthase 1 adapter protein (NOS1AP) gene with MetS in schizophrenia. NOS1AP regulates neuronal nitric oxide synthase, which controls intracellular calcium levels and may influence insulin secretion. The aim of the investigation was to study polymorphic variants of the NOS1AP gene as possible markers of MetS in patients with schizophrenia. A total of 489 Caucasian patients with schizophrenia (ICD-10) from Siberia (Russia) were included in the study, and 131 (26.8%) patients had MetS (IDF classification, 2007). The participants were genotyped for three single-nucleotide polymorphisms in NOS1AP (rs12143842, rs10494366, and rs12029454). Logistic regression was used for association analysis. Single-nucleotide polymorphisms, sex, and age served as covariates; the dependent variable was the coded parameter of the presence/absence of MetS. Polymorphisms rs12143842 and rs10494366 showed a stable association even after Bonferroni’s correction for multiple comparisons (p = 0.005 and 0.002, respectively), indicating a statistically significant contribution of these polymorphic variants to the pathogenesis of MetS. Our results suggest that in patients with schizophrenia, NOS1AP may be involved in MetS pathophysiology.
Objectives:
Diabetes has been strongly associated with periodontal diseases. The periodontal ligament (PDL) has an abundant extracellular matrix (ECM). Lysyl oxidases (LOXs) are closely associated with various diseases caused by abnormal ECM functions, however, the role of LOXs in periodontal diseases induced by diabetes remains unclear.
Methodology:
In this study, 8-week-old Zucker diabetic fatty rats were used to establish a type 2 diabetes mellitus (T2DM) model. After 9 and 16 weeks, hematoxylin and eosin (H&E), Masson's trichrome, and immunohistochemical staining were performed.
Results:
After 9 weeks, loose collagen fibers were found in the interradicular area of the diabetic group, in opposition to the control group. There were no significant differences in LOX expression between the diabetic and control groups (p>0.05). However, after 16 weeks, the diabetic group presented a disordered arrangement of the PDL, showing decreased collagen content and significantly increased lysyl oxidase-like protein 3 (LOXL3) expression when compared with the control group (p<0.05). This suggests that LOXL3 plays a significant role in periodontal histopathological changes in diabetic rats.
Conclusion:
Our study showed elevated LOXL3 expression in the PDL of diabetic rats after 16 weeks, suggesting that LOXL3 may be involved in the occurrence and development of periodontal histopathological changes in diabetic rats. LOXL3 could be further used as an indicator for the early diagnosis of diabetic periodontitis in T2DM patients in clinical settings.
Purpose:
To compare safety and therapeutic effect of three treatment protocols on patients with naive proliferative diabetic retinopathy.
Methods:
A total of 207 eyes with proliferative diabetic retinopathy were randomly divided into three groups: full panretinal photocoagulation group; intravitreal bevacizumab (IVB) group with four monthly IVB injections; and modified combination group with two bimonthly IVB injections and a modified laser therapy. The best-corrected visual acuity and area of neovascularization leakage were compared at 1-year follow-up.
Results:
The difference in final best-corrected visual acuity was not significant between the groups (P = 0.77). The modified combination group had the lowest final leakage area (P = 0.006). The difference in final mean deviation of visual field was not significant between IVB and modified combination groups (mean difference = 0.25, P = 0.23, 95% confidence interval, 0.12-1.38). There was no difference in rate of new-onset diabetic macular edema between IVB and modified combination groups (mean difference = 1.5%, P = 0.31, 95% confidence interval, 1.1-1.88). Mean of total IVB injections were 3.5, 7.4, and 6.2 for panretinal photocoagulation, IVB, and modified combination groups, respectively (P = 0.002). Patients in the IVB group underwent more visits (P = 0.001). In subgroup analysis, the difference in the final leakage area was significant for the eyes with diabetic macular edema (P = 0.005).
Conclusion:
A combination protocol of photocoagulation and IVB can be recommended for proliferative diabetic retinopathy, especially with baseline diabetic macular edema.
Diabetes mellitus (DM) characterised by pancreatic β -cell dysfunction and insulin resistance is already prevalent worldwide, and the complications of DM increased the mortality of diabetic patients. More and more reports showed that long non-coding RNA (lncRNA) plays key roles in DM, and in this study we explored the effect of long non-coding RNA SNHG14 (SNHG14) in DM. Quantitative reverse transcription PCR (qRT-PCR) was used to analyze the expression of SNHG14 and microRNA (miR)-206 in peripheral blood from 60 pairs of healthy and DM samples. Then the effect of SNHG14 on the insulin secretion of pancreatic β -cells was investigated. Moreover, the effects of SNHG14 on the viability and apoptosis of pancreatic β -cells were determined by 3-(4, 5)-dimethylthiahiazo (-z-y1)-3, 5-di- phenytetrazoliumromide (MTT) assay and flow cytometry (FCM) respectively using INS-1 cells transfected with SNHG14-plasmid and/or miR-206 mimic. Bioinformatics and Daul luciferase reporter assay were used to confirm the direct target of miR-206. Our data showed that SNHG14 level was decreased but miR-206 was increased significantly in the peripheral blood of DM patients. Furthermore, over-expression of SNHG14 enhanced insulin secretion and cell viability but inhibited apoptosis of pancreatic β -cells, whereas, miR-206 over-expression reversed these effects. In addition, insulin-like growth factor-1 (IGF1) was proved to be regulated by miR-206 negatively and over-expression of SNHG14 increased the expression of IGF1 and IGF1R in pancreatic β -cells. In conclusion, we found that SNHG14 was significantly down-regulated in DM patients, and SNHG14/miR-206/IGF1 may serve as a potential candidate for the clinical target of DM.
Autophagy is an important and conserved cellular pathway in which cells transmit cytoplasmic contents to lysosomes for degradation. It plays an important role in maintaining the balance of cell composition synthesis, decomposition and reuse, and participates in a variety of physiological and pathological processes. The nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome can induce the maturation and secretion of Interleukin-1 beta (IL-1β) and IL-18 by activating caspase-1. It is involved in many diseases. In recent years, the interplay between autophagy and NLRP3 inflammasome has been reported to contribute to many diseases including metabolic disorders related diseases. In this review, we summarized the recent studies on the interplay between autophagy and NLRP3 inflammasome in metabolic disorders to provide ideas for the relevant basic research in the future.
Macrophage polarization toward the M1 phenotype and its subsequent inflammatory response have been implicated in the progression of diabetic complications. Despite adverse consequences of autophagy impairment on macrophage inflammation, the regulation of macrophage autophagy under hyperglycemic conditions is incompletely understood. Here, we report that the autophagy–lysosome system and mitochondrial function are impaired in streptozotocin (STZ)-induced diabetic mice and high glucose (HG)-stimulated RAW 264.7 cells. Mitochondrial dysfunction promotes reactive oxygen species (ROS) production and blocks autophagic flux by impairing lysosome function in macrophages under hyperglycemic conditions. Conversely, inhibition of mitochondrial ROS by Mito-TEMPO prevents HG-induced M1 macrophage polarization, and its effect is offset by blocking autophagic flux. The role of mitochondrial ROS in lysosome dysfunction and M1 macrophage polarization is also demonstrated in mitochondrial complex I defective RAW 264.7 cells induced by silencing NADH:ubiquinone oxidoreductase subunit-S4 (Ndufs4). These findings prove that mitochondrial ROS plays a key role in promoting macrophage polarization to inflammatory phenotype by impairing autophagy–lysosome system, which might provide clue to a novel treatment for diabetic complications.
Background and Aim: Diabetes can lead to reduced fertility in men by production of free radicals. Crocin (the effective component of saffron) with its antioxidant property can be effective in elimination of free radicals. We evaluated the effects of crocin on the reproductive parameters of the STZ –induced diabetic male Wistar rats.
Materials and Method: Rats were made diabetic with STZ (55 mg/kg). The rats were divided randomly into 8 groups of seven: control group (normal Saline), STZ induced diabetic group, groups receiving 12.5, 25 and 50 mg/kg doses of crocin and STZ induced diabetic groups receiving the same doses of the crocin. These animals were kept under experimental conditions for 30 days. LH, FSH, testosterone and insulin hormones are measured .The significance of the results was examined by ANOVA statistical method.
Results:
Groups receiving crocin and STZ simultaneously showed significant increase (P
Critical limb ischemia (CLI) is the most severe manifestation of peripheral artery disease. It is characterized by chronic pain at rest, skin ulcerations, and gangrene tissue loss. CLI is a highly morbid condition, resulting in a severely diminished quality of life and a significant risk of mortality. The primary goal of therapy for CLI is to restore blood flow to the affected limb, which is only possible by surgery, but is inadvisable in up to 50% of patients. This subset of patients who are not candidates for revascularisation are referred to as “no-option” patients and are the focus of investigation for novel therapeutic strategies. Angiogenesis, arteriogenesis and vasculogenesis are the processes whereby new blood vessel networks form from the pre-existing vasculature and primordial cells, respectively. In therapeutic angiogenesis, exogenous stimulants are administered to promote angiogenesis and augment limb perfusion, offering a potential treatment option for “no option” patients. However, to date, very few clinical trials of therapeutic angiogenesis in patients with CLI have reported clinically significant results, and it remains a major challenge. Ghrelin, a 28-amino acid peptide, is emerging as a potential novel therapeutic for CLI. In pre-clinical models, exogenous ghrelin has been shown to induce therapeutic angiogenesis, promote muscle regeneration, and reduce oxidative stress via the modulation of microRNAs (miRs). miRs are endogenous, small, non-coding ribonucleic acids of ~20–22 nucleotides which regulate gene expression at the post-transcriptional level by either translational inhibition or by messenger ribonucleic acid cleavage. This review focuses on the mounting evidence for the use of ghrelin as a novel therapeutic for CLI, and highlights the miRs which orchestrate these physiological events.
Gestational diabetes mellitus (GDM) is conventionally confirmed with oral glucose tolerance test (OGTT) in 24 to 28 weeks of gestation, but it is still uncertain whether it can be predicted with secondary use of electronic health records (EHRs) in early pregnancy. To this purpose, the cost-sensitive hybrid model (CSHM) and five conventional machine learning methods are used to construct the predictive models, capturing the future risks of GDM in the temporally aggregated EHRs. The experimental data sources from a nested case-control study cohort, containing 33,935 gestational women in West China Second Hospital. After data cleaning, 4,378 cases and 50 attributes are stored and collected for the data set. Through selecting the most feasible method, the cost parameter of CSHM is adapted to deal with imbalance of the dataset. In the experiment, 3940 samples are used for training and the rest 438 samples for testing. Although the accuracy of positive samples is barely acceptable (62.16%), the results suggest that the vast majority (98.4%) of those predicted positive instances are real positives. To our knowledge, this is the first study to apply machine learning models with EHRs to predict GDM, which will facilitate personalized medicine in maternal health management in the future.
To assess the efficacy and safety of the SGLT-2 inhibitors as adjunct therapy to insulin in T1DM, clinical trials indexed in PubMed, Cochrane Library, EMbase from inception through April 5, 2016. A meta-analysis was conducted on trials of SGLT-2 inhibitors in patients with T1DM on insulin therapy using RevMan 5.3 software. Of the 371 articles identified, ten met eligibility criteria. Seven clinical trials including four randomized controlled trials and 581 patients were included. Compared with the control group, SGLT-2 inhibitors group had significantly reduced fasting plasma glucose by 0.69 mmol/L [1.32; 0.07], glycosylated hemoglobin A1C by 0.37% [0.54; 0.20], body weight by 2.54 kg [3.48; 1.60] and total daily insulin dose by 6.22 IU [8.04; 4.40]. The total incidence of adverse events (AEs), hypoglycemia, and genital and urinary infections were also similar to placebo, while an increased incidence of diabetic ketoacidosis (DKA) (n = 16) was seen in SGLT-2 inhibitors group. The present study demonstrates that SGLT-2 inhibitors are effective as adjunct therapy to insulin in T1DM, heralding improved glycemic control, reduced body weight and total daily insulin dose without an increase in total AEs, hypoglycemia, or genital and urinary infections. However, the risk of DKA should be carefully monitored in future clinical trials.
Diabetes is a chronic disease associated with micro- and macrovascular complications and is a well-established risk factor for cardiovascular disease. Cardiovascular complications associated with diabetes are among the most important causes of death in diabetic patients. Interestingly, several sex-gender differences have been reported to significantly impact in the pathophysiology of diabetes. In particular, sex-gender differences have been reported to affect diabetes epidemiology, risk factors, as well as cardiovascular complications associated with diabetes. This suggests that different therapeutic approaches are needed for managing diabetes-associated cardiovascular complications in men and women. In this review, we will discuss about the sex-gender differences that are known to impact on diabetes, mainly focusing on the cardiovascular complications associated with the disease. We will then discuss the therapeutic approaches for managing diabetes-associated cardiovascular complications and how differences in sex-gender can influence the existing therapeutic approaches.
Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease.
METHODS:
In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.
RESULTS:
During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). There were no significant between-group differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32).
CONCLUSIONS:
Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events. (Funded by Merck Sharp & Dohme; TECOS ClinicalTrials.gov number, NCT00790205.).
Background:
We investigated whether intensive glycemic control, combination therapy for dyslipidemia, and intensive blood-pressure control would limit the progression of diabetic retinopathy in persons with type 2 diabetes. Previous data suggest that these systemic factors may be important in the development and progression of diabetic retinopathy.
Methods:
In a randomized trial, we enrolled 10,251 participants with type 2 diabetes who were at high risk for cardiovascular disease to receive either intensive or standard treatment for glycemia (target glycated hemoglobin level, <6.0% or 7.0 to 7.9%, respectively) and also for dyslipidemia (160 mg daily of fenofibrate plus simvastatin or placebo plus simvastatin) or for systolic blood-pressure control (target, <120 or <140 mm Hg). A subgroup of 2856 participants was evaluated for the effects of these interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy.
Results:
At 4 years, the rates of progression of diabetic retinopathy were 7.3% with intensive glycemia treatment, versus 10.4% with standard therapy (adjusted odds ratio, 0.67; 95% confidence interval [CI], 0.51 to 0.87; P=0.003); 6.5% with fenofibrate for intensive dyslipidemia therapy, versus 10.2% with placebo (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; P=0.006); and 10.4% with intensive blood-pressure therapy, versus 8.8% with standard therapy (adjusted odds ratio, 1.23; 95% CI, 0.84 to 1.79; P=0.29).
Conclusions:
Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov numbers, NCT00000620 for the ACCORD study and NCT00542178 for the ACCORD Eye study.)
Significance
Subcutaneous injections of insulin sustain life in mammals unable to produce insulin (type 1 diabetes) but do not prevent hyperglycemic and hypoglycemic swings or decrease hemoglobin A1c levels to normal amounts. In mice treated with insulin alone, repeated episodes of transient elevated blood glucose cause long-term damage. We show that in mice with type 1 diabetes treated with insulin, the transient high blood glucose levels require production of glucagon, a hormone that will cause the liver to produce more glucose. Blocking the action of glucagon with an antibody to the glucagon receptor completely normalizes blood glucose and hemoglobin A1c in the complete absence of insulin therapy. Suppressing glucagon action in combination with low-dose insulin would be a superior treatment for type 1 diabetes.
BACKGROUND:
The cardiovascular safety and efficacy of many current antihyperglycemic agents, including saxagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, are unclear.
METHODS:
We randomly assigned 16,492 patients with type 2 diabetes who had a history of, or were at risk for, cardiovascular events to receive saxagliptin or placebo and followed them for a median of 2.1 years. Physicians were permitted to adjust other medications, including antihyperglycemic agents. The primary end point was a composite of cardiovascular death, myocardial infarction, or ischemic stroke.
RESULTS:
A primary end-point event occurred in 613 patients in the saxagliptin group and in 609 patients in the placebo group (7.3% and 7.2%, respectively, according to 2-year Kaplan-Meier estimates; hazard ratio with saxagliptin, 1.00; 95% confidence interval [CI], 0.89 to 1.12; P=0.99 for superiority; P<0.001 for noninferiority); the results were similar in the "on-treatment" analysis (hazard ratio, 1.03; 95% CI, 0.91 to 1.17). The major secondary end point of a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure occurred in 1059 patients in the saxagliptin group and in 1034 patients in the placebo group (12.8% and 12.4%, respectively, according to 2-year Kaplan-Meier estimates; hazard ratio, 1.02; 95% CI, 0.94 to 1.11; P=0.66). More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%; hazard ratio, 1.27; 95% CI, 1.07 to 1.51; P=0.007). Rates of adjudicated cases of acute and chronic pancreatitis were similar in the two groups (acute pancreatitis, 0.3% in the saxagliptin group and 0.2% in the placebo group; chronic pancreatitis, <0.1% and 0.1% in the two groups, respectively).
CONCLUSIONS:
DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, though the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes. (Funded by AstraZeneca and Bristol-Myers Squibb; SAVOR-TIMI 53 ClinicalTrials.gov number, NCT01107886.).
Background
To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome. Methods
We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. ResultsA total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo. Conclusions
Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.)
Epidemiologic studies have shown a relationship between glycated hemoglobin levels and cardiovascular events in patients with type 2 diabetes. We investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors.
In this randomized study, 10,251 patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level from 7.0 to 7.9%). Of these patients, 38% were women, and 35% had had a previous cardiovascular event. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up.
At 1 year, stable median glycated hemoglobin levels of 6.4% and 7.5% were achieved in the intensive-therapy group and the standard-therapy group, respectively. During follow-up, the primary outcome occurred in 352 patients in the intensive-therapy group, as compared with 371 in the standard-therapy group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P=0.16). At the same time, 257 patients in the intensive-therapy group died, as compared with 203 patients in the standard-therapy group (hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04). Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (P<0.001).
As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)
Objective:
To evaluate the efficacy and safety of basal insulin peglispro (BIL) versus insulin glargine in patients with type 2 diabetes (hemoglobin A1c [HbA1c] ≤9% [75 mmol/mol]) treated with basal insulin alone or with three or fewer oral antihyperglycemic medications.
Research design and methods:
This 52-week, open-label, treat-to-target study randomized patients (mean HbA1c7.42% [57.6 mmol/mol]) to BIL (n = 307) or glargine (n = 159). The primary end point was change from baseline HbA1c to 26 weeks (0.4% [4.4 mmol/mol] noninferiority margin).
Results:
At 26 weeks, reduction in HbA1c was superior with BIL versus glargine (-0.82% [-8.9 mmol/mol] vs. -0.29% [-3.2 mmol/mol]; least squares mean difference -0.52%, 95% CI -0.67 to -0.38 [-5.7 mmol/mol, 95% CI -7.3 to -4.2; P < 0.001); greater reduction in HbA1c with BIL was maintained at 52 weeks. More BIL patients achieved HbA1c <7% (53 mmol/mol) at weeks 26 and 52 (P < 0.001). With BIL versus glargine, nocturnal hypoglycemia rate was 60% lower, more patients achieved HbA1c <7% (53 mmol/mol) without nocturnal hypoglycemia at 26 and 52 weeks (P < 0.001), and total hypoglycemia rates were lower at 52 weeks (P = 0.03). At weeks 26 and 52, glucose variability was lower (P < 0.01), basal insulin dose was higher (P < 0.001), and triglycerides and aminotransferases were higher with BIL versus glargine (P < 0.05). Liver fat content (LFC), assessed in a subset of patients (n = 162), increased from baseline with BIL versus glargine (P < 0.001), with stable levels between 26 and 52 weeks.
Conclusions:
BIL provided superior glycemic control versus glargine, with reduced nocturnal and total hypoglycemia, lower glucose variability, and increased triglycerides, aminotransferases, and LFC.
Background:
Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease.
Methods:
In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.
Results:
During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). There were no significant between-group differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32).
Conclusions:
Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events. (Funded by Merck Sharp & Dohme; TECOS ClinicalTrials.gov number, NCT00790205.).
Background
The cardiovascular safety and efficacy of many current antihyperglycemic agents, including saxagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, are unclear. Methods
We randomly assigned 16,492 patients with type 2 diabetes who had a history of, or were at risk for, cardiovascular events to receive saxagliptin or placebo and followed them for a median of 2.1 years. Physicians were permitted to adjust other medications, including antihyperglycemic agents. The primary end point was a composite of cardiovascular death, myocardial infarction, or ischemic stroke. ResultsA primary end-point event occurred in 613 patients in the saxagliptin group and in 609 patients in the placebo group (7.3% and 7.2%, respectively, according to 2-year Kaplan-Meier estimates; hazard ratio with saxagliptin, 1.00; 95% confidence interval [CI], 0.89 to 1.12; P=0.99 for superiority; P<0.001 for noninferiority); the results were similar in the on-treatment analysis (hazard ratio, 1.03; 95% CI, 0.91 to 1.17). The major secondary end point of a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure occurred in 1059 patients in the saxagliptin group and in 1034 patients in the placebo group (12.8% and 12.4%, respectively, according to 2-year Kaplan-Meier estimates; hazard ratio, 1.02; 95% CI, 0.94 to 1.11; P=0.66). More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%; hazard ratio, 1.27; 95% CI, 1.07 to 1.51; P=0.007). Rates of adjudicated cases of acute and chronic pancreatitis were similar in the two groups (acute pancreatitis, 0.3% in the saxagliptin group and 0.2% in the placebo group; chronic pancreatitis, <0.1% and 0.1% in the two groups, respectively). ConclusionsDPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, though the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes.
People with type 2 diabetes are at risk of cognitive impairment and brain atrophy. We aimed to compare the effects on cognitive function and brain volume of intensive versus standard glycaemic control.
The Memory in Diabetes (MIND) study was done in 52 clinical sites in North America as part of Action to Control Cardiovascular Risk in Diabetes (ACCORD), a double two-by-two factorial parallel group randomised trial. Participants (aged 55-80 years) with type 2 diabetes, high glycated haemoglobin A(1c) (HbA(1c)) concentrations (>7·5%; >58 mmol/mol), and a high risk of cardiovascular events were randomly assigned to receive intensive glycaemic control targeting HbA(1c) to less than 6·0% (42 mmol/mol) or a standard strategy targeting HbA(1c) to 7·0-7·9% (53-63 mmol/mol). Randomisation was via a centralised web-based system and treatment allocation was not masked from clinic staff or participants. We assessed our cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, at baseline and at 20 and 40 months. We assessed total brain volume (TBV), our primary brain structure outcome, with MRI at baseline and 40 months in a subset of participants. We included all participants with follow-up data in our primary analyses. In February, 2008, raised mortality risk led to the end of the intensive treatment and transition of those participants to standard treatment. We tested our cognitive function hypotheses with a mixed-effects model that incorporated information from both the 20 and 40 month outcome measures. We tested our MRI hypotheses with an ANCOVA model that included intracranial volume and factors used to stratify randomisation. This study is registered with ClinicalTrials.gov, number NCT00182910.
We consecutively enrolled 2977 patients (mean age 62·5 years; SD 5·8) who had been randomly assigned to treatment groups in the ACCORD study. Our primary cognitive analysis was of patients with a 20-month or 40-month DSST score: 1378 assigned to receive intensive treatment and 1416 assigned to receive standard treatment. Of the 614 patients with a baseline MRI, we included 230 assigned to receive intensive treatment and 273 assigned to receive standard treatment in our primary MRI analysis at 40 months. There was no significant treatment difference in mean 40-month DSST score (difference in mean 0·32, 95% CI -0·28 to 0·91; p=0·2997). The intensive-treatment group had a greater mean TBV than the standard-treatment group (4·62, 2·0 to 7·3; p=0·0007).
Although significant differences in TBV favoured the intensive treatment, cognitive outcomes were not different. Combined with the non-significant effects on other ACCORD outcomes, and increased mortality in participants in the intensive treatment group, our findings do not support the use of intensive therapy to reduce the adverse effects of diabetes on the brain in patients with similar characteristics to those of our participants.
US National Institute on Aging and US National Heart, Lung, and Blood Institute.
The Action to Control Cardiovascular Risk in Diabetes Study Group
The Action to Control Cardiovascular Risk in Diabetes Study Group.
Effects of intensive glucose lowering
in type 2 diabetes. N Engl J Med
2008; 358: 2545-2559.
At the two highest doses (60 μg/kg once-daily and 30 μg/kg twice-daily), mean HbA1c fell 0.4% in 14 days (P < 0.01 vs placebo). The highest dose was also associated with a significant weight reduction of 2.1 kg (~4.6 lb) over 14 days (P < 0.001). AZP-531 was well-tolerated across all doses
- Alizé Pharma
Alizé Pharma (Ecully, France) announced positive Phase 1b results for its unacylated ghrelin analog
AZP-531 in type 2 diabetes (T2D). The double-blind 14-day multiple ascending dose trial (n = 36)
investigated three doses of AZP-531 compared with placebo in patients with T2D on metformin.
At the two highest doses (60 μg/kg once-daily and 30 μg/kg twice-daily), mean HbA1c fell 0.4%
in 14 days (P < 0.01 vs placebo). The highest dose was also associated with a significant weight
reduction of 2.1 kg (~4.6 lb) over 14 days (P < 0.001). AZP-531 was well-tolerated across all
doses.
November 4:
Adocia announced positive Phase 1b results from a double-blind cross-over study comparing its
BioChaperone Combo (75% glargine + 25% lispro) with Humalog Mix 75/25 (75% lispro protamine +
25% lispro) in 28 people with type 1 diabetes (T1D). The study met its primary endpoint, demonstrating
superior post-meal glucose control (area under the curve 0-2 h) with BioChaperone Combo versus
Humalog Mix (89 vs 118 mg·h/dL;