Angiotensin converting enzyme (ACE) activity levels in insulin-independent diabetes mellitus and effect of ACE levels on diabetic patients with nephropathy

Involvement of complications is considered to be one of the major factors in the prognosis of diabetes mellitus (DM). Recent studies indicate that most diabetic complications such as nephropathy and hypertension are vascular-originated. Renin-angiotensin involvement, especially changes in ACE activity level, is considered to be a key factor since ACE converts angiotensin I to angiotensin II which is a potent vasoconstrictor and plays a vital role in the regulation of blood pressure. Our present study focused on ACE activity levels along with blood glucose and HbA(1c) levels in diabetic patients with (n=18) or without (n=25) nephropathy as compared to control subjects (n=25). Blood glucose levels were significantly higher in both diabetic groups compared to controls (p<0.001). On the other hand, compared to controls, blood HbA(1c) levels were slightly higher in DM patients without complications whereas they were significantly increased in nephropatic DM patients (p<0.001). There was a very strong increase (p<0.001) at the level of ACE activity in both of the diabetic groups (with nephropathy: 47.11+/-3.70 U l(-1); without complications: 43.72+/-2.93 U l(-1); controls: 25.15+/-2.30 U l(-1)). ACE activity levels were also significantly higher in diabetic patients with nephropathy than in type II DM patients without complication (p<0.01). Our results demonstrate that ACE activity levels are increased in diabetic patients. Additional significant increase in ACE activity levels in diabetic patients with complications such as nephropathy supports the hypothesis that ACE activity has an essential role in the development of complications in diabetes.     

Emerging role of Akt kinase/protein kinase B signaling in pathophysiology of diabetes and its complications

In addition to a number of deleterious effects on cellular integrity and functions, diabetic metabolic milieu has been implicated in a rapidly growing number of alterations in signal transduction. In this review we focus on Akt kinase physiology, its alterations in diabetes mellitus (DM), and on the emerging role of this signaling system in the pathophysiology of diabetic microvascular complications. Studies focusing on Akt in diabetes suggest both decrease and increase of Akt activity in DM. Alterations of Akt activity have been found in various tissues and cells in diabetes depending on experimental and clinical contexts. There is convincing evidence suggesting defective Akt signaling in the development of insulin resistance. Similar defects, as in insulin-sensitive tissues, have been reported in endothelia of DM Type 2 models, possibly contributing to the development of endothelial dysfunction under these conditions. In contrast, Akt activity is increased in some tissues and vascular beds affected by complications in DM Type 1. Identification of the role of this phenomenon in DM-induced growth and hemodynamic alterations in affected vascular beds remains one of the major challenges for future research in this area. Future studies should include the evaluation of therapeutical benefits of pharmacological modulators of Akt activity.     

Insulin resistance,lipotoxicity and endothelial dysfunction

The number of people with the insulin-resistant conditions of type 2 diabetes mellitus (T2DM) and obesity has reached epidemic proportions worldwide. Eighty percent of people with T2DM will die from the complications of cardiovascular atherosclerosis. Insulin resistance is characterised by endothelial dysfunction, which is a pivotal step in the initiation/progression of atherosclerosis. A hallmark of endothelial dysfunction is an unfavourable imbalance between the bioavailability of the antiatherosclerotic signalling molecule nitric oxide (NO) and proatherosclerotic reactive oxygen species. In this review we discuss the mechanisms linking insulin resistance to endothelial dysfunction, with a particular emphasis on a potential role for a toxic effect of free fatty acids on endothelial cell homeostasis.     

Protective potential of cerium oxide nanoparticles in diabetes mellitus

BackgroundDiabetes mellitus (DM) is a non-communicable metabolic disease which is closely related to excessive oxidative stress after constant exposure to high plasma glucose. Although the current antidiabetic medications are effective in lowering blood glucose, these medications do not prevent or reverse the disease progression. Thus, there is a crucial need to explore new therapeutic interventions that could address this shortcoming. As cerium oxide nanoparticles (CONPs) possess antioxidant property, this agent may be used as a treatment option for the management of DM.PurposeThis review aims to provide a critical evaluation of the pharmacological and antidiabetic effects of CONPs in cell and animal models. The roles of CONPs in attenuating DM complications are also presented in this report.MethodsWe conducted a literature search in the PubMed database using the keywords “cerium oxide”, “cerous oxide”, “ceria”, “nanoceria”, and “diabetes” from inception to December 2020. The inclusion criteria were primary source articles that investigated the role of CONPs in DM and diabetic complications.ResultsWe identified 47 articles from the initial search. After the thorough screening, only 31 articles were included in this study. We found that CONPs can attenuate parameters that are related to DM and diabetic complications in various animals and cell culture models.ConclusionCONPs could potentially be used in the treatment of those with DM and complications caused by the disease.     

Hyperglycemia-induced oxidative stress in diabetic complications

Reactive oxygen species are increased by hyperglycemia. Hyperglycemia, which occurs during diabetes (both type 1 and type 2) and, to a lesser extent, during insulin resistance, causes oxidative stress. Free fatty acids, which may be elevated during inadequate glycemic control, may also be contributory. In this review, we will discuss the role of oxidative stress in diabetic complications. Oxidative stress may be important in diabetes, not just because of its role in the development of complications, but because persistent hyperglycemia, secondary to insulin resistance, may induce oxidative stress and contribute to beta cell destruction in type 2 diabetes. The focus of this review will be on the role of oxidative stress in the etiology of diabetic complications.     

Dysregulated autophagy: A key player in the pathophysiology of type 2 diabetes and its complications

Autophagy is essential in regulating the turnover of macromolecules via removing damaged organelles, misfolded proteins in various tissues, including liver, skeletal muscles, and adipose tissue to maintain the cellular homeostasis. In these tissues, a specific type of autophagy maintains the accumulation of lipid droplets which is directly related to obesity and the development of insulin resistance. It appears to play a protective role in a normal physiological environment by eliminating the invading pathogens, protein aggregates, and damaged organelles and generating energy and new building blocks by recycling the cellular components. Ageing is also a crucial modulator of autophagy process. During stress conditions involving nutrient deficiency, lipids excess, hypoxia etc., autophagy serves as a pro-survival mechanism by recycling the free amino acids to maintain the synthesis of proteins. The dysregulated autophagy has been found in several ageing associated diseases including type 2 diabetes (T2DM), cancer, and neurodegenerative disorders. So, targeting autophagy can be a promising therapeutic strategy against the progression to diabetes related complications. Our article provides a comprehensive outline of understanding of the autophagy process, including its types, mechanisms, regulation, and role in the pathophysiology of T2DM and related complications. We also explored the significance of autophagy in the homeostasis of β-cells, insulin resistance (IR), clearance of protein aggregates such as islet amyloid polypeptide, and various insulin-sensitive tissues. This will further pave the way for developing novel therapeutic strategies for diabetes-related complications.     

Coconut products alleviate hyperglycaemic,hyperlipidimic and nephropathy indices in streptozotocin-induced diabetic wistar rats

Type 2 diabetes mellitus (T2DM) is a chronic and one of the most common metabolic diseases affecting large proportion of world population. Diabetes-induced changes in lipid and renal parameters are major risk factors contributing to diabetic complications such as diabetic nephropathy and cardiovascular diseases. Due to adverse effects associated with pharmacological intervention in the T2DM treatment, there is an increased interest in the research focussing on identifying novel plant based therapeutic agents. Here we report the effects of various coconut products on diabetic, lipid and renal parameters in streptozotocin (STZ)-induced diabetic rat model. Diabetic rats demonstrated a significant increase in serum glucose, and glycated haemoglobin levels (HbA1c). Lipid parameters including triglycerides, total cholesterol, low density lipoprotein cholesterol (LDL-cholesterol) and very low density lipoprotein cholesterol (VLDL-cholesterol) were found to be significantly increased, while high density lipoprotein cholesterol (HDL-cholesterol) was significantly declined in diabetic rats. Diabetic rats also displayed increased serum and kidney creatinine, urea, and total protein levels and increased urine glucose, urea, albumin and creatinine levels. Contrastingly, treatment with virgin and filtered coconut oils, coconut water and coconut milk resulted in a significant reversal in the levels of above studied parameters in diabetic rats. Further, these coconut products markedly prevented diabetes induced histopathological changes in kidney tissue. Collectively, the data demonstrate the antidiabetic, hypolipidemic and renal protective properties of various coconut products and underscore the importance of regular consumption of plant based medicinal products in the treatment of T2DM and its complications.     

Sorghum phytochemicals and their potential impact on human health

Sorghum is a rich source of various phytochemicals including tannins, phenolic acids, anthocyanins, phytosterols and policosanols. These phytochemicals have potential to significantly impact human health. Sorghum fractions possess high antioxidant activity in vitro relative to other cereals or fruits. These fractions may offer similar health benefits commonly associated with fruits. Available epidemiological evidence suggests that sorghum consumption reduces the risk of certain types of cancer in humans compared to other cereals. The high concentration of phytochemicals in sorghum may be partly responsible. Sorghums containing tannins are widely reported to reduce caloric availability and hence weight gain in animals. This property is potentially useful in helping reduce obesity in humans. Sorghum phytochemicals also promote cardiovascular health in animals. Such properties have not been reported in humans and require investigation, since cardiovascular disease is currently the leading killer in the developed world. This paper reviews available information on sorghum phytochemicals, how the information relates to current phytonutrient research and how it has potential to combat common nutrition-related diseases including cancer, cardiovascular disease and obesity.     

Effects of curcumin on sodium currents of dorsal root ganglion neurons in type 2 diabetic neuropathic pain rats

Along with the development of economy and society, type 2 diabetic mellitus(T2DM) has become one of the most common diseases at the global level. As one of the complications of T2 DM, diabetic neuropathic pain(DNP) stubbornly and chronically affects the health and life of human beings. In the pain field, dorsal root ganglion(DRG) is generally considered as the first stage of the sensory pathway where the hyperexcitability of injured neurons is associated with different kinds of peripheral neuropathic pains. The abnormal electrophysiology is mainly due to the changed properties of voltage-gated sodium channels(VGSCs) and the increased sodium currents(INa). Curcumin is an active ingredient extracted from turmeric and has been demonstrated to ameliorate T2 DM and its various complications including DNP effectively. The present study demonstrates that the INa of small-sized DRG neurons are significantly increased with the abnormal electrophysiological characteristics of VGSCs in type 2 diabetic neuropathic pain rats. And these abnormalities can be ameliorated efficaciously by a period of treatment with curcumin.     

Alterations in circulating angiogenic and anti‐angiogenic factors in type 2 diabetic patients with neuropathy

Diabetic peripheral neuropathy (DPN) is one of the most common diabetic chronic complications. There is an increased attention directed towards the role of angiogenic factors including vascular endothelial growth factor (VEGF) and anti‐angiogenic factors including soluble endoglin (sEng) as contributors to diabetic microvascular complications including neuropathy. The purposes of this study were to determine the role of these angiogenesis regulators in the prognosis of DPN. The study group included 60 patients with type 2 diabetes mellitus (T2DM) and 20 clinically healthy individuals. The patients were divided into two groups. Group I included 20 T2DM patients without peripheral neuropathy, and Group II consisted of 40 T2DM patients with DPN. In all groups, plasma VEGF, sEng and endothelin‐1 (ET‐1), nitric oxide and ET‐1 mRNA were estimated. Plasma levels of VEGF, sEng, ET‐1 and nitric oxide were significantly elevated in diabetic patients (Groups I and II) compared with healthy control subjects, with a higher increase in their levels in patients with DPN compared with diabetic patients without peripheral neuropathy. Measurement of plasma levels of angiogenesis‐related biomarkers in high‐risk diabetic patients might identify who later develop DPN, thus providing opportunities for early detection and targets for novel treatments. Copyright © 2013 John Wiley & Sons, Ltd.     

Association of Genetic polymorphism of PPARγ-2, ACE,MTHFR, FABP-2 and FTO genes in risk prediction of type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a non-autoimmune, complex, heterogeneous and polygenic metabolic disease condition characterized by persistent elevated blood glucose levels (hyperglycemia). India as said to be the diabetic capital of the world is likely to experience the largest increase in T2DM and a greater number of diabetic individuals in the world by the year 2030. Identification of specific genetic variations in a particular ethnic group has a critical role in understanding the risk of developing T2DM in a much efficient way in future. These genetic variations include numerous types of polymorphisms among which single nucleotide polymorphisms (SNPs) is the most frequent. SNPs are basically located within the regulatory elements of several gene sequences. There are scores of genes interacting with various environmental factors affecting various pathways and sometimes even the whole signalling network that cause diseases like T2DM. This review discusses the biomarkers for early risk prediction of T2DM. Such predictions could be used in order to understand the pathogenesis of T2DM and to better diagnostics, treatment, and eventually prevention.     

Mitochondrial dysfunction in diabetes and the regulatory roles of antidiabetic agents on the mitochondrial function

The prevalence of type 2 diabetes mellitus (T2DM) is increasing rapidly with its associated morbidity and mortality. Many pathophysiological pathways such as oxidative stress, inflammatory responses, adipokines, obesity-induced insulin resistance, improper insulin signaling, and beta cell apoptosis are associated with the development of T2DM. There is increasing evidence of the role of mitochondrial dysfunction in the onset of T2DM, particularly in relation to the development of diabetic complications. Here, the role of mitochondrial dysfunction in T2DM is reviewed together with its modulation by antidiabetic therapeutic agents, an effect that may be independent of their hypoglycemic effect.     

Modulation of inflammatory signaling pathways by phytochemicals in ovarian cancer

Inflammation has been suggested to be involved in cancer development and progression. Many clinical and experimental studies have shown that inflammation could contribute to ovarian carcinogenesis through activation of the NF-κB and AP-1 pathways by chronic inflammatory mediators. Phytochemicals, which are natural compounds derived from fruits and vegetables, have shown anti-inflammatory and anti-cancer effects. Due to their relatively low toxicity and easy accessibility, phytochemicals have been investigated for their chemopreventive potential against various cancers. In this review, we discuss the role of phytochemicals in preventing ovarian cancer through anti-inflammatory mechanisms.     

基因技术在治疗2型糖尿病中的应用*

2型糖尿病(type 2 diabetes mellitus, T2DM)是一类由于胰岛β细胞损伤和机体对胰岛素耐受引发的慢性代谢性疾病,其快速增长的患病率和并发症所带来的高病死率已成为人类面临的医学难题。目前,T2DM主要是以降糖药物及胰岛素增敏剂等药物进行治疗,但是这类药物会产生严重的副作用,而且不能长期良好控制血糖和防止各种慢性并发症。因此,基因治疗是未来医疗发展的主要方向。基因治疗不仅可以靶向调控血糖水平进而提高降糖的效果,而且能够减少糖代谢异常引起的并发症,保护组织器官免受损伤。在认识传统药物治疗糖尿病的基础上,综述了基因技术在治疗T2DM中的应用,讨论了基因技术治疗T2DM的意义及存在的问题。基因技术的应用不仅有利于T2DM的预防和个体化治疗,同时也为糖尿病并发症提供了新的治疗途径。     

Altered profile of secondary metabolites in the root exudates of Arabidopsis ATP-binding cassette transporter mutants

Following recent indirect evidence suggesting a role for ATP-binding cassette (ABC) transporters in root exudation of phytochemicals, we identified 25 ABC transporter genes highly expressed in the root cells most likely to be involved in secretion processes. Of these 25 genes, we also selected six full-length ABC transporters and a half-size transporter for in-depth molecular and biochemical analyses. We compared the exuded root phytochemical profiles of these seven ABC transporter mutants to those of the wild type. There were three nonpolar phytochemicals missing in various ABC transporter mutants compared to the wild type when the samples were analyzed by high-performance liquid chromatography-mass spectrometry. These data suggest that more than one ABC transporter can be involved in the secretion of a given phytochemical and that a transporter can be involved in the secretion of more than one secondary metabolite. The primary and secondary metabolites present in the root exudates of the mutants were also analyzed by gas chromatography-mass spectrometry, which allowed for the identification of groups of compounds differentially found in some of the mutants compared to the wild type. For instance, the mutant Atpdr6 secreted a lower level of organic acids and Atmrp2 secreted a higher level of amino acids as compared to the wild type. We conclude that the release of phytochemicals by roots is partially controlled by ABC transporters.     

Differential expression of proteins in kidney, eye, aorta, and serum of diabetic and non-diabetic rats

Diabetes mellitus (DM) is a chronic progressive disease that often results in microvascular and macrovascular complications, yet its pathogenesis is not clear. Automated proteomic technology, coupled with powerful bioinformatics and statistical tools, can provide new insights into the molecular alterations implicated in DM. Following our previous findings of redox changes in the eye and aorta of diabetic rats, as well as the activities of different antioxidant enzymes during the development of DM, this study is further launched to find potential biomarkers by comparing the serum and tissue samples of 26 diabetic rats (8 weeks after streptozotocin [STZ] administration) with 29 normal controls using surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) technology. Eight potential biomarkers were found in the serum, one potential biomarker was found in the kidney and eye, respectively, whereas three potential biomarkers were discovered in the aorta. One of the serum biomarker candidates was found to match the C-reactive protein (CRP) in the Swiss-Prot knowledgebase. Further validation has been conducted by ELISA kit to confirm the role of CRP during the development of DM. To conclude, the increased level of CRP in diabetic serum demonstrated in this study indicates that the development of DM is associated with inflammation. This is also the first report demonstrating that some potential lysate biomarkers in the kidney, eye, and aorta may be involved in the development of diabetes and its complications. Further identification and evaluation of these potential biomarkers will help unravel the underlying mechanisms of the disease.     

Diagnostic utility of BNP,corin and furin as biomarkers for cardiovascular complications in type 2 diabetes mellitus patients

Abstract

Context: The number of patients with type 2 diabetes mellitus (T2DM) is progressively increasing, and diabetic cardiovascular complications have become a public health problem. Brain or B-type natriuretic peptide (BNP) is a cardiac hormone synthesized as a pre-pro-peptide. pro-BNP is produced by cleaving the signal peptide then two proprotein convertases, corin and furin cleave pro-BNP to form a biologically active hormone. Two corin single nucleotide polymorphisms (SNPs) have been reported to alter corin protein conformation and impair its biological activity.

Objective: We aimed to investigate the potential role of corin and furin in comparison to BNP as biomarkers for predicting cardiovascular complications in T2DM patients. The association of corin gene SNPs with corin levels was also examined.

Methods: Seventy-five subjects were recruited in this study, including 25 T2DM patients with complications, 25 T2DM patients without complications as well as 25 healthy subjects. Plasma BNP, corin and furin levels were measured using enzyme-linked immunosorbent assays. Two corin SNPs were genotyped using allele specific oligonucleotide-polymerase chain reaction.

Results: Both furin and BNP were found to be more sensitive than corin (80% versus 56%, p?=?0.008), whereas furin showed higher specificity when compared to BNP (96% versus 84%, p?=?0.041) and corin (96% versus 64%, p?<?0.0001) in predicting cardiovascular complications in T2DM patients. Corin SNPs are not associated with corin levels, neither in the entire study cohort nor in the subgroup of T2DM patients with cardiovascular complications (p?>?0.05).

Conclusions: Furin may be useful, either alone or in combination with other biomarkers, for cardiovascular risk stratification assessment in T2DM patients.     

An insight into the mechanisms of COVID-19, SARS-CoV2 infection severity concerning β-cell survival and cardiovascular conditions in diabetic patients

A significantly high percentage of hospitalized COVID-19 patients with diabetes mellitus (DM) had severe conditions and were admitted to ICU. In this review, we have delineated the plausible molecular mechanisms that could explain why there are increased clinical complications in patients with DM that become critically ill when infected with SARS-CoV2. RNA viruses have been classically implicated in manifestation of new onset diabetes. SARS-CoV2 infection through cytokine storm leads to elevated levels of pro-inflammatory cytokines creating an imbalance in the functioning of T helper cells affecting multiple organs. Inflammation and Th1/Th2 cell imbalance along with Th17 have been associated with DM, which can exacerbate SARS-CoV2 infection severity. ACE-2-Ang-(1–7)-Mas axis positively modulates β-cell and cardiac tissue function and survival. However, ACE-2 receptors dock SARS-CoV2, which internalize and deplete ACE-2 and activate Renin-angiotensin system (RAS) pathway. This induces inflammation promoting insulin resistance that has positive effect on RAS pathway, causes β-cell dysfunction, promotes inflammation and increases the risk of cardiovascular complications. Further, hyperglycemic state could upregulate ACE-2 receptors for viral infection thereby increasing the severity of the diabetic condition. SARS-CoV2 infection in diabetic patients with heart conditions are linked to worse outcomes. SARS-CoV2 can directly affect cardiac tissue or inflammatory response during diabetic condition and worsen the underlying heart conditions.

     

Identification of Novel Aldose Reductase Inhibitors from Spices: A Molecular Docking and Simulation Study

Hyperglycemia in diabetic patients results in a diverse range of complications such as diabetic retinopathy, neuropathy, nephropathy and cardiovascular diseases. The role of aldose reductase (AR), the key enzyme in the polyol pathway, in these complications is well established. Due to notable side-effects of several drugs, phytochemicals as an alternative has gained considerable importance for the treatment of several ailments. In order to evaluate the inhibitory effects of dietary spices on AR, a collection of phytochemicals were identified from Zingiber officinale (ginger), Curcuma longa (turmeric) Allium sativum (garlic) and Trigonella foenum graecum (fenugreek). Molecular docking was performed for lead identification and molecular dynamics simulations were performed to study the dynamic behaviour of these protein-ligand interactions. Gingerenones A, B and C, lariciresinol, quercetin and calebin A from these spices exhibited high docking score, binding affinity and sustained protein-ligand interactions. Rescoring of protein ligand interactions at the end of MD simulations produced binding scores that were better than the initially docked conformations. Docking results, ligand interactions and ADMET properties of these molecules were significantly better than commercially available AR inhibitors like epalrestat, sorbinil and ranirestat. Thus, these natural molecules could be potent AR inhibitors.