Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 12, Issue 2, 2012

Diabetes epidemic represents one of the major threats to the health and life of contemporary people as well as to the budget of the national health systems in both the developed and developing countries. Diabetes is a metabolic disease. Nonetheless, it is equally often considered a cardiovascular pathology, owing to its prevalent association with cardiovascular morbidity and mortality. In fact, in diabetic people, cardiovascular events are not only more frequent but they also result in more severe outcomes [1]. Although these facts are generally accepted, a more systematic characterization of the vicious diabetes attack to the heart and the vessels in various bodily districts and the molecular and cellular mechanisms underpinning these are only partially accomplished. Moreover, the majority of research focuses on the most notorious targets, including large vessels, the kidneys and they eyes. In this thematic issue, a series of seven excellent review articles target cardiovascular complications of diabetes from several complementary focuses. We start with the definition of recently described epigenetic mechanisms, which endure on the vascular chromatin under diabetic conditions [2]. Epigenetics is emerging as a fundamental area of basic and translational research. It represents a phenomenon of altered gene expression without changes in DNA sequence and which is heritable from mother cells to daughter cells and sometimes from parents to off-springs. Epigenetic modifications are mainly mediated by DNA methylation and histone modifications affecting the chromatin status and hence gene transcription. Epigenetics controls embryonic development, as it guides stem cell differentiation and cell lineage specification. Moreover, epigenetics is heavily involved in pathologies such as cancers and, as discussed here, diabetes. In fact, here, we detail how diabetes-induced epigenetic changes can affect gene expression in vascular cells and ensure a long-term memory, whereby epigenetic changes are maintained even long after restoring normo-glycaemic conditions [2]. Abdominal obesity is a major risk factor for both type 2 diabetes and cardiovascular disease. This is in part explained by the fact that the adipose tissue produces adipokines that regulate carbohydrate and lipid metabolism [3]. Adipokines include hormones, inflammatory cytokines and other proteins. Obesity and particularly visceral fat accumulation contributes to impaired insulin sensitivity and atherosclerosis, including through dysregulated production of adipokines [4]. In fact, in obesity, adipose tissue becomes dysfunctional, thus overproducing proinflammatory adipokines, while decreasing the production of beneficial adipokines, including adiponectin [5]. In their review for EMID-DT, Kishida and colleagues focus on adiponectin and illustrate the evidences suggesting that increase in visceral fat brings over hypoadiponectinemia, which in turn contributes to diabetes and atherosclerosis. They also present evidence of how positive changes in life style (proper sleep, nutrition and exercise), body weight loss and medications may increase circulating adiponectin levels and consequently help preventing diabetes and atherosclerosis [4]. Diabetes (both type 1 and type 2) targets the heart not only through contributing into coronary artery disease, but also and often independently by inducing a specific cardiomyopathy characterized by microangiopathy and deposition of interstitial fibrosis, which further limits myocardial perfusion. The overall results are alterations in systolic and diastolic function and ultimately heart failure [6-8]. It has been recently shown that diabetes brings over low or dysfunctional HDL, which in turn alters glucose metabolism. Hence, the existence of a vicious circle emerges. Here, Spillmann and colleagues give an overview of the influence of hyperglycemia, hyperinsulinemia, and dyslipidemia on diabetic cardiomyopathy. Moreover, they report the metabolic features and pleiotropic effects of HDL and explain how HDL could protect the diabetic heart [9]. It is well known that diabetic patients are more susceptible to stroke and that they are more prone to stroke-induced death or severe disabilities. Here, Ergul et al. illustrate the mechanisms and consequences of diabetes-induced cerebrovascular damage, focusing on the role of diabetes-induced brain microvascular disease in stroke pathogenesis and outcome [10]. One possible mechanistic explanation of increased number and severity of cardiovascular events in diabetic people is the diabetes-induced impairment of the cellular machinery, which contributes to tissue protection and repair. In their review, Mangialardi and colleagues focus on post-ischemic vascular regeneration in diabetes. Cumulative evidences suggest the contribution of heart- and/or vessel-resident progenitor cells in post-ischemic angiogenesis and blood flow recovery. In addition, a wide spectrum of inflammatory and/or proangiogenic cells is actively released from the bone marrow and recruited by the ischemic tissue to contribute into its healing. Diabetes severely affects the structure of the bone marrow, by inducing bone marrow microangiopathy [11]. This is associated with an altered stem and progenitor cells compartmentalization in the bone marrow endosteal and vascular niches, which result in changes in hematopoietic progenitor cell egression from the bone marrow and homing at sites of ischemic injury [1,11].....

Vascular dysfunction is a common consequence of diabetes mellitus. Stable propagation of gene expression from cell to cell generation during development of diseases (like diabetes) is regulated by epigenetic mechanisms. These are heritable patterns of gene expression that cannot solely be explained by changes in DNA sequence. Recent evidence shows that diabetes-induced epigenetic changes can affect gene expression in vascular endothelial cells and vascular smooth muscles cells. Such effects further influence inflammatory and insulin production pathways in these cells and thus ensure a long-term memory, whereby epigenetic changes are maintained even long after restoring normo-glycaemic conditions by appropriate therapeutic approaches. This review focuses on the epigenetic marks, which endure on the vascular chromatin under diabetic conditions.

Type 2 diabetes mellitus (T2DM) is a disease characterized by inadequate beta-cell response due to progressive insulin resistance that typically accompanies physical inactivity and weight gain. T2DM is associated with substantial morbidity and mortality related to the associated atherosclerotic cardiovascular risks and diabetic vasculopathies, including microangiopathies (e.g., blindness and renal failure) and macroangiopathies (atherosclerosis). The increasing global prevalence of T2DM is linked to the rising rates of obesity, especially abdominal obesity. Visceral fat accumulation is upstream of obesity-related disorders including atherosclerotic cardiovascular disease (ACVD), and is associated with impaired insulin sensitivity and atherosclerosis through dysregulated production of adipocytokines, especially hypoadiponectinemia. This review article discusses the pathophysiological mechanisms responsible for T2DM and atherosclerosis, focusing on adiponectin. Clinical and experimental studies have shown that hypoadiponectinemia contributes to a variety of life style-related diseases including T2DM and atherosclerosis. It is likely that life-style modification, visceral fat reduction and use of medications that increase serum adiponectin levels (e.g., rimonabant, thiazolidinediones, fibrates, angiotensin receptor blocker and mineralocorticoid receptor blockade) when provided in combination can improve hypoadiponectinemia and thus prevent the development of life style-related diseases including T2DM and ACVD.

Diabetic cardiopathy includes a specific cardiomyopathy, which occurs in the absence of coronary heart disease and hypertension under diabetes mellitus. Hyperglycemia, hyperinsulinemia, and hyperlipidemia, characteristic metabolic disturbances evident in diabetes mellitus, all three lead to a specific altered cardiac structure and function. Recently, it has been demonstrated that altered HDL, be it low HDL or dysfunctional HDL is not only a consequence of diabetes mellitus, but can also contribute to the development of diabetes mellitus, and therefore also of diabetic cardiomyopathy. This review summarizes how HDL can indirectly affect diabetic cardiomyopathy via their influence on the metabolic triggers hyperglycemia, hyperinsulinemia, and hyperlipidemia, and how they can directly influence the cardiac cellular consequences, typical for diabetic cardiomyopathy, including inflammation, oxidative stress, apoptosis, fibrosis, Ca2+ handling, glucose homeostasis, and endothelial dysfunction.

Cerebrovascular complications make diabetic patients 2-6 times more susceptible to a stroke event and this risk is magnified in younger individuals and in patients with hypertension and complications in other vascular beds. In addition, when patients with diabetes and hyperglycemia experience an acute ischemic stroke they are more likely to die or be severely disabled and less likely to benefit from the one FDA-approved therapy, intravenous tissue plasminogen activator. Experimental stroke models have revealed that chronic hyperglycemia leads to deficits in cerebrovascular structure and function that may explain some of the clinical observations. Increased edema, neovascularization and protease expression as well as altered vascular reactivity and tone may be involved and point to potential therapeutic targets. Further study is needed to fully understand this complex disease state and the breadth of its manifestation in the cerebrovasculature.

Diabetes mellitus is considered a cardiovascular disease owing to its prevalent association with cardiovascular morbidity and mortality. Cardiovascular events are not only more frequent but also complicated with more severe outcomes in diabetic patients as compared with non-diabetic patients. One mechanism accounting for this difference consists of the impairment of the regenerative cellular machinery, which contributes to tissue healing. Recent evidence indicates the contribution of resident progenitor cells in post-ischemic tissue remodeling. In addition, a wide spectrum of cells from distant sources, including the bone marrow, is attracted and home to the healing tissue. Diabetes affects the process of mobilization and recruitment as well as intrinsic functional properties of bone marrow-derived progenitor cells. This review highlights current evidence for diabetes-induced damage of bone marrow hematopoietic progenitor cells in the endosteal and vascular niches.

Diabetic neuropathy (DN), the most common complication of diabetes, frequently leads to foot ulcers and may progress to limb amputations. Despite continuous increase in incidence, there is no clinical therapy to effectively treat DN. Pathogenetically, DN is characterized by reduced vascularity in peripheral nerves and deficiency in angiogenic and neurotrophic factors. We will briefly review the pathogenetic mechanism of DN and address the effects and the mechanisms of cell therapies for DN. To reverse the changes of DN, studies have attempted to deliver neurotrophic or angiogenic factors for treatment in the form of protein or gene therapy; however, the effects turned out to be very modest if not ineffective. Recent studies have demonstrated that bone marrow (BM)-derived cells such as mononuclear cells or endothelial progenitor cells (EPCs) can effectively treat various cardiovascular diseases through their paracrine effects. As BM-derived cells include multiple angiogenic and neurotrophic cytokines, these cells were used for treating experimental DN and found to reverse manifestations of DN. Particularly, EPCs were shown to exert favorable therapeutic effects through enhanced neural neovascularization and neuro-protective effects. These findings clearly indicate that DN is a complex disorder with pathogenetic involvement of both vascular and neural components. Studies have shown that cell therapies targeting both vascular and neural elements are shown to be advantageous in treating DN.

Diabetes mellitus and cardiovascular diseases act as two sides of the same coin: diabetes is an important risk factor for cardiovascular disease while patients with ischemic cardiovascular diseases often have diabetes or pre-diabetes. As firstly shown by Framingham study, diabetic women have an increased cardiovascular risk about 3.5 fold higher than non diabetic women, against an increase of “only” 2.1 fold found in male subjects. In view of the impact of sexual hormones on glucose homeostasis, the molecular pathways involved in insulin resistance suggest a sex-gender specificity mechanism in the development of diabetic complications leading to the unmet need of sex-gender therapeutic approaches. This has also been seen in other diabetic complications such as renal diseases, which seems to progress at a faster rate in females compared with males and women benefit less from treatment than do men. Of note, none of the trials done so far are primarily designed to assess sex-gender differences in the benefit from a specific intervention strategy, de facto excluding fertile women from experimentation. In order to provide a more evidence based medicine for women and to reach equity between men and women, sex-gender epidemiological reports, preclinical and clinical research are mandatory to evaluate the impact of gender on the outcomes and to improve sex-gender awareness and competency in the health care system. Future studies should consider sex-gender differences in the setting of randomized controlled trials with drugs.

Glycerolipid acyltransfereases play important roles in physiological and pathophysiological processes of triglyceride (TAG) metabolism and energy balance. Glycerol-3-phosphate acyltransferases (GPATs) are key enzymes in the triglyceride biosynthetic pathway. In addition to the mitochondrial GPAT1 that was first cloned and studied, novel microsomal enzyme isoforms have been discovered in recent years. The potential function of one of the GPATs, GPAT4, was studied in GPAT4 deficient mice that suggested its role in TAG synthesis in multiple tissues. Monoacylglycerol and diacylglycerol acyltransferases (MGAT2 and DGAT1) are important enzymes involved in intestinal triglyceride absorption, and studies in recent years from knockout mice have revealed their important role in whole body energy metabolism through changes in intestinal TAG absorption kinetics. Both MGAT2 and DGAT1 mice are resistant to dietinduced obesity and have improved insulin sensitivity and hepatic TAG accumulation. These data suggest that these enzymes are intimately involved in TAG metabolism and whole body energy homeostasis and that inhibition of these enzymes may provide therapeutic benefits for metabolic disorders such as obesity, metabolic syndrome, and type 2 diabetes.

Celiac disease is a common and lifelong food intolerance, affecting approximately 1% of the population. Because of a mechanism not completely understood, the ingestion of wheat gluten, and of homologue proteins of barley and rye, induces in genetically predisposed individuals pronounced inflammatory reactions mainly at the site of small intestine. Gluten, the triggering factor, is a complex protein mixture highly resistant to the gastrointestinal enzymatic proteolysis, and this results in the presence of large, and potentially immunogenic, peptides at the intestinal mucosa surface. During the last decade, several studies have defined gluten peptides able to stimulate adaptive T cells, of either CD4 or CD8 phenotype, and to activate innate (non T) immune cells. This review examines the complete repertoire of gluten peptides recognized by celiac T cells and discusses the several translational implications that the identification of these epitopes opens.