The role of melatonin in the treatment of type 2 diabetes mellitus and Alzheimer's disease

In type 2 diabetes mellitus (T2DM) and its related disorders like obesity, the abnormal protein processing, oxidative stress and proinflammatory cytokines will drive the activation of inflammatory pathways, leading to low-grade chronic inflammation and insulin resistance (IR) in the periphery and impaired neuronal insulin signaling in the brain. Studies have shown that such inflammation and impaired insulin signaling contribute to the development of Alzheimer''s disease (AD). Therefore, new therapeutic strategies are needed for the treatment of T2DM and T2DM-linked AD. Melatonin is primarily known for its circadian role which conveys message of darkness and induces night-state physiological functions. Besides rhythm-related effects, melatonin has anti-inflammatory and antioxidant properties. Melatonin levels are downregulated in metabolic disorders with IR, and activation of melatonin signaling delays disease progression. The aim of this Review is to highlight the therapeutic potentials of melatonin in preventing the acceleration of AD in T2DM individuals through its therapeutic mechanisms, including antioxidative effects, anti-inflammatory effects, restoring mitochondrial function and insulin sensitivity.     

Insulin resistance, hyperglycemia, and atherosclerosis

Progress in preventing atherosclerotic coronary artery disease (CAD) has been stalled by the epidemic of type 2 diabetes. Further advances in this area demand a thorough understanding of how two major features of type 2 diabetes, insulin resistance and hyperglycemia, impact atherosclerosis. Insulin resistance is associated with systemic CAD risk factors, but increasing evidence suggests that defective insulin signaling in atherosclerotic lesional cells also plays an important role. The role of hyperglycemia in CAD associated with type 2 diabetes is less clear. Understanding the mechanisms whereby type 2 diabetes exacerbates CAD offers hope for new therapeutic strategies to prevent and treat atherosclerotic vascular disease.     

The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis

Endothelial cells play essential roles in maintenance of vascular integrity, angiogenesis, and wound repair. We show that an endothelial cell-restricted microRNA (miR-126) mediates developmental angiogenesis in vivo. Targeted deletion of miR-126 in mice causes leaky vessels, hemorrhaging, and partial embryonic lethality, due to a loss of vascular integrity and defects in endothelial cell proliferation, migration, and angiogenesis. The subset of mutant animals that survives displays defective cardiac neovascularization following myocardial infarction. The vascular abnormalities of miR-126 mutant mice resemble the consequences of diminished signaling by angiogenic growth factors, such as VEGF and FGF. Accordingly, miR-126 enhances the proangiogenic actions of VEGF and FGF and promotes blood vessel formation by repressing the expression of Spred-1, an intracellular inhibitor of angiogenic signaling. These findings have important therapeutic implications for a variety of disorders involving abnormal angiogenesis and vascular leakage.     

Reciprocal relationships between abnormal metabolic parameters and endothelial dysfunction

PURPOSE OF REVIEW: Endothelial dysfunction plays a crucial role in the pathogenesis of atherosclerosis and related cardiovascular diseases. Glucotoxicity, lipotoxicity, and inflammation all independently contribute to development of both endothelial dysfunction and insulin resistance. We review pathophysiological mechanisms underlying reciprocal relationships between endothelial dysfunction and insulin resistance and recent insights from therapeutic interventions to improve both metabolic and vascular function. RECENT FINDINGS: Shared causal factors such as glucotoxicity, lipotoxicity, and inflammation interact at multiple levels creating reciprocal relationships between insulin resistance and endothelial dysfunction that help to explain frequent clustering of metabolic and cardiovascular disorders. Metabolic abnormalities implicated in the development of insulin resistance, including hyperglycemia, elevated levels of free fatty acids, accumulation of advanced glycation end products, dyslipidemias, and decreased levels of adiponectin, also contribute importantly to endothelial dysfunction. Diet, exercise, cardiovascular drugs, and insulin sensitizers simultaneously improve endothelium-dependent vascular function, reduce inflammation, and improve insulin sensitivity by both distinct and interrelated mechanisms. SUMMARY: Pathophysiological mechanisms underlying reciprocal relationships between endothelial dysfunction and insulin resistance contribute to clustering of metabolic and cardiovascular diseases represented by the metabolic syndrome. Therapeutic interventions that target endothelial dysfunction or insulin resistance often simultaneously improve both metabolic and vascular function.     

Mechanoresponse of stem cells for vascular repair

Stem cells have shown great potential in vascular repair. Numerous evidence indicates that mechanical forces such as shear stress and cyclic strain can regulate the adhesion, proliferation, migration, and differentiation of stem cells via serious signaling pathways. The enrichment and differentiation of stem cells play an important role in the angiogenesis and maintenance of vascular homeostasis. In normal tissues, blood flow directly affects the microenvironment of vascular endothelial cells (ECs); in pathological status, the abnormal interactions between blood flow and vessels contribute to the injury of vessels. Next, the altered mechanical forces are transduced into cells by mechanosensors to trigger the reformation of vessels. This process occurs when signaling pathways related to EC differentiation are initiated. Hence, a deep understanding of the responses of stem cells to mechanical stresses and the underlying mechanisms involved in this process is essential for clinical translation. In this the review, we provide an overview of the role of stem cells in vascular repair, outline the performance of stem cells under the mechanical stress stimulation, and describe the related signaling pathways.     

Insulin allergy and extensive lipoatrophy in child with type 1 diabetes

Insulin allergy and lipoatrophy in type 1 diabetic patients have been previously reported but the mechanisms are not well documented. Here, we report a case emphasizing the role of abnormal local immune reaction associated with cytokine hyper production. The patient is a 7-year-old boy with a familial history of common variable immunodeficiency. Eight months after the diagnosis of type 1 diabetes, he developed signs of insulin allergy expressed as continuously extensive and profound lipoatrophy contrasting with a well-preserved metabolic control. Specific insulin allergy was confirmed by skin prick tests that showed lymphoid activated cells in the subcutaneous tissue at the site of insulin injection. All therapies reported in the literature (antihistaminic, local steroid, change to lispro insulin, immunosuppressive treatment, subcutaneous insulin pump, peritoneal insulin infusion) were not efficient. It is suggested that familial disorders of immune cell functions with abnormal and excessive cytokine production might explain these adverse effects triggered by insulin with severe allergic reactions and lipoatrophy.     

Loss of Urokinase Receptor Sensitizes Cells to DNA Damage and Delays DNA Repair

DNA damage induced by numerous exogenous or endogenous factors may have irreversible consequences on the cell leading to cell cycle arrest, senescence and cell death. The DNA damage response (DDR) is powerful signaling machinery triggered in response to DNA damage, to provide DNA damage recognition, signaling and repair. Most anticancer drugs induce DNA damage, and DNA repair in turn attenuates therapeutic efficiency of those drugs. Approaches delaying DNA repair are often used to increase efficiency of treatment. Recent data show that ubiquitin-proteasome system is essential for signaling and repair of DNA damage. However, mechanisms providing regulation of proteasome intracellular localization, activity, and recruitment to DNA damage sites are elusive. Even less investigated are the roles of extranuclear signaling proteins in these processes. In this study, we report the involvement of the serine protease urokinase-type plasminogen activator receptor (uPAR) in DDR-associated regulation of proteasome. We show that in vascular smooth muscle cells (VSMC) uPAR activates DNA single strand break repair signaling pathway. We provide evidence that uPAR is essential for functional assembly of the 26S proteasome. We further demonstrate that uPAR mediates DNA damage-induced phosphorylation, nuclear import, and recruitment of the regulatory subunit PSMD6 to proteasome. We found that deficiency of uPAR and PSMD6 delays DNA repair and leads to decreased cell survival. These data may offer new therapeutic approaches for diseases such as cancer, cardiovascular and neurodegenerative disorders.     

Proapoptotic and antiapoptotic effects of hyperglycemia: role of insulin signaling

Glucose toxicity is an important initiator of cardiovascular disease, contributing to the development of insulin resistance, impaired contractile function, abnormal energy metabolism, cardiomyocyte and endothelial cell death, coronary heart disease, and heart failure. High blood glucose can, however, paradoxically protect the heart against a variety of insults, including ischemia, hypoxia, and calcium overload. To provide information on the underlying basis of these divergent actions of high glucose, the present study examined the hypothesis that the adverse effects of high glucose are linked to impaired insulin signaling, leading to a reduction in the levels of cytoprotective factors, and that the beneficial effects of high glucose occur in the absence of insulin and result in an improvement in Akt signaling. This hypothesis was evaluated by using an in vitro cardiomyocyte model that is amenable to manipulations in glucose and insulin. Prolonged exposure of the isolated neonatal cardiomyocyte to medium containing insulin and high glucose led to increased susceptibility to angiotensin II-mediated apoptosis, an effect associated with reduced levels of phospho-Akt and an increased Bax/Bcl-2 ratio. By contrast, exposure to high glucose levels in the absence of insulin rendered the cardiomyocyte resistant to angiotensin II-mediated apoptosis. Because the beneficial effects of high glucose were associated with elevations in phospho-Akt and Bcl-2 content, the cardioprotective activity of high glucose resembles the actions of insulin. Hence, the activation state of Akt is largely determined by the activity of insulin and other growth factors. Because high glucose diminishes insulin signaling, it reduces phospho-Akt levels and renders the cell susceptible to damaging insults. In the absence of insulin, however, the natural activity of high glucose is unmasked. As a result, Akt signaling is increased and the cell is rendered resistant to cell death.     

Regulation of adult stem cell behavior by nutrient signaling

Adult stem cells play an essential role?throughout life, maintaining tissue and organ function by providing a reservoir of cells for homeostasis and repair. Maintenance and activity of adult stem cells have been the focus of numerous studies that have revealed stem cell-intrinsic factors and signals from the local microenvironment that regulate stem cell behavior. A growing body of work has provided evidence that circulating, systemic factors also contribute to the regulation of stem cell behavior in numerous tissues. We have demonstrated that Drosophila male germline stem cells (GSCs) and intestinal stem cells (ISCs) respond to changes in nutrient availability, specifically amino acids. Furthermore, we have shown that insulin signaling plays an important role in mediating the effects of changes in nutritional conditions. Notably, insulin signaling is cell-autonomously required within male GSCs for maintenance. Here we discuss our data regarding the effects and mechanisms by which changes in systemic nutritional conditions may influence the maintenance and activity of adult stem cells via insulin signaling.     

p66Shc-generated oxidative signal promotes fat accumulation

Reactive oxygen species (ROS) and insulin signaling in the adipose tissue are critical determinants of aging and age-associated diseases. It is not clear, however, if they represent independent factors or they are mechanistically linked. We investigated the effects of ROS on insulin signaling using as model system the p66(Shc)-null mice. p66(Shc) is a redox enzyme that generates mitochondrial ROS and promotes aging in mammals. We report that insulin activates the redox enzyme activity of p66(Shc) specifically in adipocytes and that p66(Shc)-generated ROS regulate insulin signaling through multiple mechanisms, including AKT phosphorylation, Foxo localization, and regulation of selected insulin target genes. Deletion of p66(Shc) resulted in increased mitochondrial uncoupling and reduced triglyceride accumulation in adipocytes and in vivo increased metabolic rate and decreased fat mass and resistance to diet-induced obesity. In addition, p66(Shc-/-) mice showed impaired thermo-insulation. These findings demonstrate that p66(Shc)-generated ROS regulate the effect of insulin on the energetic metabolism in mice and suggest that intracellular oxidative stress might accelerate aging by favoring fat deposition and fat-related disorders.     

Genetics of common forms of glycaemia with pathological impact on vascular biology: are we on the right track?

The common forms of abnormal glucose regulation including type 2 diabetes and impaired glucose tolerance with pathological implications on vascular biology have a complex aetiology involving multiple cross-talks between genetic influences and important environmental modifying factors. Due to complexity of the genetics and the clinical heterogeneity of these disorders it has proven difficult to apply the same methodological approaches that have recently given insights into the molecular genetics of several single-gene disorders of glucose metabolism. This review gives some reflections on the challenges posed by the current hypotheses about the genetics of the widespread forms of abnormal glucose regulation as well as on the strengths and limitations of the methodological approaches applied to unravel the genetic components of common disorders. Also, we review recent progress in relation to a model for the pathogenesis of the various stages of abnormal glucose regulation based on the concepts of thrifty genes of metabolism and pro-inflammation and genes responsible for the appearance of impaired pancreatic beta-cell function and insulin signalling under the pressure of a westernized environment.     

Regulation of angiogenesis: wound healing as a model

Normal tissue function requires adequate supply of oxygen through blood vessels. Understanding how blood vessels form is a challenging objective because angiogenesis is vital to many physiological and pathological processes. Unraveling mechanisms of angiogenesis would offer therapeutic options to ameliorate disorders that are currently leading causes of mortality and morbidity, including cardiovascular diseases, cancer, chronic inflammatory disorders, diabetic retinopathy, excessive tissue defects, and chronic non-healing wounds. Restoring blood flow to the site of injured tissue is a prerequisite for mounting a successful repair response, and wound angiogenesis represents a paradigmatic model to study molecular mechanisms involved in the formation and remodeling of vascular structures. In particular, repair of skin defects offers an ideal model to analyze angiogenesis due to its easy accessibility to control and manipulate this process. Most of those growth factors, extracellular matrix molecules, and cell types, recently discovered and considered as crucial factors in blood vessel formation, have been identified and analyzed during skin repair and the process of wound angiogenesis. This article will review cellular and molecular mechanisms controlling angiogenesis in cutaneous tissue repair in light of recent reports and data from our laboratories. In this article we will discuss the contribution of growth factors, basement membrane molecules, and mural cells in wound angiogenesis. The article provides a rationale for targeting the angiogenic response in order to modulate the outcome of the healing response.     

The role of transforming growth factor (TGF)-β in modulating the immune response and fibrogenesis in the gut

Transforming growth factor (TGF)-β, a pleiotropic cytokine released by both immune and non-immune cells in the gut, exerts an important tolerogenic action by promoting regulatory T cell differentiation. TGF-β also enhances enterocyte migration and regulates extracellular matrix turnover, thereby playing a crucial role in tissue remodeling in the gut. In this review we describe the mechanisms by which abnormal TGF-β signaling impairs intestinal immune tolerance and tissue repair, thus predisposing to the onset of immune-mediated bowel disorders, such as inflammatory bowel disease and celiac disease. Additionally, we will discuss potential therapeutic strategies aiming at restoring physiologic TGF-β signaling in chronic intestinal diseases.     

Vascular effects of non-esterified fatty acids: implications for the cardiovascular risk factor cluster.

Insulin resistance emerges as a central component of the risk factor cluster and is a likely contributor to vascular disease independently of traditional risk factors such as hypertension and diabetes mellitus. However, the intermediary mechanisms by which atherosclerosis is accelerated among patients with the insulin resistance syndrome remain inadequately defined. Most of the attention has centered on hyperinsulinemia and defects of insulin-mediated glucose disposal. However, we observed that obese hypertensive patients have elevated plasma concentrations of non-esterified fatty acids (NEFAs), including oleic acid, which are highly resistant to suppression by insulin. Resistance to insulin's fatty acid lowering action correlate with blood pressure in obese subjects independently of defects in glucose disposal. This observation raises the possibility that NEFAs have biologically significant effects on the cardiovascular system. In fact, oleic acid impairs nitric oxide synthase activity and endothelium-dependent vasorelaxation in vitro. Moreover, raising NEFAs in normal human volunteers to levels observed in obese hypertensive patients impairs lower extremity endothelium-dependent vasodilation and augments local and systemic vascular alpha1-adrenoceptor reactivity in normal volunteers. Thus, raising NEFAs replicates in healthy subjects important functional vascular changes implicated in the hypertension and atherosclerosis observed in patients with the risk factor cluster. At a molecular level, experiments in cultured vascular smooth muscle cells demonstrate that oleic acid activates a mitogenic signaling cascade which includes protein kinase C, reactive oxygen species and extracellular signal-regulated kinases. Each of these signaling events has been implicated in the structural and functional vascular changes which accompany the risk factor cluster. Collectively, these observations raise the possibility that fatty acids contribute to functional and structural vascular changes among insulin-resistant individuals. A better understanding of the signaling mechanisms by which NEFAs exert their vascular effects may facilitate novel and more effective therapeutic approaches to managing the cardiovascular risk factor cluster.     

BMP signaling in vascular biology and dysfunction

The vascular system is critical for developmental growth, tissue homeostasis and repair but also for tumor development. Bone morphogenetic protein (BMP) signaling has recently emerged as a fundamental pathway of the endothelium by regulating cardiovascular and lymphatic development and by being causative for several vascular dysfunctions. Two vascular disorders have been directly linked to impaired BMP signaling: pulmonary arterial hypertension and hereditary hemorrhagic telangiectasia. Endothelial BMP signaling critically depends on the cellular context, which includes among others vascular heterogeneity, exposure to flow, and the intertwining with other signaling cascades (Notch, WNT, Hippo and hypoxia). The purpose of this review is to highlight the most recent findings illustrating the clear need for reconsidering the role of BMPs in vascular biology.     

Regulation of adult stem cell behavior by nutrient signaling

Adult stem cells play an essential role throughout life, maintaining tissue and organ function by providing a reservoir of cells for homeostasis and repair. Maintenance and activity of adult stem cells have been the focus of numerous studies that have revealed stem cell-intrinsic factors and signals from the local microenvironment that regulate stem cell behavior. A growing body of work has provided evidence that circulating, systemic factors also contribute to the regulation of stem cell behavior in numerous tissues. We have demonstrated that Drosophila male germline stem cells (GSCs) and intestinal stem cells (ISCs) respond to changes in nutrient availability, specifically amino acids. Furthermore, we have shown that insulin signaling plays an important role in mediating the effects of changes in nutritional conditions. Notably, insulin signaling is cell-autonomously required within male GSCs for maintenance. Here we discuss our data regarding the effects and mechanisms by which changes in systemic nutritional conditions may influence the maintenance and activity of adult stem cells via insulin signaling.Key words: Drosophila, stem cells, nutrition, insulin, niche     

Endothelial dysfunction — A major mediator of diabetic vascular disease

The vascular endothelium is a multifunctional organ and is critically involved in modulating vascular tone and structure. Endothelial cells produce a wide range of factors that also regulate cellular adhesion, thromboresistance, smooth muscle cell proliferation, and vessel wall inflammation. Thus, endothelial function is important for the homeostasis of the body and its dysfunction is associated with several pathophysiological conditions, including atherosclerosis, hypertension and diabetes. Patients with diabetes invariably show an impairment of endothelium-dependent vasodilation. Therefore, understanding and treating endothelial dysfunction is a major focus in the prevention of vascular complications associated with all forms of diabetes mellitus. The mechanisms of endothelial dysfunction in diabetes may point to new management strategies for the prevention of cardiovascular disease in diabetes. This review will focus on the mechanisms and therapeutics that specifically target endothelial dysfunction in the context of a diabetic setting. Mechanisms including altered glucose metabolism, impaired insulin signaling, low-grade inflammatory state, and increased reactive oxygen species generation will be discussed. The importance of developing new pharmacological approaches that upregulate endothelium-derived nitric oxide synthesis and target key vascular ROS-producing enzymes will be highlighted and new strategies that might prove clinically relevant in preventing the development and/or retarding the progression of diabetes associated vascular complications.     

MG53 and disordered metabolism in striated muscle

MG53 is a member of tripartite motif family (TRIM) that expressed most abundantly in striated muscle. Using rodent models, many studies have demonstrated the MG53 not only facilitates membrane repair after ischemia reperfusion injury, but also contributes to the protective effects of both pre- and post-conditioning. Recently, however, it has been shown that MG53 participates in the regulation of many metabolic processes, especially insulin signaling pathway. Thus, sustained overexpression of MG53 may contribute to the development of various metabolic disorders in striated muscle. In this review, using cardiac muscle as an example, we will discuss muscle metabolic disturbances associated with diabetes and the current understanding of the underlying molecular mechanisms; in particular, the pathogenesis of diabetic cardiomyopathy. We will focus on the pathways that MG53 regulates and how the dysregulation of MG53 leads to metabolic disorders, thereby establishing a causal relationship between sustained upregulation of MG53 and the development of muscle insulin resistance and metabolic disorders. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.