Recently oxidative stress has been proposed as the cause of hypertension. An imbalance in superoxide and nitric oxide production may account for reduced vasodilation, which in turn can favor the ...development of hypertension. In vitro and in human studies support this hypothesis. The supplementation of antioxidants, particularly in the form of fresh fruit and vegetables, reduces blood pressure, supporting a role for free radicals in hypertension.
Abstract Large randomized studies have established that early intensive glycaemic control reduces the risk of diabetic complications, both micro and macrovascular. However, epidemiological and ...prospective data support a long-term influence of early metabolic control on clinical outcomes. This phenomenon has recently been defined as “metabolic memory”. Potential mechanisms for propagating this “memory” are the non-enzymatic glycation of cellular proteins and lipids, and an excess of cellular reactive oxygen and nitrogen species, in par ticular originated at the level of glycated-mitochondrial proteins, perhaps acting in concert with one another to maintain stress signaling. Furthermore, the emergence of this “metabolic memory” suggests the need of a very early aggressive treatment aiming to “nor malize” the metabolic control and the addition of agents which reduce cellular reactive species and glycation in addition to normalizing glucose levels in diabetic patients in order to minimize long-term diabetic complications.
Several studies suggest that, together with glucose variability, the variability of other risk factors, as blood pressure, plasma lipids, heart rate, body weight, and serum uric acid, might play a ...role in the development of diabetes complications. Moreover, the variability of each risk factor, when contemporarily present, may have additive effects. However, the question is whether variability is causal or a marker. Evidence shows that the quality of care and the attainment of the target impact on the variability of all risk factors. On the other hand, for some of them causality may be considered. Although specific studies are still lacking, it should be useful checking the variability of a risk factor, together with its magnitude out of the normal range, in clinical practice. This can lead to an improvement of the quality of care, which, in turn, could further hesitate in an improvement of risk factors variability.
New Insights on Oxidative Stress and Diabetic Complications May Lead to a “Causal” Antioxidant Therapy
Antonio Ceriello , MD
From the Department of Pathology and Medicine, Experimental and Clinical, ...Chair of Internal Medicine, University of Udine,
Udine, Italy
Abstract
Evidence implicates hyperglycemia-derived oxygen free radicals as mediators of diabetic complications. However, intervention
studies with classic antioxidants, such as vitamin E, failed to demonstrate any beneficial effect. Recent studies demonstrate
that a single hyperglycemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain
seems to be the first and key event in the activation of all other pathways involved in the pathogenesis of diabetic complications.
These include increased polyol pathway flux, increased advanced glycosylation end product formation, activation of protein
kinase C, and increased hexosamine pathway flux. Superoxide overproduction is accompanied by increased nitric oxide generation,
due to an endothelial NOS and inducible NOS uncoupled state, a phenomenon favoring the formation of the strong oxidant peroxynitrite,
which in turn damages DNA. DNA damage is an obligatory stimulus for the activation of the nuclear enzyme poly(ADP-ribose)
polymerase. Poly(ADP-ribose) polymerase activation in turn depletes the intracellular concentration of its substrate NAD + , slowing the rate of glycolysis, electron transport, and ATP formation, and produces an ADP-ribosylation of the GAPDH. These
processes result in acute endothelial dysfunction in diabetic blood vessels that, convincingly, also contributes to the development
of diabetic complications. These new findings may explain why classic antioxidants, such as vitamin E, which work by scavenging
already-formed toxic oxidation products, have failed to show beneficial effects on diabetic complications and may suggest
new and attractive “causal” antioxidant therapy. New low–molecular mass compounds that act as SOD or catalase mimetics or
l -propionyl-carnitine and lipoic acid, which work as intracellular superoxide scavengers, improving mitochondrial function
and reducing DNA damage, may be good candidates for such a strategy, and preliminary studies support this hypothesis. This
“causal” therapy would also be associated with other promising tools such as LY 333531, PJ34, and FP15, which block the protein
kinase β isoform, poly(ADP-ribose) polymerase, and peroxynitrite, respectively. While waiting for these focused tools, we
may have other options: thiazolinediones, statins, ACE inhibitors, and angiotensin 1 inhibitors can reduce intracellular oxidative
stress generation, and it has been suggested that many of their beneficial effects, even in diabetic patients, are due to
this property.
AT1, angiotensin 1
NF, nuclear factor
NO, nitric oxide
NOS, nitric oxide synthase
Footnotes
Address correspondence and reprint requests to Prof. Antonio Ceriello, Chair of Internal Medicine, University of Udine, P.le
S. Maria della Misericordia, 33100 Udine, Italy. E-mail: antonio.ceriello{at}dpmsc.uniud.it .
Received for publication 2 May 2002 and accepted in revised form 12 February 2003.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
DIABETES CARE
The link between diabetes and atherosclerosis La Sala, Lucia; Prattichizzo, Francesco; Ceriello, Antonio
European journal of preventive cardiology,
12/2019, Volume:
26, Issue:
2_suppl
Journal Article
Peer reviewed
Open access
Atherosclerosis is one of the main complications of diabetes involving multiple causative factors. Dysfunction of the vascular endothelium is a hallmark of most conditions that are associated with ...both diabetes and atherosclerosis. Although the pathological link between diabetes and atherosclerosis is well-established, better comprehension of the underlying mechanisms is of utmost importance to identify novel potential molecular targets. It is difficult to separate the effects of hyperglycaemia from those of other atherogenic factors: recent evidence shows that they share many common mechanisms, such as endothelial activation and inflammation, mitochondrial oxidative stress, changes in extracellular matrix components and disruption of cellular defence systems. The plausible hypothesis of the ‘common soil’ between diabetes and atherosclerosis seems to be born from a unique ‘ancestor’: the nuclear factor κB, a transcription factor able to guide multiple molecular processes. It seems that this master regulator triggers either some hyperglycaemia-induced effects on the endothelial function, or the expression of certain microRNAs (in particular miR-126, -21 and miR-146a-5p) involved in favouring atherosclerosis. Here, we review the latest evidence and proposed mechanisms, aiming to understand the link between diabetes and atherosclerosis.
To review the role of oxidative stress in the development of complications of diabetes.
Evidence that implicates hyperglycemia-derived oxygen free radicals as mediators of diabetes-associated ...complications is presented and discussed.
Recent studies have indicated that a hyperglycemia-induced overproduction of superoxide seems to be the first and main event in the activation of all pathways involved in the pathogenesis of complications of diabetes. Superoxide overproduction is accompanied by increased generation of nitric oxide and, consequently, formation of the strong oxidant peroxynitrite and by poly(adenosine diphosphate-ribose) polymerase activation, which in turn further activates the pathways involved in the pathogenesis of diabetes-related complications. This process results in acute endothelial dysfunction and activation of inflammation in blood vessels of patients with diabetes, and these factors contribute to the development of complications of diabetes.
In vivo evidence supports the major contribution of hyperglycemia in producing oxidative stress and, ultimately, acute endothelial dysfunction in blood vessels of patients with diabetes.
The global prevalence of diabetes is predicted to increase dramatically in the coming decades as the population grows and ages, in parallel with the rising burden of overweight and obesity, in both ...developed and developing countries. Cardiovascular disease represents the principal cause of death and morbidity among people with diabetes, especially in those with type 2 diabetes mellitus. Adults with diabetes have 2–4 times increased cardiovascular risk compared with adults without diabetes, and the risk rises with worsening glycaemic control. Diabetes has been associated with 75% increase in mortality rate in adults, and cardiovascular disease accounts for a large part of the excess mortality. Diabetes-related macrovascular and microvascular complications, including coronary heart disease, cerebrovascular disease, heart failure, peripheral vascular disease, chronic renal disease, diabetic retinopathy and cardiovascular autonomic neuropathy are responsible for the impaired quality of life, disability and premature death associated with diabetes. Given the substantial clinical impact of diabetes as a cardiovascular risk factor, there has been a growing focus on diabetes-related complications. While some population-based studies suggest that the epidemiology of such complications is changing and that rates of all-cause and cardiovascular mortality among individuals with diabetes are decreasing in high-income countries, the economic and social burden of diabetes is expected to rise due to changing demographics and lifestyle especially in middle- and low-income countries. In this review we outline data from population-based studies on recent and long-term trends in diabetes-related complications.
Antioxidant Anti-Inflammatory Treatment in Type 2 Diabetes
Antonio Ceriello , MD 1 and
Roberto Testa , MD 2
1 Centre of Excellence in Diabetes and Endocrinology, University Hospital of Coventry and ...Warwickshire, Warwick Medical School,
University of Warwick, Coventry, U.K.;
2 Department of Gerontological Research, Diabetology Unit, Istituto Nazionale Ricerca e Cura Anziani, Ancona, Italy.
Corresponding author: Antonio Ceriello, antonio.ceriello{at}warwick.ac.uk .
In the last few decades, the occurrence of type 2 diabetes has rapidly increased internationally, and it has been estimated
that the number of diabetic patients will more than double within 15 years ( 1 ). Type 2 diabetes is mainly characterized by the development of increased morbidity and mortality for cardiovascular disease
(CVD); thus, it has been suggested that diabetes may be considered a CVD ( 1 ). However, diabetes is also characterized by dramatic microangiophatic complications, such as retinopathy, nephropathy, and
neuropathy ( 1 ).
Recent evidence suggests that glucose overload may damage the cells through oxidative stress ( 2 ). This is currently the basis of the “unifying hypothesis” that hyperglycemia-induced oxidative stress may account for the
pathogenesis of all diabetic complications ( 2 ).
CENTRAL ROLE OF OXIDATIVE STRESS IN THE PATHOGENESIS OF DIABETIC COMPLICATIONS
It has been suggested that the following four key biochemical changes induced by hyperglycemia are all activated by a common
mechanism—overproduction of superoxide radicals ( 2 ): 1 ) increased flux through the polyol pathway (in which glucose is reduced to sorbitol, reducing levels of both NADPH and reduced
glutathione); 2 ) increased formation of advanced glycation end products (AGEs); 3 ) activation of protein kinase C (with effects ranging from vascular occlusion to expression of proinflammatory genes), and
4 ) increased shunting of excess glucose through the hexosamine pathway (mediating increased transcription of genes for inflammatory
cytokines). Excess plasma glucose drives excess production of electron donors (mainly -NADH/H + ) from the tricarboxylic acid cycle; in turn, this surfeit results in the transfer of single electrons (instead of the usual
electron pairs) to oxygen, producing superoxide radicals and other reactive oxygen species (instead of the usual H 2 O end product). The superoxide anion itself inhibits the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GADPH),
and consequently, glucose and glycolytic intermediates spill into the polyol and hexosamine pathways, as well as additional
pathways that culminate in protein kinase …
Full Text of this Article
ABSTRACT—Type 2 diabetes is a worldwide increasing disease resulting from the interaction between a subjectʼs genetic makeup and lifestyle. In genetically predisposed subjects, the combination of ...excess caloric intake and reduced physical activity induces a state of insulin resistance. When beta cells are no longer able to compensate for insulin resistance by adequately increasing insulin production, impaired glucose tolerance appears, characterized by excessive postprandial hyperglycemia. Impaired glucose tolerance may evolve into overt diabetes. These 3 conditions, ie, insulin resistance, impaired glucose tolerance, and overt diabetes, are associated with an increased risk of cardiovascular disease. Because all these conditions are also accompanied by the presence of an oxidative stress, this article proposes oxidative stress as the pathogenic mechanism linking insulin resistance with dysfunction of both beta cells and endothelium, eventually leading to overt diabetes and cardiovascular disease. This hypothesis, moreover, may also contribute to explaining why treating cardiovascular risk with drugs, such as calcium channel blockers, ACE inhibitors, AT-1 receptor antagonists, and statins, all compounds showing intracellular preventive antioxidant activity, results in the onset of new cases of diabetes possibly being reduced.
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