Complicated diabetes complicating pregnancy.
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Acute Disease↗
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Effect of Mg2+ on Na(+)-dependent inositol transport. Role for Mg2+ in etiology of diabetic complications.
Diabetes mellitus is associated with a significant reduction in the serum concentration of Mg2+. Several studies have suggested that hypomagnesemia may be implicated in the etiology of diabetic complications; however, no mechanism has been proposed. This study demonstrates that Mg2+ is a positive effector of inositol transport and is capable of promoting a 2.5-fold increase in the affinity of the transporter for inositol. Analysis of the kinetics of inositol transport shows that, at physiological concentrations of inositol, the reductions in Mg2+ concentrations that occur in diabetic patients would result in a significant decline in the rate of inositol transport (1.5- to 2-fold). We suggest that hypomagnesemia may be linked to the development of diabetic complications via reduction in the rate of inositol transport and subsequent intracellular inositol depletion. This assertion allows hypomagnesemia and the polyol theory to be unified into one mechanistic model for the development of diabetic complications.
Biological Transport↗
The role of antioxidant micronutrients in the prevention of diabetic complications.
Diabetes mellitus is associated with an increased production of reactive oxygen species and a reduction in antioxidant defenses. This leads to oxidative stress, which is partly responsible for diabetic complications. Tight glycemic control is the most effective way of preventing or decreasing these complications. Nevertheless, antioxidant micronutrients can be proposed as adjunctive therapy in patients with diabetes. Indeed, some minerals and vitamins are able to indirectly participate in the reduction of oxidative stress in diabetic patients by improving glycemic control and/or are able to exert antioxidant activity. This article reviews the use of minerals (vanadium, chromium, magnesium, zinc, selenium, copper) and vitamins or cofactors (tocopherol [vitamin E], ascorbic acid [vitamin C], ubidecarenone [ubiquinone; coenzyme Q], nicotinamide, riboflavin, thioctic acid [lipoic acid], flavonoids) in diabetes, with a particular focus on the prevention of diabetic complications. Results show that dietary supplementation with micronutrients may be a complement to classical therapies for preventing and treating diabetic complications. Supplementation is expected to be more effective when a deficiency in these micronutrients exists. Nevertheless, many clinical studies have reported beneficial effects in individuals without deficiencies, although several of these studies were short term and had small sample sizes. However, a randomized, double-blind, placebo-controlled, multicenter trial showed that thioctic acid at an oral dosage of 800 mg/day for 4 months significantly improved cardiac autonomic neuropathy in type 2 diabetic patients. Above all, individuals with diabetes should be educated about the importance of consuming adequate amounts of vitamins and minerals from natural food sources, within the constraints of recommended sugar and carbohydrate intake.
Antioxidants↗
Genetic analysis of aldose reductase in diabetic complications.
Diabetes Mellitus is an increasing concern, worldwide in terms of health. Long-term diabetes often leads to secondary diseases such as cataract, retinopathy, neuropathy, nephropathy, and cardiovascular diseases. The enzyme aldose reductase (AR) has been implicated in the pathogenesis of some of these diseases and inhibitors of AR (ARIs) were effective in preventing some of the diabetic complications in animal models. However, clinical trials of these drugs were disappointing, casting doubt on the role of AR in these diseases. This review focuses on the recent studies using transgenic and gene knockout mice to analyze the role of AR in diabetic cataract and neuropathy. These studies clearly demonstrated that AR is crucial to the pathogenesis of these diseases, and that the mechanism leading to diabetic cataract may be different from that which causes diabetic neuropathy. A number of studies showed that there is a correlation between AR gene markers and susceptibility to develop complications among diabetic patients, suggesting that AR is also involved in the pathogenesis of diabetic complications in human. Together, these genetic studies strongly indicate that AR is an important target for the prevention of diabetic complications in human. This may provide impetus to develop more effective ARIs and to conduct better-designed clinical trials for ARIs in the prevention and treatment of these diseases.
Aldehyde Reductase↗
The effect of whole organ pancreas transplantation and PIT on diabetic complications.
Diabetes mellitus is a leading cause of morbidity and mortality in the Western world. Currently, the only forms of beta-cell replacement are whole organ pancreas transplantation and pancreatic islet transplantation. Whole organ transplantation has demonstrated benefits in prevention and reversal of diabetic complications with sustainable long-term outcomes. Pancreatic islet transplantation continues to be a field that needs further study to ascertain the true benefit of islet transplantation for diabetic complications. This can only be achieved with improvement in long-term islet allograft survival.
Diabetes Complications↗
TAGE (toxic AGEs) theory in diabetic complications.
Diabetic complication is a leading cause of acquired blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis. Chronic hyperglycemia is initially involved in the pathogenesis of diabetic micro- and macro-vascular complications via various metabolic derangements. High glucose increased production of various types of advanced glycation end-products (AGEs). Recently, we found that glyceraldehyde-derived AGEs (AGE-2) play an important role in the pathogenesis of angiopathy in diabetic patients. There is considerable interest in receptor for AGEs (RAGE) found on many cell types, particularly those affected in diabetes. Recent studies suggest that interaction of AGE-2 (predominantly structure of toxic AGEs; TAGE) with RAGE alters intracellular signaling, gene expression, release of pro-inflamatory molecules and production of reactive oxygen species (ROS) that contribute towards the pathology of diabetic complications. We propose three pathways for the in vivo formation of AGE-2 precursor, glyceraldehyde, such as i) glycolytic pathway, ii) polyol pathway, and iii) fructose metabolic pathway. Glyceraldehyde can be transported or can leak passively across the plasma membrane. It can react non-enzymatically with proteins to lead to accelerated formation of TAGE at both intracellularly and extracellularly. In this review, we discuss the molecular mechanisms of diabetic complications, especially focusing on toxic AGEs (TAGE) and their receptor (RAGE) system.
Diabetes Complications↗
Molecular understanding of hyperglycemia's adverse effects for diabetic complications.
Diabetic complications are the major cause of morbidity and mortality in persons with diabetes. Chronic hyperglycemia is a major initiator of diabetic microvascular complications (eg, retinopathy, neuropathy, nephropathy). Glucose processing uses a variety of diverse metabolic pathways; hence, chronic hyperglycemia can induce multiple cellular changes leading to complications. Several predominant well-researched theories have been proposed to explain how hyperglycemia can produce the neural and vascular derangements that are hallmarks of diabetes. These theories can be separated into those that emphasize the toxic effects of hyperglycemia and its pathophysiological derivatives (such as oxidants, hyperosmolarity, or glycation products) on tissues directly and those that ascribe pathophysiological importance to a sustained alteration in cell signaling pathways (such as changes in phospholipids or kinases) induced by the products of glucose metabolism. This article summarizes these theories and the potential therapeutic interventions that may prevent diabetic complications in the presence of hyperglycemia, control of which is often difficult with current therapeutic options.
Aldehyde Reductase↗
Advanced glycation end products and diabetic complications.
Diabetic complications are major cause of morbidity and mortality in patients with diabetes. While the precise pathogenic mechanism(s) underlying conditions such as diabetic retinopathy, diabetic nephropathy and increased risk of atherosclerosis remain ill-defined, it is clear that hyperglycaemia is a primary factor that initiates and promotes complications. Formation of advanced glycation end products (AGEs) correlate with glycaemic control, and these reactive adducts form on DNA, lipids and proteins where they represent pathophysiological modifications that precipitate dysfunction at a cellular and molecular level. Many of these adducts form rapidly during diabetes and promote progression of a raft of diabetes-related complications. Recent evidence also suggests an important interaction with other pathogenic mechanisms activated within the diabetic milieu. This review outlines the nature of AGE formation in biological systems and highlights accumulative evidence that implicates these adducts in diabetic complications. As more therapeutic agents are developed to inhibit AGE formation or limit their pathogenic influence during chronic diabetes, it is becoming clear that these anti-AGE strategies have an important role to play in the treatment of diabetic patients.
Animals↗
Targets to trials in diabetic complications.
Diabetes is now the leading cause of end-stage renal disease, blindness, lower-extremity amputations and impotence. In addition, the risk of death from cardiovascular disease such as myocardial infarction and stroke is more than doubled in diabetics. In September 2001, scientists from around the world met in Melbourne to discuss the mechanisms underlying neuronal and vascular changes in diabetic complications. This report summarizes the meeting and attempts to identify potential targets for drug intervention in diabetic complications. (c) 2001 Prous Science. All rights reserved.
Journal Article↗
Association of the C825T polymorphism of the G-protein beta3 subunit gene with hypertension, obesity, hyperlipidemia, insulin resistance, diabetes, diabetic complications, and diabetic therapies among Japanese.
A C825T polymorphism of the gene encoding the G-protein beta3 subunit (GNB3) is associated with increased intracellular signal transduction. We know that this C825T polymorphism may influence hypertension and obesity. In whites, the C825T polymorphism has been reported to induce hypertension, obesity, and diabetic nephropathy. Thus, we investigated how genetic variation in the GNB3 gene is associated with hypertension, obesity, insulin resistance, diabetes, diabetic complications, and diabetic therapies in 427 Japanese subjects with type 2 diabetes mellitus and in 368 Japanese subjects who underwent general health examinations. The frequency of the GNB3 gene polymorphism was 0.48 and 0.47 in subjects with diabetes and in those who had general health examinations, respectively. The amount of hyperlipidemia of the CT allele was significantly lower than the amount in the CC allele in the Japanese subjects with diabetes. Our results suggest that the C825T polymorphism influences lipid metabolism and is not associated with hypertension, obesity, insulin resistance, diabetes, diabetic complications, or diabetic therapies.
Adult↗
Circulating nucleic acids and diabetic complications.
Diabetes mellitus is a major health problem across the world. Diabetic retinopathy (DR) and nephropathy are two of the major complications of diabetes. DR is the leading cause of blindness and diabetic nephropathy is the leading cause of end-stage renal failure. We have examined the potential value of circulating nucleic acids in the detection and monitoring of these two complications of diabetes. mRNA for nephrin was significantly higher in all diabetics compared to healthy controls and it was significantly higher in normoalbuminuric patients compared to healthy controls. This may indicate progression to microalbuminuric stage. Circulating rhodopsin mRNA was detectable in healthy subjects and in diabetic patients. It was significantly raised in diabetic patients with retinopathy. Higher rhodopsin mRNA in diabetic patients without retinopathy suggests that some of them may go on to develop it or already have it subclinically. Circulating nucleic acids have the potential to be noninvasive molecular tests for diabetic complications.
Adult↗
Transcriptome profiling and the pathogenesis of diabetic complications.
Diabetes is an escalating problem worldwide and a major cause of vascular disease, renal failure, and blindness, among other complications. The cellular mediators of high glucose-induced injury include activation of protein kinase C, accumulation of cell sorbitol from increased flux through the aldose reductase pathway, and generation of advanced glycosylation end products and reactive oxygen species, among others. Current strategies for preventing and slowing the progression of the macrovascular and microvascular complications of diabetes include optimization of glycemic control and BP, angiotensin-converting enzyme inhibitors and angiotensin II blockers, and HMG CoA reductase inhibitors. However, there is an urgent need to develop new therapeutic strategies, as these interventions, although they may slow, rarely halt the progression of diabetic complications. Central to this process is the elucidation of the molecular events that drive this complex disease and that are potential therapeutic targets. This review discusses the promise offered in this regard by global monitoring of cellular or tissue mRNA expression (so-called transcriptomics) and illustrates the potential of this approach by focusing on recent studies on the pathogenesis of diabetic nephropathy.
Actins↗
Advanced glycation endproducts--role in pathology of diabetic complications.
Diabetes mellitus is a common endocrine disorder characterised by hyperglycaemia and predisposes to chronic complications affecting the eyes, blood vessels, nerves and kidneys. Hyperglycaemia has an important role in the pathogenesis of diabetic complications by increasing protein glycation and the gradual build-up of advanced glycation endproducts (AGEs) in body tissues. These AGE form on intra- and extracellular proteins, lipids, nucleic acids and possess complex structures that generate protein fluorescence and cross-linking. Protein glycation and AGE are accompanied by increased free radical activity that contributes towards the biomolecular damage in diabetes. There is considerable interest in receptors for AGEs (RAGE) found on many cell types, particularly those affected in diabetes. Recent studies suggest that interaction of AGEs with RAGE alter intracellular signalling, gene expression, release of pro-inflammatory molecules and free radicals that contribute towards the pathology of diabetic complications. This review introduces the chemistry of glycation and AGEs and examines the mechanisms by which they mediate their toxicity. The role of AGEs in the pathogenesis of retinopathy, cataract, atherosclerosis, neuropathy, nephropathy, diabetic embryopathy and impaired wound healing are considered. There is considerable interest in anti-glycation compounds because of their therapeutic potential. The mechanisms and sites of action of selected inhibitors, together with their potential in preventing diabetic complications are discussed.
Animals↗
[A central pathological mechanism explaining diabetic complications?].
Diabetes mellitus is associated to micro- and macro-vascular lesions responsible for myocardial infarction, nephropathy, retinopathy and polyneuropathy. Four main pathogenic mechanisms have been proposed, all associated with hyperglycaemia: 1) increased flux in the polyol pathway; 2) increased flux in the hexosamine pathway; 3) protein kinase C activation; and 4) increased formation of advanced glycation endproducts. A common mechanism seems to play a central role in the activation of these various pathways. Indeed, an increased production of free radicals by mitochondria induced by hyperglycaemia may be responsible for the observed metabolic disturbances. The present article describes that theory and presents its possible therapeutic implications.
Blood Glucose↗
Antiglycation properties of aged garlic extract: possible role in prevention of diabetic complications.
Diabetes mellitus is a common endocrine disorder characterized by hyperglycemia and long-term complications affecting the eyes, nerves, blood vessels, skin, and kidneys. Increased glycation of proteins and accumulation of advanced glycation endproducts (AGEPs) have been implicated in the pathogenesis of diabetic complications. Glycation and AGEP formation are also accompanied by formation of free radicals via autoxidation of glucose and glycated proteins. Compounds with combined antiglycation and antioxidant properties may offer therapeutic potential. Recent studies suggest that aged garlic extract (AGE) inhibits formation of AGEPs in vitro and formation of glycation-derived free radicals. S-Allylcysteine, a key component of aged garlic, is a potent antioxidant and can inhibit AGEP formation. Aged garlic extract and S-allylcysteine deserve more attention and should be investigated to see whether they can reduce AGEPs in vivo.
Diabetes Complications↗
[Screening, diagnosis and management of diabetes mellitus and diabetic complications].
Diabetes mellitus comprises a group of metabolic disturbances that are characterized by hyperglycemia. In 1997 the American Diabetes Association (ADA) proposed new criteria for the diagnosis and classification of diabetes mellitus, which was also adopted by WHO. Although the criteria is the same, the ADA puts emphasis on the use of the fasting plasma glucose (FPG) for screening and diagnosis, whereas WHO maintains the use of the OGTT and recommends the FPG only if an OGTT can not be performed. Different pathogenetic processes are involved in the development of diabetes ranging from autoimmune destruction of beta-cells resulting in an absolute insulin deficiency to insulin with a defect on insulin secretion. The new classification is based on the etiology of the disease. Diabetes is classified into one of four categories: Type-1, type-2 Diabetes mellitus, specific forms of diabetes, and gestational diabetes. For screening and diagnosis FPG or the two hour value after the OGTT can be used. Glycosylated hemoglobin is not suitable for screening and diagnosis of diabetes despite some contradictory statements. For many decades clear evidence was missing that chronic hyperglycemia caused diabetic late complications; complications including dysfunction or failure of several organ systems, in particular eyes, kidneys, nerves, and the cardiovascular system. The results of two large prospective trials--the Diabetes Control and Complications Trial (DCCT; 1993) and the United Kingdom Prospective Study (UKPDS; 1998)--that were recently published provided the final proof that normoglycemia prevents or delays the progression of these late complications. Due to the insidious nature of these complications they are often not diagnosed and have to be looked for in each patients with diabetes and have to be controlled regularly. Based on the results of the UKPDS and other studies, evidence based therapeutic goals could be defined. Multifactorial interventions with increased physical activity, cessation of smoking, aspirin treatment, lowering of HbA1c, blood pressure, and lipids in patients with type 2 diabetes have been proven to drastically reduce the risk of developing diabetic nephropathy or cardiovascular complications drastically. We recommend the following treatment strategy for patients with type 2 diabetes in clinical practice: 1) Treatment should be individualized. 2) Treatment should be started step by step to document efficacy of treatment and compliance of patients. 3) Plasma glucose and blood pressure should be normalized in all patients with type 2 diabetes (up to an age of 70 years), since there are no threshold values for HbA1c and blood pressure. 4) Therapeutic goals should be checked every three to six months. 5) In the case that therapeutic goals can not be met, treatment should be intensified. Often a combination therapy with many different drugs is required. 6) A specialist for diabetes should be consulted, if the therapeutic goals can not be met over a period of six months.
Adult↗
[Magnesium deficiency and development of late diabetic complications].
Diabetics have a higher prevalence of recurrent angina, myocardial infarction and hypertension compared with healthy individuals. This is partly due to the metabolic control, and partly to the development of nephropathy, but inherited factors also seem to contribute to their development. Another factor, to some extent inherited, could be magnesium-deficiency. Up to 30% of all diabetics suffer from magnesiumdepletion, which in other disease entities has been related to angina pectoris, myocardial infarction, and changes in blood lipids. Furthermore, magnesium-deficiency might be related to the development of hypertension. In diabetes, magnesium-depletion has been linked with the development of retinopathy, and an increase in abortions and malformations in diabetic pregnancies. No intervention trials with magnesium, to elucidate the question of magnesium depletion and diabetic late complications have hitherto been made. No methods for assessing magnesium-status in diabetes are available as yet, to select patients for this type of trial.
Diabetes Mellitus, Type 1↗
Role of nitric oxide in diabetic complications.
Diabetic vascular disease is accompanied by decreased formation of the vasodilators, nitric oxide (NO), and prostacyclin and increased formation of vasoconstrictor eicosanoids, which exacerbate the progression of vascular disease. Similarities between the dysfunction introduced by short-term effects of elevated glucose and long-term effects of diabetes suggest that the alteration in endothelial factors in diabetes primarily results from exposure of endothelial cells to elevated glucose, although undoubtedly hyperlipidemia contributes as well. A key alteration in endothelial cell phenotype is increased formation of reactive oxygen species. This is in part due to uncoupling of endothelial NO synthase such that it generates superoxide anion in addition to NO. This is responsible for NO synthase to produce peroxynitrite, a damaging molecule. Peroxynitrite inactivates prostacyclin synthase leading to the accumulation of inflammatory and prothrombotic eicosanoids. This not only helps to explain the impairment of endothelial vasodilator mechanisms, but also increased progression of vascular disease. Many of these cellular abnormalities can be prevented by adequate scavenging of oxygen-derived free radicals or by blocking the actions of the eicosanoids at thromboxane (TP) receptors. Exposure to elevated glucose also gives rise to oxidants in smooth muscle, and recent studies indicate that oxidation of cysteine thiols under these conditions may prevent physiological NO signaling. As a result, the responsiveness to NO is impaired and accounts in part for abnormal endothelium-dependent vasodilation.
Diabetes Complications↗