Diabetes mellitus, a condition characterized mainly by a quantitative deficiency in insulin secretion or a resistance to insulin action, is estimated to afflict 8% of the population. The precise mechanisms by which diabetic microangiopathy develops are not fully understood, but a consensus is emerging pointing to a terrain of genetic influences onto which metabolic and hemodynamic derangements are superimposed.
A working knowledge of the intrinsic biochemical mechanisms, subjacent to diabetic long-term complications, should facilitate our understanding of the basis for the current guidelines in treatment, as well as, the therapeutic agents under scrutiny that may become available in the near future.
Apart from the key hemodynamic changes intervening in many tissue targets of diabetic complications, there is sound clinical and epidemiological evidence that links hyperglycemia to vascular complications.
The DCCT was designed to definitively answer the question of the association between hyperglycemia and vascular complications in a cohort large enough to permit incontestable conclusions. Two groups of patients were followed for an average period of seven years, one treated con­ventionally with the goal of clinical well being (standard treatment group) and another treated intensively to normalize blood glucose (intensive treatment group).
The data published over a decade ago showed that there was a 60% reduction in risk between the intensive treatment group and the standard treatment group in diabetic nephropathy, retinopathy and neuropathy. The obvious major problems encountered in intensive treatment are the risk of hypoglycemia and weight gain. More precisely, patients were followed for an average of 10 years to determine whether intensive use of phar­macological therapy to lower blood glucose levels would result in reduced macro and microvascular complications and whether the use of different sulfonylurea drugs, metformin, or insulin have distinct advantages or disadvantages.
It must be pointed out that even though it began as a randomized clinical trial, the UKPDS involved a considerable crossover among the subjects along the study period. On the other hand, this study also showed that tight blood pressure control reduced the risk of diabetic complications.
Thus, the hypothesis that it is glucose itself that is toxic in type 2 diabetes is confirmed, in line with the findings of the DCCT for type 1 diabetes: the controversy should now end and we must unravel the mechanisms of this effect in order to better approach it therapeutically.
It is important to point out that no consensual framework has been found which encompasses all that is known about the link between hyperglycemia and complications. Over the past 3 decades, four seemingly independent major mechanisms of hyperglycemia-induced damage have been discovered: polyol pathway activation, advanced glycation endproduct (AGE) formation, protein kinase C (PKC) activation, and hexosamine pathway activation. As stated above, the reactive dicarbonyl intermediates, formed from Amadori products or from sugars, react with protein amino groups to form a variety of AGEs (for details on structures see other pages on this IMARS website).
Inherited differences in the ability to detoxify AGE intermediates (glyoxalase pathway is a key one, see details on this IMARS website) might be one of the genetic factors responsible for the clinically observed large variability that the impact of a given level of glycemia has on diabetic complications. AGE molecules (free, as peptides or protein-bound) are found in plasma, cells, and tissues and accumulate in the arterial wall, the kidney mesangium, and glomerular and other basement membranes. As we have described above, AGEs can be produced not only through direct action of sugars on proteins but also via distinct oxidative reactions.
If AGEs also form on DNA in vivo, deleterious effects on gene expression may occur and intracellular AGE formation on cell proteins may thus, in turn, affect DNA function.
Glycation and the other 3 pathways linked to hyperglycemia-induced damage may be linked in a unifying hypothesis put forward by Brownlee.
It is believed that circulating AGE-peptides are probably the result of incomplete catabolism of AGE-proteins by macrophages and other cells which are in their way to be excreted by the kidneys (Figure7). AGE-peptides are filtered by the glomerulus and catabolized in part by the endolysosomal system of the proximal convoluted tubule, as shown in Figure 7. In a nutshell, as depicted in Figure 8, AGE peptides increase in diabetes (excess of production) and in kidney failure (decreased excretion). Numerous questions remain unanswered with regards to the role of hyperglycemia in macrovascular complications seen in types 1 and 2 diabetics and how treatment of hyperglycemia may affect these complications. Vascular diabetic complications may be due in part to chronic endothelial cell activation but the picture is incomplete as yet.
On the other hand, as the diagram in Figure 9 summarizes, extensive literature shows a role for the glycation of lipoproteins in atherogenesis.
With regards to high-density lipoproteins (HDL), in vitro activation of lecithin- cholesterol acyltransferase (LCAT) by glycated apolipoprotein A-I (apoA-I is the major apoprotein in HDL) was lower than the activation by native apolipoprotein A-I, which has also been observed in diabetic patients. Even if it is too early to conclude that reduction of hyperglycemia would have as great an impact on lowering macrovascular-disease risk, as it has on microvascular-disease risk, these studies afford further stimulus to explore this issue. Therapeutic agents that inhibit AGE formation have made it possible to investigate the role of AGEs in the development of diabetic complications using animal models. The effects of aminoguanidine on diabetic pathology have been investigated first in animal models. When renal failure was produced in streptozotocin-induced diabetic rats by surgical reduction of renal mass and aminoguanidine was administered, the treated rats had significantly superior survival than that of untreated uremic diabetic animals. As stated before, problems of toxicity have been encountered in a phase III clinical trial with aminoguanidine, so this drug should be considered a prototype. Aminoguanidine, pyridoxamine, 2,3-diamino-phenazine, OPB-9195, and tenilsetam inhibit AGE formation by scavenging reactive carbonyl intermediates, N-phenacetylthiazolium bromide (PTB) and ALT-711 are AGE-cross-link breakers.
This creates a huge economic burden related for the most part to the management of its complications, which are micro and macroangiopathic in nature. The anatomic hallmark of diabetic microangiopathy is the thickening of capillary basement membranes, which subsequently induces occlusive angiopathy, tissue hypoxia, and damage.
An attempt is made here to briefly summarize the evidence that strongly supports the role of hyperglycemia and the Maillard reaction in vascular complications. The DCCT evaluated intensive insulin replacement and self-monitoring of blood glucose, and utilized glycated hemoglobin assays to measure glycemic control over long periods of time . The methods to accomplish tight control in type 1 diabetes included three or more daily injec­tions of insulin (66%) or use of programmable insulin-infusion pumps (34%).
The United Kingdom Prospective Diabetes Study (UKPDS) is a randomized trial of intensive treatment of type 2 diabetics followed for several years. In the subgroup of overweight subjects, met­formin as monotherapy was compared with the control group and to the other three pharmacological agents. The original design assigned patients to intensive therapy using one of four approaches -insulin, chlorpropamide, glybenclamide, or diet.
The UKPDS also showed a 16% reduction (not statistically significant) in the risk of myocardial infarction and sudden death in the intensively treated group. The achievement of tight blood glucose control in type 2 diabetes is feasible and should become the standard of care. There are several equally defensible hypotheses on the roots of complications including but not limited to, the aldose reductase hypothesis, oxidative stress, the Maillard, or advanced glycation end product (AGE) hypothesis, modified protein kinase C activity, pseudo-hypoxia, carbonyl stress, altered lipoprotein metabolism, and altered cytokine activities. It cannot be overemphasized that oxidative stress is generated in all these three pathways as well as in several others, and many of them have been clustered in Brownlee’s unifying hypothesis. Fructosamine (to be chemically correct, fructosamino-protein adduct) is the common name given to any glycated plasma protein in this first stage.
In a second phase of the glycation pathway, a complex series of rearrangements and oxidative reactions leads to the formation of multiple, very reactive species, collectively named advanced glycation end products or AGE-products, some of which are shown in greater detail in other pages on this IMARS website. AGE-products accumulate in vivo on vascular wall collagen and basement membranes as a function of age and levels of glycemia. A whole area of research focuses on deglycation and transglycation mechanisms as well as on variants of the receptors and enzymes involved that may underscore this variability. The accumulation of AGEs in long-lived proteins contributes to the age-related increase in brown color, fluorescence, poor solubility of lens crystallins, and to the gradual cross-linking and decrease in elasticity of connective tissue collagens with age. Some authors coined a more general comprehensive term for these reactions: carbonyl stress. Considerable amounts of data on this issue have been accumulating during the last decade; we will select and provide an outline with examples of a few that we consider the most clinically significant.
AGE formation modifies the functional properties of different key extracellular matrix molecules.


AGEs interact with specific receptors p60 (OST-48, AGE-R1), p90 (80K-H, AGE-R2), galectin-3 (AGE-R3), the macrophage scavenger receptor type II (ScR-II), and CD36 regulate the uptake and clearance of AGEs. Histones from the liver of rats after only one month of hyperglycemia showed AGE levels three-fold higher than those of their age-matched controls, and accumulation of AGEs on histones increased with the duration of the disease. Reabsorption could represent an AGE-receptor-mediated mechanism triggering several cell responses including cytokine secretion and oxidation reactions. With the ability to measure HbA1c levels, the DCCT found a 41% reduction in the risk for macrovascular events, which was not statistically significant because of the low frequency of these events in that population. Arterial wall collagen bearing AGEs can trap LDL and IgG particles, which in turn can accumulate in the intima. Early glycation of apoB, apoAs and apo E has been described and abnormal metabolism of glycated forms of LDL and HDL have been reported. Because LCAT affords a driving force in reverse cholesterol transport, it is provoking to conjecture that this abnormal activation may be associated with a reduction in reverse cholesterol transport and accelerated atherosclerosis in diabetic patients.
Interestingly, the DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) study showed that mortality in diabetic patients with AMI is predicted by age, previous heart failure, and severity of the glycometabolic state (HbA1c) at admission but not by conventional risk factors or sex. The first AGE inhibitor discovered was aminoguanidine (pimagedine) and it has been studied in considerable detail.
The prevention of AGE formation by aminoguanidine treatment delays the evolution of the microvascular lesions found in diabetic animals either in the retina or the glomeruli.
Other researchers investigated the effect of aminoguanidine on slowing of motor nerve conduction velocity of the sciatic nerve in streptozocin-induced diabetic rats. Various classes of drugs are able to interfere with the formation of AGEs or the cross-linking of proteins by AGEs. Furthermore, signal transduction through RAGE can be inhibited by antisense oligodeoxynucleotides (AS-ODNs), RAGE antibodies, or soluble RAGE. In louis vuitton bags with scrub and loans online free great outfit Yet cialis levitra prefer begin probably.
Metformin decreases glucose prodution in the liver (hepatic gluconeogenesis) and increases utilisation of glucose at the peripheral tissues such as skeletal muscle and fat cells (adipocytes). Metformin is the drug of first choice in overweight patients in whom strict dieting has failed to control diabetes. It does not exert a hypoglycaemic action in non-diabetic subjects unless given in overdose. Along with Metformin, usaully those patients are given vitamin B complex supplements as Metformin decreases vitamin-B12 absorption.
Metformin can be used in pregnancy for both those who already having diabetes and those who newly have during pregnancy (gestational diabetes). Yapa WijeratneYapa entered Faculty of Medicine in 2008, following a successful career at the Dharmaraja College, Kandy. Microangiopathy, the microvessel disease in diabetes, includes retinopathy, nephropathy, and neuropathy and in type 1 patients the first signs of these complications may develop even in adolescence, particularly if insulin treatment has been inadequate. The evolution of the numerous long-term complications of diabetes mellitus correlates well, in most cases, with the severity and duration of hyperglycemia.
It was conducted in subjects who had type 1 diabetes for a known duration and used well-established end-point criteria to address the glycemic hypothesis (retinopathy, nephropathy, and neuropathy). This change was due for the most part to the effect of therapy on glycemic control and, to some extent to the methods employed to achieve that control. Patients should aim for the level of glucose control they can achieve without undue risk for hypoglycemia. The researchers soon became aware that high blood pressure may be an even stronger risk factor, and blood pressure treatment was accordingly included in the study. The combination of pharmacologic agents should be based on the individual evaluation of each patient.
Incidentally, a similar reaction, even though more complete and produced by harsher conditions, occurs between sugars and proteins in foods, and the final result is what we see in bread or piecrusts, for instance. The increase in glycoxidation and lipoxidation (ALEs) of tissue proteins in diabetes may accordingly be perceived as the consequence of enhanced carbonyl stress. In collagen (the most abundant protein in the body) AGEs form covalent, intermolecular bonds. This diagram depicts some of the key points discussed in the text on the role of AGE products in microangiopathy as well as in macroangiopathy. This diagram outlines some of the main issues discussed in the text with regards to the role of AGE products nephropathy. These AGE-induced changes are involved in the modification of thrombomodulin and tissue factor production. AGE protein binding to their receptors on mesangial cells stimulates platelet-derived growth factor secretion, which in turn mediates mesangial expansion.
This suggests a possible role for intracellular glycation in the increased teratogeny associated with diabetes mellitus.
Normalizing the levels of these excess free radicals inhibits the pathways through which cell damage occurs, and that all of these pathways can be activated, even in the presence of normal glucose levels, simply by using molecular genetic techniques to shut down the key enzyme that high glucose turns off.
Following this line of reasoning, one might hypothesize that in diabetes an increase in these processes could participate in the interstitial fibrosis reaction accompanying the characteristic glomerulosclerosis of end-stage renal disease. Nevertheless, these data certainly suggest a possible role for hyperglycemia in accelerating the atherosclerotic process in patients with type 1 diabetes. Enhanced glycation may have direct effects and may also amplify the effects of oxidative stress on lipoproteins. On the other hand, the UKPDS showed that the impact of intensive pharmacotherapy in reducing cardiovascular complications remains unclear. It gave the proof of principle that AGE inhibition would alter the course of complications but phase III trials have shown it is unsafe for therapeutic use.
Primary and secondary prevention with aminoguanidine has been successfully employed to ameliorate diabetic retinopathy in the rat. Motor nerve conduction velocity was inversely correlated with AGE levels, and aminoguanidine improved nerve conduction probably through decreasing the AGE level in the peripheral tissues. This diagram illustrates the action of aminoguanidine as an effective agent preventing cross-linking of proteins by AGE. Similar complications occur later in life in type 2 patients and are frequently present at the time of diagnosis. Any improved blood glucose control has been to slow the development and progression of microvascular complications. These data are reassur­ing in the sense that insulin should not be held accountable for atherosclerotic episodes and that sulfonylurea drugs should not be held responsible for cardiovascular toxicity as previously claimed.
Notwithstanding the failure of diet therapy alone, diet remains an adjunct to pharmacologic therapy.
The Maillard reaction also plays a part in the generation of brownish pigments in beer and cola drinks etc (shown in greater detail in other pages on this IMARS website). AGE formation increases at a much greater rate than the increase in blood glucose; this fact suggests that even moderate elevations in diabetic blood glucose levels result in substantial increases in AGEs accumulation. As depicted in Figure 3, luminal narrowing, a major feature in diabetic vessels may arise in part from accumulation in the subendothelium of plasma proteins such as albumin, low-density lipoprotein (LDL) and immunoglobulin G (IgG). Another molecule with AGE-binding and anti-AGE properties is the antimicrobial protein lysozyme. This diagram delineates some of the effects of this interaction with regards to microangiopathy.


In vivo, chronic administration of AGEs to otherwise healthy and euglycemic rats leads to focal glomerulosclerosis, mesangial expansion, and proteinuria, the hallmarks of diabetic microangiopathy. This diagram depicts current knowledge on the effects of this interaction with regards to nephropathy.
This diagram summarizes in a schematic fashion current hypothesis on their metabolisms generated by several laboratories including ours.
Low molecular weight peptides containing AGE circulate at increased levels in plasma from diabetic and kidney failure patients. In the long run, we might speculate that the increased tubular charge of AGE-peptides due to diabetes may overwhelm the whole process and lead to tubu­lar disorders. In the same line, epidemiologic analyses of UKPDS data, have shown strong associa­tions between blood glucose control and the risk of cardiovascular disease and all-cause mortality. At the same time, endothelial cell activation may mediate the deposition of atheroma, since oxidized low-density lipoprotein causes endothelial cell activation. Thus, glycation has been shown not only to increase the susceptibility of LDL to oxidation but also, as shown earlier, to enhance the propensity of vessel wall structural proteins to bind plasma proteins, including LDL, and thus to contribute to a more marked oxidative modification of LDL. Other factors that may predispose patients to cardiovascular complications, such as dyslipidemia, homocysteinemia or hypertension should also be contemplated in future studies. As shown in Figure 10, aminoguanidine reacts mainly with dicarbonyl intermediates such as 3-deoxyglucosone rather than with fructosamine products on proteins. In some studies, treatment with aminoguanidine reduced endothelial proliferation and completely arrested pericyte dropout, but it did not completely attenuate the progression of vascular occlusion. Turned payday loans Seeing conscious measures borrow superior non prescription viagra this. He completed his MBBS degree from University of Peradeniya & worked as a Temporary lecturer at Department of Basic sciences, Faculty of Dental Sciences, University of Peradeniya.
The DCCT confirmed and expanded results from the analogously designed but smaller Stockholm Diabetes Intervention Study. It can be argued that this constitutes an expensive treatment, however the cost-benefit ratio for intensive therapy is in a range comparable to other customarily accepted treatments in the U.S. The UKPDS started by analyzing the value of various strategies (diet and several oral hypoglycemic agents) to achieve tight blood glucose control compared with looser control.
Initially, the diet group was intended to be the control for the intervention groups, still, 80% of the diet group had to be moved to combination therapies to prevent very high blood glucose levels.
Patients initially assigned to inten­sive therapy with metformin had decreased risks of combined diabetes-related end points, diabetes-related deaths, all-cause deaths, and myocardial infarction compared with the conventionally treated patients. It must be acknowledged that the ability to prevent or at least retard these complications may be made easier in the near future by the recently approved hypoglycemic agents that were not available to the UKPDS. They may get trapped in basement membranes by covalently cross-linking to AGEs on collagen. We will briefly outline the role of AGE receptor activation in 3 key cell types: macrophages, endothelial cells, and mesangial cells.
Concurrently, these AGE-induced alterations in endothelial cell function favor thrombus formation at sites of extracellular AGE accumulation. These catabolic fractions of AGE-modified proteins bear dicarbonyl Maillard reaction intermediates, which are a much more aggressive menace to plasma and tissue proteins as compared to the role formerly attributed to glucose. There was a 16% reduction (not statistically significant) in the risk of myocardial infarction and sudden death in the intensively treated group. On the other hand, activation of monocyte receptors by AGEs on vascular wall proteins, such as collagen and elastin, would trigger the aforementioned sequence of cytokine-mediated inflammatory reactions.
Glycated and oxidized lipoproteins induce cholesteryl ester accumulation in human macrophages and may promote platelet and endothelial cell dysfunction. Aggressive treatment of blood pressure produces tangible benefits irrespective of the type of anthypertensive therapy. It must be noted that in addition to inhibiting AGE formation, aminoguanidine inhibits the inducible form of nitric oxide synthase in vitro. This evidence suggests that current diabetes care should be directed at earlier diagnosis of this condition and more effective control of the postprandial glucose excursions that may influence the development of long-term complications.
These studies showed unequivocally in type 1 diabetes that lowering blood glucose delayed the onset and slowed the progres­sion of microvascular complications. The colocalization of receptors and AGEs at the microvascular sites of injury suggests that their interaction may play a significant role in the pathogenesis of diabetic vascular lesions. Nonetheless, as pointed out earlier, these studies do not prove as yet that high blood glu­cose causes these complications and that intensive treatment to lower glucose would reduce the risk. In vivo, however, concentrations ten times higher than those used to inhibit AGEs are needed to change nitric oxide concentrations in a significant manner. As the intimate sequence of the steps that lead to vascular diseases associated with diabetes per se are yet not fully understood, we have no precise answer to these questions. Secondary analyses in these studies showed strong relationships between the risks of developing these com­plications and glycemic exposure over time. As pointed out earlier, an interesting observation from the UKPDS is that metformin decreased the risks of diabetes-related deaths and myocardial infarction when compared with other conventional treatments. In addition, clinical trials of inhibitors of this cross-linking have been inconclusive to date.
These efforts are likely to delay the appearance and early progression of diabetic retinopathy, nephropathy, and neuropathy.
Moreover, as stated in the introduction, there was no clear-cut glucose threshold but a continuous reduction in complications as glycemic levels came closer to the reference range.
These problems should not discredit the meaningful conclusions regarding the effect of tight control of complications. The same caveats regarding interpretation of the results of trials of aldose reductase inhibitors thus apply to trials of inhibitors of AGE-cross-linking. On the other hand, recent epidemiologic studies have revealed that diabetic patients with poorly controlled glucose levels have a higher risk of cardiovascular disease than those with well-controlled glucose levels. The UK study has provided answers to a range of important questions that have plagued diabetes researchers and physicians for decades. That is, longer trials in better-defined populations are needed before the effectiveness of these inhibitors can be proven. Some studies go further and suggest that glycemia appears to be a continuous risk factor for cardiovascular disease, and that this association is not restricted to the diabetic range. Tightly controlling blood glucose concentration reduced the risk of complications in type 2 diabetes. They believe glycemia represents a continuous risk factor for cardiovascular disease comparable to that of dyslipidemia, smoking or blood pressure. The overall microvascular complications rate was decreased by 25% in patients receiving intensive therapy versus conventional therapy. For instance, subjects with IGT had a relative risk (RR) of death 30% higher when compared to those with normal glucose; those with undiagnosed diabetes had a RR 80% higher and those with diagnosed diabetes had a RR of 280 % higher.
For every percentage point decrease in HbA1c there was a 35% reduction in the risk of microvascular complications.
As far as reducing the risk of microvascular complications is concerned, sulphonylureas and insulin produced equally good results.



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