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      Therapies for hyperglycaemia-induced diabetic complications: from animal models to clinical trials

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          Key Points

          • Diabetic complications — the long-term damage to various organ systems — are a great cause of mortality and morbidity in both type 1 and type 2 diabetes. There are currently few therapeutic options to prevent or ameliorate these complications.

          • High blood glucose levels and the subsequent metabolic consequences of hyperglycaemia are widely considered the primary event that initiates diabetic complications, although there is accumulating evidence that impaired insulin signalling arising from insulin deficiency and insulin resistance may also have a pathogenic role.

          • Vascular dysfunction is a prominent complication of diabetes that is widely held to underlie damage to organ systems such as the macrovasculature, kidneys, eyes and nerves. Other consequences of diabetes, such as dyslipidaemia and hypertension, are key modifiers of vascular injury and act as accelerators of diabetic complications.

          • Numerous pathogenic mechanisms, including increased polyol pathway flux and mitochondrial activity, activation of protein kinase C and NADPH oxidase and signalling through the receptor for advanced glycation end products (RAGE) pathway, seem to form a central pathogenic axis that is common to most, if not all, of the complications of diabetes. These disorders all promote excess production of pro-oxidative molecules. Organ-specific mechanisms, such as diminished growth factor support and repair pathway activation, must also be considered.

          • Few animal models of diabetic complications faithfully reflect the advanced stages of organ pathology seen in humans. Current models can be viewed as potentially illustrating early biochemical and functional disorders of diabetes that ultimately lead to advanced pathology. New animal models are being developed using both a reductionist approach for examining specific gene products of interest and also by combining diverse molecular and physiological risk factors.

          • Control of blood glucose levels and lipids remains the most meaningful approach for preventing diabetic complications. This strategy is likely to be complemented by a diverse range of more focused therapeutics that have emerged from mechanistic studies in animal models and which are currently in clinical development. Some of these, such as those targeting cardiovascular disease, have the potential to affect several diabetic complications, whereas others focus on intervening in organ-specific pathogenic mechanisms. It is probable that combination therapies aimed at the hyperglycaemia-driven pathogenic axis and also at organ-specific disorders will provide the most effective approach to treating the diverse complications of diabetes.

          Abstract

          Long-term diabetes increases the likelihood of developing complications such as macrovascular disease, nephropathy, retinopathy and neuropathy. This Review highlights the range of pathologies that are precipitated by hyperglycaemia and discusses recent developments in preclinical and clinical research for each of these complications.

          Abstract

          Long-term diabetes increases the likelihood of developing secondary damage to numerous systems, and these complications represent a substantial cause of morbidity and mortality. Establishing the causes of diabetes remains the key step towards eradicating the disease, but the prevention and amelioration of diabetic complications is equally important for the millions of individuals who already have the disease or are likely to develop it before prophylaxis or a cure become routinely available. In this Review, we focus on four common complications of diabetes, discuss the range of pathologies that are precipitated by hyperglycaemia and highlight emerging targets for therapeutic intervention.

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          Most cited references 152

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          Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia

          The current goal of diabetes therapy is to reduce time-averaged mean levels of glycemia, measured as HbA1c, to prevent diabetic complications. However, HbA1c only explains <25% of the variation in risk of developing complications. Because HbA1c does not correlate with glycemic variability when adjusted for mean blood glucose, we hypothesized that transient spikes of hyperglycemia may be an HbA1c–independent risk factor for diabetic complications. We show that transient hyperglycemia induces long-lasting activating epigenetic changes in the promoter of the nuclear factor κB (NF-κB) subunit p65 in aortic endothelial cells both in vitro and in nondiabetic mice, which cause increased p65 gene expression. Both the epigenetic changes and the gene expression changes persist for at least 6 d of subsequent normal glycemia, as do NF-κB–induced increases in monocyte chemoattractant protein 1 and vascular cell adhesion molecule 1 expression. Hyperglycemia-induced epigenetic changes and increased p65 expression are prevented by reducing mitochondrial superoxide production or superoxide-induced α-oxoaldehydes. These results highlight the dramatic and long-lasting effects that short-term hyperglycemic spikes can have on vascular cells and suggest that transient spikes of hyperglycemia may be an HbA1c–independent risk factor for diabetic complications.
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            MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.

            Individuals with diabetes are at increased risk of cardiovascular morbidity and mortality, although typically their plasma concentrations of LDL cholesterol are similar to those in the general population. Previous evidence about the effects of lowering cholesterol in people with diabetes has been limited, and most diabetic patients do not currently receive cholesterol-lowering therapy despite their increased risk. 5963 UK adults (aged 40-80 years) known to have diabetes, and an additional 14573 with occlusive arterial disease (but no diagnosed diabetes), were randomly allocated to receive 40 mg simvastatin daily or matching placebo. Prespecified analyses in these prior disease subcategories, and other relevant subcategories, were of first major coronary event (ie, non-fatal myocardial infarction or coronary death) and of first major vascular event (ie, major coronary event, stroke or revascularisation). Analyses were also conducted of subsequent vascular events during the scheduled treatment period. Comparisons are of all simvastatin-allocated versus all placebo-allocated participants (ie, intention to treat), which yielded an average difference in LDL cholesterol of 1.0 mmol/L (39 mg/dL) during the 5-year treatment period. Both among the participants who presented with diabetes and among those who did not, there were highly significant reductions of about a quarter in the first event rate for major coronary events, for strokes, and for revascularisations. For the first occurrence of any of these major vascular events among participants with diabetes, there was a definite 22% (95% CI 13-30) reduction in the event rate (601 [20.2%] simvastatin-allocated vs 748 [25.1%] placebo-allocated, p<0.0001), which was similar to that among the other high-risk individuals studied. There were also highly significant reductions of 33% (95% CI 17-46, p=0.0003) among the 2912 diabetic participants who did not have any diagnosed occlusive arterial disease at entry, and of 27% (95% CI 13-40, p=0.0007) among the 2426 diabetic participants whose pretreatment LDL cholesterol concentration was below 3.0 mmol/L (116 mg/dL). The proportional reduction in risk was also about a quarter among various other subcategories of diabetic patient studied, including: those with different duration, type, or control of diabetes; those aged over 65 years at entry or with hypertension; and those with total cholesterol below 5.0 mmol/L (193 mg/dL). In addition, among participants who had a first major vascular event following randomisation, allocation to simvastatin reduced the rate of subsequent events during the scheduled treatment period. The present study provides direct evidence that cholesterol-lowering therapy is beneficial for people with diabetes even if they do not already have manifest coronary disease or high cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rate of first major vascular events by about a quarter in a wide range of diabetic patients studied. After making allowance for non-compliance, actual use of this statin regimen would probably reduce these rates by about a third. For example, among the type of diabetic patient studied without occlusive arterial disease, 5 years of treatment would be expected to prevent about 45 people per 1000 from having at least one major vascular event (and, among these 45 people, to prevent about 70 first or subsequent events during this treatment period). Statin therapy should now be considered routinely for all diabetic patients at sufficiently high risk of major vascular events, irrespective of their initial cholesterol concentrations.
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              Diabetic retinopathy.

               Daniel Frank (2004)
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                Author and article information

                Contributors
                ncalcutt@ucsd.edu
                Journal
                Nat Rev Drug Discov
                Nat Rev Drug Discov
                Nature Reviews. Drug Discovery
                Nature Publishing Group UK (London )
                1474-1776
                1474-1784
                2009
                : 8
                : 5
                : 417-430
                Affiliations
                [1 ]GRID grid.266100.3, ISNI 0000 0001 2107 4242, Department of Pathology, , University of California, San Diego, ; La Jolla, 92093 California USA
                [2 ]GRID grid.1051.5, ISNI 0000 0000 9760 5620, Diabetes Division, , Baker IDI Heart and Diabetes Institute, ; Melbourne, 3004 Victoria Australia
                [3 ]GRID grid.67105.35, ISNI 0000 0001 2164 3847, Department of Medicine, , Case Western Reserve University, ; 434 Biomedical Research Building, 2109 Adelbert Road, Cleveland, 441064951 Ohio USA
                [4 ]GRID grid.21729.3f, ISNI 0000000419368729, College of Physicians and Surgeons, Columbia University, ; 630 West 168th Street, P&S 17401, New York, 10032 New York USA
                Article
                BFnrd2476
                10.1038/nrd2476
                7097138
                19404313
                © Nature Publishing Group 2009

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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                © Springer Nature Limited 2009

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