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

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.