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

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.

Figure 1. Selected therapeutic approaches showing either pan-complication or organ-specific efficacy in animal models of diabetes.

Vascular dysfunction contributes to all diabetic complications, and therapeutic approaches that target the vasculature (shown centre in dark pink, where the three areas overlap) show some efficacy against all complications. The kidneys, eyes and nerves could also be targeted by organ-specific approaches. ARI, aldose reductase inhibitor; GAG, glycosaminoglycan; RAGE, receptor for advanced glycation end products; VEGF, vascular endothelial growth factor.

Figure 2. Important glucotoxicity pathways contributing to diabetic complications.

Organ damage can be triggered by both extracellular and intracellular hyperglycaemia. Increased extracellular glucose leads to non-enzymatic glycosylation of proteins and subsequent formation of advanced glycation end products (AGE) that interact with the receptor for AGE (RAGE) on the plasma membrane and promote the production of reactive oxygen species (ROS). Increased intracellular glucose drives mitochondrial activity, increases the activity of protein kinase C (PKC) and NADPH oxidase and promotes increased flux through the polyol pathway, all of which have many effects on cellular metabolism and phenotype. This figure highlights the consequences of excessive ROS production in the vasculature, where ROS-driven changes in cell phenotype are mediated by a range of signalling pathways and transcription factors. Cells of the kidneys, eyes and nervous system also undergo cell- and organ-specific phenotypic changes as a result of hyperglycaemia-mediated ROS production. ROS production, ROS-unrelated pathogenic consequences of hyperglycaemia and hyperglycaemia-independent mechanisms, such as impaired insulin signalling, are likely to collectively mediate the organ-specific pathologies of diabetic complications. Other pathways that are relevant to diabetic complications but are unrelated to hyperglycaemia per se, such as disruption of the renin–angiotensin system (Fig. 3), are described in the main text. AP1, activator protein 1; AR, aldose reductase; CCL2, CC-chemokine ligand 2 (also known as MCP1); CDC42, cell division cycle 42; EGR1, early growth response protein 1; ERK, extracellular signal-regulated kinase; ICAM1, intercellular adhesion molecule 1; JAK, Janus-activated kinase; JNK, Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; PI3K, phosphoinositide 3-kinase; RNS, reactive nitrogen species; SDH, sorbitol dehydrogenase; STAT, signal transducer and activator of transcription; VCAM1, vascular cell adhesion molecule 1.

Figure 3. The proposed interactions between haemodynamic and metabolic disorders in diabetes that together mediate diabetic nephropathy.

It is notable that many of the metabolic disorders of the kidney reflect those occurring in other organs that are compromised by diabetes (Fig. 2), whereas aspects of the haemodynamic component may be more specific to nephropathy. Therapeutic approaches that intervene in the core pathogenic mechanisms that are common to all diabetic complications may therefore require combination with organ-specific therapies for maximal benefit. AGE, advanced glycation end product; CTGF, connective tissue growth factor; MAPK, mitogen-activated protein kinase; PKC, protein kinase C; RAGE, receptor of AGE, TGFβ, transforming growth factor-β; VEGF, vascular endothelial growth factor.

Figure 4. Peroneal nerve biopsy from a diabetic cat.

This image shows nerve fibre loss (A) and the presence of pathological features (B), including thin myelin (a), dystrophic axons (b), a cluster of small regenerating axons (c) and a putative supernumenary Schwann cell (d) that are rare in the common rodent models of diabetic neuropathy. The pathologic changes found in the nerves of diabetic domestic cats closely resemble those seen in patients with diabetes. The growing number of domestic cats with diabetes may offer an experimental bridge between preclinical studies in rodents and clinical trials that allows direct measurement of efficacy against degenerative diabetic neuropathy and may also provide an additional market for such drugs. Images courtesy of A. Mizisin, University of California, San Diego, USA.