Review Articles in 2009

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.

The growing appreciation of the regulatory role of the central nervous system (CNS) in energy and glucose homeostasis has the potential to lead to more effective long–term treatments for obesity and type 2 diabetes. Here, Sandoval and colleagues discuss the CNS pathways involved, identify promising therapeutic targets and strategies for diabetes and consider the associated challenges hampering the development of new agents.

The glucose-phosphorylating enzyme glucokinase acts as a glucose sensor of the insulin-producing pancreatic islet β-cells, controls the conversion of glucose to glycogen in the liver and also regulates hepatic glucose production, and is therefore a potential therapeutic target for the treatment of type 2 diabetes. Here, Matschinsky discusses the physiological roles of glucokinase and the most recent progress in the development of pharmacological glucokinase activators.

Therapies based on the incretin hormone glucagon-like peptide 1 (GLP1) have proved to be successful in the treatment of type 2 diabetes. In this article, Ahrén reviews recent progress in the development of improved GLP1 modulators and discusses the therapeutic potential of other islet β-cell G protein-coupled receptors that are involved in the regulation of islet function, including GPR40 and GPR119.

Thyroid hormone excess has potentially useful effects, including lowering of serum cholesterol and reduction of body fat. However, the therapeutic application of this hormone has so far been hampered by deleterious effects on the heart, muscle and bone. This article reviews recent progress in the development of selective thyroid hormone mimetics that seem to lack the adverse actions associated with thyroid hormone itself, making them a promising new strategy for the treatment of atherosclerosis, obesity and type 2 diabetes.

Scholich and colleagues highlight how an increased knowledge of the physiological functions of different mammalian adenylyl cyclases, combined with advances in the development of isoform-selective adenylyl cyclase modulators indicates that these enzymes could be useful drug targets.

The regulation of endothelia is vital for the maintenance of homeostasis, and their disruption is observed in many disease states. Sphingosine-1-phosphate (S1P) receptors have emerged as reversible modulators of endothelial barriers, which could lead to the development of highly specific, barrier-oriented small-molecule-based therapeutics for treating conditions ranging from multiple sclerosis to acute respiratory distress syndrome.

The central roles of members of the fibroblast growth factor (FGF) family in human developmental processes and disease have been well documented. In their Review, Beenken and Mohammadi discuss the more established applications of FGF-related therapies in the treatment of cancer and cardiovascular disease, emphasizing their potential to modulate aspects of the metabolic syndrome and hypophosphataemic diseases.

The field of cancer chemoprevention has reported its first major successes, but broad translation to the clinic is not yet a reality. Here, Lippman and colleagues review the unique challenges encountered in this field, and the promise of personalized, molecularly targeted chemoprevention strategies.

Oligosaccharides are key to the mode of action of recombinant monoclonal antibodies. This article reviews current understanding of the role of antibody glycosylation on antibody effector function and the strategies that are being explored to produce homogeneous natural antibody glycoforms with optimized therapeutic efficacy.

RNA interference holds vast potential as a therapeutic strategy for both disease prevention and treatment, but its use has so far been hampered by a lack of safe and effective delivery techniques. In their Review, Anderson and colleagues discuss the challenges associated with small interfering RNA delivery and highlight promising novel synthetic delivery agents.

The recent discovery of a new family of oxygen sensors — including prolyl hydroxylase domain-containing proteins 1–3 (PHD1–3) — has provided novel insights into how cells sense oxygen and keep oxygen supply and consumption in balance. This review describes how advances in understanding of the role of these oxygen sensors in hypoxia tolerance, ischaemic preconditioning and inflammation are creating new opportunities for pharmacological interventions in ischaemic and inflammatory diseases.

Transient receptor potential (TRP) channels are the most prominent family of nociceptive ion-channel transducer proteins. This Review highlights evidence supporting particular TRP channels as targets for analgesics, indicates the likely efficacy profiles of TRP-channel-acting compounds and looks at recent clinical trials with TRP-channel-acting drugs.

G protein–coupled receptors (GPCRs) represent one of the most targeted protein families in pharmaceutical research. Traditionally, drug discovery programmes have searched for ligands that act at endogenous orthosteric sites. Here, Conn and colleagues discuss recent advances in the identification of novel GPCR ligands that act at allosteric sites, highlighting their potential in the treatment of psychiatric and neurological disorders.