Preface [Hot topic: Diabetes (Guest Editor: Alex M. DePaoli)]

Type 2 Diabetes Mellitus (T2DM) is an enormous global public health problem that has been increasing in scope at an astonishing pace over the past two decades. Efforts to implement nutritional and exercise recommendations in the US have not prevented an explosion of new cases. This dramatic rise in new diagnoses of T2DM is also occurring in the EU, Canada, Asia, and most of the developed world. Among the most important factors driving this recent epidemic are the increased availability of calories and the development of obesity. Current therapies for T2DM that improve glycemic control are effective at reducing both microvascular and macrovascular complications. Unfortunately, the natural history of both impaired insulin action and insulin secretion that underlie T2DM is not substantially altered by current pharmacological interventions. Indeed, the impact of single drugs to reduce hyperglycemia is often reduced over time and multiple drug regimens become necessary. This treatment paradigm entails progressive complexity, cumulative adverse effects, and increased costs that significantly limit effective control of blood glucose in the average patient. Ideal therapeutic candidates for T2DM would improve glucose homeostasis while also slowing or reversing the natural history of disease. At present, it is not clear how progression of T2DM can be slowed or reversed beyond the limited effectiveness of appropriate diet and exercise. Thus, it is imperative to identify new approaches to the effective treatment of T2DM. These need to provide novel options to safely and economically control hyperglycemia and prevent the devastating cardiovascular, renal, and ocular complications that arise. An important point of caution is that many strategies to identify therapeutic targets involve rodent models. These include the candidate gene / pathway approach, genetic screening, proteomics, and mass screening of rodent knock-out models. The premise is that developing a comprehensive understanding of the molecular defects causing insulin resistance and hyperglycemia in rodents will lead to identification of appropriate targets for intervention in T2DM in humans. An important part of validating targets identified in rodent models is to show clear relevance for T2DM in humans. Complicating this task is the fact that the clinical diagnosis of Type 2 DM is defined somewhat arbitrarily. An enormous body of work clearly documents a continuum, from the early stages of the Metabolic Syndrome, (insulin resistance, dyslipidemia, hypertension, and obesity), to the end stages of T2DM, with its vascular complications. Exploring this continuum has provided clues into the connectivity of pathways that have previously been considered distinct. For example, interactions between insulin and leptin action and resistance, the contributions of inflammation to disorders of glucose and lipid metabolism, and CNS regulation of glucose and energy homeostasis. These insights have underscored the complexity and heterogeneity of factors that contribute to T2DM and the mechanisms by which they lead to increased morbidity and mortality. The papers presented within this 'Hot Topics in DM' issue highlight a set of pathways that provide important insights into this continuum of disordered glucose and insulin homeostasis. These pathways suggest an array of exciting therapeutic targets that impact on multiple aspects of insulin / glucose dysregulation. Some of these targets may lead to drugs that prevent the development or progression of cardiovascular complications associated with T2DM. If we are fortunate, one or more of these targets may lead to the development of therapies that significantly improve or even reverse the underlying pathophysiology. The hope is to provide a more meaningful long term impact on the health and well-being of patients suffering from diabetes. I would like to thank the contributing authors for their significant efforts and insights. It will be fascinating to follow progress in these areas in the years to come.