Abstract
Type 2 diabetes (T2D) is a complex and heterogeneous disease which affects millions of people worldwide. The classification of diabetes is at an interesting turning point and there have been several recent reports on sub-classification of T2D based on phenotypical and metabolic characteristics. An important, and perhaps so far underestimated, factor in the pathophysiology of T2D is the role of oxidative stress and reactive oxygen species (ROS). There are multiple pathways for excessive ROS formation in T2D and in addition, beta-cells have an inherent deficit in the capacity to cope with oxidative stress. ROS formation could be causal, but also contribute to a large number of the metabolic defects in T2D, including beta-cell dysfunction and loss. Currently, our knowledge on beta-cell mass is limited to autopsy studies and based on comparisons with healthy controls. The combined evidence suggests that beta-cell mass is unaltered at onset of T2D but that it declines progressively. In order to better understand the pathophysiology of T2D, to identify and evaluate novel treatments, there is a need for in vivo techniques able to quantify beta-cell mass. Positron emission tomography holds great potential for this purpose and can in addition map metabolic defects, including ROS activity, in specific tissue compartments. In this review, we highlight the different phenotypical features of T2D and how metabolic defects impact oxidative stress and ROS formation. In addition, we review the literature on alterations of beta-cell mass in T2D and discuss potential techniques to assess beta-cell mass and metabolic defects in vivo.
Highlights
In the year 2030, it is estimated that 439 million people will be affected by diabetes (American Diabetes Association, 2009) and that the number will rise to 642 million by 2040 (Zimmet et al, 2016)
We have recently demonstrated that selective NOX4 inhibitors protect human islets and reduce beta-cell death under in vitro conditions mimicking the Type 2 diabetes (T2D) environment (Wang et al, 2018a), making it a potential drug target
Besides oxidative stress related to glucolipotoxicity, Advanced glycation end products (AGEs), and dietary factors, there are many other environmental factors associated with deterioration of beta-cell function that are less well understood
Summary
In the year 2030, it is estimated that 439 million people will be affected by diabetes (American Diabetes Association, 2009) and that the number will rise to 642 million by 2040 (Zimmet et al, 2016). Hyperglycemia and coupled metabolic defects in diabetes increase the production of oxidative stress and reactive oxygen species (ROS) which can have vast deleterious effects and contribute to beta-cell dysfunction, failure, and loss. Besides oxidative stress related to glucolipotoxicity, AGEs, and dietary factors, there are many other environmental factors associated with deterioration of beta-cell function that are less well understood One such factor is disruption of the islets circadian rhythm, which has recently been suggested to cause increased ROS production and a decreased production of antioxidant genes in beta-cells, leading to beta-cell dysfunction and diabetes (Lee et al, 2018). In a study where exogenous insulin analogs were administered to T2D patients who failed to achieve satisfactory glycemic control on Metformin and sulfonylurea alone, showed a significant decrease in oxidative stress markers (Tuzcu et al, 2013) This was not related to changes in mean glucose levels, suggesting instead some direct inhibitory effects on ROS formation. PET imaging using tracers targeting ROS will likely soon be available in the clinical setting, which will be a valuable contribution in many fields of medicine, not the least in diabetes research
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