Heterogeneity of Metabolic Defects in Type 2 Diabetes and Its Relation to Reactive Oxygen Species and Alterations in Beta-Cell Mass

Andris Elksnis, Mats Martinell, Olof Eriksson, Daniel Espes, Andris Elksnis, Mats Martinell, Olof Eriksson, Daniel Espes

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.

Keywords: beta-cell; beta-cell mass; diabetes classification; imaging; oxygen stress; positron emission tomography; reactive oxygen species; type 2 diabetes.

Figures

FIGURE 1
FIGURE 1
Proportions of diabetes subtypes by (A) the current classification, (B) subtyping of type 2 diabetes by Li et al. (2015) and (C) cluster classification by Ahlqvist et al. (2018) SAID (severe auto-immune diabetes), SIDD (severe insulin deficient diabetes), SIRD (severe insulin resistant diabetes), MOD (mild obestity-related diabetes) and MARD (mild age-related diabetes).
FIGURE 2
FIGURE 2
Illustration of the possible role of NOX activation in the development of beta-cell failure, hyperglycemia, and diabetes. Metabolic dysregulation leading to hyperactivity in the NOX-enzymes results in excessive ROS production and oxidative stress. This increased oxidative stress may subsequently be responsible for beta-cell failure, which in turn contributes to increased metabolic dysregulation. Various other factors may also influence these steps in different ways. For instance, diet can contribute to increased oxidative stress directly by containing excessive AGEs, or indirectly by contributing to the metabolic dysregulation. Inhibition of the NOX enzymes seems to be a promising solution for breaking this deleterious cycle.

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