Abstract
Increasing evidence of a role of chronic inflammation in type 2 diabetes progression has led to the development of therapies targeting the immune system. We develop a model of interleukin-1β dynamics in order to explain principles of disease onset. The parameters in the model are derived from in vitro experiments and patient data. In the framework of this model, an IL-1β switch is sufficient and necessary to account for type 2 diabetes onset. The model suggests that treatments targeting glucose bear the potential of stopping progression from pre-diabetes to overt type 2 diabetes. However, once in overt type 2 diabetes, these treatments have to be complemented by adjuvant anti-inflammatory therapies in order to stop or decelerate disease progression. Moreover, the model suggests that while glucose-lowering therapy needs to be continued all the way, dose and duration of the anti-inflammatory therapy needs to be specifically controlled. The model proposes a framework for the discussion of clinical trial outcomes.
Highlights
Despite more than 350 million patients worldwide and the concomitant expensive socioeconomic burden, the pathogenesis of type 2 diabetes (T2D) is not yet completely understood
The most important physiological components of T2D are insulin resistance, which is characterized by impaired response to insulin in insulin-sensitive tissues, and b-cell failure, which is characterized by b-cell dysfunction and reduced b-cell mass
While insulin resistance is always present in the early phase, it is b-cell failure that determines the pace of the disease onset
Summary
Despite more than 350 million patients worldwide and the concomitant expensive socioeconomic burden, the pathogenesis of type 2 diabetes (T2D) is not yet completely understood. The progression of T2D is clearly divided into at least two phases, pre-diabetes and overt diabetes [1,2,3,4,5]. In the pre-diabetes phase, insulin resistance is compensated by increased single b-cell secretion capacity and/or b-cell number. If insulin resistance is not completely compensated, the blood glucose level would grow slowly, manifested as higher fasting glucose (impaired fasting glucose, IFG) and/or higher post-load glucose (impaired glucose tolerance, IGT) [6]. Overt T2D is characterized by compensation failure and continuous loss of functional b-cells [7,8], accompanied by continuously aggravated hyperglycaemia
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