Glucose Homeostasis, Insulin Resistance and β Cell Failure
Humans rely on that their blood glucose levels maintain within a physiological range of 4–6 mM during the day with periods of fasting and refeeding. Therefore, glucose intake, storage, mobilization and breakdown are tightly regulated, in particular by the peptide hormones insulin and glucagon. The insulin signaling axis is composed of a number of critical nodes including the insulin receptor (IR), the adaptor protein IRS, the kinases PI3K and AKT as well as the transcription factor forkhead box O (FOXO). Each of these nodes is represented by several protein isoforms and is interconnected with a number of other signal transduction cascades. For example, multiple upstream pathways regulate FOXO activity through post-translational modifications and nuclear-cytoplasmic shuttling of both the transcription factor and its co-regulators. In this way, insulin is controlling a number of physiological functions, but is also sensible to several cellular processes that, when misbalanced, affect insulin signaling, what might lead to insulin resistance. In insulin resistance, normal concentrations of insulin cause an insufficient response of the major insulin target tissues, such as skeletal muscle, liver and adipose tissue. Three main processes can lead to insulin resistance in skeletal muscle and liver: an ectopic overload of lipids, a chronic inflammatory response and ER stress. Similarly, glucotoxic and lipotoxic stress to β cells are mediated via inflammatory response, oxidative stress and ER stress eventually resulting in the failure of the cells.
In this chapter, we will describe the molecular principles of glucose homeostasis and insulin signaling. Using the example of FOXO transcription factors we will analyze the mechanisms how a central signal transduction cascade interacts with environmental challenges mediated via multiple other pathways, in order to keep cells and tissues in homeostasis. This mechanistic understanding will help to integrate the complexity of insulin resistance. We will summarize our insight on chronic inflammation (Sect. 7.2) and the unfolded protein response (Sect. 7.5), in order to interpret the response of muscle and liver cells while developing insulin resistance and that of β cells in the process towards their failure.