Abstract
The purpose of this review is to integrate the role of nutrient-sensing pathways into β-cell organelle dysfunction prompted by nutrient excess during type 2 diabetes (T2D). T2D encompasses chronic hyperglycemia, hyperlipidemia, and inflammation, which each contribute to β-cell failure. These factors can disrupt the function of critical β-cell organelles, namely, the ER, mitochondria, lysosomes, and autophagosomes. Dysfunctional organelles cause defects in insulin synthesis and secretion and activate apoptotic pathways if homeostasis is not restored. In this review, we will focus on mTORC1 and OGT, two major anabolic nutrient sensors with important roles in β-cell physiology. Though acute stimulation of these sensors frequently improves β-cell function and promotes adaptation to cell stress, chronic and sustained activity disturbs organelle homeostasis. mTORC1 and OGT regulate organelle function by influencing the expression and activities of key proteins, enzymes, and transcription factors, as well as by modulating autophagy to influence clearance of defective organelles. In addition, mTORC1 and OGT activity influence islet inflammation during T2D, which can further disrupt organelle and β-cell function. Therapies for T2D that fine-tune the activity of these nutrient sensors have yet to be developed, but the important role of mTORC1 and OGT in organelle homeostasis makes them promising targets to improve β-cell function and survival.
Highlights
Analogous to the way in which dysfunctional organs can cause diseases and death, intracellular organelles that deviate from their normal physiological performance can disturb the functions and vitality of the cells in which they reside
Dysregulated activity driven by chronic nutrient excess and inflammation during Type 2 diabetes (T2D) leads to profound changes in the ability of β-cell organelles to fulfill their roles (Figure 1)
There are many studies that examine mTOR complex 1 (mTORC1) hyperactivity and β-cell function and many that demonstrate the role of mTORC1 in endoplasmic reticulum (ER), mitochondrial, lysosomal, and autophagic function and dysfunction
Summary
Analogous to the way in which dysfunctional organs can cause diseases and death, intracellular organelles that deviate from their normal physiological performance can disturb the functions and vitality of the cells in which they reside. Important parameters of β-cell function include responsiveness to stimulation by nutrients (i.e., glucose and amino acids) and sufficient β-cell mass to regulate nutrient homeostasis in the bloodstream. We will address AMPK in this review when relevant, but our discussion of nutrient sensors will largely focus on mTOR and OGT In addition to these nutrientsensing proteins, we discuss autophagy and inflammation, two mechanisms that regulate organelle homeostasis and are sensitive to nutrients status. MTORC1 hyperactivity and mTORC2 hypoactivity in the context of T2D have many diverse and complex outcomes on a number of metabolic pathways, but in this review, we will focus on the junctions between mTOR signaling and organelle performance. As described in the subsequent sections of this review, dysregulated nutrient sensing through this pathway compromises the activities of several organelles crucial for β-cell function
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