Nutrient Sensor mTOR and OGT: Orchestrators of Organelle Homeostasis in Pancreatic β-Cells

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.

Sex Differences in Pancreatic β-Cell Physiology and Glucose Homeostasis in C57BL/6J Mice

“…6A and D ). Ogt is another critical nutrient sensor protein that integrates macronutrient signaling to regulate β-cell mass and function [ 22 , 23 ]. Total Ogt expression is not significantly different between sexes, but RL2 levels, indicative of Ogt activity, O-GlcNAcylation, is reduced in female islets ( Fig.…”

Metabolomic Profiling of Amino Acids in Human Plasma Distinguishes Diabetic Kidney Disease From Type 2 Diabetes Mellitus

“…Four possible mechanisms underlie these associations. First, an increased plasma level of BCAAs leads to hyperactivation of the mammalian target of rapamycin (mTOR) signaling pathway, thereby resulting in the dysfunction and destruction of pancreatic beta-cells ( 20 ). Second, BCAAs may facilitate glucose uptake, as well as glycogen synthesis, via the phosphatidylinositol 3-kinase (PI3K) or protein kinase C (PKC) signaling pathways, in an insulin-independent manner ( 21 ).…”

β Cell and Autophagy: What Do We Know?

“…It has been demonstrated that surplus and restricted β cells’ nutrient access can induce autophagy. For example, calorie intake changes in mice, from a high-fat diet to a nutrient-restricted diet, led to an increased p62 degradation and LC3II/LC3I ratio as two primary autophagy-related markers [ 90 ]. Moreover, a later study reported that nuclear factor erythroid 2-related factor 2 (NRF2), an antioxidant factor, is crucial for β cells’ response to temporary high-fat intake changes [ 91 ].…”