Insulin Regulation of Proteostasis and Clinical Implications

Maintenance and modification of the cellular proteome are at the core of normal cellular physiology. Although insulin is well known for its control of glucose homeostasis, its critical role in maintaining proteome homeostasis (proteostasis) is less appreciated. Insulin signaling regulates protein synthesis and degradation as well as posttranslational modifications at the tissue level and coordinates proteostasis at the organism level. Here, we review regulation of proteostasis by insulin in postabsorptive, postprandial, and diabetic states. We present the effects of insulin on amino acid flux in skeletal muscle and splanchnic tissues, the regulation of protein quality control, and turnover of mitochondrial protein pools in humans. We also review the current evidence for the mechanistic control of proteostasis by insulin and insulin-like growth factor 1 receptors based on preclinical studies. Finally, we discuss irreversible posttranslational modifications of the proteome in diabetes and how future investigations will provide new insights into mechanisms of diabetic complications. James et al. provide a comprehensive review of insulin's crucial role in maintaining human proteostasis. They discuss current knowledge and gaps in the molecular mechanisms regulating protein turnover, modification, and quality control, and also highlight detrimental clinical effects of insulin deficiency and resistance on proteostasis, and its role in diabetic complications.