Nutrient Sensing, Autophagy, and Diabetic Nephropathy
- Shinji Kume1,
- Merlin C. Thomas2 and
- Daisuke Koya3⇓
- 1Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
- 2Baker IDI Heart and Diabetes Institute, Melbourne, Australia
- 3Division of Diabetes and Endocrinology, Kanazawa Medical University, Kahoku-Gun, Ishikawa, Japan
- Corresponding author: Daisuke Koya, koya0516{at}kanazawa-med.ac.jp.
The prevalence of diabetic nephropathy, a serious complication of diabetes, has been increasing worldwide. Therefore, there is an urgent need to identify a new therapeutic target to prevent diabetic nephropathy. “Nutrient-sensing” pathways are generally well conserved among eukaryotes. Accumulating evidence indicates that alteration of nutrient-sensing pathways and subsequent impairment of cell function in insulin-sensitive organs of mammals are involved in the pathogenesis of type 2 diabetes. According to recent reports, nutrient-sensing in the kidney also seems to be altered under diabetic conditions. In this review, we discuss the possibility that nutrient-sensing pathways can be a therapeutic target for diabetic nephropathy and suggest future directions for research.
NUTRIENT SENSING, AUTOPHAGY, AND DIABETIC NEPHROPATHY
Each cell has the ability to recognize and specifically respond to nutrient fuel substrates, such as glucose, lipids, and amino acids, to ensure their efficient use. These nutrient-sensing pathways appear critical for cellular homeostasis, for coping with starvation, and making the most of nutrient abundance. These pathways also represent important regulators of cell growth and proliferation, motility, mitochondrial function, autophagy, and survival (1–4).
Nutrient sensing is highly conserved across eukaryotic species. These pervasive regulatory pathways use posttranslational modifications of target proteins to link substrate availability to cellular homeostasis and stress responses (1–4). The best known of these pathways include the mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and the sirtuins (SIRT). Under low-energy conditions, AMPK and SIRT are activated by increases in intracellular AMP and NAD+ levels, respectively (1,2). In excessive nutrient conditions, mTOR is activated (3,4).
Each of these nutrient-sensing pathways has been implicated in the pathogenesis of obesity and diabetes, including actions on β-cell, adipocyte, hepatic and skeletal muscle metabolism, and the central regulation of nutrition (1–4). However, the same pathways may also be directly relevant to …
