Insulin-induced mTOR signaling and gluconeogenesis in renal proximal tubules: A mini-review of current evidence and therapeutic potential

Abstract

Energy is continuously expended in the body, and gluconeogenesis maintains glucose homeostasis during starvation. Gluconeogenesis occurs in the liver and kidneys. The proximal tubule is the primary location for renal gluconeogenesis, accounting for up to 25% and 60% of endogenous glucose production during fasting and after a meal, respectively. The mechanistic target of rapamycin (mTOR), which exists downstream of the insulin pathway, plays an important role in regulating proximal tubular gluconeogenesis. mTOR is an atypical serine/threonine kinase present in two complexes. mTORC1 phosphorylates substrates that enhance anabolic processes such as mRNA translation and lipid synthesis and catabolic processes such as autophagy. mTORC2 regulates cytoskeletal dynamics and controls ion transport and proliferation via phosphorylation of SGK1. Therefore, mTOR signaling defects have been implicated in various pathological conditions, including cancer, cardiovascular disease, and diabetes. However, concrete elucidations of the associated mechanisms are still unclear. This review provides an overview of mTOR and describes the relationship between mTOR and renal.

Exploring mechanisms of insulin action and strategies to treat diabetes

“…It was shown that gluconeogenesis is suppressed by insulin signaling mediated by IRS-1/2 in the proximal tubules, and impaired insulin signaling in the tissue leads to systemic insulin resistance [31]. We also showed that inactivation of the forkhead box O 1 (FoxO1), one of the key downstream molecules of insulin signaling [3,33], via interaction with peroxisome proliferator-activated receptor gamma coactivator (PGC) 1α, is important in this context [31], although the contribution of the mammalian target of rapamycin (mTOR) pathway was also proposed recently [28]. Insulin receptor is considered to be expressed in the basolateral side of the proximal tubules [34], but glucose reabsorbed by SGLT1/2 expressed on the luminal side of the proximal tubules was also shown to suppress gluconeogenesis via suppression of Sirtuin 1 activity (Fig.…”

“…Gluconeogenesis in the liver plays a pivotal role in supplying glucose to glucose-utilizing tissues in a fasted state, but gluconeogenesis in the proximal tubules of the kidney also matters, especially during prolonged fasting [27,28]. Insulin receptor is abundantly expressed in the cortex of the kidney, mainly consisting of the proximal tubules [29], and indeed, deletion of insulin receptor in the proximal tubules causes hyperglycemia [30].…”

Effects of alcohol and PARP inhibition on RNA ribosomal engagement in cortical excitatory neurons

“…Insulin signaling can activate the mTOR pathway through the activation of PI3K/Akt signaling. mTOR also regulates insulin signaling by modulating the activity of insulin receptor substrate-1 (IRS-1) ( Nakamura et al, 2022 ). Similarly, IGF-I can activate the mTOR pathway through the activation of PI3K/Akt and Ras/MAPK signaling ( Mendoza et al, 2011 ).…”

RISING STARS: Mechanistic insights into maternal–fetal cross talk and islet beta-cell development

“…Placental expression levels of the macronutrient transporters discussed above are regulated by various hormones such as maternal insulin, IGF-1, leptin, and cytokines ( Jansson et al 2003 , Magnusson-Olsson et al 2006 , Jones et al 2009 , Roos et al 2009 b , Mousiolis et al 2012 , Baumann et al 2014 , Nogues et al 2021 , Anam et al 2022 ). A common downstream intracellular target of these hormonal signals is the nutrient sensor protein kinase, mechanistic target of rapamycin (mTOR) ( Maya-Monteiro & Bozza 2008 , Dong et al 2019 , Nakamura et al 2022 ). mTOR is one of the master nutrient sensor proteins that integrate extracellular signaling pathways such as insulin and nutrient availability to promote growth and development of the cell through regulation of key protein translation complexes and mitochondrial biogenesis ( Roos et al 2009 b ).…”