Protein-Rich or Amino-Acid Only Diets Entrain the Liver Clock: Time to Scrap Insulin?

Daily rotation of the Earth on its axis and yearly revolution around the Sun impose periodicity on most organisms. Molecular circadian clocks might have evolved to synchronize internal metabolic rhythms to predictable environmental cycles, in order to most advantageously time functions such as feeding, mating, and general patterns of activity (Tevy et al., 2013). Moreover, a growing body of evidence suggests reciprocal links between nutrient sensing pathway and circadian clocks (Tevy et al., 2013). In mammals, a process integrated by the circadian clock network in mammals is glucose homeostasis (Tevy et al., 2013; Mazzoccoli et al., 2012). The hormones cortisol and melatonin convey the rhythmic output of the suprachiasmatic nucleus (SCN) to peripheral oscillators and modulate glucose homeostasis (Tevy et al., 2013; Mazzoccoli et al., 2012). Circadian rhythmicity of cortisol secretion is implicated in nycthemeral changes of insulin sensitivity (Tevy et al., 2013; Mazzoccoli et al., 2012). Melatonin modulates glucosestimulated insulin secretion (Tevy et al., 2013; Mazzoccoli et al., 2012). Additionally, peripheral clocks, such as the liver clock, are directly entrained by food and other stimuli, independently of the SCN (Wehrens et al., 2017). Pancreatic insulin production is clearly required in this process. In type 2 diabetes, hitting adults, the body stops responding properly to its own insulin. Type 1 diabetes, characterized by pancreatic islet damage, usually appears earlier, with the dramatic effect of nearly vanished insulin production. Administration of insulin to streptozotocin (STZ)-treated rodents lacking insulin, a classical animal model of type 1 diabetes has been shown to restore oscillation of circadian clock genes in rats (Hofmann et al., 2013). Moreover, the liver clock of STZ-treated mice can also be entrained by scheduled feeding (Oishi et al., 2004). Then, how the hepatic peripheral clock of type I diabetic patients can be entrained by food ingestion, in absence of insulin production? A new study by Ikeda et al., published on EBioMedicine (Ikeda et al., 2018), attempts to answer to this important medical question. The authors demonstrate, with the help of PER2::LUC bioluminescence, that a protein-only diet and/or cysteine – only among the 20 amino acids administration, which does not increase insulin levels, elicits entrainment of the liver clock via glucagon secretion and/or