The islet circadian clock: entrainment mechanisms, function and role in glucose homeostasis

Abstract

Circadian regulation of glucose homeostasis and insulin secretion has long been appreciated as an important feature of metabolic control in humans. Circadian disruption is becoming increasingly prevalent in today’s society and is likely responsible in part for the considerable rise in Type 2 diabetes (T2DM) and metabolic syndrome worldwide. Thus, understanding molecular mechanisms driving the inter-relationship between circadian disruption and T2DM is important in context of disease prevention and therapeutics. In this regard, the goal of this manuscript is to highlight the role of the circadian system, and islet circadian clocks in particular, as potential regulators of β-cell function and survival. To date, studies have shown that islet clocks respond to changes in feeding patterns, and regulate a multitude of critical cellular processes in insulin secreting β-cells (e.g. insulin exocytosis, mitochondrial function and response to oxidative stress). Subsequently, either genetic or environmental disruption of normal islet clock performance compromises β-cell function and leads to loss of glycemic control. Future work is warranted to further unravel the role of circadian clocks in human islet function in health and contributions to pathogenesis of T2DM.

Postnatal Ontogenesis of the Islet Circadian Clock Plays a Contributory Role in β-Cell Maturation Process

“…Our results show gradual emergence of circadian oscillations in islets starting at postnatal day 15, which coincides with the development of gastrointestinal adaptions for independent feeding activity cycles (40). Notably, establishment of circadian feeding cycles has been demonstrated to entrain the phase of peripheral circadian clocks (e.g., liver) (41,42), an observation recently extended to pancreatic islets (43). Consistent with these observations, our studies show that postnatal establishment of global behavioral circadian rhythms in activity and feeding cycles is required for the emergence of circadian clock function in pancreatic islets.…”

Chronomedicine and type 2 diabetes: shining some light on melatonin

“…Both rodent and human studies confirm that daily rhythms of blood glucose and insulin secretion are regulated by the timing system [53][54][55], whilst lesions of the SCN or environmental circadian disruption can lead to insulin resistance and obesity [56,57]. The molecular clock is essential for glucose metabolism, as evidenced by the impairment of glucose tolerance and insulin sensitivity upon disruption of core clock gene expression [51,[58][59][60][61][62][63]. Though SCN-driven neuroendocrine and autonomic outflow influence glucose homeostasis [64], peripheral clocks in the liver and pancreas also play a role in glucose management [10,[65][66][67][68][69].…”

MicroRNAs modulate core-clock gene expression in pancreatic islets during early postnatal life in rats

“…Rodent and human pancreatic beta cells, like most cells in the body, possess self-sustained molecular clocks that coordinate the timing of metabolism throughout the day and modulate insulin secretion to maintain blood glucose homeostasis [4][5][6][7]. The circadian oscillators operative in beta cells and other peripheral cells are synchronised by systemic signals (e.g.…”