Oral Presentation The Annual Scientific Meeting of the Australian Diabetes Society and the Australian Diabetes Educators Association 2013

The consequences of disrupting the expression of clock genes and circadian rhythms (#5)

David Kennaway 1
  1. University of Adelaide, ADELAIDE, SA, Australia

Circadian (24 hour) rhythms are generated in the hypothalamic suprachiasmatic nucleus (SCN) by a suite of “clock genes” and entrained to the photoperiod by light perception via the retina. This SCN “central master clock” coordinates cellular clocks in peripheral organs, such as the liver, muscle and pancreas, directly through multi-synaptic neural connections and indirectly via hormones such as melatonin and corticoids. Two key genes, Bmal1 and Clock, are responsible for both the generation of cellular rhythmicity and output signals in peripheral tissues, including liver and muscle. The BMAL1/CLOCK heterodimer drives the expression of other transcription factors and functional genes, many of which are involved in glucose and lipid metabolism. Plasma glucose concentrations change substantially and predictably across the night in humans. This implies that there may be circadian rhythms in insulin sensitivity, secretion and other determinants of glucose homeostasis. The SCN is pre-eminent in this rhythmicity, as its ablation in the rat eliminates changes in glucose tolerance across 24 hours. Peripheral tissues including the liver, muscle and pancreas also express clock genes, which as well as generating cellular rhythmicity, alter the expression of a wide range of genes, including those intimately involved in glucose homeostasis. Recently it has been shown that Clock mutant and Bmal1 null mice have disrupted circadian rhythmicity and glucose metabolism. The extent of disruption from genetic causes varies with background strain of the mice, but a consistent finding in these and other models is that disrupted rhythmicity at the central or cellular level impairs glucose tolerance and insulin secretion. Studies in humans involving simulated shift work or forced desynchrony have provided evidence that circadian rhythm disruption alters metabolic state, but direct evidence has been lacking, and the nature of the mechanisms responsible are unknown.