Hyperglycaemia reversibly disrupts circadian behaviour in mice

Abstract

Disrupted sleep and circadian rhythms are among the most common features of diabetes, and are known to raise the risk of developing the disease. Whether the relationship also runs the other way, with diabetes itself disrupting the clock, has remained unresolved. Using an inducible mouse model of diabetes, in which hyperglycaemia can be induced and then reversed within the same animal, we show that elevated blood glucose is a reversible cause of circadian disruption. Raising blood glucose reduced the amplitude of circadian rest-activity rhythms by 50%, in proportion to the degree of hyperglycaemia, and shortened the free-running period of the clock. Restoring normoglycaemia reversed both effects. Diabetic animals had a delayed phase of activity onset, i.e. later chronotype, and re-entrained more slowly after a simulated jet lag. However, phase shifting to nocturnal light pulses was intact, suggesting normal photic responses. Brain glucose and O-GlcNAcylation, a nutrient-sensitive protein modification, were both elevated in diabetic animals, showing that peripheral hyperglycaemia reaches the brain and alters its metabolic state, and providing a molecular readout of that exposure. Together, these findings establish that a peripheral metabolic state is a reversible determinant of circadian rest-activity behaviour, completing a bidirectional link between blood glucose and the clock and arguing that the two must be treated together rather than in isolation.