Chronic phase shifting in rats impairs glucose tolerance and insulin secretion and sensitivity — ASN Events

Chronic phase shifting in rats impairs glucose tolerance and insulin secretion and sensitivity (#198)

Michael J Boden 1 , Leewen Rattanatray 1 , Mel Tran 1 , Athena Voultsios 1 , Nicole M Wright 1 , Mark D Salkeld 1 , Tamara J Varcoe 1 , Julie A Owens 1 , David J Kennaway 1
  1. Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia

Over 1.4 million Australians are shiftworkers and are known to be at increased risk of developing insulin resistance, obesity and metabolic dysfunction. Although the mechanism behind disease progression remains unclear, it is likely disruption of endogenous circadian rhythms is playing a causative role. Here we investigate the impact of disrupting circadian rhythms in rats on behaviour, gene expression and glucose homeostasis.

Albino Wistar rats (5 wk) were housed under controlled light conditions and experienced twice weekly 12 hour phase shifts for 4 weeks. Feeding behaviour, liver gene expression and plasma melatonin and corticosterone concentrations were analysed across in the first 72 hours to measure early adaptations to a 12 hour phase shift. At the end of the 4 week protocol, the above parameters were again measured and metabolic function tested 1 day and 1 week after resumption of normal photoperiod using glucose tolerance test (GTT), insulin tolerance test (ITT) and hyperinsulinemic euglycemic clamp (HEC).

After the initial 12 hour phase shift, the rhythm in plasma melatonin concentration adjusted swiftly, whereas other rhythms changed slowly (feeding behaviour), became suppressed (activity) poorly regulated (plasma corticosterone) or did not begin to adjust until 40-48hrs after the change in photoperiod (Liver clock gene expression). As such, neither gene expression nor feeding behaviour have realigned by the time of the next 12 hour phase shift.

After 4 weeks, activity levels were significantly reduced and rhythm in food consumption was lost, although total food consumption was unchanged. Glucose tolerance was significantly impaired both 1 day (38%) and 1 week (60%) after resumption of normal photoperiod and was coincident with a decrease in insulin secretion. Insulin sensitivity assessed by ITT and HEC was also reduced at 1 day post resumption of normal photoperiod before returning to baseline after 1 week. This impairment of function is coincident with disrupted liver gene expression, for both the core clock genes as well as genes involved in glucose and lipid metabolism (Pfkfb3, PEPCK, PGC1a, IRS2, Glut2, Glucokinase).

Together these results suggest circadian rhythms maintain an important role in regulating glucose homeostasis, and even short-term disruption can have significant detrimental effects.

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