Administration of Melatonin and Metformin Prevents Deleterious Effects of Circadian Disruption and Obesity in Male Rats

Endocrinology. 2016 Dec;157(12):4720-4731. doi: 10.1210/en.2016-1309. Epub 2016 Sep 21.


Circadian disruption and obesity synergize to predispose to development of type 2 diabetes mellitus (T2DM), signifying that therapeutic targeting of both circadian and metabolic dysfunctions should be considered as a potential treatment approach. To address this hypothesis, we studied rats concomitantly exposed to circadian disruption and diet-induced obesity (CDO), a rat model recently shown to recapitulate phenotypical aspects of obese T2DM (eg, circadian disruption, obesity, insulin resistance, and islet failure). CDO rats were subsequently treated daily (for 12 wk) by timed oral gavage with vehicle, melatonin (a known chronobiotic), metformin, or combination treatment of both therapeutics. Melatonin treatment alone improved circadian activity rhythms, attenuated induction of β-cell failure, and enhanced glucose tolerance. Metformin alone did not modify circadian activity but enhanced insulin sensitivity and glucose tolerance. Importantly, the combination of melatonin and metformin had synergistic actions to modify progression of metabolic dysfunction in CDO rats through improved adiposity, circadian activity, insulin sensitivity, and islet cell failure. This study suggests that management of both circadian and metabolic dysfunctions should be considered as a potential preventative and therapeutic option for treatment of obesity and T2DM.

MeSH terms

  • Adiposity / drug effects*
  • Animals
  • Central Nervous System Depressants / pharmacology
  • Central Nervous System Depressants / therapeutic use
  • Circadian Rhythm / drug effects*
  • Glucose Intolerance / drug therapy*
  • Glucose Intolerance / metabolism
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use
  • Insulin Resistance / physiology
  • Male
  • Melatonin / pharmacology*
  • Melatonin / therapeutic use
  • Metformin / pharmacology*
  • Metformin / therapeutic use
  • Obesity / drug therapy*
  • Obesity / metabolism
  • Rats


  • Central Nervous System Depressants
  • Hypoglycemic Agents
  • Metformin
  • Melatonin