Circadian rhythms play critical roles in regulating metabolism, including daily feeding/fasting periods and oscillating expressions of certain genes. Glucokinase (Gck) , expressed in the liver and pancreas, is central for whole-body glucose homeostasis by acting as a glucose sensor and regulating metabolism according to prevailing glucose levels. Gck expression has also been shown to follow a circadian rhythm. Gck activators (GKAs) effectively reduce hyperglycemia, however, adverse events have also involved hypoglycemia, hyperlipidemia, and hepatic steatosis. Given the circadian rhythmicity and natural postprandial activation of Gck, we hypothesized that GKA treatment would benefit from being timed specifically during feeding periods. We compared the metabolic effects following differentially timed administrations of the GKA AZD1656 in the obese, insulin resistant Zucker rat. Four weeks of continuous treatment significantly improved glycemic control; however, hepatic steatosis and inflammation manifested. In contrast, a robust reduction in hepatic steatosis and inflammation on top of improved glycemia, was observed when AZD1656 administration was timed to feeding periods only. When AZD1656 was timed to fasting periods, detrimental metabolic effects were observed, including impaired glycemic control, severe liver steatosis and elevated inflammation. Mechanistically, timing AZD1656 administration to feeding periods was found to divert de novo lipogenesis-derived lipids away from hepatic storage towards VLDL synthesis and secretion, without affecting plasma triglyceride levels. In conclusion, intermittent AZD1656 dosing timed to feeding periods promotes glucose disposal when needed the most, while the daily drug holiday allows for maintained metabolic flexibility and avoids hepatic steatosis. Chronotherapeutic approaches should be considered for the development of GKAs and other drugs acting on metabolic targets.
T. Kroon: Employee; AstraZeneca. I. Alexandersson: Employee; AstraZeneca. A. Ferm: Employee; AstraZeneca. M. Petersson: Employee; AstraZeneca. S. Maurer: Employee; AstraZeneca, Merck Sharp & Dohme Corp. B. Zarrouki: Employee; AstraZeneca. K. Wallenius: Employee; AstraZeneca. N.D. Oakes: Employee; AstraZeneca. J. Boucher: Employee; AstraZeneca, Evotec International GmbH.