title: Mechanism and management of AKT inhibitor-induced hyperglycemia.
abstract: OBJECTIVE
  Insulin-like growth factor-I receptor and phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathways are among the most active areas of drug discovery in cancer research. However, due to their integral roles in insulin signaling, inhibitors targeting these pathways often lead to hyperglycemia and hyperinsulinemia. We investigated the mechanism of hyperglycemia induced by GSK690693, a pan-AKT kinase inhibitor in clinical development, as well as methods to ameliorate these side effects.
  
  
  METHODS
  The effect of GSK690693 on blood glucose, insulin, and glucagon levels was characterized in mice. We then evaluated the effects of commonly prescribed antidiabetic agents on GSK690693-induced hyperglycemia. The mechanism of blood glucose increase was evaluated using fasting and tracer uptake studies and by measuring liver glycogen levels. Finally, approaches to manage AKT inhibitor-induced hyperglycemia were designed using fasting and low carbohydrate diet.
  
  
  RESULTS
  We report that treatment with antidiabetic agents does not significantly affect GSK690693-induced hyperglycemia in rodents. However, administration of GSK690693 in mice significantly reduces liver glycogen (approximately 90%), suggesting that GSK690693 may inhibit glycogen synthesis and/or activate glycogenolysis. Consistent with this observation, fasting before drug administration reduces baseline liver glycogen levels and attenuates hyperglycemia. Further, GSK690693 also inhibits peripheral glucose uptake and introduction of a low-carbohydrate (7%) or 0% carbohydrate diet after GSK690693 administration effectively reduces diet-induced hyperglycemia in mice.
  
  
  CONCLUSIONS
  The mechanism of GSK690693-induced hyperglycemia is related to peripheral insulin resistance, increased gluconeogenesis, and/or hepatic glycogenolysis. A combination of fasting and low carbohydrate diet can reduce the magnitude of hyperglycemia induced by an AKT inhibitor.
authors.affiliation: Oncology Biology, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA.
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Crouthamel
authors.forename: Jason A
authors.initials: JA
authors.lastname: Kahana
authors.forename: Susan
authors.initials: S
authors.lastname: Korenchuk
authors.forename: Shu-Yun
authors.initials: SY
authors.lastname: Zhang
authors.forename: Gobalakrishnan
authors.initials: G
authors.lastname: Sundaresan
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Eberwein
authors.forename: Kathleen K
authors.initials: KK
authors.lastname: Brown
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000818:Animals; D050528:Diet, Carbohydrate-Restricted; D005215:Fasting; D005260:Female; D006943:Hyperglycemia / Q000139:chemically induced* / Q000517:prevention & control; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010069:Oxadiazoles / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C528328:GSK690693; D008112:Liver Glycogen; D010069:Oxadiazoles; D051057:Proto-Oncogene Proteins c-akt