Mechanism and management of AKT inhibitor-induced hyperglycemia.
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.
Crouthamel
Ming-Chih
MC
Oncology Biology, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA.
Kahana
Jason A
JA
Korenchuk
Susan
S
Zhang
Shu-Yun
SY
Sundaresan
Gobalakrishnan
G
Eberwein
Derek J
DJ
Brown
Kathleen K
KK
Kumar
Rakesh
R
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
C528328:GSK690693; D008112:Liver Glycogen; D010069:Oxadiazoles; D051057:Proto-Oncogene Proteins c-akt