Inhibition of GSK3 promotes replication and survival of pancreatic beta cells.
Recent developments indicate that the regeneration of beta cell function and mass in patients with diabetes is possible. A regenerative approach may represent an alternative treatment option relative to current diabetes therapies that fail to provide optimal glycemic control. Here we report that the inactivation of GSK3 by small molecule inhibitors or RNA interference stimulates replication of INS-1E rat insulinoma cells. Specific and potent GSK3 inhibitors also alleviate the toxic effects of high concentrations of glucose and the saturated fatty acid palmitate on INS-1E cells. Furthermore, treatment of isolated rat islets with structurally diverse small molecule GSK3 inhibitors increases the rate beta cell replication by 2-3-fold relative to controls. We propose that GSK3 is a regulator of beta cell replication and survival. Moreover, our results suggest that specific inhibitors of GSK3 may have practical applications in beta cell regenerative therapies.
Mussmann
Rainer
R
DeveloGen AG, Marie-Curie-Strasse 7, Göttingen 37079, Germany.
Geese
Marcus
M
Harder
Friedrich
F
Kegel
Simone
S
Andag
Uwe
U
Lomow
Alexander
A
Burk
Ulrike
U
Onichtchouk
Daria
D
Dohrmann
Cord
C
Austen
Matthias
M
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000737:chemistry; D005786:Gene Expression Regulation; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D010168:Palmitates / Q000737:chemistry; D034622:RNA Interference; D051381:Rats
D004791:Enzyme Inhibitors; D005227:Fatty Acids; D010168:Palmitates; D038362:Glycogen Synthase Kinase 3; D005947:Glucose