Protective role of glucagon-like peptide-1 against glucosamine-induced cytotoxicity in pancreatic beta cells.
High doses of glucosamine have been known to induce apoptosis of pancreatic beta cells. The mechanism for this phenomenon has not been clearly elucidated. We aimed to explore the potential mechanisms for glucosamine toxicity in the rat insulinoma cell line INS-1 and in rat native beta cells. We also investigated whether glucagon-like peptide (GLP)-1 could be protective against glucosamine. Glucosamine exhibited dose-dependent inhibition of cell survival and an increase in the cell population at the sub-G1 phase. Glucosamine was revealed to inhibit cellular glucose uptake, resulting in the activation of AMP-activated protein kinase (AMPK). Accordingly, phosphorylation of P70S6K and ribosomal protein S6 (S6RP) was decreased. Protein glycosylation appeared not to be involved in this cytotoxicity. Pretreatment with GLP-1 alleviated glucosamine-mediated inhibition of glucose uptake and lessened AMPK activation, thus allowing recovery of the phosphorylation levels of P70S6K and S6RP. The effect of GLP-1 was blocked by the adenylyl cyclase inhibitor MDL12330A but not by the protein kinase A inhibitor H89. Taken together, these data demonstrate that glucosamine may inhibit beta-cell survival by diminishing cellular glucose uptake independent of glycosylation. This glucosamine toxicity can be blocked by GLP-1, which leads to recovery of the glucose uptake through a PKA-independent, cAMP-dependent mechanism.
Kim
Yu-Kyung
YK
Department of Physiology & Chronic Disease Research Center, Daegu 700-712, Republic of Korea.
Park
Jae-Hyung
JH
Park
Sung-Hee
SH
Lim
Bora
B
Baek
Won-Ki
WK
Suh
Sung-Il
SI
Lim
Jung-Geun
JG
Ryu
Gyeong Ryul
GR
Song
Dae-Kyu
DK
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D016193:G1 Phase; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000502:physiology*; D005944:Glucosamine / Q000633:toxicity*; D005947:Glucose / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D038601:Ribosomal Protein S6 / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism
D038601:Ribosomal Protein S6; D052216:Glucagon-Like Peptide 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D005944:Glucosamine