Studies of TNF- α-induced -GSIS Inhibition in INS-1 β-cell

BACKGRAUND AND AIMS: Pancreatic β-cell which produce and secrete insulin, is responsible for regulation of plasma glucose concentration. GSIS depends on coordinated glucose uptakes, oxidative metabolism nd Ca(2+)+-triggered insulin exocytosis. Imparied GSIS is a hallmark of type Ⅱ Diabetes. It has been reported that TNF-α, proinflammatory cytokine, was increased in obese type Ⅱ Diabetes states and it inhibits GSIS in INS-1 β-cell. This mechanism has not been examined in detail. So we investigated the mechanism which TNF-α inhibits GSIS in INS-1 β-cell. RESULT: TNF-α suppressed significantly GSIS on dose and time dependent manner. When TNF-α has been removed from medium, the decreased GSIS was recovered completely. Insulinotropic stimuli -aminoacid, sulfonylurea, imidazolin-induced insulin secretion was also decreased about 40-50% by TNF-α (10ng/ml) treatment for 24 hours. Bay K8644, Ca(2+)+ channel agonist, induced insulin secretion decreased about 50% by pretreatment of TNF-α in INS-1 cell. But KCl-induced insulin serection, evocked by depolarization, was decreased a little. And PMA, forskolin induced insulin secretion was not decreased by TNF-α. This indicates that insulin secretory machinary did not affect by TNF-α. After pretreatment of TNF-α for 24h, expression of insulin, GLUT2 and GK did not affect. ATP production didn't, neither. This indicates that insulin biosynthesis, glucose uptake and oxidative metabolism have no effect by TNF-α treatment. Glucose stimulated Ca(2+)+ influx and Ca(2+)+ oscillation was decreased by TNF-α treatment. Both DZX, KATP channel opener, and Nifedipine, L-type Ca(2+)+ channel blocker, markedly improved the decreased GSIS by TNF-α. This indicates that the decrease of Ca(2+)+ influx through L-type Ca(2+)+ channel could be involved in TNF-α-induced GSIS inhibition. Thus we investigated both expression and trafficking of channels but didn't change. We tested whether TNF-α activated signal molecule is related in the TNF-α-induced GSIS inhibition. Decreased GSIS was recoverd by SN50, NFkB inhibitor. TNF-α-induced NFkB activation is thought to be reponsible for TNF-α-induced GSIS inhibition. CONCLUSION: Glucose and insulinotropic stimuli-aminoacid, sulfonylurea, imidazolin-induced insulin secretion was significantly suppressed by TNF-α. TNF-α inhibited glucos-stimulated Ca(2+)+ influx and oscillation through L-type Ca(2+)+ channel. The decreased GSIS was recoverd by inhibition of NFkB. Thus TNF-α-induced NFkB activation decreased GSIS with abnormality of glucose-stimulated [Ca(2+)+]i influx in INS-1 cell. Our studies indicated that elevation of basal Ca(2+)+ and decrease of glucose induced Ca(2+)+ influx by TNF-α may contribute to insulin secretion deficiency, phathogenesis of type II Diabetes.

Author dc:creator

• 김, 효은

Contributors dc:contributor

• 강, 엽
• 대학원 의학과
• 200324503

• 포도당 자극 인슐린 분비 (GSIS)
• Tumor necrosis factor-α (TNF-α)
• Glucose stimulated insulin secretion (GSIS)
• K_(ATP) channel
• L-type Ca^(2+) channel
• NFkB
• SN50

Language dc:language

ko

Identifier

http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000000699
000000000699

OAI identifier oai:identifier

oai:repository.ajou.ac.kr:201003/1504