2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces calcium influx through T-type calcium channel and enhances lysosomal exocytosis and insulin secretion in INS-1 cells.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been associated with diabetes in several epidemiological studies. However, the diabetogenic action of TCDD on pancreatic cells is unclear. Here, we investigated the direct toxic effects of TCDD on a rat insulin-secreting beta cell line. We found that TCDD enhances exocytosis of MTT formazan and lysosomal proteins such as beta-hexosaminindase and Lamp-1. This TCDD-induced exocytosis was abrogated by T-type calcium channel blockers (mibefradil, flunarizine) but not by an aryl hydrocarbon receptor antagonist (alpha-naphtoflavone). Indeed, cytosolic calcium levels were increased by TCDD. Furthermore, TCDD stimulated insulin secretion, which was inhibited by flunarizine. Taken together, our results suggest that TCDD-induced calcium influx via T-type channels regulates vesicular trafficking, such as lysosomal and secretory granule exocytosis, and that TCDD might exert adverse effects on beta cells by continuous insulin release followed by beta cell exhaustion. This could contribute to the link between TCDD exposure and the risk of developing diabetes.
Kim
Youn-Hee
YH
Department of Pharmacology, Korea University College of Medicine, 126-1, 5-Ga Anam-Dong, Sungbuk-Gu, Seoul, Korea.
Shim
Young-Jun
YJ
Shin
Yong-Jae
YJ
Sul
Donggeun
D
Lee
Eunil
E
Min
Bon-Hong
BH
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004785:Environmental Pollutants / Q000633:toxicity*; D005089:Exocytosis / Q000187:drug effects*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors; D055571:Secretory Pathway / Q000187:drug effects
D020747:Calcium Channels, T-Type; D004785:Environmental Pollutants; D007328:Insulin; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D002118:Calcium