Metallothionein induction in islets of Langerhans and insulinoma cells.
Isolated pancreatic islets from rat and mouse and the insulinoma cell lines, betaHC9 and RINm5F, were investigated to determine the regulation of metallothionein (MT). Dexamethasone (DEX) increased rat and mouse islet and insulinoma cell MT levels in a time- and concentration-dependent manner. Rat islet MT expression was increased with interleukin-1beta (IL-1beta), but not tumor necrosis factor-alpha (TNF). However, MT induction by IL-1beta and TNF was synergistic with DEX in rat islets and insulinoma cells. Mouse islet MT failed to respond to IL-1beta alone, although IL-1beta and TNF were synergistic. IL-1beta and TNF did not synergize with DEX for mouse islet MT induction. Zinc sulfate induced MT in rat islets but not mouse islets. MT messenger RNA levels were significantly increased in rat islets in response to DEX and IL-1beta plus DEX. The inducible nitric oxide synthase inhibitors N(G)-monomethyl-L-arginine and aminoguanidine failed to inhibit IL-1beta induced MT levels in insulinoma cells, and the nitric oxide generating agent sodium nitroprusside failed to significantly affect MT levels. Phorbol dibutyrate increased MT levels in rat islets and betaHC9 cells, but phorbol dibutyrate and IL-1beta effects were not additive. Transgenic MT-null and wild-type mouse islets had similar insulin contents, but basal and glucose-stimulated insulin release from MT-null islets were significantly lower than in wild-type islets. Blood glucose levels in MT-null mice were, however, slightly lower than those in wild-type mice. Thus, MT induction in pancreatic islets and beta-cells is regulated by cytokines and DEX, and protein kinase C activation may play a role. However, regulation of MT induction in mouse and rat islets differs. MT also appears to modulate insulin release from pancreatic islets.
Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, 102 Fanber Hall, Buffalo, NY 14214, USA. laychock@acsu.buffalo.edu
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D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007340:Insulinoma / Q000378:metabolism*; D007375:Interleukin-1 / Q000008:administration & dosage / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008668:Metallothionein / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology
D001786:Blood Glucose; D005938:Glucocorticoids; D007328:Insulin; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D015240:Phorbol 12,13-Dibutyrate; D003907:Dexamethasone; D008668:Metallothionein; D011493:Protein Kinase C