Conroy, SJ, Green, I, Dixon, G, Byrne, PM, Nolan, J, Abdel-Wahab, Yasser, McClenaghan, Neville, Flatt, Peter and Newsholme, P (2002) Evidence for a sustained increase in clonal beta-cell basal intracellular Ca2+ levels after incubation in the presence of newly diagnosed type-1 diabetic patient sera. Possible role in serum-induced inhibition of insulin secretion. JOURNAL OF ENDOCRINOLOGY, 173 (1). pp. 53-62. [Journal article]
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We have previously reported that newly diagnosed Type-1 diabetic patient sera potently suppressed insulin secretion from a clonal rat pancreatic beta-cell line (BRIN BD11) but did not alter cell viability. Here, we report that apoptosis in BRIN BD11 cells incubated in various sera types (fetal calf serum (FCS), normal human serum and Type-1 diabetic patient) was virtually undetectable. Although low levels of necrosis were detected, these were not significantly different between cells incubated in sera from different sources. ATP levels were reduced by approximately 30% while nitrite production increased twofold from BRIN BD 11 cells incubated for 24 h in the presence of Type-1 diabetic patient sera compared with normal human sera. Additionally, ATP levels were reduced by approximately 40% and DNA fragmentation increased by more than 20-fold in BRIN BD11 cells incubated in FCS in the presence of a pro-inflammatory cytokine cocktail (interleukin-1beta, tumour necrosis factor-a and interferon-gamma), compared with cells incubated in the absence of cytokines. Nitric oxide production from BRIN BD 11 cells was markedly increased (up to 10-fold) irrespective of sera type when the cytokine cocktail was included in the incubation medium. Type-1 diabetic patient sera significantly (P<0-001) raised basal levels of intracellular free Ca2+ concentration ([Ca2+](i)) in BRIN BD11 cells after a 24-h incubation. The alteration in [Ca2+](i) concentration was complement dependent, as removal of the early complement components C1q and C3 resulted in a significant reduction (P<0.01) of sera-induced [Ca2+](i) changes. We propose that the mechanism of Type-1 diabetic patient sera-induced inhibition of insulin secretion from clonal beta-cells may involve complement-stimulated elevation of [Ca2+](i) which attenuates the nutrient-induced insulin secretory process possibly by desensitizing the cell to further changes in Ca2+.
|Item Type:||Journal article|
|Faculties and Schools:||Faculty of Life and Health Sciences|
Faculty of Life and Health Sciences > School of Biomedical Sciences
|Research Institutes and Groups:||Biomedical Sciences Research Institute|
Biomedical Sciences Research Institute > Diabetes
|Deposited By:||Professor Peter Flatt|
|Deposited On:||14 Jan 2010 11:09|
|Last Modified:||15 Jun 2011 11:10|
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