Inflammatory blockade improves human pancreatic islet function and viability.
The pathogenesis of pancreatic beta-cell death in diabetes mellitus is still under investigation. Inflammation is likely to be one of the factors responsible for beta-cell death during disease development. In this study, we have used a novel antiinflammatory compound, Lisofylline (LSF), to investigate the role of inflammatory blockade in protecting human pancreatic islets. LSF is a small synthetic molecule that reduces inflammatory cytokine production and action, improves beta-cell mitochondrial metabolism, and regulates immune activities. The present study has demonstrated that the treatment of human islets with LSF not only allows the retention of glucose responsiveness and insulin secretion in the presence of multiple proinflammatory cytokines, but also enhances basal insulin secretion of beta cells in vitro. LSF also significantly reduces islet apoptosis, protects beta cells from proinflammatory cytokine damage, and maintains cellular viability. In a mouse transplantation model, insulin independence could be reached in diabetic recipient mice by implantation of 30% fewer islets when LSF was used in islet culture compared to the control group. These results demonstrate that LSF profoundly enhances beta-cell function, and suggest the potential of using inflammatory blockade, such as LSF, to improve beta-cell function for islet transplantation.
Yang
Zandong
Z
Department of Internal Medicine, Division of Endocrinology, Metabolism, University of Virginia, Charlottesville, VA 22908, USA. zy4q@virginia.edu
Chen
Meng
M
Ellett
Justin D
JD
Carter
Jeffrey D
JD
Brayman
Kenneth L
KL
Nadler
Jerry L
JL
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008297:Male; D010431:Pentoxifylline / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010766:Phosphorylation; D050797:STAT4 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004268:DNA-Binding Proteins; D007328:Insulin; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators; D005947:Glucose; C025189:lisofylline; D010431:Pentoxifylline