Palmitate induces a pro-inflammatory response in human pancreatic islets that mimics CCL2 expression by beta cells in type 2 diabetes.
OBJECTIVE
Beta cell failure is a crucial component in the pathogenesis of type 2 diabetes. One of the proposed mechanisms of beta cell failure is local inflammation, but the presence of pancreatic islet inflammation in type 2 diabetes and the mechanisms involved remain under debate.


METHODS
Chemokine and cytokine expression was studied by microarray analysis of laser-capture microdissected islets from pancreases obtained from ten non-diabetic and ten type 2 diabetic donors, and by real-time PCR of human islets exposed to oleate or palmitate at 6 or 28 mmol/l glucose. The cellular source of the chemokines was analysed by immunofluorescence of pancreatic sections from individuals without diabetes and with type 2 diabetes.


RESULTS
Microarray analysis of laser-capture microdissected beta cells showed increased chemokine and cytokine expression in type 2 diabetes compared with non-diabetic controls. The inflammatory response in type 2 diabetes was mimicked by exposure of non-diabetic human islets to palmitate, but not to oleate or high glucose, leading to the induction of IL-1beta, TNF-alpha, IL-6, IL-8, chemokine (C-X-C motif) ligand 1 (CXCL1) and chemokine (C-C motif) ligand 2 (CCL2). Interference with IL-1beta signalling abolished palmitate-induced cytokine and chemokine expression but failed to prevent lipotoxic human islet cell death. Palmitate activated nuclear factor kappaB (NF-kappaB) in human pancreatic beta and non-beta cells, and chemically induced endoplasmic reticulum stress caused cytokine expression and NF-kappaB activation similar to that occurring with palmitate.


CONCLUSIONS
Saturated-fatty-acid-induced NF-kappaB activation and endoplasmic reticulum stress may contribute to IL-1beta production and mild islet inflammation in type 2 diabetes. This inflammatory process does not contribute to lipotoxicity ex vivo, but may lead to local chemokine release.
Igoillo-Esteve
M
M
Laboratory of Experimental Medicine, Université Libre de Bruxelles, CP-618, Route de Lennik 808, 1070, Brussels, Belgium.
Marselli
L
L
Cunha
D A
DA
Ladrière
L
L
Ortis
F
F
Grieco
F A
FA
Dotta
F
F
Weir
G C
GC
Marchetti
P
P
Eizirik
D L
DL
Cnop
M
M
D000368:Aged; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism*; D054360:Chemokine CXCL1; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D066298:In Vitro Techniques; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010168:Palmitates / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011863:Radioimmunoassay; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D010168:Palmitates; D014409:Tumor Necrosis Factor-alpha