Mouse vanin-1 is cytoprotective for islet beta cells and regulates the development of type 1 diabetes.
OBJECTIVE
Islet cell death is a key initiating and perpetuating event in type 1 diabetes and involves both immune-mediated and endogenous mechanisms. The epithelial pantetheinase vanin-1 is proinflammatory and cytoprotective via cysteamine release in some tissues. We investigated the impact of a vanin-1 deficiency on islet death and type 1 diabetes incidence.


METHODS
Vanin-1-deficient mice were produced and tested in drug-induced and autoimmune diabetes models. The contribution of vanin-1 to islet survival versus immune responses was evaluated using lymphocyte transfer and islet culture experiments.


RESULTS
The vanin-1/cysteamine pathway contributes to the protection of islet beta cells from streptozotocin-induced death in vitro and in vivo. Furthermore, vanin-1-deficient NOD mice showed a significant aggravation of diabetes, which depended upon loss of vanin-1 expression by host tissues. This increased islet fragility was accompanied by greater CD4+ insulitis without impairment of regulatory cells. Addition of cystamine, the product of pantetheinase activity, protected islets in vitro and compensated for vanin-1 deficiency in vivo.


CONCLUSIONS
This study unravels a major cytoprotective role of cysteamine for islet cells and suggests that modulation of pantetheinase activity may offer alternative strategies to maintain islet cell homeostasis.
Roisin-Bouffay
C
C
Aix Marseille Université, Faculté des Sciences de Luminy, Centre d'Immunologie de Marseille-Luminy, Marseille, France.
Castellano
R
R
Valéro
R
R
Chasson
L
L
Galland
F
F
Naquet
P
P
D000581:Amidohydrolases; D000818:Animals; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D003538:Cystamine / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D058851:GPI-Linked Proteins; D006706:Homeostasis / Q000502:physiology; D015994:Incidence; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008817:Mice, Mutant Strains; D050378:T-Lymphocytes, Regulatory / Q000473:pathology; D018417:Th1 Cells / Q000473:pathology
D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D007328:Insulin; D000581:Amidohydrolases; C022314:pantetheinase; D003538:Cystamine