Novel experimental strategies to prevent the development of type 1 diabetes mellitus.
Type 1 diabetes is an autoimmune disease leading to extensive destruction of the pancreatic beta-cells. Our research focusses on the role of beta-cells during the course of the disease, aiming at finding novel strategies to enhance beta-cell resistance against the cytotoxic damage inflicted by the immune system. Special attention has been paid to the possibility that cytokines released by the immune cells infiltrating the pancreatic islets can directly suppress and kill beta-cells. Certain cytokines (interleukin-1beta, tumor necrosis factor-alpha and interferon-gamma) either alone or in combination, are able to activate signal transduction pathways in beta-cells leading to transcription factor activation and de novo gene expression. In this context, it has been found that induction of inducible nitric oxide synthase mediates an elevated production of nitric oxide, which impairs mitochondrial function and causes DNA damage eventually leading to apoptosis and necrosis. However, other induced proteins SUCH AS heat shock protein 70 and superoxide dismutase may reflect a defense reaction elicited in the beta-cells by the cytokines. Our strategy is to further seek for proteins involved in both destruction and protection of beta-cells. Based on this knowledge, we plan to apply gene therapeutic approaches to increase expression of protective genes in beta-cells. If this is feasible we will then evaluate the function and survival of such modified beta-cells in animal models of type 1 diabetes such as the NOD mouse. The long-term goal for this research line is to find novel approaches to influence beta-cell resistance in humans at risk of developing type 1 diabetes.
Sandler
S
S
Department of Medical Cell Biology, Uppsala University, Sweden. Stellan.Sandler@medcellbiol.uu.se
Andersson
A K
AK
Barbu
A
A
Hellerström
C
C
Holstad
M
M
Karlsson
E
E
Sandberg
J O
JO
Strandell
E
E
Saldeen
J
J
Sternesjö
J
J
Tillmar
L
L
Eizirik
D L
DL
Flodström
M
M
Welsh
N
N
D016207:Cytokines / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D015316:Genetic Therapy; D006801:Humans; D007515:Islets of Langerhans / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000502:physiology; D052247:Nitric Oxide Synthase Type II
D016207:Cytokines; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II