Apoptotic signal transduction pathways in diabetes.
Failure of insulin producing pancreatic beta-cells is a common characteristic of type 1 (insulin-dependent) and type 2 (insulin non-dependent) diabetes mellitus. Accumulating evidence suggests that programmed cell death (apoptosis) is the main form of beta-cell death in these disorders. The beta-cell is particularly sensitive to apoptotic stimuli due to the inherent features of the specialized beta-cell phenotype. In type 1 diabetes anti-beta-cell autoimmune reactivity delivers the apoptotic signals in the form of inflammatory mediators or T-cell effectors. In type 2 diabetes, the metabolic derangement is associated with production of inflammatory mediators in insulin-sensitive tissues leading elevated levels of circulating inflammatory mediators such as IL-6 and TNF. Further glucose has been suggested to induce beta-cell apoptosis via the induction of beta-cell synthesis of IL-1 which via autocrine action may elicit signalling cascades analogous to those seen in beta-cell destruction in type 1 diabetes. Considering the apparent importance of IL-1-beta signalling in beta-cell failure in both type 1 and type 2 diabetes, we here review the modulatory effect exerted on IL-1signalling by cellular characteristics related to the specialized beta-cell phenotype. We conclude that beta-cell differentiation signals (Pdx-1), glucose metabolism, calcium handling as well as regulation of naturally occurring inhibitors of cytokine signalling contribute to sensitize the beta-cell to apoptotic stimuli. We hypothesize that immunological stimuli in type 1 diabetes and metabolic/inflammatory signals in type 2 diabetes converge on common signalling pathways leading to beta-cell failure and destruction in these two diseases.
Mandrup-Poulsen
Thomas
T
Steno Diabetes Center, 2 Niels Steensens Vej, DK-2820 Gentofte, Denmark. tmpo@steno.dk
D000818:Animals; D017209:Apoptosis; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D007515:Islets of Langerhans / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*