III. Conclusion

During recent decades, it has been shown that T1D and T2D are both characterized by pathologic inflammation that leads to reduction in functional β-cell mass and function. This has opened up new investigations on anti-inflammatory therapies as a unifying target for diabetes. IL-1β may be a promising treatment for preservation of β-cell mass and insulin sensitivity. Long-lasting humanized anti-IL-1β antibodies are currently being tested in phase 2 and phase 3 clinical trials (XOMA-052, canakinumab, gevokizumab)12,16; they have a longer plasma half-life (several weeks) than recombinant IL-1Ra (anakinra) and block IL-1β with no cross-reactivity with other members of the IL-1 family. The large, ongoing CANTOS study (Canakinumab ANti-inflammatory Thrombosis Outcomes Study) has begun in 17 200 patients with stable post myocardial infarction and persistent elevation of CRP levels (>2 mg/L). It aims to determine whether IL-1–targeting therapies can effectively prevent and/or treat T2D and cardiovascular diseases16 (Christian Herder, Marc Donath Lectures). Moreover, many data have been obtained from studies using the salicylate class of anti-inflammatory medications as blockers of IL-1 receptor signaling.17 Indeed, salicylates have long been recognized to have glucose-lowering properties and have been shown to inhibit the activity of the NF-κB pathway, leading to a decrease in inflammation and improvement in insulin sensitivity and lipid metabolism. In T2D patients, high doses of salicylates lowered blood glucose, and in obese nondiabetic persons, relatively shortterm use of salicylates lowered fasting glucose and/or improved systemic inflammation and lipid profiles. The effects of the molecule on insulin sensitivity are still a matter of debate. It was recently shown that in patients with impaired fasting glucose and/or impaired glucose tolerance, treatment with salsalate lowered fasting glucose, increased adiponectin, and reduced adipose tissue NF-κB activity. However, these changes were not related to changes in peripheral insulin sensitivity, suggesting additional mechanisms for metabolic improvement.17

Inhibition or reduction of 12-LO activity may be another tool for the treatment of T1D and T2D and protection of human β-cells from inflammatory injury.18 12-LO gene deletion or pharmacological suppression prevented the development of diabetes in NOD mice (T1D model), ZDF rats (T2D model), and diet-induced obese mice (T2D model). Accordingly, it was recently demonstrated that 12-LO, activated by acute exposure to proinflammatory cytokines, increased NADPH oxidase-1 (NOX-1) expression and subsequent ROS induction leading to β-cell dysfunction and death. Importantly, human pancreatic islets cells exposed to 12-LO products had impaired insulin secretion and viability and a high level of NOX-1 expression was measured in islets from T2D donors. This suggests that inhibitors of this integrated pathway may provide a new therapeutic strategy to preserve β-cell mass in diabetes. Preliminary data in INS-1 β-cells are encouraging19 (Jerry Nadler, Lecture). Among other promising therapies, vitamin D supplementation could provide an interesting approach for prevention rather than treatment of diabetes.2 In NOD mice, 1,25-(OH)2D3 or nonhypercalcemic analogs were able to inhibit the development of insulitis and prevent the onset of T1D. The findings on human T1D and T2D are unclear due to incomplete protocols and small sample size. Thus, many studies are still needed to determine the timing of treatment and the optimal dose of vitamin D supplementation in combination or not with other therapeutics such as immunosuppressants2 (Chantal Mathieu, Lecture).
Finally, considering the complex pathogenesis of T1D and T2D, combined therapy rather than targeting a single cytokine, molecule, or cell type may be needed.

“Islet Inflammation”
I. General points on islet inflammation in diabetes
II. What are the actors in inflammation in diabetes?
III. Conclusion
Lectures during IGIS meeting