Abstract 9030: Islet Inflammation Induced by Free Fatty Acid-TLR4 Pathway Leads to β Cell Dysfunction in Type 2 Diabetes
Recent studies have demonstrated that inflammation is crucially involved in metabolic abnormalities suggesting similarities with atherogenesis. However, it is still unclear whether inflammation is involved in pancreatic β cell dysfunction seen in type 2 diabetes (T2D). Serum free fatty acid (FFA) levels are increased in obese subjects and associated with increased risks of cardiovascular and metabolic diseases. The deleterious effects of FFAs on β cells in vitro are well known, which is termed “lipotoxicity”. To elucidate if FFAs induce β cell dysfunction in vivo, we established a novel method to selectively increase the circulating free palmitate level and found that palmitate induces rapid β cell dysfunction in mice via TLR4/MyD88 pathway. However, the TLR4/MyD88 pathway was dispensable for palmitate-induced β cell dysfunction in vitro, indicating mechanisms other than the previously known lipotoxicity are essential in vivo. Interestingly, palmitate infusion induced expression of CCL2 and CXCL1 in β cells, suggesting involvement of inflammatory processes. Indeed, flow cytometric analysis showed that palmitate induced accumulation of CD11b+Ly-6C+ M1 inflammatory macrophages within islets, which was not observed in Tlr4−/− or Myd88−/− mice. Moreover, depletion of M1 macrophages protected mice from palmitate-induced β cell dysfunction. Coculture experiments of β cells and macrophages combined with cytokine neutralizing antibody demonstrated that palmitate-induced reciprocal interactions between these cells further augment macrophage recruitment and β cell dysfunction. Finally, we found that same mechanisms are playing causative roles in β cell dysfunction in db/db mice, a T2D model. Those results suggest a model in which β cells respond to saturated FFAs and recruit macrophages, and subsequent interactions propagate inflammation within islets that lead to β cell dysfunction. We also found that palmitate activates inflammatory processes and exacerbates neointima formation. Our results thus highlight the causative involvement of inflammation in β cell dysfunction in T2D and suggest that saturated FFAs and chronic inflammation are the unified pathogenic factor and mechanism for both cardiovascular and metabolic diseases.
- © 2010 by American Heart Association, Inc.