Type 2 diabetes: Fatty acids deliver double whammy

Lipidomics Gateway (25 April 2012) [doi:10.1038/lipidmaps.2012.12]

In response to increased palmitate levels, β cells secrete chemokines, thereby promoting macrophage recruitment, inflammation and subsequent dysfunction.

CORBIS

That eating foods rich in saturated fat increases the risk of developing type 2 diabetes is widely acknowledged; undefined, though, is how, precisely, fatty acids bring about β-cell dysfunction to induce this disease in an insulin-resistant setting. In Cell Metabolism, Eguchi et al. describe how palmitate induces β cells, through Toll-like receptor-4 (TLR4) signalling, to produce chemokines that recruit proinflammatory monocytes/macrophages to islets, bringing about their demise.

The authors first showed that selectively increasing circulating free palmitate levels in mice using ethyl palmitate infusion reduced the expression of genes involved in β-cell function, such as Pdx1, Insulin and Ins2 pre-mRNA. On the basis of previously published data, they investigated the potential involvement of TLR4 signalling in palmitate-induced β-cell dysfunction. Ethyl palmitate failed to reduce the expression of Pdx1, Insulin and Ins2 pre-mRNA or to impair glucose-induced insulin secretion when infused into mice lacking TLR4 and its adaptor protein MyD88; however, similar effects were not evoked in the pancreatic β-cell line MIN6, hinting that non-β cells might be involved in palmitate-induced β-cell dysfunction. Eguchi et al. used flow cytometry to show that CD11b+Ly-6C+ M1-type proinflammatory monocytes/macrophages accumulated within islets in response to palmitate, but only when TLR4 and MyD88 were present, indicating that TLR4 signalling was involved.

Next, the researchers tested the hypothesis that β cells initiated macrophage recruitment in response to palmitate. They found that palmitate induced MIN6 β cells and isolated islet β cells to secrete the chemokines CC-chemokine ligand 2 (CCL2) and CXC-chemokine ligand 1 (CXCL1) via TLR4–MyD88 signalling to the nuclear factor κ pathway, and that knocking down CCL2 prevented the accumulation of CD11b+Ly-6C+ cells in islets in response to palmitate.

Once recruited to the islets, though, how do macrophages influence β cells? Using Boyden chambers to prevent direct cell–cell interactions, Eguchi et al. showed that macrophages secreted interleukin (IL)-1β and tumor necrosis factor (TNF) in response to palmitate, which subsequently impaired MIN6 β-cell function. Interestingly, palmitate also induced Ccl2 and Cxcl1 in MIN6 cells and the further expression of Il1b and Tnfa in macrophages when both cell types were cocultured, indicating that interactions between macrophages and β cells are likely to exacerbate palmitate-induced inflammation and β-cell dysfunction. In vivo, using clodronate-filled liposomes to deplete macrophages, and, consequently, prevent the accumulation of CD11b+Ly-6C+ cells within islets in response to palmitate, inhibited the downregulation of Pdx1, Insulin and Ins2 pre-mRNA and the upregulation of Il1b and Tnfa in islets. So CD11b+Ly-6C+ inflammatory macrophages have a key role in palmitate-induced β-cell dysfunction.

Finally, the authors demonstrated the involvement of M1-type cell recruitment and inflammation in β-cell dysfunction in two mouse models of type 2 diabetes. In db/db mice, which showed increased levels of free fatty acids and increased expression of Ccl2, Cxcl1, Il1b and Tnfa, clodronate liposomes suppressed CD11b+Ly-6C+ cell accumulation within islets, as well as increasing the expression of Pdx1, Insulin and Ins2 pre-mRNA, leading to improved insulin secretion in response to glucose. Similarly, clodronate liposomes increased the expression of Insulin, Ins2 pre-mRNA and Pdx1 RNA in addition to ameliorating β-cell dysfunction in KKAy mice.

Eguchi et al. propose a model in which saturated free fatty acids induce β cells to recruit macrophages through the TLR4–MyD88-mediated production of chemokines; subsequent interactions between β cells and macrophages exacerbate the inflammation, leading to β-cell dysfunction. So, free fatty acids can deliver a double whammy in terms of β-cell lipotoxicity: they can induce inflammatory processes as well as conferring direct deleterious effects.

Katrin Legg

- Copyright © 2012 Nature Publishing Group, a division of Macmillan Publishers Limited; used with permission

References:

ORIGINAL RESEARCH PAPER

  1. Eguchi, K. et al. Saturated fatty acid and TLR signaling link β cell dysfunction and islet inflammation.

    Cell Metabolism 15, 518-533 (2012). doi:10.1016/j.cmet.2012.01.023

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