Abstract
Commensal flora and pathogenic microbes influence the incidence of diabetes in animal models yet little is known about the mechanistic basis of these interactions. We hypothesized that Myd88, an adaptor molecule in the Toll-like-receptor (TLR) pathway, regulates pancreatic β-cell function and homeostasis. We first examined β-cells histologically and found that Myd88−/− mice have smaller islets in comparison to C57Bl/6 controls. Myd88−/− mice were nonetheless normoglycemic both at rest and after an intra-peritoneal glucose tolerance test (IPGTT). In contrast, after low-dose streptozotocin (STZ) challenge, Myd88−/−mice had an abnormal IPGTT relative to WT controls. Furthermore, Myd88−/− mice suffer enhanced β-cell apoptosis and have enhanced hepatic damage with delayed recovery upon low-dose STZ treatment. Finally, we treated WT mice with broad-spectrum oral antibiotics to deplete their commensal flora. In WT mice, low dose oral lipopolysaccharide, but not lipotichoic acid or antibiotics alone, strongly promoted enhanced glycemic control. These data suggest that Myd88 signaling and certain TLR ligands mediate a homeostatic effect on β-cells primarily in the setting of injury.
Highlights
Toll-like receptors (TLRs) recognize structurally conserved microbial products and mediate the initiation of inflammatory and immune defense responses [1]
To test the hypothesis that TLR signaling was critical for b-cell homeostasis, we first examined the impact of TLR signaling on pancreatic b-cell size and function in the absence of injury
We looked for phenotypic differences between WT mice and knockout mice for Myd88, TLR2, TLR3, TLR4 and TLR5
Summary
Toll-like receptors (TLRs) recognize structurally conserved microbial products and mediate the initiation of inflammatory and immune defense responses [1]. All TLRs, with the exception of TLR3, can signal via the adaptor Myd, leading to activation of NF-kB as well as mitogen-activated protein (MAP) kinase pathways These pathways have been shown to regulate immune response genes such as cytokines and chemokines that modulate both innate and adaptive immunity [2,3]. In conjunction with their role in host defense, TLRs play concomitant roles limiting tissue damage and promoting wound healing at sites of injury. These include TGF-b1 [8], VEGF [9], KGF-1 [10] KGF-2 [11], HGF [12] and prostaglandins [13]
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