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The toll-like receptor signaling molecule Myd88 contributes to pancreatic beta-cell homeostasis in response to injury.

Bollyky PL, Bice JB, Sweet IR, Falk BA, Gebe JA, Clark AE, Gersuk VH, Aderem A, Hawn TR, Nepom GT - PLoS ONE (2009)

Bottom Line: We hypothesized that Myd88, an adaptor molecule in the Toll-like-receptor (TLR) pathway, regulates pancreatic beta-cell function and homeostasis.Finally, we treated WT mice with broad-spectrum oral antibiotics to deplete their commensal flora.These data suggest that Myd88 signaling and certain TLR ligands mediate a homeostatic effect on beta-cells primarily in the setting of injury.

View Article: PubMed Central - PubMed

Affiliation: Benaroya Research Institute, Seattle, Washington, United States of America. pbollyky@benaroyaresearch.org

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 beta-cell function and homeostasis. We first examined beta-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 beta-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 beta-cells primarily in the setting of injury.

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Transaminase Levels Following STZ Treatment.Data shown are for A. AST and B. ALT for 8 WT mice and 8 Myd88−/− mice who received low-dose STZ treatment for 4 days. The animals in this experiment were the same set of mice described in Figure 4 and data for the same time points 7, 14, and 24 days post completion of the low-dose STZ treatment course are shown.
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pone-0005063-g005: Transaminase Levels Following STZ Treatment.Data shown are for A. AST and B. ALT for 8 WT mice and 8 Myd88−/− mice who received low-dose STZ treatment for 4 days. The animals in this experiment were the same set of mice described in Figure 4 and data for the same time points 7, 14, and 24 days post completion of the low-dose STZ treatment course are shown.

Mentions: In order to evaluate whether the enhanced responsiveness of Myd88−/− mice was a systemic feature of the Myd88−/− phenotype, we looked for evidence of heightened injury in another cell type susceptible to STZ damage—the hepatocyte. We evaluated aspartate transaminase (AST) and alanine transaminase (ALT) for the same time points as were evaluated with IPGTT. AST and ALT are liver transaminases which, when found in the peripheral circulation at elevated levels, are indicative of hepatocellular damage. We predicted that systemic administration of STZ would have a parallel impact on hepatocytes as on β-cells, as both cell types are sensitive to STZ. This was indeed the case for both AST and ALT (Figure 5A,B). These data are consistent with systemic hyper-responsiveness to STZ treatment in the absence of Myd88−/− signaling.


The toll-like receptor signaling molecule Myd88 contributes to pancreatic beta-cell homeostasis in response to injury.

Bollyky PL, Bice JB, Sweet IR, Falk BA, Gebe JA, Clark AE, Gersuk VH, Aderem A, Hawn TR, Nepom GT - PLoS ONE (2009)

Transaminase Levels Following STZ Treatment.Data shown are for A. AST and B. ALT for 8 WT mice and 8 Myd88−/− mice who received low-dose STZ treatment for 4 days. The animals in this experiment were the same set of mice described in Figure 4 and data for the same time points 7, 14, and 24 days post completion of the low-dose STZ treatment course are shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2666970&req=5

pone-0005063-g005: Transaminase Levels Following STZ Treatment.Data shown are for A. AST and B. ALT for 8 WT mice and 8 Myd88−/− mice who received low-dose STZ treatment for 4 days. The animals in this experiment were the same set of mice described in Figure 4 and data for the same time points 7, 14, and 24 days post completion of the low-dose STZ treatment course are shown.
Mentions: In order to evaluate whether the enhanced responsiveness of Myd88−/− mice was a systemic feature of the Myd88−/− phenotype, we looked for evidence of heightened injury in another cell type susceptible to STZ damage—the hepatocyte. We evaluated aspartate transaminase (AST) and alanine transaminase (ALT) for the same time points as were evaluated with IPGTT. AST and ALT are liver transaminases which, when found in the peripheral circulation at elevated levels, are indicative of hepatocellular damage. We predicted that systemic administration of STZ would have a parallel impact on hepatocytes as on β-cells, as both cell types are sensitive to STZ. This was indeed the case for both AST and ALT (Figure 5A,B). These data are consistent with systemic hyper-responsiveness to STZ treatment in the absence of Myd88−/− signaling.

Bottom Line: We hypothesized that Myd88, an adaptor molecule in the Toll-like-receptor (TLR) pathway, regulates pancreatic beta-cell function and homeostasis.Finally, we treated WT mice with broad-spectrum oral antibiotics to deplete their commensal flora.These data suggest that Myd88 signaling and certain TLR ligands mediate a homeostatic effect on beta-cells primarily in the setting of injury.

View Article: PubMed Central - PubMed

Affiliation: Benaroya Research Institute, Seattle, Washington, United States of America. pbollyky@benaroyaresearch.org

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 beta-cell function and homeostasis. We first examined beta-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 beta-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 beta-cells primarily in the setting of injury.

Show MeSH
Related in: MedlinePlus