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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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Histologic measurement of β-cell volume, mass and islet number for WT and TLR KO mice.A&B Representative histological sections from A) Myd88−/− and B) B6 mice. C. β-cell volume as a percentage of total pancreas volume. D. Islet cell number per histologic field examined. E. Total β-cell mass. The ages, body weights, and pancreatic weights of the mice used for these studies are shown in Table 1. * = p<0.05.
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pone-0005063-g001: Histologic measurement of β-cell volume, mass and islet number for WT and TLR KO mice.A&B Representative histological sections from A) Myd88−/− and B) B6 mice. C. β-cell volume as a percentage of total pancreas volume. D. Islet cell number per histologic field examined. E. Total β-cell mass. The ages, body weights, and pancreatic weights of the mice used for these studies are shown in Table 1. * = p<0.05.

Mentions: We focused initially on islet cell mass and volume because the cell mass of islets present in the pancreas, particularly that of β-cells, plays an essential role in determining the amount of insulin secreted. The numbers, ages and body weights of the mice used are shown in Table 1. Both TLR2−/− and Myd88−/− mice were found to have significantly smaller relative β-cell volume as a percentage of total pancreas volume (Figure 1C). However, the number of islets per field between the different mouse strains remained intact (Figure 1D), suggesting that Myd88−/− islets were smaller than WT islets. When total β-cell mass was calculated, only Myd88−/− mice had diminished β-cell mass (Figure 1E). Therefore, in our subsequent work, we elected to focus solely on the comparison between Myd88−/− and WT animals.


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)

Histologic measurement of β-cell volume, mass and islet number for WT and TLR KO mice.A&B Representative histological sections from A) Myd88−/− and B) B6 mice. C. β-cell volume as a percentage of total pancreas volume. D. Islet cell number per histologic field examined. E. Total β-cell mass. The ages, body weights, and pancreatic weights of the mice used for these studies are shown in Table 1. * = p<0.05.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0005063-g001: Histologic measurement of β-cell volume, mass and islet number for WT and TLR KO mice.A&B Representative histological sections from A) Myd88−/− and B) B6 mice. C. β-cell volume as a percentage of total pancreas volume. D. Islet cell number per histologic field examined. E. Total β-cell mass. The ages, body weights, and pancreatic weights of the mice used for these studies are shown in Table 1. * = p<0.05.
Mentions: We focused initially on islet cell mass and volume because the cell mass of islets present in the pancreas, particularly that of β-cells, plays an essential role in determining the amount of insulin secreted. The numbers, ages and body weights of the mice used are shown in Table 1. Both TLR2−/− and Myd88−/− mice were found to have significantly smaller relative β-cell volume as a percentage of total pancreas volume (Figure 1C). However, the number of islets per field between the different mouse strains remained intact (Figure 1D), suggesting that Myd88−/− islets were smaller than WT islets. When total β-cell mass was calculated, only Myd88−/− mice had diminished β-cell mass (Figure 1E). Therefore, in our subsequent work, we elected to focus solely on the comparison between Myd88−/− and WT animals.

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