Date of Degree
PhD (Doctor of Philosophy)
Patrick M. Schlievert
Background: Obesity has a strong correlation with the development of type two diabetes. As adipocytes accrue in obesity, adipose tissue may induce peripheral insulin resistance through production of pro-inflammatory cytokines and unregulated lipolysis after stimulation by endotoxin or environmental cues. In addition, obesity poses high risks of Staphylococcal aureus colonization and infection. S. aureus can cause a myriad of serious illnesses in both immunocompromised and healthy individuals. Among the S. aureus virulence factors, superantigens are essential for the organism's pathogenesis. Considering the importance of the microbiome in human illnesses, we've examined whether a staphylococcal superantigen has an impact on the development of type two diabetes via affecting adipocytes.
Methodology/Principal Findings: Immortalized human adipocytes and primary rabbit adipocytes that were exposed to staphylococcal superantigen toxic shock syndrome toxin-1 (TSST-1), stimulated proinflammatory cytokine and chemokine production, and such effect could be significantly enhanced by endotoxin and other proinflammatory signals. TSST-1 also induced lipolysis in both human and rabbit adipocytes. Prolonged treatment of rabbits with subclinical doses of TSST-1 induced chronic systemic inflammation and an increase in circulating endotoxin levels, which ultimately resulted in adipocyte insulin resistance and systemic impaired glucose intolerance.
Conclusions/Significance: Endotoxin has been proposed to contribute to type two diabetes through enhanced insulin resistance after chronic exposure and stimulation of adipocytes to produce cytokines. Our data indicate that staphylococcal superantigen(s) can also induce proinflammatory cytokine production and lipolysis in adipocytes. In addition, rabbits, which are chronically exposed to superantigens, experience asymptomatic systemic inflammation, high circulating endotoxin levels, and glucose metabolism deficiency that are common symptoms observed in type two diabetic patients. This is the first study that has shown that bacterial exotoxins, like S. aureus superantigen, may directly contribute to the development of type two diabetes.
Excessive weight and obesity are associated with the development of type II diabetes mellitus. They also pose high risks of Staphylococcal aureus colonization and infection. S. aureus causes a wide range of illnesses in both healthy and immunocompromised individuals. Among its virulence factors, superantigens are essential for the pathogenicity. In this study, we show that rabbits, which are chronically exposed to a S. aureus superantigen, experience impaired glucose tolerance, systemic inflammation, and elevated endotoxin levels in the circulation, all of which are common signs seen in type II diabetes. Additionally, these outcomes can be mediated through superantigen effects on liver and adipose tissue. Collectively, our findings indicate that chronic exposure to S. aureus superantigens contributes directly to development of type II diabetes, and might be targetable for therapeutic intervention.
publicabstract, Inflammation, S. aureus, Type Two Diabetes
xiv, 125 pages
Includes bibliographical references (pages 109-125).
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