Regulation of blood glucose by xenobiotic and microbial impactors of RIPK2 signalling
| dc.contributor.advisor | Schertzer, Jonathan D. | |
| dc.contributor.author | Duggan, Brittany M. | |
| dc.contributor.department | Medical Sciences | en_US |
| dc.date.accessioned | 2020-08-18T19:11:17Z | |
| dc.date.available | 2020-08-18T19:11:17Z | |
| dc.date.issued | 2020 | |
| dc.description.abstract | Obesity is characterized by hyperinsulinemia and chronic inflammation, contributing to insulin resistance and type 2 diabetes (T2D) risk. Pattern recognition receptors (PRRs) of the innate immune system, including Toll-like Receptors (TLRs) and Nod-like Receptors (NLRs), have been identified as propagators of metabolic inflammation. Circulating bacterial components exert distinct effects on inflammation and insulin sensitivity via TLRs and NLRs. Specific types of bacterial peptidoglycan engage NOD1 and NOD2. Activators of NOD1 increase inflammation and insulin resistance, while activators of NOD2 promote immune tolerance and insulin sensitivity. NOD1 and NOD2 use the common downstream adaptor RIPK2 to drive immune responses, but the role of RIPK2 in glucose homeostasis was unknown. RIPK2 is positioned to mediate effects of xenobiotics and microbial components on blood glucose. For example, tyrosine kinase inhibitors (TKIs) are being investigated for diabetes treatment. Improvements in blood glucose control have been observed in diabetic cancer patients receiving TKI therapy but the mechanism underlying these changes remains unclear. Several TKIs inhibit RIPK2. We sought to understand if TKIs that inhibit RIPK2 block inflammatory and metabolic consequences of NOD signalling. We hypothesized inhibition of inflammation via NOD1-RIPK2 by certain TKIs contributes to lowered blood glucose/improved insulin sensitivity in pre-clinical models of obesity. We showed that RIPK2 was required for acute glycemic consequences of NOD1 and NOD2 activation, and RIPK2-specific TKIs attenuated these glycemic effects. We found TKI-mediated improvements in blood glucose are independent of NOD-RIPK2 signalling during diet-induced obesity. However, RIPK2 mediated the effects of certain TKIs on blood insulin. Finally, we tested if RIPK2 mediated the effects of bacterial components derived from commensal microbiota. We found injection of upper intestinal microbe components lowered blood glucose via NOD2-RIPK2 signalling. These findings demonstrate that modulation of RIPK2 signalling by xenobiotic or microbial factors is an important contributor to blood glucose and insulin homeostasis. | en_US |
| dc.description.degree | Doctor of Philosophy (PhD) | en_US |
| dc.description.degreetype | Thesis | en_US |
| dc.description.layabstract | Obesity increases the risk of chronic diseases, including Type 2 Diabetes (T2D). Obesity stops insulin from working properly, leading to the inability to lower blood glucose. Obesity and T2D are linked to chronic, low-grade activation of the immune system. The immune system normally defends the body against microbes by inducing a pro-inflammatory response. Inflammation can also be activated or inhibited by drugs (xenobiotics), and different aspects of inflammation can increase or decrease blood glucose and insulin. A major unanswered question was how certain cancer drugs and bacterial components interact with the immune system to change blood glucose or insulin. This work tested how an innate immune pathway that detects bacterial cell wall components is influenced by cancer drugs and alters blood glucose and insulin in pre-clinical models. This work is targeted at understanding how new prebiotics or existing drugs can be tasked as therapeutic strategies for prediabetes and T2D. | en_US |
| dc.identifier.uri | http://hdl.handle.net/11375/25707 | |
| dc.language.iso | en | en_US |
| dc.subject | immunometabolism, Type 2 Diabetes, blood glucose, inflammation, NOD signalling | en_US |
| dc.title | Regulation of blood glucose by xenobiotic and microbial impactors of RIPK2 signalling | en_US |
| dc.type | Thesis | en_US |