Type 1 Diabetes (T1D) is a chronic autoimmune condition where pancreatic β-cells are destroyed by autoreactive T-cells. This process, known as insulitis, occurs years before diabetes clinically presents itself. When insulitis starts to occur during early pre-symptomatic stages of T1D, most of the β-cell mass still remain and secretion of insulin remains significant enough that blood glucose can still be regulated. Thus, therapeutic intervention during the early stages of insulitis to preserve β-cell mass is ideal. However, there are currently no clinically available modality to non-invasively image disease progression leading to T1D. Pancreatic islets are densely vascularized, and their microvasculature reorganizes during the progression of diabetes. It has been demonstrated that Contrast Enhanced Ultrasound (CEUS) measurement of pancreatic blood flow dynamics can predict T1D progression in preclinical models. Here, we test whether CEUS measurements of pancreatic blood flow dynamics can predict a successful therapeutic treatment outcome for T1D. Using a small animal ultrasound machine, we measured the reperfusion values of size-isolated microbubbles ablated within the pancreas of two mouse models: Non-Obese Diabetic (NOD mice) and NOD-scid mice treated with an adoptive transfer of diabetogenic splenocytes (AT mice). Our study looked at each the following T1D treatments: 1) antiCD4 to deplete CD4+ T-cells; 2) antiCD3 to block T-cell activation, 3) Verapamil to reduce β-cell decline and 4) TUDCA to reduce β-cell ER stress. Our findings were consistent with the findings of previous demonstrations of CEUS measurements of pancreatic blood flow dynamics where NOD mice >10 weeks of age and AT mice >2 weeks following splenocyte transfer both showed increased reperfusion rate (blood flow speed) and decreased reperfusion amplitude (blood flow volume)—both predictors of T1D. Next, our findings show that AT mice responding to antiCD4, antiCD3 and verapamil had a significant delay or absence of diabetes, whereas AT mice non-responders had similar blood flow dynamics as untreated AT mice. These findings show that CEUS measurements of pancreatic blood flow dynamics can predict whether therapeutic treatments for T1D are successful. Ultimately, the use of CEUS to predict the therapeutic treatment success of T1D will allow clinicians to noninvasively determine the efficacy of T1D treatments and allow clinicians to establish more effective β-cell loss intervention strategies for patients.
|Advisor:||Benninger, Richard K|
|Commitee:||Hunter, Kendall, Jacot, Jeffrey, Shandas, Robin|
|School:||University of Colorado at Denver|
|School Location:||United States -- Colorado|
|Source:||MAI 81/10(E), Masters Abstracts International|
|Keywords:||CEUS, Contrast enhanced ultrasound, Diabetes, Islet blood flow, Noninvasive imaging, Type 1 diabetes|
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