Type II diabetes is chronic disease characterized by temporal loss of ?-cell function and gradual insulin deficiency. Despite years of intensive research into the mechanisms of ?-cell functional decline, progress in understanding the pathogenesis of diabetes has been hampered by our inability to monitor the fate of ?-cells during progression of the disease or during therapeutic recovery. Although various molecular imaging approaches have been demonstrated in vitro, non-invasive imaging of ?-cell mass and function in vivo remains elusive. Over the past 5 years, our lab has improved upon the original design of a responsive MRI contrast agent that responds to release of Zn2+ ions from secretory tissues and demonstrated that release of insulin and Zn2+ from pancreatic ?-cells initiated by a bolus of glucose bolus can be imaged in rodents and in the macaque non-human primate. The monkey imaging studies showed that Zn2+ and insulin secretion is not uniform throughout the pancreas, consistent with known data on the non-uniform distribution of islets throughout the pancreas. A reduction in agent Zn2+ binding affinity (by ~103) resulted in a dramatic improvement in the sensitivity for detection of Zn2+ secretion from the pancreas in vivo. Furthermore, we have demonstrated that one can detect ?first responder islets? as ?hot spots? in the tail of the pancreas by MRI using either a low or high affinity Zn2+ sensor. In this continuation project, we will monitor first responder islets in two well-established T2DM model, the Zucker Diabetic Fatty (ZDF) rat (obese model) and the Goto-Kakizaki (GK) rat (non-obese model). Animals will be imaged every 2 weeks during progression of the disease and as they respond to clinically approved T2DM drugs. The imaging methods will be validated by independent measures of insulin content (fluorescence) and Zn2+ content by SR-XRF. Our goal is to demonstrate that ?-cell function can be monitored in the head and tail regions of the pancrease reproducibly by MRI and that this technology will provide new insights into ?-cell function that will catalyze development of new drugs for T2DM.
This project involves application of new imaging methods to monitor insulin secretion by MRI. Preliminary data in both rodents and non-human primates show that this imaging method provides new insights into ?-cell function in pancreatic islets than cannot be obtained by traditional blood plasma measurements of insulin. Thus, this new technology has the potential of significantly impacting the development of more specific drugs for improved glycemic care in diabetic patients.
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