Type II diabetes is chronic disease characterized by temporal loss of beta-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. Although a few antibodies and small molecules that target the -cell are showing promise for monitoring -cell mass by positron emission tomography (PET), the preferred imaging modality for detecting biological function continues to be magnetic resonance imaging (MRI) because it is more widely available clinically and offers the much greater image resolution. However, novel MRI agents that respond to -cell function are sparse and only a few have been applied in vivo. We recently demonstrated in control mice, in STZ-treated mice, and in mice fed a high fat diet over a period of sixteen weeks that the low molecular weight Zn2+ sensor molecule, GdDOTA-diBPEN, enhances the pancreas after a bolus injection of glucose to initiate glucose stimulated insulin secretion (GSIS). Other tissues surrounding the pancreas are not enhanced by the agent at the low concentration provided. The pancreas is also not enhanced in the absence of the glucose bolus nor is it enhanced in animals lacking -cells (STZ-treated animals). These observations are consistent with the hypothesis that this agent senses release of Zn2+ from pancreatic -cells only during glucose stimulated insulin secretion (GSIS). Images of mice collected over a prolonged period of high-fat (60%) feeding show dramatic contrast enhancement throughout the abdomen, consistent with expansion of pancreatic -cell mass during progression of type II diabetes. In this project, we will optimize the protocol for delivery of glucose and the agent for imaging -cell function, image Zn2+ release during both the fast and slow phases of insulin secretion, image -cell function in rat models of type I and type II diabetes, and image -cell function in Ossabaw mini-pigs using a clinical 3T scanner. Our goal is to determine the general utility of this novel MRI agent for imaging -cell function in anticipationof translating this technology to clinical imaging.
Imaging -cell function in vivo has been an elusive goal for many years. A simple MRI Zn2+ sensor that responds to release of insulin from the pancreas is a highly significant discovery that could lead to a clinical imaging method for monitoring development of type 2 diabetes with age in human patients and, perhaps more importantly, for monitoring its reversal during pharmacological interventions or changes in dietary lifestyle.
|Lux, Jacques; Sherry, A Dean (2018) Advances in gadolinium-based MRI contrast agent designs for monitoring biological processes in vivo. Curr Opin Chem Biol 45:121-130|
|Zhang, Lei; Martins, André F; Zhao, Piyu et al. (2017) Lanthanide-Based T2ex and CEST Complexes Provide Insights into the Design of pH Sensitive MRI Agents. Angew Chem Int Ed Engl 56:16626-16630|
|Clavijo Jordan, M Veronica; Lo, Su-Tang; Chen, Shiuhwei et al. (2016) Zinc-sensitive MRI contrast agent detects differential release of Zn(II) ions from the healthy vs. malignant mouse prostate. Proc Natl Acad Sci U S A 113:E5464-71|
|Yu, Jing; Martins, André F; Preihs, Christian et al. (2015) Amplifying the sensitivity of zinc(II) responsive MRI contrast agents by altering water exchange rates. J Am Chem Soc 137:14173-9|
|De León-Rodríguez, Luis M; Martins, André F; Pinho, Marco C et al. (2015) Basic MR relaxation mechanisms and contrast agent design. J Magn Reson Imaging 42:545-65|
|Sherry, A Dean; Wu, Yunkou (2013) The importance of water exchange rates in the design of responsive agents for MRI. Curr Opin Chem Biol 17:167-74|
|De Leon-Rodriguez, Luis; Lubag Jr, Angelo Josue M; Sherry, A Dean (2012) Imaging free zinc levels in vivo - what can be learned? Inorganica Chim Acta 393:12-23|
|De León-Rodríguez, Luis M; Lubag, Angelo J M; López, Jorge A et al. (2012) A second generation MRI contrast agent for imaging zinc ions in vivo. Medchemcomm 3:480-483|