Radiomanganese PET Detects Changes in Functional β-cell Mass in Mouse Models of Diabetes

Reinier Hernandez, Stephen A. Graves, Trillian Gregg, Halena R. VanDeusen, Rachel J. Fenske, Haley N. Wienkes, Christopher G. England, Hector F. Valdovinos, Justin J. Jeffery, Todd E. Barnhart, Gregory Severin, Robert J. Nickles, Michelle E Kimple, Matthew J. Merrins, Weibo Cai

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    Abstract

    The noninvasive measurement of functional β-cell mass would be clinically valuable for monitoring the progression of type 1 and type 2 diabetes, as well as the viability of transplanted insulin-producing cells. Although previous work employing magnetic resonance imaging has shown promise for functional β-cell mass determination through voltage-dependent Ca2+ channel (VDCC)-mediated internalization of Mn2+, the clinical utility of this technique is limited by the cytotoxic levels of Mn2+ contrast agent. Here, we show that positron emission tomography (PET) is advantageous for determining functional β-cell mass using 52Mn2+ (t1/2: 5.6 d). We investigated the whole-body distribution of 52Mn2+ in healthy adult mice by dynamic and static PET imaging. Pancreatic VDCC uptake of 52Mn2+ was successfully manipulated pharmacologically in vitro and in vivo using glucose, nifedipine (VDCC blocker), the sulfonylureas tolbutamide and glibenclamide (KATP channel blockers), and diazoxide (KATP channel opener). In a mouse model of streptozotocin (STZ)-induced type 1 diabetes, 52Mn2+ uptake in the pancreas was distinguished from healthy controls in parallel with classic histological quantification of β-cell mass from pancreatic sections. 52Mn2+-PET also reported the expected increase in functional β-cell mass in the ob/ob model of pre-type 2 diabetes, a result corroborated by histological β-cell mass measurements and live-cell imaging of β-cell Ca2+ oscillations. These results indicate that 52Mn2+-PET is a sensitive new tool for the non-invasive assessment of functional β-cell mass.
    Original languageEnglish
    JournalDiabetes
    Volume66
    Issue number8
    Pages (from-to)2163-2174
    ISSN0012-1797
    DOIs
    Publication statusPublished - 2017

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