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

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 using MRI 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 the 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 days). 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-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 pretype 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 noninvasive assessment of functional β-cell mass.

Manganese in PET imaging: Opportunities and challenges

“…Mn +2 was shown to be taken up significantly by the pancreas (see also above), possibly by mimicking Ca 2+ in pancreatic metabolic pathways. This feature was used by Hernandez et al to monitor ß‐cell mass with [ 52g Mn]MnCl 2 by ex vivo and in vivo imaging of ß‐cell metabolism in type 1 and type 2 diabetes mouse models . Previous work on this topic using MRI and nonradioactive manganese ions as contrast agents showed that the utility of this method was limited by the toxicity of free Mn 2+ ions.…”

Anatomy, Functionality, and Neuronal Connectivity with Manganese Radiotracers for Positron Emission Tomography

“…In recent years, there has been a renewed interest in using radioactive manganese for PET imaging, in particular manganese-52 [32][33][34][35][36][37]. Mn-52 is a positron emitter with a long halflife of 5.6 days, which allows longitudinal biodistribution studies in the body and brain.…”

Magnetic Retrieval of Encapsulated Beta Cell Transplants from Diabetic Mice Using Dual‐Function MRI Visible and Retrievable Microcapsules

“…Transplanted islets have previously been tracked in vivo through cellular labeling with fluorescent dyes, nanoparticle‐based contrast agents, or radiolabels 15–23. Co‐encapsulation of contrast agents within hydrogels capsules has also been used to locate encapsulated islets via magnetic resonance imaging (MRI) in vitro21,24 and recently, to track the movement of unconstrained capsules implanted in vivo 25.…”