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

The noninvasive measurement of functional -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 -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 -cell mass using Mn-52(2+) (t(1/2): 5.6 days). We investigated the whole-body distribution of Mn-52(2+) in healthy adult mice by dynamic and static PET imaging. Pancreatic VDCC uptake of Mn-52(2+) was successfully manipulated pharmacologically in vitro and in vivo using glucose, nifedipine (VDCC blocker), the sulfonylureas tolbutamide and glibenclamide (K-ATP channel blockers), and diazoxide (K-ATP channel opener). In a mouse model of streptozotocin-induced type 1 diabetes, Mn-52(2+) uptake in the pancreas was distinguished from healthy controls in parallel with classic histological quantification of -cell mass from pancreatic sections. Mn-52(2+)-PET also reported the expected increase in functional -cell mass in the ob/ob model of pretype 2 diabetes, a result corroborated by histological -cell mass measurements and live-cell imaging of -cell Ca2+ oscillations. These results indicate that Mn-52(2+)-PET is a sensitive new tool for the noninvasive assessment of functional -cell mass.