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

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⁺ (t_1/2: 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.