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⁺ (t_1/2: 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 (K_ATP channel blockers), and diazoxide (K_ATP 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.