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 W. Severin, Robert J. Nickles, Michelle E. Kimple, Matthew J. Merrins, Weibo Cai

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 Ca(2+) channel (VDCC)-mediated internalization of Mn(2+), the clinical utility of this technique is limited by the cytotoxic levels of Mn(2+) contrast agent. Here, we show that positron emission tomography (PET) is advantageous for determining functional β-cell mass using (52)Mn(2+) (t1/2: 5.6 d). We investigated the whole-body distribution of (52)Mn(2+) in healthy adult mice by dynamic and static PET imaging. Pancreatic VDCC uptake of (52)Mn(2+) 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, (52)Mn(2+) uptake in the pancreas was distinguished from healthy controls in parallel with classic histological quantification of β-cell mass from pancreatic sections. (52)Mn(2+)-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 Ca(2+) oscillations. These results indicate that (52)Mn(2+)-PET is a sensitive new tool for the non-invasive assessment of functional β-cell mass.