Background. In vitro labeling of pancreatic islets by iron nanoparticles enables their detection as hypoitnense spots on serial magnetic resonance (MR) images. We report the first results of a pilot trial aiming to test the feasibility and safety of this technique in humans. Methods. Islets were labeled in culture with 5 μL/mL ferucarbotran for 6 to 48 hr and transplanted into the portal vein (12 infusions) in 8 C-peptide negative recipients. The liver area was examined the next day and 1, 4, and 24 weeks posttransplant using a 3T MR scanner. Results. In all recipients, significant C-peptide levels and near-normal HbA1c values were achieved with 50% to 80% insulin dose reduction. No side effects related to the labeling procedure were documented. Typically, a significant islet spot number decrease (on average 60%) was detected at week 1 with subsequent only slight decrease for up to 24 weeks. In two subjects with labeling period of less than 6 and 10 hr, only few islet spots were detected corresponding to poor islet visualization in phantoms labeled for the same period of time. Conclusion. Pancreatic islets (PI) visualization was safe and successful in all recipients but was less efficient if labeling period was less than 16 hr. Significant decrease of islet spots occurred at week 1, suggesting early islet destruction or impaired engraftment. Afterward, the islet spot numbers remained stable for up to 24 weeks. Data show that MR detection of ferucarbotran-labeled islets enables their long-term noninvasive visualization and correlates with sustained C-peptide production.

We have recently described a magnetic resonance (MR) method for detection of rat pancreatic islets transplanted into the liver after labeling with superparamagnetic iron oxide nanoparticles. The aim of this work was to study whether this technique could be applicable over a longer period after transplantation and whether it could help to detect islet rejection. Islets from Lewis and Wistar rats were cultured in the presence of iron oxide nanoparticles. Two thousand of Lewis (n=6) or Wistar (n=8) iron-labeled islets were transplanted into the portal vein of Lewis diabetic animals. Serial MR imaging of the liver were performed at 1, 2, 3, 4, 5, and 6 weeks. Although all allogeneic islets were rejected by 12 days, syngeneic animals remained normoglycemic throughout the study. At week 1, the labeled islets were visualized on MR scans as distinct hypointense spots homogeneously distributed in the liver. While their number declined only insignificantly in the syngeneic group, in the allogeneic group the number of spots gradually decreased until approximately 35% of their initial count. Although syngeneic islets showed a normal histology, the allogeneic islets were completely rejected. Iron particles, localized in macrophages, were detected only in the syngeneic islets and were absent in the rejected islet structures. In vitro incubation tests did not reveal any differences in insulin secretion between labeled and nonlabeled islets. MR imaging of iron-labeled pancreatic islets can be used for verification of the technical success of the transplantation procedure itself and for the detection of the decreasing relative islet mass due to rejection.

Diabetes is a metabolic disease that involves the death or dysfunction of the insulin-secreting β cells in the pancreas. Consequently, most diabetes research is aimed at understanding the molecular and cellular bases of pancreatic development, islet formation, β-cell survival, and insulin secretion. Complex interactions of signaling pathways and transcription factor networks regulate the specification, growth, and differentiation of cell types in the developing pancreas. Many of the same regulators continue to modulate gene expression and cell fate of the adult pancreas. The transcription factor NEUROD1 is essential for the maturation of β cells and the expansion of the pancreatic islet cell mass. Mutations of the Neurod1 gene cause diabetes in humans and mice. However, the different aspects of the requirement of NEUROD1 for pancreas development are not fully understood. In this study, we investigated the role of NEUROD1 during the primary and secondary transitions of mouse pancreas development. We determined that the elimination of Neurod1 impairs the expression of key transcription factors for α- and β-cell differentiation, β-cell proliferation, insulin production, and islets of Langerhans formation. These findings demonstrate that the Neurod1 deletion altered the properties of α and β endocrine cells, resulting in severe neonatal diabetes, and thus, NEUROD1 is required for proper activation of the transcriptional network and differentiation of functional α and β cells.