In pancreas recipients with advanced diabetic eye disease, conflicting ophthalmologic results over different follow-up periods have been reported. In the present prospective study we performed ophthalmologic evaluation groups of type I diabetic patients: 1) normoglycemic recipients of pancreas and kidney grafts (group SPK, n = 43, follow-up 44.9 +/- 35.1 months), 2) pancreas and kidney graft recipients with nonfunctioning pancreatic graft, and recipients of isolated kidney graft (group K, n = 45, follow-up 60.3 +/- 34.2 months). The examinations were performed before transplantation, at the end of follow-up (at least 1 year), and in 63 recipients also at 3 years posttransplant. Visual acuity results at baseline and at the end of follow-up were 0.48 +/- 0.39 vs. 0.50 +/- 0.39 in the SPK group, and 0.46 +/- 0.38 vs. 0.40 +/- 0.39 in the K group. While intragroup changes were not significant, the changes were significantly different between the groups (p < 0.05). Fundoscopic findings at the end of follow-up were improved, stabilized, or deteriorated in the SPK group in 21.3%, 61.7%, and 17.0%, respectively. The respective figures for the K group were 6.1%, 48.8%, and 45.1% (p < 0.001). Similar results were obtained when evaluating findings at 3 years posttransplant. Before transplantation, 78% of the SPK group and 81% of the K group had been treated by laser. The need for additional posttransplant laser therapy was significantly lower in the SPK (31%) than in the K group (58%; p < 0.001). In conclusion, pancreas transplant exerts a beneficial effect on the course of diabetic retinopathy even in its late stage.

Reparixin is an inhibitor of CXCR1/2 chemokine receptor shown to be an effective anti-inflammatory adjuvant in a pilot clinical trial in allotransplant recipients. RESEARCH DESIGN AND METHODSA phase 3, multicenter, randomized, double-blind, parallel-assignment study (NCT01817959) was conducted in recipients of islet allotransplants randomized (2:1) to reparixin or placebo in addition to immunosuppression. Primary outcome was the area under the curve (AUC) for C-peptide during the mixed-meal tolerance test at day 75 6 5 after the first and day 365 6 14 after the last transplant. Secondary end points included insulin independence and standard measures of glycemic control. RESULTSThe intention-to-treat analysis did not show a significant difference in C-peptide AUC at both day 75 (27 on reparixin vs. 18 on placebo, P 5 0.99) and day 365 (24 on reparixin vs. 15 on placebo, P 5 0.71). There was no statistically significant difference between treatment groups at any time point for any secondary variable. Analysis of patient subsets showed a trend for a higher percentage of subjects retaining insulin independence for 1 year after a single islet infusion in patients receiving reparixin as compared with patients receiving placebo (26.7% vs. 0%, P 5 0.09) when antithymocyte globulin was used as induction immunosuppression. CONCLUSIONSIn this first double-blind randomized trial, islet transplantation data obtained with reparixin do not support a role of CXCR1/2 inhibition in preventing islet inflammationmediated damage.Pancreatic islet transplantation has become a feasible option in the treatment of uncontrolled type 1 diabetes (T1D) that allows long-term sustained function and improved metabolic control even when exogenous insulin is required (1). Although significant progress has been made in islet transplantation, several limitations remain that preclude its widespread application (2). Among others, the loss of up to 75% of

Hypertrophic pancreatic islets (PI) of Goto Kakizaki (GK) diabetic rats contain a lower number of β-cells vs. non-diabetic Wistar rat PI. Remaining β-cells contain reduced mitochondrial (mt) DNA per nucleus (copy number), probably due to declining mtDNA replication machinery, decreased mt biogenesis or enhanced mitophagy. We confirmed mtDNA copy number decrease down to <30% in PI of one-year-old GK rats. Studying relations to mt nucleoids sizes, we employed 3D superresolution fluorescent photoactivable localization microscopy (FPALM) with lentivirally transduced Eos conjugate of mt single-stranded-DNA-binding protein (mtSSB) or transcription factor TFAM; or by 3D immunocytochemistry. mtSSB (binding transcription or replication nucleoids) contoured “nucleoids” which were smaller by 25% (less diameters >150 nm) in GK β-cells. Eos-TFAM-visualized nucleoids, composed of 72% localized TFAM, were smaller by 10% (immunochemically by 3%). A theoretical ~70% decrease in cell nucleoid number (spatial density) was not observed, rejecting model of single mtDNA per nucleoid. The β-cell maintenance factor Nkx6.1 mRNA and protein were declining with age (>12-fold, 10 months) and decreasing with fasting hyperglycemia in GK rats, probably predetermining the impaired mtDNA replication (copy number decrease), while spatial expansion of mtDNA kept nucleoids with only smaller sizes than those containing much higher mtDNA in non-diabetic β-cells.

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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.