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Objectives Diabetes mellitus (DM) is a common condition that requires intensive treatment and markedly impacts the welfare of affected cats. The aim of this study was to identify DM-associated perturbations in the feline pancreatic islet microenvironment. The utility of CUBIC (clear, unobstructed brain/body imaging cocktails and computational analysis) for three-dimensional (3D) pancreatic analysis was investigated. Methods Formalin fixed paraffin embedded tissues from cats with DM, or control cats without pancreatic pathology, were retrospectively identified. Immunohistochemistry for synaptophysin and ionised calcium binding adaptor molecule 1 (IBA1), and immunofluorescence for insulin and synaptophysin, were used to assess changes in islets. An image analysis pipeline was developed to analyse images acquired from two-dimensional immunofluorescence. CUBIC was used to optically clear selected pancreas samples prior to immunofluorescence and deep 3D confocal microscopy. Results Diabetic cats have a significant reduction in synaptophysin-positive islet area. Whilst islets from diabetic patients have similar numbers of β cells to islets from control cats, significantly lower intensity of insulin expression can be observed in the former. CUBIC facilitates clear visualisation of pancreatic islets in 3D. Clinical significance The data presented support the theory that there is a decrease in function of β cells prior to their destruction, suggesting a potentially significant step in the pathogenesis of feline DM. In parallel, we demonstrate CUBIC technology as a valuable new tool to visualise the shape of feline pancreatic islets and to interrogate pathology occurring in the islets of diabetic pets.

OBJECTIVE: IKZF1 encoding Ikaros, an essential regulator of lymphopoiesis and immune homeostasis, has been implicated in the development of childhood acute lymphoblastic leukemia (C-ALL). Because recent genome-wide association (GWA) studies have linked a region of the 3'-UTR of IKZF1 with C-ALL susceptibility, we tested whether IKZF1 is associated with the autoimmune disease type 1 diabetes. RESEARCH DESIGN AND METHODS: rs10272724 (T>C) near IKZF1 at 7p12 was genotyped in 8,333 individuals with type 1 diabetes, 9,947 control subjects, and 3,997 families of European ancestry. Association was tested using logistic regression in the case-control data and by the transmission disequilibrium test in the families. Expression data for IKZF1 by rs10272724 genotype were obtained using quantitative PCR of mRNA/cDNA generated from peripheral blood mononuclear cells from 88 individuals, whereas expression data for five other neighboring genes were obtained from the online Genevar dataset. RESULTS: The minor allele of rs10272724 (C) was found to be protective from type 1 diabetes (odds ratio 0.87 [95% CI 0.83-0.91]; P = 1.1 × 10(-11)). rs10272724 was not correlated with levels of two transcripts of IKZF1 in peripheral blood mononuclear cells. CONCLUSIONS: The major susceptibility genotype for C-ALL confers protection from type 1 diabetes. Our finding strengthens the link between autoimmunity and lymphoid cancers. Further investigation is warranted for the genetic effect marked by rs10272724, its impact on IKZF1, and the role of Ikaros and other family members, Ailios (IKZF3) and Eos (IKZF4), in autoimmunity.

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$\textbf{Background}$: Canine diabetes mellitus (DM) is a common endocrinopathy with a complex genetic architecture. Disease susceptibility in several breeds has been found to be associated with polymorphisms in immune response genes, but in the Labrador retriever breed no genetic associations with DM have been identified to date. Recently, a deletion in the pro-opiomelanocortin ($\textit{POMC}$) gene has been reported in Labrador retrievers, which has been associated with increased appetite and risk of obesity in this breed. $\textbf{Hypothesis / Objectives}$: To characterise the POMC deletion in Labrador retrievers, to develop a simple genetic test for this mutation and to test the hypothesis that the $\textit{POMC}$ gene deletion is associated with an increased risk of DM in this breed. $\textbf{Animals}$: Sixty one non-diabetic Labrador retrievers aged >6 years and fifty seven Labrador retrievers affected with DM. $\textbf{Methods}$: Case-control genotyping study to compare the frequency of the $\textit{POMC}$ deletion in dogs with and without DM. Following polymerase chain reaction and sequencing to characterise the mutation, a PCR-based test was developed and validated using two different restriction fragment length polymorphism assays. $\textbf{Results}$: A 14-base-pair deletion was confirmed and localised to exon 3 of the canine $\textit{POMC}$ gene. A PCR-based test for the deletion was successfully developed. There was no association between the presence of the $\textit{POMC}$ deletion mutation and DM in this population of Labrador retriever dogs. $\textbf{Conclusions and clinical importance}$: This study adds to the existing scientific literature indicating that there is little evidence for a direct link between obesity and DM in dogs.