Deep learning-based pancreas volume assessment in individuals with type 1 diabetes.

Pancreas volume is reduced in individuals with diabetes and in autoantibody positive individuals at high risk for developing type 1 diabetes (T1D). Studies investigating pancreas volume are underway to assess pancreas volume in large clinical databases and studies, but manual pancreas annotation is time-consuming and subjective, preventing extension to large studies and databases. This study develops deep learning for automated pancreas volume measurement in individuals with diabetes. A convolutional neural network was trained using manual pancreas annotation on 160 abdominal magnetic resonance imaging (MRI) scans from individuals with T1D, controls, or a combination thereof. Models trained using each cohort were then tested on scans of 25 individuals with T1D. Deep learning and manual segmentations of the pancreas displayed high overlap (Dice coefficient = 0.81) and excellent correlation of pancreas volume measurements (R2 = 0.94). Correlation was highest when training data included individuals both with and without T1D. The pancreas of individuals with T1D can be automatically segmented to measure pancreas volume. This algorithm can be applied to large imaging datasets to quantify the spectrum of human pancreas volume.

A century past the discovery of insulin: global progress and challenges for type 1 diabetes among children and adolescents in low-income and middle-income countries.

Type 1 diabetes is on the rise globally; however, the burden of mortality remains disproportionate in low-income and middle-income countries (LMICs). As 2021 marks 100 years since the discovery of insulin, we revisit progress, global burden of type 1 diabetes trends, and understanding of the pathogenesis and management practices related to the disease. Despite much progress, inequities in access and availability of insulin formulations persist and are reflected in differences in survival and morbidity patterns related to the disease. Some of these inequities have also been exacerbated by health-system challenges during the COVID-19 pandemic. There is a clear opportunity to improve access to insulin and related essential technologies for improved management of type 1 diabetes in LMICs, especially as a part of universal health coverage. These improvements will require concerted action and investments in human resources, community engagement, and education for the timely diagnosis and management of type 1 diabetes, as well as adequate health-care financing. Further research in LMICs, especially those in Africa, is needed to improve our understanding of the burden, risk factors, and implementation strategies for managing type 1 diabetes.

The Feasibility and Applicability of Stem Cell Therapy for the Cure of Type 1 Diabetes.

Stem cell therapy using islet-like insulin-producing cells derived from human pluripotent stem cells has the potential to allow patients with type 1 diabetes to withdraw from insulin therapy. However, several issues exist regarding the use of stem cell therapy to treat type 1 diabetes. In this review, we will focus on the following topics: (1) autoimmune responses during the autologous transplantation of stem cell-derived islet cells, (2) a comparison of stem cell therapy with insulin injection therapy, (3) the impact of the islet microenvironment on stem cell-derived islet cells, and (4) the cost-effectiveness of stem cell-derived islet cell transplantation. Based on these various viewpoints, we will discuss what is required to perform stem cell therapy for patients with type 1 diabetes.

The Use of Atomic Force Microscopy in Comprehensive Assessment of the "Mother-Placenta-Fetus" System in Obstetric and Endocrine Pathology during Pregnancy.

Atomic force microscopy is not very popular in practical health care, therefore, its potential is not studied enough, for example, in obstetrics when studying the "mother-placenta-fetus" system. Our study summarizes the possibilities of using atomic force microscopy for detection of various circulatory disorders and vascular changes at the microscopic level in the uterus (endometrium and myometrium), placenta, and umbilical cord in the main variants of obstetric and endocrine pathology. For instance, in the case of endocrine pathologies, changes in the form of stasis, sludge, diapedesis, ischemia, destruction and separation of endotheliocytes in villous blood vessels were found in the mother. The oxygen content in erythrocytes also naturally decreased in pathologies; poikilo- and anisocytosis were observed.

Assessment of metals induced histopathological and gene expression changes in different organs of non-diabetic and diabetic rats.

Diabetes is a complex metabolic disorder and different environmental toxicants including heavy metals have been involved in diabetes induction. Therefore, assessment of the environmental risk factors and heavy metals induced toxicity have become critical for reducing the consequences of metals pollutants. Previously, we reported heavy metals induced nephrotoxicity in non-diabetic and diabetic rats. Here, we extended our analysis by examining the heavy metals induced organs (heart, kidney, liver, pancreas, and spleen) damage in diabetic and non-diabetic Wistar rats using histopathology and quantitative real-time PCR (qRT-PCR). Following the generation of the diabetic rat model, the animals were exposed to heavy metals including lead (Pb), arsenic (As), manganese (Mn) and cadmium (Cd). Both non-diabetic and diabetic rats were exposed to heavy metals for 30 days and subsequently, the heart, kidney, liver, pancreas and spleen tissues were examined. Heavy metal treatment resulted in irregularly arranged myofibrils and vacuolization in the heart tissue of metal treated groups as evident from hematoxylin and eosin (H & E) staining. The kidney tissue of rats treated with heavy metals showed tubular degeneration, fibrosis, hemorrhage, and vacuolation. The liver of the heavy metals treated rats exhibited cellular degeneration and necrosis. The pancreatic tissue of streptozotocin injected untreated and metal treated rats revealed severe degeneration, necrosis, degranulation, shrinkage, and depression in the islets of Langerhans. Increased red pulp area and congestion were observed in the spleen of the metal mixture treated non-diabetic and diabetic rats. In line with the histological data, the qRT-PCR analysis showed downregulated expression of Bcl2 and upregulation of Caspase-3 in non-diabetic and diabetic metal treated rats as compared to the non-diabetic untreated rats. In conclusion, the present study revealed, diabetic rats are more prone to metal alone as well as metal mixture induced organ damage as compared to non-diabetic rats.

Application of computerized 3D-CT texture analysis of pancreas for the assessment of patients with diabetes.

OBJECTIVE: To evaluate the role of computerized 3D CT texture analysis of the pancreas as quantitative parameters for assessing diabetes. METHODS: Among 2,493 patients with diabetes, 39 with type 2 diabetes (T2D) and 12 with type 1 diabetes (T1D) who underwent CT using two selected CT scanners, were enrolled. We compared these patients with age-, body mass index- (BMI), and CT scanner-matched normal subjects. Computerized texture analysis for entire pancreas was performed by extracting 17 variable features. A multivariate logistic regression analysis was performed to identify the predictive factors for diabetes. A receiver operator characteristic (ROC) curve was constructed to determine the optimal cut off values for statistically significant variables. RESULTS: In diabetes, mean attenuation, standard deviation, variance, entropy, homogeneity, surface area, sphericity, discrete compactness, gray-level co-occurrence matrix (GLCM) contrast, and GLCM entropy showed significant differences (P < .05). Multivariate analysis revealed that a higher variance (adjusted OR, 1.002; P = .005), sphericity (adjusted OR, 1.649×104; P = .048), GLCM entropy (adjusted OR, 1.057×105; P = .032), and lower GLCM contrast (adjusted OR, 0.997; P < .001) were significant variables. The mean AUCs for each feature were 0.654, 0.689, 0.620, and 0.613, respectively (P < .05). In subgroup analysis, only larger surface area (adjusted OR, 1.000; P = .025) was a significant predictor for T2D. CONCLUSIONS: Computerized 3D CT texture analysis of the pancreas could be helpful for predicting diabetes. A higher variance, sphericity, GLCM entropy, and a lower GLCM contrast were the significant predictors for diabetes.

In-vivo assessment of T cell kinetics in individuals at risk for type 1 diabetes.

We previously assessed the kinetics of T cell turnover in vivo by labeling cells with 2 H-H2 O over 42 days in individuals with type 1 diabetes (T1D) and demonstrated an increased turnover of CD4 memory T cells. We have now tested T cell turnover in individuals at risk for T1D using a 3-4-day labeling protocol with 2 H-glucose. We studied 30 relatives with T1D with and without autoantibodies, and 10 healthy controls. Peripheral blood mononuclear cells (PBMC) were flow-sorted into T cell subsets of interest; 2 H-DNA enrichment was measured by mass spectrometry and in-vivo turnover was calculated as maximum fractional enrichment of deuterated adenosine (Fmax ). Among CD4+ cells, Fmax was highest in regulatory T cells (Treg ), followed by effector and central memory T cells and lowest in naive cells. Similarly, CD8+ central and effector memory T cells had a higher turnover than CD8+ terminally differentiated effector memory T cells (TEMRA) and CD8+ -naive T cells. Relatives as a group showed significantly increased Treg turnover by Fmax compared to controls (1·733 ± 0·6784% versus 1·062 ± 0·3787%, P = 0·004), suggesting pre-existing immune dysfunction within families with T1D. However, there was no significant difference in Fmax between groups according to autoantibody or glucose tolerance status. Repeat testing in 20 subjects 1 year later demonstrated relatively higher within-subject compared to between-subject variability for the measurement of Fmax in various T cell subsets. The short labeling protocol with 2 H-glucose should be applied in the context of a clinical trial in which the therapy is expected to have large effects on T cell turnover.

Pharmacovigilance assessment of the association between Fournier's gangrene and other severe genital adverse events with SGLT-2 inhibitors.

Objective: Sodium glucose cotransporter-2 inhibitors (SGLT2i) exert cardiorenal protection in people with diabetes. By inducing glycosuria, SGLT2i predispose to genital infections. In addition, rare occurrence of Fournier's gangrene (FG) has been reported. We aimed to investigate such association through the U.S. Food and Drug Administration (FDA) adverse event (AE) reporting system (FAERS). Research design and methods: We mined the FAERS up to 2018q3 (before FDA warning about SGLT2i-associated FG) to retrieve reports including FG as an AE and SGLT2i as suspect or concomitant drugs, and calculated proportional reporting ratios (PRR). Results: We retrieved 47 cases of FG and 17 cases of other severe AEs of the genital area associated with SGLT2i. Patients with FG were ~10 years older than those with other severe genital AEs. Overall, 77% occurred in men. Three patients were concomitantly treated with systemic immunosuppressive drugs. Increased reporting frequency emerged for SGLT2i compared with other drugs, with a PRR ranging from 5 to 10. The disproportional reporting of FG with SGLT2i remained robust and consistently significant when restricting to the period when SGLT2i were available, to reports filed for glucose-lowering medications or for drugs with the diabetes indication, and after refining the definition of FG. FG was disproportionally associated with psoriasis and with the combination of immunosuppressants and SGLT2i. Conclusions: Although causality cannot be demonstrated, SGLT2i may predispose to FG and other severe genital AEs. Since the use of SGLT2i is expected to increase significantly, clinicians should be aware of these severe, although rare, AEs and their predisposing factors.

Standard complication screening information can be used for risk assessment for first time foot ulcer among patients with type 1 and type 2 diabetes.

AIM: Diabetic foot ulcer (DFU) is a major complication of both Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D); however research into risk factors for DFU does not separate between these two types. The purpose of the present investigation was to identify risk factors for development of first time DFU (FTDFU) over a period of 15 years in patients with T1D and T2D separately. METHODS: This retrospective cohort study included 25,220 feet from 5588 patients with T1D and 7113 patients with T2D treated in the period 2001-2015. Data on baseline characteristics and comorbidities were collected from electronic patient records. Influences of various risk factors for the development of FTDFU were assessed by hazard ratios (HR) from Cox proportional hazard regression models on time from enrolment to FTDFU diagnosis or end-of-follow-up. RESULTS: In T1D independent risk factors were male sex, age >60 years, high HbA1c, long diabetes duration, history of cardiovascular disease, macro-albuminuria, decreased visual acuity, advanced diabetic retinopathy, decreased/absent vibration sense, presence of patient reported symptoms of neuropathy, and absence of foot pulses. In T2D the independent risk factors were the same except age >60 years, a history of cardiovascular disease, and long diabetes duration. CONCLUSIONS: This study documents that much of the standard clinical information obtained as part of the routine follow-up are also independent risk factors for development of FTDFU. This may be used to create a basis for in which patient and when prevention should be started.

Diabetes education and health insurance: How they affect the quality of care provided to people with type 1 diabetes in Latin America. Data from the International Diabetes Mellitus Practices Study (IDMPS).

AIMS: This study aimed to evaluate the impact of diabetes education and access to healthcare coverage on disease management and outcomes in Latin America. METHODS: Data were obtained from a sub-analysis of 2693 patients with type 1 diabetes mellitus recruited from 9 Latin American countries as part of the International Diabetes Mellitus Practices Study (IDMPS), a multinational, observational survey of diabetes treatment in developing regions. RESULTS: Results from the Latin American cohort show that only 25% of participants met HbA1c target value (< 7% [53 mmol/mol]). Attainment of this target was significantly higher among participants who had received diabetes education than those who hadn't (28% vs. 19%, p < 0.001), and among those who practiced self-management (27% vs. 21% no self-management, p = 0.001). Multivariate analysis showed that participants who had received diabetes education were more likely to manage their diabetes (OR:1.65 [95% CI: 1.24, 2.19]; p = 0.001), and to attain HbA1c target values (OR:1.48 [95% CI: 1.14, 1.93]; p = 0.003). CONCLUSIONS: Given the association between uncontrolled diabetes and long-term complications, health authorities and care providers should increase efforts to ensure widespread healthcare coverage and access to self-management education to reduce the socioeconomic and humanistic burden of type 1 diabetes.

Assessment of dental caries and gingival status among a group of type 1 diabetes mellitus and healthy children of South India - a comparative study.

Background Diabetes mellitus is a metabolic disorder. However, dental caries and periodontal health have not attracted much interest in diabetic patients. This study was carried out to assess the dental caries status and gingival health status in children with type 1 diabetes mellitus (T1DM). Methods The study group consisted of 80 children, aged 6-18 years, with T1DM. The dental caries status was recorded using the World Health Organisation (WHO) criteria. Gingival health was assessed using the Loe and Silness gingival index (GI). Data obtained were subjected to statistical analysis. Results The mean dental caries status for primary (decayed, extracted, filled teeth [deft]) and permanent dentition (decayed, missing, filled teeth [DMFT]) scores in diabetic children were 0.44±1.28 and 1.26±2.49, respectively. The GI scores of diabetic children were 0.33±0.48. GI in the study group significantly correlated with DMFT (p<0.001) and deft (p≤0.05). Conclusions Dental caries in primary dentition was lower in diabetic children but was not statistically significant, whereas dental caries in permanent dentition was significantly higher. The gingival condition of diabetic children was healthy.

Comparison of fractal dimension analysis and panoramic-based radiomorphometric indices in the assessment of mandibular bone changes in patients with type 1 and type 2 diabetes mellitus.

OBJECTIVES: This study compared the fractal dimension (FD) and radiomorphometric indices in the assessment of mandibular bone of patients with type 1 (T1 DM) and type 2 diabetes mellitus (T2 DM). STUDY DESIGN: Panoramic radiographs of 104 patients were evaluated to calculate FD, mandibular cortical width (MCW), panoramic mandibular index (PMI), and mandibular cortical index (MCI) in the mandible. RESULTS: No statistically significant differences were found in FD when T1 DM and T2 DM groups were compared with controls (P ≥ .168). Patients with T1 DM had significantly lower MCW (P < .001) and PMI (P = .030) compared with controls. Patients with T2 DM had no significant differences in MCW (P = .228) or PMI (P = .137) compared with controls. No significant differences were observed between patients with T1 DM and those with T2 DM for FD, MCW, and PMI (P > .05). In the T1 DM and T2 DM groups, there was a significant correlation between MCW and FD (P ≤ .011). No correlation was observed between FD and PMI in either the T1 DM group or the T2 DM group (P ≥ .142). No significant differences in MCI were observed between the DM groups and controls (P = .740) or between the T1 DM and T2 DM groups (P = 1.000). CONCLUSIONS: The cortical and trabecular bone architectures of patients with T1 DM and T2 DM were not different. Patients with T1 DM had lower cortical measurements compared with controls.

TG/HDL-C ratio and visceral adiposity index may be useful in assessment of insulin resistance in adults with type 1 diabetes in clinical practice.

BACKGROUND: Insulin resistance (IR) is an important clinical issue in patients with type 1 diabetes due to worse metabolic control and risk of development of chronic complications. OBJECTIVE: The aim of the study was to evaluate simple and easily available parameters as indirect markers of IR in adults with type 1 diabetes and correlate it with the results of hyperinsulinemic-euglycemic clamp. METHODS: The study included 88 patients (62 men), aged 34.1 ± 6.5 years, with type 1 diabetes with a median disease duration of 8 (7-13) years and mean HbA1c of 7.6 ± 1.5%. Tissue sensitivity to insulin was assessed on the basis of glucose distribution rate (GDR) obtained in the course of hyperinsulinemic-euglycemic clamp. In addition, indirect markers of IR, such as estimated GDR, presence of features of metabolic syndrome, visceral adiposity index (VAI), and the triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) ratio, were evaluated. RESULTS: In the study group, IR defined as GDR <4 mg/kg/min was observed in 33 (37.5%) patients. Group with IR had significantly higher postprandial glycemia (9.1 ± 2.0 vs 8.4 ± 1.1 mmol/L, P = .04), serum TG level (1.11 [0.75-1.92] vs 0.85 [0.60-1.08] mmol/L, P = .001), lower HDL-C level (1.59 ± 0.38 vs 1.8 ± 0.5 mmol/L, P = .02), higher TG/HDL-C ratio (1.60 [1.00-3.13] vs 1.05 [0.62-1.53], P = .001), and higher VAI (2.61 [1.31-4.25] vs 1.56 [0.96-2.25], P = .002). Significant relationship between GDR and TG/HDL-C ratio and VAI, adjusted for age, sex, HbA1c, and duration of diabetes was revealed (respectively, odds ratio 1.90 [95% confidence interval 1.15-3.15], P = .01 and odds ratio 1.47 [95% confidence interval 1.06-2.04], P = .01). CONCLUSIONS: TG/HDL-C ratio and VAI appear to be clinically useful tools to assess IR in adults with type 1 diabetes.

Assessment of Serum Concentrations of Ghrelin, Obestatin, Omentin-1, and Apelin in Children with Type 1 Diabetes.

The increasing knowledge on the functions of gastric peptides and adipokines in the body allows the assumption of their major role linking the process of food intake, nutritional status, and body growth, largely through the regulation of glucose metabolism and insulin resistance. The aim of the study was the assessment of serum levels of selected gastric peptides and adipocytokines in children with type 1 diabetes, with respect to the disease duration. The study involved 80 children aged 4-18 years (M/F -37/43). Children with type 1 diabetes (n = 46) were compared to the control group (n = 34). The study group was divided into 4 subgroups: (I) patients with newly diagnosed type 1 diabetes, after an episode of ketoacidosis (n = 10), (II) patients with type 1 diabetes of duration no longer than 5 years (n = 9), (III) patients with 5 to 10 years of DT1 (n = 20), and (IV) patients with type 1 diabetes of duration longer than 10 years (n = 7). The concentrations of gastric peptide and adipocytokines across all subgroups were lower than in the control group. The differences were statistically significant (p < 0.0001), which may be of importance in the development of the disease complications.

[APPLICATION OF INTEGRAL INDICATOR FOR ASSESSMENT OF OXIDATIVE STRESS IN MEN WITH PATHOSPERMIA AND TYPE 1 DIABETES].

This study introduces a method for assessing the individual degree of oxidative stress (integral indicator) in men with pathospermia and type 1 diabetes, based on lipid peroxidation parameters. The study population consisted of three groups of patients. The study group included 15 men with type 1 diabetes (mean age 28 ± 3.8 years) and abnormal semen analyses: oligozoospermia, asthenozoospermia and oligoasthenozoospermia. The comparison group consisted of 20 people (average age 30 ± 2.5 years) without type 1 diabetes, but with changes in semen, similar to those in the study group. The control group was formed of 30 men (mean age 28 ± 4.3 years) with complete reproductive function and without type 1 diabetes. The mechanisms of lipid peroxidation development were found to differ between patients with and without type 1 diabetes. In pathospermic patients without carbohydrate metabolism disorders, activation of lipid peroxidation processes was most pronounced at the stage of primary product formation--diene conjugates, while in patients with type 1 diabetes and pathospermia--at the stage of formation of ketodienes and conjugated trienes, and TBA- active products. It is recommended to take into account the integral indicator of the lipid peroxidation intensity in the development of methods for correction and prevention of reproductive disorders in men with type 1 diabetes and impaired spermatogenesis.

Longitudinal assessment of neuroanatomical and cognitive differences in young children with type 1 diabetes: association with hyperglycemia.

Significant regional differences in gray and white matter volume and subtle cognitive differences between young diabetic and nondiabetic children have been observed. Here, we assessed whether these differences change over time and the relation with dysglycemia. Children ages 4 to <10 years with (n = 144) and without (n = 72) type 1 diabetes (T1D) had high-resolution structural MRI and comprehensive neurocognitive tests at baseline and 18 months and continuous glucose monitoring and HbA1c performed quarterly for 18 months. There were no differences in cognitive and executive function scores between groups at 18 months. However, children with diabetes had slower total gray and white matter growth than control subjects. Gray matter regions (left precuneus, right temporal, frontal, and parietal lobes and right medial-frontal cortex) showed lesser growth in diabetes, as did white matter areas (splenium of the corpus callosum, bilateral superior-parietal lobe, bilateral anterior forceps, and inferior-frontal fasciculus). These changes were associated with higher cumulative hyperglycemia and glucose variability but not with hypoglycemia. Young children with T1D have significant differences in total and regional gray and white matter growth in brain regions involved in complex sensorimotor processing and cognition compared with age-matched control subjects over 18 months, suggesting that chronic hyperglycemia may be detrimental to the developing brain.

Prospective assessment of hypoglycemia symptoms in children and adults with type 1 diabetes.

PURPOSE: To compare the characteristics of symptoms of hypoglycemia in children and in adults with type 1 diabetes. METHODS: Adults with diabetes and parents of children with diabetes who were participants were asked to call a phone system to report episodes of hypoglycemia (presence of symptoms and a blood glucose <4.0 mmol/L). For each episode, blood glucose reading and a scoring of 28 symptoms on a 7-point scale (1 = not present, 7 = very intense) were collected. RESULTS: Sixty six children (49.2% males, mean age = 12.1±2.4 years, mean age at diagnosis = 7.5±2.9 years) and 53 adults (41.2% males, mean age 38.7±14.5 years, mean age at diagnosis = 17.5±12.9 years) with type 1 diabetes participated. The most common symptoms in adults were hunger, sweating, trembling and weakness. The most common symptoms in children were weakness, trembling and hunger. The 2 most discriminating variables between children and adults were sleepiness and tiredness, which were more common in children (p<0.01). In a comparative factor analysis, 3 factors emerged: factor 1, autonomic and neuroglycopenic; factor 2, behavioural; and factor 3, general malaise. Factors 2 and 3 were significantly more common or intense in children than in adults; MANOVA: F(1, 113) = 6.72, p<0.05 and F(1, 113) = 4.64, p<0.05, respectively. CONCLUSIONS: Symptoms relating to behaviour and general malaise are more common in children than in adults with type 1 diabetes. The results of this study may assist providers in educating caregivers of children and patients with diabetes how to better recognize episodes of hypoglycemia.

Integrative analysis of the transcriptome profiles observed in type 1, type 2 and gestational diabetes mellitus reveals the role of inflammation.

BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease, while type 2 (T2D) and gestational diabetes (GDM) are considered metabolic disturbances. In a previous study evaluating the transcript profiling of peripheral mononuclear blood cells obtained from T1D, T2D and GDM patients we showed that the gene profile of T1D patients was closer to GDM than to T2D. To understand the influence of demographical, clinical, laboratory, pathogenetic and treatment features on the diabetes transcript profiling, we performed an analysis integrating these features with the gene expression profiles of the annotated genes included in databases containing information regarding GWAS and immune cell expression signatures. METHODS: Samples from 56 (19 T1D, 20 T2D, and 17 GDM) patients were hybridized to whole genome one-color Agilent 4x44k microarrays. Non-informative genes were filtered by partitioning, and differentially expressed genes were obtained by rank product analysis. Functional analyses were carried out using the DAVID database, and module maps were constructed using the Genomica tool. RESULTS: The functional analyses were able to discriminate between T1D and GDM patients based on genes involved in inflammation. Module maps of differentially expressed genes revealed that modulated genes: i) exhibited transcription profiles typical of macrophage and dendritic cells; ii) had been previously associated with diabetic complications by association and by meta-analysis studies, and iii) were influenced by disease duration, obesity, number of gestations, glucose serum levels and the use of medications, such as metformin. CONCLUSION: This is the first module map study to show the influence of epidemiological, clinical, laboratory, immunopathogenic and treatment features on the transcription profiles of T1D, T2D and GDM patients.

A genome-wide assessment of the role of untagged copy number variants in type 1 diabetes.

Genome-wide association studies (GWAS) for type 1 diabetes (T1D) have successfully identified more than 40 independent T1D associated tagging single nucleotide polymorphisms (SNPs). However, owing to technical limitations of copy number variants (CNVs) genotyping assays, the assessment of the role of CNVs has been limited to the subset of these in high linkage disequilibrium with tag SNPs. The contribution of untagged CNVs, often multi-allelic and difficult to genotype using existing assays, to the heritability of T1D remains an open question. To investigate this issue, we designed a custom comparative genetic hybridization array (aCGH) specifically designed to assay untagged CNV loci identified from a variety of sources. To overcome the technical limitations of the case control design for this class of CNVs, we genotyped the Type 1 Diabetes Genetics Consortium (T1DGC) family resource (representing 3,903 transmissions from parents to affected offspring) and used an association testing strategy that does not necessitate obtaining discrete genotypes. Our design targeted 4,309 CNVs, of which 3,410 passed stringent quality control filters. As a positive control, the scan confirmed the known T1D association at the INS locus by direct typing of the 5' variable number of tandem repeat (VNTR) locus. Our results clarify the fact that the disease association is indistinguishable from the two main polymorphic allele classes of the INS VNTR, class I-and class III. We also identified novel technical artifacts resulting into spurious associations at the somatically rearranging loci, T cell receptor, TCRA/TCRD and TCRB, and Immunoglobulin heavy chain, IGH, loci on chromosomes 14q11.2, 7q34 and 14q32.33, respectively. However, our data did not identify novel T1D loci. Our results do not support a major role of untagged CNVs in T1D heritability.

Longitudinal assessment of neuropathy in type 1 diabetes using novel ophthalmic markers (LANDMark): study design and baseline characteristics.

AIMS: Corneal nerve morphology and corneal sensation threshold have recently been explored as potential surrogate markers for the evaluation of diabetic neuropathy. We present the baseline findings of the 'Longitudinal Assessment of Neuropathy in type 1 Diabetes using novel ophthalmic Markers'(LANDMark) study. METHODS: The LANDMark study is a 4-year, two-site, natural history study of three participant groups: type 1 diabetes with neuropathy (T1W), type 1 diabetes without neuropathy (T1WO) and control participants without diabetes or neuropathy. All participants undergo a detailed annual assessment of neuropathy including corneal nerve parameters measured using corneal confocal microscopy and corneal sensitivity measured using non-contact corneal aesthesiometry. RESULTS: 76 T1W, 166 T1WO and 154 control participants were enrolled into the study. Corneal sensation threshold was significantly higher (i.e., sensitivity was lower) in T1W (1.0±1.1mbars) than T1WO (0.7±0.7mbars) and controls (0.6±0.4mbars) (p<0.001), with no difference between T1WO and controls. Corneal nerve fibre length was lower in T1W (14.0±6.4mm/mm(2)) compared to T1WO (19.1±5.8mm/mm(2)) and controls (23.2±6.3mm/mm(2)) (p<0.001). Corneal nerve fibre length was lower in T1WO compared to controls. CONCLUSIONS: The LANDMark baseline findings confirm a reduction in corneal sensitivity only in Type 1 patients with neuropathy. However, corneal nerve fibre length is reduced in Type 1 patients without neuropathy with an even greater deficit in Type 1 patients with neuropathy.