Medical and forensic aspects of performing a remote interrogation of persons with disabilities / Aspectos médicos y forenses de la realización de un interrogatorio a distancia a personas con discapacidad / Aspectos médicos e forenses da realização de um interrogatório remoto de pessoas com deficiências

The purpose of the study is to develop new proposals for improving criminal procedural legislation in the field of conducting remote investigative actions with disabled persons, taking into account their physiological and functional characteristics. Research material and methods: This study is based on an analysis of the norms regarding the criminal procedural legislation of the Republic of Kazakhstan and a number of foreign states that regulate the procedure for conducting remote investigative actions - as well as scientific publications on the research topic in the field of psychology and medicine. An integrated approach involves considering the studied phenomena of communication during an investigative action as a set of interconnected and interdependent elements, i.e., consideration of the issue from the medical, psychological and legal points of view. Situational and systemic types of analysis, complex sociological analysis, diagnostics and forecasting investigative situation were also used. Methods of analysis and synthesis, induction, deduction, methods of qualitative and quantitative analysis were employed to clarify the legal essence of the studied phenomenon. Findings: practical recommendations aimed at improving and developing the performance of remote investigative actions involving persons with disabilities (further ­ FWDs) y creating optimal conditions for the transfer of verbal, medical, and psychological information, as well as technical and forensic support for conducting RIAs. The following conclusions were made: in order to improve the current legislation, it is advisable to consider the issue of developing and including a special norm in the legislation, taking into account the characteristics of the communicative competencies of persons with disabilities. This norm regulates the procedure for conducting investigative actions involving the mute, deaf, blind and other persons with disabilities.

El objetivo del estudio es elaborar nuevas propuestas de mejora de la legislación procesal penal en el ámbito de la realización de actuaciones de investigación a distancia con personas con discapacidad, teniendo en cuenta sus características fisiológicas y funcionales. Material y métodos de investigación: Este estudio se basa en un análisis de las normas relativas a la legislación procesal penal de la República de Kazajstán y de una serie de Estados extranjeros que regulan el procedimiento para llevar a cabo acciones de investigación a distancia -, así como publicaciones científicas sobre el tema de investigación en el campo de la psicología y la medicina. Un enfoque integrado implica considerar los fenómenos estudiados de comunicación durante una acción de investigación como un conjunto de elementos interconectados e interdependientes, es decir, considerar la cuestión desde los puntos de vista médico, psicológico y jurídico. También se utilizaron los tipos de análisis situacional y sistémico, el análisis sociológico complejo, el diagnóstico y la previsión de la situación de investigación. Se emplearon métodos de análisis y síntesis, inducción, deducción, métodos de análisis cualitativo y cuantitativo para aclarar la esencia jurídica del fenómeno estudiado. Conclusiones: recomendaciones prácticas destinadas a mejorar y desarrollar la realización de acciones de investigación a distancia en las que participen personas con discapacidad (en adelante - RIA) y crear condiciones óptimas para la transferencia de información verbal, médica y psicológica, así como apoyo técnico y forense para la realización de las RIA. Se llegó a las siguientes conclusiones:con el fin de mejorar la legislación actual, es aconsejable considerar la cuestión de desarrollar e incluir una norma especial en la legislación, teniendo en cuenta las características de las competencias comunicativas de las personas con discapacidad. Esta norma regula el procedimiento para llevar a cabo acciones de investigación en las que estén implicadas personas mudas, sordas, ciegas y otras personas con discapacidad.

O objetivo do estudo é desenvolver novas propostas para aprimorar a legislação processual penal no campo da realização de ações investigativas remotas com pessoas com deficiência, levando em conta suas características fisiológicas e funcionais. Material e métodos de pesquisa: Este estudo baseia-se em uma análise das normas relativas à legislação processual penal da República do Cazaquistão e de vários países estrangeiros que regulamentam o procedimento para a realização de ações investigativas remotas, bem como em publicações científicas sobre o tópico de pesquisa no campo da psicologia e da medicina. Uma abordagem integrada envolve a consideração dos fenômenos estudados de comunicação durante uma ação investigativa como um conjunto de elementos interconectados e interdependentes, ou seja, a consideração da questão dos pontos de vista médico, psicológico e jurídico. Também foram usados tipos de análise situacional e sistêmica, análise sociológica complexa, diagnóstico e previsão da situação investigativa. Métodos de análise e síntese, indução, dedução, métodos de análise qualitativa e quantitativa foram empregados para esclarecer a essência legal do fenômeno estudado. Resultados: recomendações práticas com o objetivo de aprimorar e desenvolver o desempenho de ações investigativas remotas envolvendo pessoas com deficiência (mais adiante - FWDs), criando condições ideais para a transferência de informações verbais, médicas e psicológicas, bem como suporte técnico e forense para a realização de RIAs. Foram feitas as seguintes conclusões: para aprimorar a legislação atual, é aconselhável considerar a questão do desenvolvimento e da inclusão de uma norma especial na legislação, levando em conta as características das competências comunicativas das pessoas com deficiência. Essa norma regulamenta o procedimento para conduzir ações investigativas envolvendo pessoas mudas, surdas, cegas e outras pessoas com deficiência.

Genetics of diabetes-associated microvascular complications.

Diabetes is associated with excess morbidity and mortality due to both micro- and macrovascular complications, as well as a range of non-classical comorbidities. Diabetes-associated microvascular complications are those considered most closely related to hyperglycaemia in a causal manner. However, some individuals with hyperglycaemia (even those with severe hyperglycaemia) do not develop microvascular diseases, which, together with evidence of co-occurrence of microvascular diseases in families, suggests a role for genetics. While genome-wide association studies (GWASs) produced firm evidence of multiple genetic variants underlying differential susceptibility to type 1 and type 2 diabetes, genetic determinants of microvascular complications are mostly suggestive. Identified susceptibility variants of diabetic kidney disease (DKD) in type 2 diabetes mirror variants underlying chronic kidney disease (CKD) in individuals without diabetes. As for retinopathy and neuropathy, reported risk variants currently lack large-scale replication. The reported associations between type 2 diabetes risk variants and microvascular complications may be explained by hyperglycaemia. More extensive phenotyping, along with adjustments for unmeasured confounding, including both early (fetal) and late-life (hyperglycaemia, hypertension, etc.) environmental factors, are urgently needed to understand the genetics of microvascular complications. Finally, genetic variants associated with reduced glycolysis, mitochondrial dysfunction and DNA damage and sustained cell regeneration may protect against microvascular complications, illustrating the utility of studies in individuals who have escaped these complications.

Neuronal Dysfunction Is Linked to the Famine-Associated Risk of Proliferative Retinopathy in Patients With Type 2 Diabetes.

Persons with type 2 diabetes born in the regions of famine exposures have disproportionally elevated risk of vision-threatening proliferative diabetic retinopathy (PDR) in adulthood. However, the underlying mechanisms are not known. In the present study, we aimed to investigate the plausible molecular factors underlying progression to PDR. To study the association of genetic variants with PDR under the intrauterine famine exposure, we analyzed single nucleotide polymorphisms (SNPs) that were previously reported to be associated with type 2 diabetes, glucose, and pharmacogenetics. Analyses were performed in the population from northern Ukraine with a history of exposure to the Great Ukrainian Holodomor famine [the Diagnostic Optimization and Treatment of Diabetes and its Complications in the Chernihiv Region (DOLCE study), n = 3,583]. A validation of the top genetic findings was performed in the Hong Kong diabetes registry (HKDR, n = 730) with a history of famine as a consequence of the Japanese invasion during WWII. In DOLCE, the genetic risk for PDR was elevated for the variants in ADRA2A, PCSK9, and CYP2C19*2 loci, but reduced at PROX1 locus. The association of ADRA2A loci with the risk of advanced diabetic retinopathy in famine-exposed group was further replicated in HKDR. The exposure of embryonic retinal cells to starvation for glucose, mimicking the perinatal exposure to famine, resulted in sustained increased expression of Adra2a and Pcsk9, but decreased Prox1. The exposure to starvation exhibited a lasting inhibitory effects on neurite outgrowth, as determined by neurite length. In conclusion, a consistent genetic findings on the famine-linked risk of ADRA2A with PDR indicate that the nerves may likely to be responsible for communicating the effects of perinatal exposure to famine on the elevated risk of advanced stages of diabetic retinopathy in adults. These results suggest the possibility of utilizing neuroprotective drugs for the prevention and treatment of PDR.

Impaired activation of STAT5 upon IL-2 stimulation in Tregs and elevated sIL-2R in Sjögren's syndrome.

BACKGROUND: Interleukin-2 (IL-2) and the high-affinity IL-2 receptor (IL-2R) are essential for the survival of regulatory T cells (Tregs) which are the main players in immune tolerance and prevention of autoimmune diseases. Sjögren's syndrome (SS) is a chronic autoimmune disease predominantly affecting women and is characterised by sicca symptoms including oral and ocular dryness. The aim of this study was to investigate an association between IL-2R and Treg function in patients with SS of different severity defined by the salivary flow rate. METHODS: In a cross-sectional study, we determined plasma soluble IL-2R (sIL-2R) levels in women with SS (n=97) and healthy females (n=50) using ELISA. A subset of those (n=51) was screened for Treg function measured by the STAT5 signalling response to IL-2 using phospho-flow cytometry. RESULTS: We found that elevated plasma levels of sIL-2R were positively associated with the severity of SS reflected by a pathologically low salivary flow. Phospho-flow analysis revealed that patients with SS have a significantly lower frequency of pSTAT5+ Tregs upon IL-2 stimulation compared with healthy individuals, while the frequency of Tregs and pSTAT5 in conventional T cells remained unchanged. In addition, we observed more pSTAT5+ Tregs at baseline in patients with SS, which is significantly associated with seropositivity and elevated sIL-2R. CONCLUSIONS: Our data indicates that Tregs have a weakened immunosuppressive function in patients with SS due to impaired IL-2/IL-2R signalling capacity. This could mediate lymphocytic infiltration into salivary glands inducing sicca symptoms. We believe that sIL-2R could act as a useful indicator for SS and disease severity.

Spatial Environment Affects HNF4A Mutation-Specific Proteome Signatures and Cellular Morphology in hiPSC-Derived ß-Like Cells.

Studies of monogenic diabetes are particularly useful because we can gain insight into the molecular events of pancreatic ß-cell failure. Maturity-onset diabetes of the young 1 (MODY1) is a form of monogenic diabetes caused by a mutation in the HNF4A gene. Human-induced pluripotent stem cells (hiPSCs) provide an excellent tool for disease modeling by subsequently directing differentiation toward desired pancreatic islet cells, but cellular phenotypes in terminally differentiated cells are notoriously difficult to detect. Re-creating a spatial (three-dimensional [3D]) environment may facilitate phenotype detection. We studied MODY1 by using hiPSC-derived pancreatic ß-like patient and isogenic control cell lines in two different 3D contexts. Using size-adjusted cell aggregates and alginate capsules, we show that the 3D context is critical to facilitating the detection of mutation-specific phenotypes. In 3D cell aggregates, we identified irregular cell clusters and lower levels of structural proteins by proteome analysis, whereas in 3D alginate capsules, we identified altered levels of glycolytic proteins in the glucose sensing apparatus by proteome analysis. Our study provides novel knowledge on normal and abnormal function of HNF4A, paving the way for translational studies of new drug targets that can be used in precision diabetes medicine in MODY.

Perinatal famine is associated with excess risk of proliferative retinopathy in patients with type 2 diabetes.

PURPOSE: Intrauterine undernutrition is associated with increased risk of type 2 diabetes. Children born premature or small for gestational age were reported to have abnormal retinal vascularization. However, whether intrauterine famine act as a trigger for diabetes complications, including retinopathy, is unknown. The aim of the current study was to evaluate long-term effects of perinatal famine on the risk of proliferative diabetic retinopathy (PDR). METHODS: We studied the risk for PDR among type 2 diabetes patients exposed to perinatal famine in two independent cohorts: the Ukrainian National Diabetes Registry (UNDR) and the Hong Kong Diabetes Registry (HKDR). We analysed individuals born during the Great Famine (the Holodomor, 1932-1933) and the WWII (1941-1945) famine in 101 095 (3601 had PDR) UNDR participants. Among 3021 (251 had PDR) HKDR participants, we studied type 2 diabetes patients exposed to perinatal famine during the WWII Japanese invasion in 1942-1945. RESULTS: During the Holodomor and WWII, perinatal famine was associated with a 1.76-fold (p = 0.019) and 3.02-fold (p = 0.001) increased risk of severe PDR in the UNDR. The risk for PDR was 1.66-fold elevated among individuals born in 1942 in the HKDR (p < 0.05). The associations between perinatal famine and PDR remained statistically significant after corrections for HbA1c in available 18 507 UNDR (padditive interaction < 0.001) and in 3021 HKDR type 2 diabetes patients (p < 0.05). CONCLUSION: In conclusion, type 2 diabetes patients, exposed to perinatal famine, have increased risk of PDR compared to those without perinatal famine exposure. Further studies are needed to understand the underlying mechanisms and to extend this finding to other diabetes complications.

Starvation to Glucose Reprograms Development of Neurovascular Unit in Embryonic Retinal Cells.

Perinatal exposure to starvation is a risk factor for development of severe retinopathy in adult patients with diabetes. However, the underlying mechanisms are not completely understood. In the present study, we shed light on molecular consequences of exposure to short-time glucose starvation on the transcriptome profile of mouse embryonic retinal cells. We found a profound downregulation of genes regulating development of retinal neurons, which was accompanied by reduced expression of genes encoding for glycolytic enzymes and glutamatergic signaling. At the same time, glial and vascular markers were upregulated, mimicking the diabetes-associated increase of angiogenesis-a hallmark of pathogenic features in diabetic retinopathy. Energy deprivation as a consequence of starvation to glucose seems to be compensated by upregulation of genes involved in fatty acid elongation. Results from the present study demonstrate that short-term glucose deprivation during early fetal life differentially alters expression of metabolism- and function-related genes and could have detrimental and lasting effects on gene expression in the retinal neurons, glial cells, and vascular elements and thus potentially disrupting gene regulatory networks essential for the formation of the retinal neurovascular unit. Abnormal developmental programming during retinogenesis may serve as a trigger of reactive gliosis, accelerated neurodegeneration, and increased vascularization, which may promote development of severe retinopathy in patients with diabetes later in life.

Reduced expression of OXPHOS and DNA damage genes is linked to protection from microvascular complications in long-term type 1 diabetes: the PROLONG study.

Type 1 diabetes is a chronic autoimmune disease requiring insulin treatment for survival. Prolonged duration of type 1 diabetes is associated with increased risk of microvascular complications. Although chronic hyperglycemia and diabetes duration have been considered as the major risk factors for vascular complications, this is not universally seen among all patients. Persons with long-term type 1 diabetes who have remained largely free from vascular complications constitute an ideal group for investigation of natural defense mechanisms against prolonged exposure of diabetes. Transcriptomic signatures obtained from RNA sequencing of the peripheral blood cells were analyzed in non-progressors with more than 30 years of diabetes duration and compared to the patients who progressed to microvascular complications within a shorter duration of diabetes. Analyses revealed that non-progressors demonstrated a reduction in expression of the oxidative phosphorylation (OXPHOS) genes, which were positively correlated with the expression of DNA repair enzymes, namely genes involved in base excision repair (BER) machinery. Reduced expression of OXPHOS and BER genes was linked to decrease in expression of inflammation-related genes, higher glucose disposal rate and reduced measures of hepatic fatty liver. Results from the present study indicate that at transcriptomic level reduction in OXPHOS, DNA repair and inflammation-related genes is linked to better insulin sensitivity and protection against microvascular complications in persons with long-term type 1 diabetes.

Distinct Molecular Signatures of Clinical Clusters in People With Type 2 Diabetes: An IMI-RHAPSODY Study.

Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity, investigators of a previous study clustered people with diabetes according to five diabetes subtypes. The aim of the current study is to investigate the etiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic (N = 12,828), metabolomic (N = 2,945), lipidomic (N = 2,593), and proteomic (N = 1,170) data were obtained in plasma. For each data type, each cluster was compared with the other four clusters as the reference. The insulin-resistant cluster showed the most distinct molecular signature, with higher branched-chain amino acid, diacylglycerol, and triacylglycerol levels and aberrant protein levels in plasma were enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher levels of cytokines. The mild diabetes cluster with high HDL showed the most beneficial molecular profile with effects opposite of those seen in the insulin-resistant cluster. This study shows that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease.

Novel Reclassification of Adult Diabetes Is Useful to Distinguish Stages of ß-Cell Function Linked to the Risk of Vascular Complications: The DOLCE Study From Northern Ukraine.

BACKGROUND: Presently, persons with diabetes are classified as having type 1 (T1D) or type 2 diabetes (T2D) based on clinical diagnosis. However, adult patients exhibit diverse clinical representations and this makes treatment approaches challenging to personalize. A recent Scandinavian study proposed a novel classification of adult diabetes into five clusters based on disease pathophysiology and risk of vascular complications. The current study aimed to characterize new subgroups of adult diabetes using this strategy in a defined population from northern Ukraine. METHODS: We analyzed 2,140 patients with established diabetes from the DOLCE study (n = 887 with new-onset diabetes and n = 1,253 with long duration). We used the k-means approach to perform clustering analyses using BMI, age at onset of diabetes, HbA1c, insulin secretion (HOMA2-B), and insulin resistance (HOMA2-IR) indices and glutamic acid decarboxylase antibodies (GADA) levels. Risks of macro- (myocardial infarction or stroke) and microvascular [retinopathy, chronic kidney disease (CKD) and neuropathy] complications and associations of genetic variants with specific clusters were studied using logistic regression adjusted for age, sex, and diabetes duration. RESULTS: Severe autoimmune diabetes (SAID, 11 and 6%) and severe insulin-deficient diabetes (SIDD, 25 and 14%) clusters were twice as prevalent in patients with long-term as compared to those with new-onset diabetes. Patients with long duration in both SAID and SIDD clusters had highest risks of proliferative retinopathy, and elevated risks of CKD. Long-term insulin-resistant obese diabetes 1 (IROD1) subgroup had elevated risks of CKD, while insulin-resistant obese diabetes 2 (IROD2) cluster exhibited the highest HOMA2-B, lowest HbA1c, and lower prevalence of all microvascular complications as compared to all other clusters. Genetic analyses of IROD2 subgroup identified reduced frequency of the risk alleles in the TCF7L2 gene as compared to all other clusters, cumulatively and individually (p = 0.0001). CONCLUSION: The novel reclassification algorithm of patients with adult diabetes was reproducible in this population from northern Ukraine. It may be beneficial for the patients in the SIDD subgroup to initiate earlier insulin treatment or other anti-diabetic modalities to preserve ß-cell function. Long-term diabetes cases with preserved ß-cell function and lower risk for microvascular complications represent an interesting subgroup of patients for further investigations of protective mechanisms.

Replication and cross-validation of type 2 diabetes subtypes based on clinical variables: an IMI-RHAPSODY study.

AIMS/HYPOTHESIS: Five clusters based on clinical characteristics have been suggested as diabetes subtypes: one autoimmune and four subtypes of type 2 diabetes. In the current study we replicate and cross-validate these type 2 diabetes clusters in three large cohorts using variables readily measured in the clinic. METHODS: In three independent cohorts, in total 15,940 individuals were clustered based on age, BMI, HbA1c, random or fasting C-peptide, and HDL-cholesterol. Clusters were cross-validated against the original clusters based on HOMA measures. In addition, between cohorts, clusters were cross-validated by re-assigning people based on each cohort's cluster centres. Finally, we compared the time to insulin requirement for each cluster. RESULTS: Five distinct type 2 diabetes clusters were identified and mapped back to the original four All New Diabetics in Scania (ANDIS) clusters. Using C-peptide and HDL-cholesterol instead of HOMA2-B and HOMA2-IR, three of the clusters mapped with high sensitivity (80.6-90.7%) to the previously identified severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD) and mild obesity-related diabetes (MOD) clusters. The previously described ANDIS mild age-related diabetes (MARD) cluster could be mapped to the two milder groups in our study: one characterised by high HDL-cholesterol (mild diabetes with high HDL-cholesterol [MDH] cluster), and the other not having any extreme characteristic (mild diabetes [MD]). When these two milder groups were combined, they mapped well to the previously labelled MARD cluster (sensitivity 79.1%). In the cross-validation between cohorts, particularly the SIDD and MDH clusters cross-validated well, with sensitivities ranging from 73.3% to 97.1%. SIRD and MD showed a lower sensitivity, ranging from 36.1% to 92.3%, where individuals shifted from SIRD to MD and vice versa. People belonging to the SIDD cluster showed the fastest progression towards insulin requirement, while the MDH cluster showed the slowest progression. CONCLUSIONS/INTERPRETATION: Clusters based on C-peptide instead of HOMA2 measures resemble those based on HOMA2 measures, especially for SIDD, SIRD and MOD. By adding HDL-cholesterol, the MARD cluster based upon HOMA2 measures resulted in the current clustering into two clusters, with one cluster having high HDL levels. Cross-validation between cohorts showed generally a good resemblance between cohorts. Together, our results show that the clustering based on clinical variables readily measured in the clinic (age, HbA1c, HDL-cholesterol, BMI and C-peptide) results in informative clusters that are representative of the original ANDIS clusters and stable across cohorts. Adding HDL-cholesterol to the clustering resulted in the identification of a cluster with very slow glycaemic deterioration.

Increased Plasma Soluble Interleukin-2 Receptor Alpha Levels in Patients With Long-Term Type 1 Diabetes With Vascular Complications Associated With IL2RA and PTPN2 Gene Polymorphisms.

Type 1 diabetes (T1D) is largely considered an autoimmune disease leading to the destruction of insulin-producing pancreatic ß cells. Further, patients with T1D have 3-4-fold increased risk of developing micro- and macrovascular complications. However, the contribution of immune-related factors contributing to these diabetes complications are poorly understood. Individuals with long-term T1D who do not progress to vascular complications offer a great potential to evaluate end-organ protection. The aim of the present study was to investigate the association of inflammatory protein levels with vascular complications (retinopathy, nephropathy, cardiovascular disease) in individuals with long-term T1D compared to individuals who rapidly progressed to complications. We studied a panel of inflammatory markers in plasma of patients with long-term T1D with (n = 81 and 26) and without (n = 313 and 25) vascular complications from two cross-sectional Scandinavian cohorts (PROLONG and DIALONG) using Luminex technology. A subset of PROLONG individuals (n = 61) was screened for circulating immune cells using multicolor flow cytometry. We found that elevated plasma levels of soluble interleukin-2 receptor alpha (sIL-2R) were positively associated with the complication phenotype. Risk carriers of polymorphisms in the IL2RA and PTPN2 gene region had elevated plasma levels of sIL-2R. In addition, cell surface marker analysis revealed a shift from naïve to effector T cells in T1D individuals with vascular complications as compared to those without. In contrast, no difference between the groups was observed either in IL-2R cell surface expression or in regulatory T cell population size. In conclusion, our data indicates that IL2RA and PTPN2 gene variants might increase the risk of developing vascular complications in people with T1D, by affecting sIL-2R plasma levels and potentially lowering T cell responsiveness. Thus, elevated sIL-2R plasma levels may serve as a biomarker in monitoring the risk for developing diabetic complications and thereby improve patient care.

Liver nucleotide biosynthesis is linked to protection from vascular complications in individuals with long-term type 1 diabetes.

Identification of biomarkers associated with protection from developing diabetic complications is a prerequisite for an effective prevention and treatment. The aim of the present study was to identify clinical and plasma metabolite markers associated with freedom from vascular complications in people with very long duration of type 1 diabetes (T1D). Individuals with T1D, who despite having longer than 30 years of diabetes duration never developed major macro- or microvascular complications (non-progressors; NP) were compared with those who developed vascular complications within 25 years from diabetes onset (rapid progressors; RP) in the Scandinavian PROLONG (n = 385) and DIALONG (n = 71) cohorts. The DIALONG study also included 75 healthy controls. Plasma metabolites were measured using gas and/or liquid chromatography coupled to mass spectrometry. Lower hepatic fatty liver indices were significant common feature characterized NPs in both studies. Higher insulin sensitivity and residual ß-cell function (C-peptide) were also associated with NPs in PROLONG. Protection from diabetic complications was associated with lower levels of the glycolytic metabolite pyruvate and APOCIII in PROLONG, and with lower levels of thiamine monophosphate and erythritol, a cofactor and intermediate product in the pentose phosphate pathway as well as higher phenylalanine, glycine and serine in DIALONG. Furthermore, T1D individuals showed elevated levels of picolinic acid as compared to the healthy individuals. The present findings suggest a potential beneficial shunting of glycolytic substrates towards the pentose phosphate and one carbon metabolism pathways to promote nucleotide biosynthesis in the liver. These processes might be linked to higher insulin sensitivity and lower liver fat content, and might represent a mechanism for protection from vascular complications in individuals with long-term T1D.

A diabetes-associated genetic variant is associated with diastolic dysfunction and cardiovascular disease.

AIMS: Although the epidemiological association between Type 2 diabetes and congestive heart failure (CHF) as well as cardiovascular disease (CVD) is well established, associations between diabetes-related single-nucleotide polymorphisms (SNPs), CHF, and CVD have been surprisingly inconclusive. Our aim is to examine if 43 diabetes-related SNPs were associated with prevalent diastolic dysfunction assessed by echocardiography and incident CVD and/or CHF. METHODS AND RESULTS: We genotyped 43 SNPs that previously reported genome-wide significant associations with Type 2 diabetes, in 1444 subjects from the population-based Malmö Preventive Project-Re-examination Study (MPP-RES) (mean age 68 years; 29% women, 36% prevalent diabetes) (discovery cohort) and in 996 subjects from the VARA cohort (mean age 51 years, 52% women, 7% prevalent diabetes) (replication cohort). Multivariable logistic regression was assessed. Genetic variants that reached significant association with diastolic dysfunction in both cohorts were then analysed for association with incident CVD/CHF in a larger sample of the MPP-RES cohort (3,407 cases and 11,776 controls, median follow up >30 years) using Cox regression analysis. A common variant at the HNF1B [major allele (T) coded, also the risk allele for diabetes] was the only SNP associated with increased risk of prevalent diastolic dysfunction in both the discovery [MPP-RES; odds ratio (OR) 1.21, P = 0.024), and the replication cohort (VARA; OR 1.38, P = 0.042]. Cox regression analysis showed that carriers of the T-allele of rs757210 had an increased risk of future CVD (HR 1.05, P = 0.042). No significant association was seen for incident CHF. CONCLUSIONS: The diabetes susceptibility locus HNF1B is associated with prevalent diastolic dysfunction in two independent Swedish cohorts as well as incident cardiovascular disease.

Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.

Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control.

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value <1 × 10-5 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like (NVL) was associated with DR in European discovery cohorts (P = 2.1 × 10-9), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity (P = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in NVL, as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.

A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes.

PURPOSE: Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy. METHODS: A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant Single Nucleotide Polymorphisms (SNPs) were taken forward for meta-analysis using multiple Caucasian cohorts. RESULTS: Five hundred and sixty cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 4.05 × 10-9 . Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values = 7.41 × 10-8 and 1.23 × 10-8 , respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (p = 0.003 and 0.007, respectively), while the p value of rs3913535 was not significant (p = 0.429). CONCLUSION: This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.

Sense of Coherence is associated with LDL-cholesterol in patients with type 1 diabetes - The PROLONG-Steno study.

AIM: It is a constant challenge for people with type 1 diabetes to maintain appropriate levels of HbA1c, blood pressure and blood lipids in order to prevent or delay deleterious effects of their illness. This study sought to investigate if Sense of Coherence (SOC) is associated with clinical risk factors in people with type 1 diabetes. METHODS: Questionnaire data, including measure of SOC, was collected from 125 patients with long duration of type 1 diabetes and linked to electronic patient records to obtain clinical measures on HbA1c, blood pressure, and blood lipids. Linear regressions and generalized additive models were applied to explore the associations between SOC and clinical biomarkers. RESULTS: Mean age of the participants was 60.7 years (standard deviation = 10.0), 44.0% were men. Medium and high SOC were associated with lower levels of LDL-cholesterol (p = 0.005). This association was non-linear with medium and high levels of SOC being advantageous whereas low SOC was associated with elevated levels of LDL-cholesterol. Moreover, we observed non-significant tendencies to associations between low SOC and low HDL-cholesterol, and elevated HbA1c. CONCLUSIONS: Findings from this study suggest that high SOC may be protective against elevated LDL-cholesterol among people with type 1 diabetes. Interventions to improve self-management among people with low SOC may prove effective to prevent deterioration of metabolic risk factors.

The Genetic Landscape of Renal Complications in Type 1 Diabetes.

Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4×10-3). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2×10-5) and the risk of type 2 diabetes (P=6.1×10-4) associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1×10-4). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0×10-6), and pentose and glucuronate interconversions (P=3.0×10-6) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.