Development of Type 1 Diabetes may occur through a Type 2 Diabetes mechanism

BackgroundAt diagnosis of Type 1 Diabetes (T1D), 30% of the beta cells are dormant, i.e. alive, but inactive. This could reduce beta cell destruction, as cellular stress contributes to beta cell damage. However, the beta cells, that are still active, must produce more insulin and are therefore more vulnerable. The inactive beta cells represent a potential for restoring the insulin secretion.MethodsWe analyzed the expression of selected genes in islets from live, newly diagnosed T1D patients from the DiViD study and organ doners with longer duration of T1D, type 2 diabetes (T2D), or no diabetes from the nPOD study. Additionally, analysis of polymorphisms was performed on all the investigated genes.FindingsVarious possibilities were considered for the inactivity of the beta cells: secretion defect, fetal state, hibernation, and insulin resistance. We analyzed genes related to the ceramide and sphingomyelin synthesis and degradation, secretion, circadian rhythm and insulin action, and found changes in T1D islets that resemble fetal dedifferentiation and asynchrony. Furthermore, we found low levels of insulin receptor mRNA in the islets. No polymorphisms were found.InterpretationOur findings suggest a secretion defect, but also fetal dedifferentiation and desynchronization in the inactive beta cells. Together with previous evidence, that predisposing factors for T2D are also present for T1D development, we raise the idea to treat individuals with ongoing T1D development prophylactically with T2D medicine like GLP-1 receptor agonists, metformin, or others, combined with anti-inflammatory compounds, in order to reactivate the dormant beta cells, and to prevent autoimmune destruction. T2D mechanisms during T1D development should be investigated further

Reliability and validity of the Norwegian child and parent versions of the DISABKIDS Chronic Generic Module (DCGM-37) and Diabetes-Specific Module (DSM-10)

<p>Abstract</p> <p>Background</p> <p>International guidelines on type 1 diabetes advocate routine screening of health-related quality of life (HRQOL). DISABKIDS questionnaires are the first instruments developed across cultures and nations to provide age-appropriate measures of HRQOL in children with chronic diseases. DISABKIDS includes a Chronic Generic Module 37 (DCGM-37) and disease-specific modules. The purpose of this study was to examine reliability and validity of the Norwegian versions of the DISABKIDS questionnaires in children and adolescents with type 1 diabetes.</p> <p>Methods</p> <p>The DCGM-37 and the Diabetes Specific Module-10 (DDM-10) were translated into Norwegian using standard forward-backward translation. Eight to 19 year old children and adolescents with type 1 diabetes scheduled for routine follow-up at three diabetic clinics in Norway and one of their parents were invited to complete the DCGM-37 and the DDM-10. Internal consistency was determined using Cronbach's alpha. Results were compared with those of the Child Health Questionnaire Children Form-87 (CHQ-CF87) and Child Health Questionnaire Parent Form-50 which are established generic questionnaires. DISABKIDS results were related to age, gender, duration of diabetes, mode of insulin delivery and metabolic control. Clinical data were obtained from the Norwegian Childhood Diabetes Registry.</p> <p>Results</p> <p>Of 198 eligible child-parent dyads, 103 (52%) completed the questionnaires. Mean age was 13.6 (2.6), range 8-19 yrs, 52% were boys. Cronbach's alpha was > 0.70 for all the DISABKIDS sub-scales except two (physical ability and social inclusion). There were moderate to high correlations (0.65-0.81) between the DISABKIDS scales and mental/emotional sub-scales of CHQ-CF87. Increasing age and higher HbA1c were significantly associated with reduced HRQOL scores. Parents tended to score their child's HRQOL lower than the children/adolescents themselves.</p> <p>Conclusions</p> <p>The study shows that the DISABKIDS instruments are applicable to a Norwegian childhood diabetes population. They seem to be a relevant supplement to other clinical indicators in medical practice and research.</p

Differential insulitic profiles determine the extent of beta cell destruction and the age at onset of type 1 diabetes

Published onlineJOURNAL ARTICLEType 1 diabetes (T1D) results from a T-cell mediated destruction of pancreatic beta cells following the infiltration of leukocytes (including CD8+, CD4+ and CD20+ cells) into and around pancreatic islets ("insulitis"). Recently, we reported that two distinct patterns of insulitis occur in patients with recent-onset T1D from the UK and that these differ principally in the proportion of infiltrating CD20+ B-cells (designated "CD20Hi" and "CD20Lo" respectively). We have now extended this analysis to include patients from the nPOD (USA) and DiViD (Norway) cohorts and confirm that the two profiles of insulitis occur more widely. Moreover, we show that patients can be directly stratified according to their insulitic profile and that those receiving a diagnosis before the age of 7 years always display the CD20Hi profile. By contrast, individuals diagnosed beyond the age of 13 years are uniformly defined as CD20Lo. This implies that the two forms of insulitis are differentially aggressive and that patients with a CD20Hi profile lose their beta cells at a more rapid rate. In support of this, we also find that the proportion of residual insulin-containing islets (ICIs) increases in parallel with age at onset of T1D. Importantly, those diagnosed in, or beyond, their teenage years retain ∼40% ICIs at diagnosis, implying that a functional deficit rather than absolute beta cell loss may be causal for disease onset in these patients. We conclude that appropriate patient stratification will be critical for correct interpretation of the outcomes of intervention therapies targeted to islet-infiltrating immune cells in T1D

Small- and large-fiber neuropathy after 40 years of type 1 diabetes associations with glycemic control and advanced protein glycation: the Oslo Study

OBJECTIVE To study large- and small-nerve fiber function in type 1 diabetes of long duration and associations with HbA1c and the advanced glycation end products (AGEs) N-&#949-(carboxymethyl)lysine (CML) and methylglyoxal-derived hydroimidazolone. RESEARCH DESIGN AND METHODS In a long-term follow-up study, 27 persons with type 1 diabetes of 40 &#177 3 years duration underwent large-nerve fiber examinations, with nerve conduction studies at baseline and years 8, 17, and 27. Small-fiber functions were assessed by quantitative sensory thresholds (QST) and intraepidermal nerve fiber density (IENFD) at year 27. HbA1cwas measured prospectively through 27 years. Serum CML was measured at year 17 by immunoassay. Serum hydroimidazolone was measured at year 27 with liquid chromatography– mass spectrometry. RESULTS Sixteen patients (59%) had large-fiber neuropathy. Twenty-two (81%) had smallfiber dysfunction by QST. Heat pain thresholds in the foot were associated with hydroimidazolone and HbA1c. IENFD was abnormal in 19 (70%) and significantly lower in diabetic patients than in age-matched control subjects (4.3 &#177 2.3 vs. 11.2 &#177 3.5 mm, P , 0.001). IENFD correlated negatively with HbA1c over 27 years (r = 20.4, P = 0.04) and CML (r = 20.5, P = 0.01). After adjustment for age, height, and BMI in a multiple linear regression model, CML was still independently associated with IENFD. CONCLUSIONS Small-fiber sensory neuropathy is a major manifestation in type 1 diabetes of 40 years duration and more prevalent than large-fiber neuropathy. HbA1c and the AGEs CML and hydroimidazolone are important risk factors in the development of large- and small-fiber dysfunction in long-term type 1 diabetes

DNA glycosylase Neil3 regulates vascular smooth muscle cell biology during atherosclerosis development.

BACKGROUND AND AIMS: Atherogenesis involves a complex interaction between immune cells and lipids, processes greatly influenced by the vascular smooth muscle cell (VSMC) phenotype. The DNA glycosylase NEIL3 has previously been shown to have a role in atherogenesis, though whether this is due to its ability to repair DNA damage or to other non-canonical functions is not yet clear. Hereby, we investigate the role of NEIL3 in atherogenesis, specifically in VSMC phenotypic modulation, which is critical in plaque formation and stability. METHODS: Chow diet-fed atherosclerosis-prone Apoe-/- mice deficient in Neil3, and NEIL3-abrogated human primary aortic VSMCs were characterized by qPCR, and immunohistochemical and enzymatic-based assays; moreover, single-cell RNA sequencing, mRNA sequencing, and proteomics were used to map the molecular effects of Neil3/NEIL3 deficiency in the aortic VSMC phenotype. Furthermore, BrdU-based proliferation assays and Western blot were performed to elucidate the involvement of the Akt signaling pathway in the transdifferentiation of aortic VSMCs lacking Neil3/NEIL3. RESULTS: We show that Neil3 deficiency increases atherosclerotic plaque development without affecting systemic lipids. This observation was associated with a shift in VSMC phenotype towards a proliferating, lipid-accumulating and secretory macrophage-like cell phenotype, without changes in DNA damage. VSMC transdifferentiation in Neil3-deficient mice encompassed increased activity of the Akt signaling pathway, supported by cell experiments showing Akt-dependent proliferation in NEIL3-abrogated human primary aortic VSMCs. CONCLUSIONS: Our findings show that Neil3 deficiency promotes atherosclerosis development through non-canonical mechanisms affecting VSMC phenotype involving activation of the Akt signaling pathway

Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes

BACKGROUND. Neutrophils and their inflammatory mediators are key pathogenic components in multiple autoimmune diseases, while their role in human type 1 diabetes (T1D), a disease that progresses sequentially through identifiable stages prior to the clinical onset, is not well understood. We previously reported that the number of circulating neutrophils is reduced in patients with T1D and in presymptomatic at-risk subjects. The aim of the present work was to identify possible changes in circulating and pancreas-residing neutrophils throughout the disease course to better elucidate neutrophil involvement in human T1D. METHODS. Data collected from 389 subjects at risk of developing T1D, and enrolled in 4 distinct studies performed by TrialNet, were analyzed with comprehensive statistical approaches to determine whether the number of circulating neutrophils correlates with pancreas function. To obtain a broad analysis of pancreas-infiltrating neutrophils throughout all disease stages, pancreas sections collected worldwide from 4 different cohorts (i.e., nPOD, DiViD, Siena, and Exeter) were analyzed by immunohistochemistry and immunofluorescence. Finally, circulating neutrophils were purified from unrelated nondiabetic subjects and donors at various T1D stages and their transcriptomic signature was determined by RNA sequencing. RESULTS. Here, we show that the decline in β cell function is greatest in individuals with the lowest peripheral neutrophil numbers. Neutrophils infiltrate the pancreas prior to the onset of symptoms and they continue to do so as the disease progresses. Of interest, a fraction of these pancreasinfiltrating neutrophils also extrudes neutrophil extracellular traps (NETs), suggesting a tissue-specific pathogenic role. Whole-transcriptome analysis of purified blood neutrophils revealed a unique molecular signature that is distinguished by an overabundance of IFN-associated genes; despite being healthy, said signature is already present in T1D-autoantibody-negative at-risk subjects. CONCLUSIONS. These results reveal an unexpected abnormality in neutrophil disposition both in the circulation and in the pancreas of presymptomatic and symptomatic T1D subjects, implying that targeting neutrophils might represent a previously unrecognized therapeutic modality

Prevalence of disturbed eating behavior and associated symptoms of anxiety and depression among adult males and females with type 1 diabetes

Background The increased prevalence of disturbed eating behaviors (DEB), depression, and anxiety in type 1 diabetes (T1D) is generally well established; however the majority of existing research to date has focused on female adolescents and young adults. Data on males and older females is scarce. The aim of this study was to assess prevalence of DEB and symptoms of depression and anxiety among adult males and females with type 1 diabetes, to investigate differences between individuals scoring below and above the cut-off on psychopathology, and to examine patterns of eating disorder psychopathology by age and weight. Methods A total of 282 adults with type 1 diabetes aged 18–79 years participated in the study. Measures included the Diabetes Eating Problem Survey – Revised (DEPS-R), the Hospital Anxiety and Depression Scale (HADS), and clinical data from the Norwegian Quality Improvement of Laboratory Examinations (NOKLUS) system. Results A total of 20.3% of the whole sample (13.3% among males and 24.8% among females) scored above the DEPS-R cut-off score for DEB. As for depression and anxiety, the prevalence in the whole sample was 6.2% and 19.0%, respectively. The prevalence was generally higher in females than males across all psychopathology measures. HbA1c was significantly associated with the DEPS-R total score (p < .01) among females, but not with depression and anxiety. Mean DEPS-R score decreased with increasing age, and when our previous reported data from children and adolescents are included, a peak prevalence in DEB in adolescence and young adult age is demonstrated. Conclusions The results of this study point to the need for increased awareness of psychological comorbidity among adults with type 1 diabetes, in particular young adult females. Screening is recommended to secure early detection and subsequent intervention for these individuals

Early reduced myocardial diastolic function in children and adolescents with type 1 diabetes mellitus a population-based study

Background Reduced diastolic myocardial function is an early sign of diabetic cardiomyopathy. The aim of this study was to test the hypothesis that children and adolescents with type 1 diabetes mellitus (T1D), but without other known complications, have early reduced diastolic myocardial function diagnosed with echocardiographic color tissue Doppler imaging (cTDI). Methods cTDI examination was carried out in 173 T1D patients and 62 age-matched controls. The T1D-patients were 8–18 years old with (mean (SD)) diabetes duration of 5.6 (3.4) years and HbA1c of 8.4 (1.3). All were treated with either insulin pumps or 4–6 daily insulin injections. cTDI early (E’) and late (A’) peak diastolic velocities and systolic peak velocity were measured from the lateral, septal, anterior and posterior mitral annulus and from the lateral tricuspidal annulus. Results Myocardial diastolic function was reduced in the T1D-patients with higher peak A’-velocity and lower E’/A’-ratio in all registrations. Overall mean (SD) mitral E’/A’-ratio was 2.3 (0.5) in T1D and 2.7 (0.6) in the controls (p 75 centile, respectively), the T1D had lower E’/A’-values in all stratified groups, except for in the highest BMI-group where both T1D and controls had the lowest E’/A’-ratio. Systolic function did not differ in any of the measurements. There were no associations with sex, diabetes duration, carotid artery intima-media-thickness, vessel elasticity or HbA1c. Conclusion Diabetic children and adolescents using modern intensive insulin treatment had echocardiographic signs of reduced diastolic myocardial function despite short duration of disease. The reduced function was associated with higher BP and higher BMI