Management of Latent Autoimmune Diabetes in Adults : A Consensus Statement From an International Expert Panel

A substantial proportion of patients with adult-onset diabetes share features of both type 1 diabetes (T1D) and type 2 diabetes (T2D). These individuals, at diagnosis, clinically resemble T2D patients by not requiring insulin treatment, yet they have immunogenetic markers associated with T1D. Such a slowly evolving form of autoimmune diabetes, described as latent autoimmune diabetes of adults (LADA), accounts for 2-12% of all patients with adult-onset diabetes, though they show considerable variability according to their demographics and mode of ascertainment. While therapeutic strategies aim for metabolic control and preservation of residual insulin secretory capacity, endotype heterogeneity within LADA implies a personalized approach to treatment. Faced with a paucity of large-scale clinical trials in LADA, an expert panel reviewed data and delineated one therapeutic approach. Building on the 2020 American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus for T2D and heterogeneity within autoimmune diabetes, we propose "deviations" for LADA from those guidelines. Within LADA, C-peptide values, proxy for beta-cell function, drive therapeutic decisions. Three broad categories of random C-peptide levels were introduced by the panel:1) C-peptide levels 2) C-peptide values >= 0.3 and 0.7 nmol/L: suggests a modified ADA/EASD algorithm as for T2D but allowing for the potentially progressive nature of LADA by monitoring C-peptide to adjust treatment. The panel concluded by advising general screening for LADA in newly diagnosed non-insulin-requiring diabetes and, importantly, that large randomized clinical trials are warranted.Peer reviewe

Glycaemic Control in People with Type 2 Diabetes Mellitus Switching from Basal Insulin to Insulin Glargine 300 U/ml (Gla-300): Results from the REALI Pooled Database

INTRODUCTION: Using pooled data from the REALI European database, we evaluated the impact of previous basal insulin (BI) type on real-life effectiveness and safety of switching to insulin glargine 300 U/ml (Gla-300) in people with suboptimally controlled type 2 diabetes. METHODS: Patient-level data were pooled from 11 prospective, open-label, 24-week studies. Participants were classified according to the type of prior BI. Of the 4463 participants, 1282 (28.7%) were pre-treated with neutral protamine Hagedorn (NPH) insulin and 2899 (65.0%) with BI analogues (BIAs), and 282 (6.3%) had undetermined prior BI. RESULTS: There were no meaningful differences in baseline characteristics between subgroups, except for a higher prevalence of diabetic neuropathy in the NPH subgroup (21.6% versus 7.8% with BIAs). Mean ± standard deviation haemoglobin A1c (HbA1c) decreased from 8.73 ± 1.15% and 8.35 ± 0.95% at baseline to 7.71 ± 1.09% and 7.82 ± 1.06% at week 24 in the NPH and BIA subgroups, respectively. Least squares (LS) mean change in HbA1c was - 0.85% (95% confidence interval - 0.94 to - 0.77) in NPH subgroup and - 0.70% (- 0.77 to - 0.64) in BIA subgroup, with a LS mean absolute difference between subgroups of 0.16 (0.06-0.26; p = 0.002). Gla-300 mean daily dose was slightly increased at week 24 by 0.07 U/kg/day (approximately 6 U/day) in both subgroups. Incidences of symptomatic and severe hypoglycaemia were low, without body weight change. CONCLUSIONS: Irrespective of previous BI therapy (NPH insulin or BIAs), switching to Gla-300 improved glycaemic control without weight gain and with low symptomatic and severe hypoglycaemia incidences. However, a slightly greater glucose-lowering effectiveness was observed in people pre-treated with NPH insulin

NOD mouse dorsal root ganglia display morphological and gene expression defects before and during autoimmune diabetes development

IntroductionDuring the development of Autoimmune Diabetes (AD) an autoimmune attack against the Peripheral Nervous System occurs. To gain insight into this topic, analyses of Dorsal Root Ganglia (DRG) from Non-Obese Diabetic (NOD) mice were carried out.MethodsHistopathological analysis by electron and optical microscopy in DRG samples, and mRNA expression analyzes by the microarray technique in DRG and blood leukocyte samples from NOD and C57BL/6 mice were performed.ResultsThe results showed the formation of cytoplasmic vacuoles in DRG cells early in life that could be related to a neurodegenerative process. In view of these results, mRNA expression analyses were conducted to determine the cause and/or the molecules involved in this suspected disorder. The results showed that DRG cells from NOD mice have alterations in the transcription of a wide range of genes, which explain the previously observed alterations. In addition, differences in the transcription genes in white blood cells were also detected.DiscussionTaken together, these results indicate that functional defects are not only seen in beta cells but also in DRG in NOD mice. These results also indicate that these defects are not a consequence of the autoimmune process that takes place in NOD mice and suggest that they may be involved as triggers for its development

Adaptation and Validation of the Diabetic Foot Ulcer Scale-Short Form in Spanish Subjects

Diabetic foot ulcer (DFU) is a chronic complication that negatively affects the quality of life (QoL) of diabetic patients. In Spain, there is no specifically designed and validated instrument to assess the QoL of patients with DFU. Our aim was to adapt the Diabetic Foot Ulcer Scale-Short Form (DFS-SF) questionnaire to a Spanish population and validate it. A prospective, observational design was used. The DFS-SF was administered by personal interview. The validated SF-36 and EQ-5D generic instruments were used as reference tools. The reliability, validity, and sensitivity to changes were assessed using standard statistical methods. A sample of 141 patients with DFU was recruited. The content validity was 3.46 on average (maximum score of 4). The internal consistency of the DFS-SF subscales showed a standardized Cronbach’s α range between 0.720 and 0.948. The DFS-SF domains showed excellent reproducibility measures (intraclass correlation coefficient from 0.77–0.92). The criterion validity was good with significant correlations between each DFS-SF subscale and its corresponding SF-36 and EQ-5D subscales (p < 0.001). However, the questionnaire structure was not validated (comparative fit index = 0.844, root mean square error of approximation = 0.095, and standardized root mean square residual = 0.093). The instrument showed high sensitivity to ulcer changes over time (p < 0.001). The adapted and validated Spanish version of the DFS-SF questionnaire has good psychometric properties and shows good sensitivity to ulcer changes, although the construct validity was not optimal. The adapted questionnaire will be a useful tool specifically to assess the QoL in subjects with diabetic foot ulcers in the clinical and research settings in Spain.CIBERDEM is an initiative from Instituto de Salud Carlos III (Plan Nacional de I + D + I and Fondo Europeo de Desarrollo Regional). M.G.-C. held a predoctoral fellowship from the Ministerio de Educación, Cultura y Deporte, FPU15/03005. This project was developed in the context of the Programme “Doctorat en Medicina de la Universitat Autònoma de Barcelona”, Autonomous University of Barcelona

Predictive value of the advanced lipoprotein profile and glycated proteins on diabetic retinopathy

This study aimed to assess whether the advanced characteristics of serum lipoprotein subclasses could better predict the risk of developing diabetic retinopathy (DR) and its severity compared to other established risk factors in subjects with type 1 (T1D) and type 2 (T2D) diabetes. This observational, cross-sectional substudy analyzed DR-related data from 309 T1D and 264 T2D subjects. The advanced lipoprotein and glycoprotein profile was determined by nuclear magnetic resonance (NMR) spectroscopy (Liposcale test). NMR analysis of lipoproteins revealed that T1D subjects with DR showed standard non-HDL particles, despite higher IDL lipid concentrations. Notably, IDL lipids were elevated in T1D subjects with worsened DR. VLDL and LDL were smaller, whereas HDL triglycerides were increased in DR compared with non-DR. On the other hand, the T2D subjects with DR showed altered characteristics in the LDL fraction, mainly revealed by a significant decrease in smaller LDL and a reduction in LDL-C. Moreover, the glycoprotein profile did not reveal significant changes among DR groups, regardless of the type of diabetes. However, lipoprotein characteristics and glycoproteins unveiled by NMR analysis did not improve the predictive value of conventional lipids or other traditional, well-established biomarkers of DR in our cohorts

Vitamin D Deficiency Is Associated with the Presence and Severity of Diabetic Retinopathy in Type 2 Diabetes Mellitus

There is very few evidences on the role of vitamin D in the development of diabetic retinopathy. The aim of the current study was to explore whether there is an association of vitamin D status and diabetic retinopathy in type 2 diabetes. Two groups of patients were selected: 139 and 144 patients with and without retinopathy, respectively, as assessed by an experienced ophthalmologist. Subjects with advanced late diabetic complications were excluded to avoid confounding biases. 25-Hydroxy-vitamin D 3 (25(OH)D) concentrations and vitamin D deficiency were associated with the presence of diabetic retinopathy. Additionally, patients with more advanced stages of retinopathy (grades 2-4) had lower concentrations of 25(OH)D and were more frequently vitamin D deficient as compared with patients not carrying this eye complication. In conclusion, our study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes. Further experimental and prospective studies on this issue are clearly warranted

Lipidome characterisation and sex-specific differences in type 1 and type 2 diabetes mellitus

Background: In this study, we evaluated the lipidome alterations caused by type 1 diabetes (T1D) and type 2 diabetes (T2D), by determining lipids significantly associated with diabetes overall and in both sexes, and lipids associated with the glycaemic state. Methods: An untargeted lipidomic analysis was performed to measure the lipid profiles of 360 subjects (91 T1D, 91 T2D, 74 with prediabetes and 104 controls (CT)) without cardiovascular and/or chronic kidney disease. Ultra-high performance liquid chromatography-electrospray ionization mass spectrometry (UHPLC-ESI-MS) was conducted in two ion modes (positive and negative). We used multiple linear regression models to (1) assess the association between each lipid feature and each condition, (2) determine sex-specific differences related to diabetes, and (3) identify lipids associated with the glycaemic state by considering the prediabetes stage. The models were adjusted by sex, age, hypertension, dyslipidaemia, body mass index, glucose, smoking, systolic blood pressure, triglycerides, HDL cholesterol, LDL cholesterol, alternate Mediterranean diet score (aMED) and estimated glomerular filtration rate (eGFR); diabetes duration and glycated haemoglobin (HbA1c) were also included in the comparison between T1D and T2D. Results: A total of 54 unique lipid subspecies from 15 unique lipid classes were annotated. Lysophosphatidylcholines (LPC) and ceramides (Cer) showed opposite effects in subjects with T1D and subjects with T2D, LPCs being mainly up-regulated in T1D and down-regulated in T2D, and Cer being up-regulated in T2D and down-regulated in T1D. Also, Phosphatidylcholines were clearly down-regulated in subjects with T1D. Regarding sex-specific differences, ceramides and phosphatidylcholines exhibited important diabetes-associated differences due to sex. Concerning the glycaemic state, we found a gradual increase of a panel of 1-deoxyceramides from normoglycemia to prediabetes to T2D. Conclusions: Our findings revealed an extensive disruption of lipid metabolism in both T1D and T2D. Additionally, we found sex-specific lipidome changes associated with diabetes, and lipids associated with the glycaemic state that can be linked to previously described molecular mechanisms in diabetes