Omics technologies accumulated an enormous amount of data that advanced knowledge about the molecular pathogenesis of type 1 diabetes mellitus and identified a number of fundamental problems focused on the transition to personalized diabetology in the future. Among them, the most significant are the following: (1) clinical and genetic heterogeneity of type 1 diabetes mellitus; (2) the prognostic significance of DNA markers beyond the HLA genes; (3) assessment of the contribution of a large number of DNA markers to the polygenic risk of disease progress; (4) the existence of ethnic population differences in the distribution of frequencies of risk alleles and genotypes; (5) the infancy of epigenetic research into type 1 diabetes mellitus. Disclosure of these issues is one of the priorities of fundamental diabetology and practical healthcare. The purpose of this review is the systemization of the results of modern molecular genetic, transcriptomic, and epigenetic investigations of type 1 diabetes mellitus in general, as well as its individual forms. The paper summarizes data on the role of risk HLA haplotypes and a number of other candidate genes and loci, identified through genome-wide association studies, in the development of this disease and in alterations in T cell signaling. In addition, this review assesses the contribution of differential DNA methylation and the role of microRNAs in the formation of the molecular pathogenesis of type 1 diabetes mellitus, as well as discusses the most currently central trends in the context of early diagnosis of type 1 diabetes mellitus.

This study aims to investigate the interplay between hepatitis C virus (HCV) infection and major forms of diabetes: type 1 diabetes (T1D), type 2 diabetes (T2D), and latent autoimmune diabetes in adults (LADA).

This multicenter study analyzed a cohort of 2699 diabetic and 7344 non-diabetic subjects who visited medical centers in China from 2014 to 2021. T1D, T2D, LADA, and HCV were diagnosed using standard procedures. High-throughput sequencing was conducted to identify genetic footprints of human leukocyte antigen (HLA) alleles and haplotypes at the DRB1, DQA1, and DQB1 loci.

HCV infection was detected in 3 % (23/766) of LADA patients, followed by 1.5 % (15/977) of T2D patients, 1.4 % (13/926) of T1D patients, and 0.5 % (38/7344) of non-diabetic individuals. HCV prevalence was significantly higher in people with diabetes than in non-diabetic individuals (p < 0.01). HLA alleles (DQB1*060101, DQB1*040101) and haplotypes (DRB1*080302-DQA1*010301-DQB1*060101) in LADA patients with HCV revealed higher frequencies than in LADA patients without HCV (adjusted p < 0.03). Furthermore, a higher risk of diabetes complications was found among LADA patients with HCV infection (p < 0.001).

LADA patients are susceptible to HCV infection, potentially associated with certain HLA alleles/haplotypes. Early diagnosis and treatment of HCV infection among people with diabetes are important for the management of severe complications.

Chalcones (designated JA1, JA2 and JA3) were prepared from aromatic aldehyde and acetophenone which were then characterized using various spectroscopic techniques. The antioxidant potential of synthesized compounds was evaluated against DPPH free radical whereas the antidiabetic potential was determined against alpha glucosidase. Further the antidiabetic potential of the synthesized compounds was evaluated in rat model which were given orally experimental animals in doses 10 and 20 mg/kg body weight. The blood biochemical parameters like total cholesterol, triglycerides, alanine phosphatase, serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, serum creatinine, HDL, and LDL levels were determined using commercially available kits. The antioxidant potential was found high for JA3 followed by JA2 with IC50 value of 64.02 ± 1.47 μg/ml whereas against alpha glucosidase again the same compound with IC50 of 63.04 μg/ml exhibited highest inhibitory potential. The blood glucose level was brought to almost normal level (126.88 and 119.13 mg/dl at 10 and 20 mg/kg body weight) in diabetic rats (induced by STZ) by compound JA3 at the tested doses in comparison to acarbose at day 28th. The blood biochemical parameters were normalized in diabetic rats by compound JA3 compared with diabetic control group. Based on the results JA3 should be considered as effective antioxidant and antidiabetic drug candidate.

Latent autoimmune diabetes (LADA) is an unique form of diabetes that has characteristics of both type 1 and type 2 diabetes. Type 1.5 diabetes also known as LADA is occasionally confused for type 2 diabetes because there is delay in presenting features and early insulin independence. LADA, on the other hand, is an autoimmune disorder that differs from type 2 diabetes in that autoantibodies against pancreatic beta cells are what characterise it. Insulin production eventually diminishes due to the autoimmune destruction of pancreatic beta cells as a result of the pathophysiology of LADA. Autoantibodies to glutamic acid decarboxylase (GAD), islet antigen-2 (IA-2), and insulin are frequently detected in LADA patients. These autoantibodies have important implications for therapy strategies and are essential in differentiating LADA from type 2 diabetes. LADA clinical management is very challenging. The aim of this article is to view the characteristics, disease presentation, diagnostic challenges, progression and treatment modalities of LADA.

Latent autoimmune diabetes in adults (LADA) is a highly heterogeneous autoimmune condition with clinical and genetic characteristics that fall between those of type 1 diabetes mellitus and type 2 diabetes mellitus; therefore, there are no uniform criteria for the selection of therapeutic agents. We conducted a network meta-analysis to evaluate the efficacy of various therapeutic agents for LADA by comparing their effects on various indicators used to reflect LADA.

We searched the PubMed, Cochrane Library, Embase and Web of Science databases from their inception to March 2023 and collected data from 14 randomized controlled trials on glucose-lowering drugs for LADA, including 23 studies and 15 treatment regimens. The effectiveness of drugs was ranked and evaluated by combining surface under the cumulative ranking (SUCRA) plots and forest plots. Factors that may influence study heterogeneity were also searched and analyzed by combining subgroup analysis, publication bias, funnel plots and sensitivity analysis.

The results of the network meta-analysis showed that insulin had the most significant effect on the control of change from baseline in glycosylated hemoglobin, type A1 (ΔHbA1c). Insulin combined with dipeptidyl peptidase-4 (DPP-4) inhibitors performed the best in reducing fasting blood glucose and body mass index. Treatment regimens involving thiazolidinediones were the most advantageous in HbA1c, fasting C-peptide and postprandial C-peptide control. Longer dosing may be more beneficial in maintaining islet β-cell function in the LADA population.

LADA is an immune condition with high heterogeneity, and treatment should be administered according to the C-peptide level of the LADA population. For this population with LADA with a certain level of β-cell function, combinations of insulin with DPP-4 inhibitors or thiazolidinediones probably can be more effective treatment options to maintain islet function and normal blood glucose.

PROSPERO CRD42023410795.

Pancreatic islet transplantation is a minimally invasive procedure aiming to reverse the effects of insulin deficiency in patients with type 1 diabetes (T1D) by transplanting pancreatic beta cells. Overall, pancreatic islet transplantation has improved to a great extent, and cellular replacement will likely become the mainstay treatment. We review pancreatic islet transplantation as a treatment for T1D and the immunological challenges faced. Published data demonstrated that the time for islet cell transfusion varied between 2 and 10 h. Approximately 54% of the patients gained insulin independence at the end of the first year, while only 20% remained insulin-free at the end of the second year. Eventually, most transplanted patients return to using some form of exogenous insulin within a few years after the transplantation, which imposed the need to improve immunological factors before transplantation. We also discuss the immunosuppressive regimens, apoptotic donor lymphocytes, anti-TIM-1 antibodies, mixed chimerism-based tolerance induction, induction of antigen-specific tolerance utilizing ethylene carbodiimide-fixed splenocytes, pretransplant infusions of donor apoptotic cells, B cell depletion, preconditioning of isolated islets, inducing local immunotolerance, cell encapsulation and immunoisolation, using of biomaterials, immunomodulatory cells, etc.

Recent success in clinical trials to delay the onset of type 1 diabetes has heralded a new era of type 1 diabetes research focused on the most accurate methods to predict risk and progression rate in the general population. Risk prediction for type 1 diabetes has been ongoing since the 1970s and 1980s when human leucocyte antigen (HLA) variants and islet autoantibodies associated with type 1 diabetes were first described. Development of prediction methodologies has relied on well-characterised cohorts and samples. The Bart's Oxford (BOX) study of type 1 diabetes has been recruiting children with type 1 diabetes and their first (and second)-degree relatives since 1985. In this review, we use the timeline of the study to review the accompanying basic science developments which have facilitated improved prediction by genetic (HLA analysis through to genetic risk scores) and biochemical strategies (islet cell autoantibodies through to improved individual tests for antibodies to insulin, glutamate decarboxylase, the tyrosine phosphatase IA-2, zinc transporter 8 and tetraspanin 7). The type 1 diabetes community are poised to move forward using the best predictive markers to predict and delay the onset of type 1 diabetes.

Accumulating evidence indicates that type 2 diabetes (T2D) is phenotypically heterogeneous. Defining and classifying variant forms of T2D are priorities to better understand its pathophysiology and usher clinical practice into an era of "precision diabetes."

We reviewed literature related to heterogeneity of T2D over the past 5 decades and identified a range of phenotypic variants of T2D. Their descriptions expose inadequacies in current classification systems. We attempt to link phenotypically diverse forms to pathophysiology, explore investigative methods that have characterized "atypical" forms of T2D on an etiological basis, and review conceptual frameworks for an improved taxonomy. Finally, we propose future directions to achieve the goal of an etiological classification of T2D.

Differences among ethnic and racial groups were early observations of phenotypic heterogeneity. Investigations that uncover complex interactions of pathophysiologic pathways leading to T2D are supported by epidemiological and clinical differences between the sexes and between adult and youth-onset T2D. Approaches to an etiological classification are illustrated by investigations of atypical forms of T2D, such as monogenic diabetes and syndromes of ketosis-prone diabetes. Conceptual frameworks that accommodate heterogeneity in T2D include an overlap between known diabetes types, a "palette" model integrated with a "threshold hypothesis," and a spectrum model of atypical diabetes.

The heterogeneity of T2D demands an improved, etiological classification scheme. Excellent phenotypic descriptions of emerging syndromes in different populations, continued clinical and molecular investigations of atypical forms of diabetes, and useful conceptual models can be utilized to achieve this important goal.

The aim of this study was to evaluate characteristics and risk of diabetic complications according to age at diagnosis among young adults with type 1 diabetes mellitus (T1DM).

A total of 255 T1DM patients aged less than 40 years were included. Patients were categorized into three groups (<20, 20 to 29, and 30 to 40 years) according to age at diagnosis. Diabetic nephropathy (DN) was defined when spot urine-albumin creatinine ratio was 300 mg/g or more and/or estimated glomerular filtration ratio (eGFR) level was 60 mL/min/1.73 m2 or less.

Median age at diagnosis was 25 years and disease duration was 14 years. Individuals diagnosed with T1DM at childhood/adolescent (age <20 years) had lower stimulated C-peptide levels. They received more intensive insulin treatment with higher total daily insulin doses compared to older onset groups. The prevalence of DN was higher in the childhood/adolescent-onset group than in older onset groups (25.3% vs. 15.3% vs. 9.6%, P=0.022). The eGFR was inversely associated with disease duration whilst the degree of decrease was more prominent in the childhood/adolescent-onset group than in the later onset group (aged 30 to 40 years; P<0.001). Childhood/adolescent-onset group was independently associated with the risk of DN compared to the older onset group (aged 30 to 40 years; odds ratio, 3.47; 95% confidence interval, 1.45 to 8.33; P=0.005).

In individuals with childhood/adolescent-onset T1DM, the reduction in renal function is more prominent with disease duration. Early age-onset T1DM is an independent risk of DN.

Although there is ample data about the prevalence of diabetes in the Middle East, little is known about the prevalence and features of autoimmune diabetes in this region. The aim of this study was to investigate the prevalence and metabolic characteristics of latent autoimmune diabetes in adults (LADA) amongst Yemeni Type 2 DM patients.

In this cross-section study, 270 Type 2 DM patients aged 30-70 years were recruited from the National Diabetes Center, Al-Thowra Hospital, Sana'a city, during the period November 2015 to August 2016. All Type 2 DM patients were diagnosed within 5 years and who did not require insulin for a minimum of 6 months following diagnosis. Levels of glutamic acid decarboxylase autoantibodies (GADA) were measured in all patients, and LADA was diagnosed in patients testing positive for anti-GAD antibodies. Further, biochemical analysis was carried out including fasting blood glucose (FBG), glycated haemoglobin (HbA1c), insulin, and lipid profile. Insulin resistance (HOMA-IR) and β-cell function (HOMA-β) were calculated.

The prevalence of LADA, as defined by GADA-positive, amongst patient with Type 2 DM was 4.4%; with no significant difference in the prevalence between male (5.8%) and female (3.4%). LADA patients were younger than GADA-negative Type 2 DM. Body mass index, waist circumference, insulin and HOMA-β were significantly lower in LADA patients, whereas triglyceride, cholesterol, HDL-c and HOMA-IR were non-significantly lower with respect to Type 2 DM. In contrast, FBG and HbA1c were significantly higher in LADA patients. Moreover, the prevalence of metabolic syndrome was significantly lower in LADA as compared with Type 2 DM. Only 2 out of the 12 GADA-positive (16.7%) were on insulin treatment at the time of the study.

The prevalence of LADA in Yemeni Type 2 DM is lower than many of those reported in the literature, with no gender preference. Metabolic syndrome was significantly lower in LADA patients. Patients with LADA share insulin resistance with Type 2 DM but display a more severe defect in β-cell function, thus highlighting the importance of an early diagnosis of LADA, to correctly treat LADA patients, allowing safe and effective therapies.

Approximately 10% of patients with type 2 diabetes suffer from latent autoimmune diabetes in adults (LADA). This study provides a systematic assessment of the pathology of the endocrine pancreas of patients with LADA and for comparison in a first rat model mimicking the characteristics of patients with LADA. Islets in human and rat pancreases were analyzed by immunohistochemistry for immune cell infiltrate composition, by in situ RT-PCR and quantitative real-time PCR of laser microdissected islets for gene expression of proinflammatory cytokines, the proliferation marker proliferating cell nuclear antigen (PCNA), the anti-inflammatory cytokine interleukin (IL) 10, and the apoptosis markers caspase 3 and TUNEL as well as insulin. Human and rat LADA pancreases showed differences in areas of the pancreas with respect to immune cell infiltration and a changed ratio between the number of macrophages and CD8 T cells toward macrophages in the islet infiltrate. Gene expression analyses revealed a changed ratio due to an increase of IL-1β and a decrease of tumor necrosis factor-α. IL-10, PCNA, and insulin expression were increased in the LADA situation, whereas caspase 3 gene expression was reduced. The analyses into the underlying pathology in human as well as rat LADA pancreases provided identical results, allowing the conclusion that LADA is a milder form of autoimmune diabetes in patients of an advanced age.

Latent autoimmune diabetes in adults (LADA) is diagnosed in up to 12% of adults with clinically diagnosed type 2 diabetes (T2D). LADA tends to have healthier cardiovascular (CV) risk profiles than T2D, but it remains uncertain whether the risk of CV events differs between the two. We examined the risk of CV events in patients enrolled in the United Kingdom Prospective Diabetes Study (UKPDS) according to LADA status.

Diabetes autoantibodies (AAb) were measured in 5062 UKPDS participants. The incidence of major adverse CV events (MACE), defined as CV death, non-fatal myocardial infarction or non-fatal stroke, was compared in those with LADA (≥1 AAb test positive) and those without LADA (AAb negative).

There were 567 participants (11.2%) with LADA. Compared with participants with T2D, they were younger, with higher mean HbA1c and HDL-cholesterol values, and with lower body mass index and total cholesterol and systolic blood pressure values (all P < 0.01). After a median (25th, 75th percentile) 17.3 (12.6-20.7) years of follow-up, MACE occurred in 157 (17.4 per 1000 person-years) participants with LADA and in 1544 (23.5 per 1000 person-years) participants with T2D (HR, 0.73; 95% confidence interval [CI], 0.62-0.86; P < 0.001). However, after adjustment for confounders, this difference was no longer significant (HR_adj , 0.90; 95% CI, 0.76-1.07; P = 0.22).

In adults thought to have newly diagnosed T2D, the long-term risk of MACE was lower in those with LADA. However, this did not differ after adjustment for traditional CV risk factors, suggesting that measurement of AAb in addition to traditional CV risk factors will not aid in stratification of CV risk in clinically diagnosed T2D.

The objective of this cross-sectional study was to explore the relationship of detectable C-peptide secretion in type 1 diabetes to clinical features and to the genetic architecture of diabetes.

C-peptide was measured in an untimed serum sample in the SDRNT1BIO cohort of 6076 Scottish people with clinically diagnosed type 1 diabetes or latent autoimmune diabetes of adulthood. Risk scores at loci previously associated with type 1 and type 2 diabetes were calculated from publicly available summary statistics.

Prevalence of detectable C-peptide varied from 19% in those with onset before age 15 and duration greater than 15 years to 92% in those with onset after age 35 and duration less than 5 years. Twenty-nine percent of variance in C-peptide levels was accounted for by associations with male gender, late age at onset and short duration. The SNP heritability of residual C-peptide secretion adjusted for gender, age at onset and duration was estimated as 26%. Genotypic risk score for type 1 diabetes was inversely associated with detectable C-peptide secretion: the most strongly associated loci were the HLA and INS gene regions. A risk score for type 1 diabetes based on the HLA DR3 and DQ8-DR4 serotypes was strongly associated with early age at onset and inversely associated with C-peptide persistence. For C-peptide but not age at onset, there were strong associations with risk scores for type 1 and type 2 diabetes that were based on SNPs in the HLA region but not accounted for by HLA serotype.

Persistence of C-peptide secretion varies widely in people clinically diagnosed as type 1 diabetes. C-peptide persistence is influenced by variants in the HLA region that are different from those determining risk of early-onset type 1 diabetes. Known risk loci for diabetes account for only a small proportion of the genetic effects on C-peptide persistence.

Latent autoimmune diabetes in adults (LADA) shows a heterogeneous clinical profile that is dependent on the glutamic acid decaroxylase antibody (GADA) titer. We speculated that LADA patients with a high or low GADA titer may have distinct T-lymphocyte subset profiles and distinct expression patterns of transcription factors involved in T-cell immunomodulation.

Patients with LADA (n = 40) and type 2 diabetes (T2DM; n = 14) were recruited to the study, and peripheral blood mononuclear cells were isolated. The proportions of T-lymphocyte subsets (Th1 [T helper type 1], Th2 [T helper type 2], Treg [regulatory T], and Th17 [T helper type 17] cells) were determined by flow cytometry. Real-time polymerase chain reaction (PCR) was performed to estimate mRNA expression levels of the T-cell subtype-enriched transcription factors T-bet (Th1), GATA3 (Th2), transcription factor forkhead box protein 3 (FOXP3) (Treg), and RORC (Th17).

The frequency of Th1 (as a percentage of total CD4⁺T cells) was greater in the LADA patients with high-titer GADA than in the LADA patients with low-titer GADA (11.06 ± 1.62 vs. 7.05 ± 0.86, P = 0.030). Compared to the T2DM group, in the low-titer GADA group the frequency of Th1 was significantly reduced (7.05 ± 0.86 vs. 16.75 ± 3.73, P = 0.017) and the frequency of Th17 frequency was signficantly increased (1.11 ± 0.09 vs. 0.74 ± 0.16, P = 0.017). Compared to T2DM patients, in the high-titer GADA group there was a significantly reduced expression of FOXP3 (0.35 ± 0.13 vs. 1.75 ± 0.54, P = 0.002), RORC (0.53 ± 0.19 vs. 2.00 ± 0.77, P = 0.046), and GATA3 (0.74 ± 0.17 vs. 2.31 ± 0.91, P = 0.046). Similarly, the high-titer GADA group expressed reduced levels of FOXP3 and RORC compared to the low-titer GADA group (0.35 ± 0.13 vs. 1.50 ± 0.41, P = 0.027; 0.53 ± 0.19 vs. 1.35 ± 0.21, P  = 0.027, respectively). There was a negative correlation between FOXP3 expression level and GADA titer for the entire cohort (r = - 0.0433, P = 0.015) and a stronger negative correlation in LADA patients (r = - 0.606, P = 0.008).

LADA patients with high-titer GADA express lower levels of T-cell transcription factors, including the Treg transcription factor FOXP3, which may contribute to differences in the clinical profile compared to LADA patients with low-titer GADA.

ClinicalTrials.gov identifier, NCT01159847.

Antibodies to posttranslationally modified insulin (oxPTM-INS-Ab) are a novel biomarker of type 1 diabetes (T1D). Here, we evaluated whether oxPTM-INS-Ab can improve T1D prediction in children with positive standard islet autoantibodies (AAB).

We evaluated sensitivity, specificity, accuracy, and risk for progression to T1D associated with oxPTM-INS-Ab and the standard islet AAB that include insulin (IAA), GAD (GADA), and tyrosine phosphatase 2 (IA-2A) in a cohort of islet AAB-positive (AAB⁺ ) children from the general population (median follow-up 8.8 years).

oxPTM-INS-Ab was the most sensitive and specific autoantibody biomarker (74% sensitivity, 91% specificity), followed by IA-2A (71% sensitivity, 91% specificity). GADA and IAA showed lower sensitivity (65% and 50%, respectively) and specificity (66% and 68%, respectively). Accuracy (AUC of ROC) of oxPTM-INS-Ab was higher than GADA and IAA (P = 0.003 and P = 0.017, respectively), and similar to IA-2A (P = 0.896). oxPTM-INS-Ab and IA-2A were more effective than IAA for detecting progr-T1D when used as second-line biomarker in GADA⁺ children. Risk for diabetes was higher (P = 0.03) among multiple AAB⁺ who were also oxPTM-INS-Ab⁺ compared with those who were oxPTM-INS-Ab^- . Importantly, when replacing IAA with oxPTM-INS-Ab, diabetes risk increased to 100% in children with oxPTM-INS-Ab⁺ in combination with GADA⁺ and IA-2A⁺ , compared with 84.37% in those with IAA⁺ , GADA⁺ , and IA-2A⁺ (P = 0.04).

Antibodies to oxidized insulin (oxPTM-INS-Ab), compared with IAA which measure autoantibodies to native insulin, improve T1D risk assessment and prediction accuracy in AAB⁺ children.

Slowly progressive type 1 insulin-dependent diabetes mellitus (SPIDDM), sometimes referred to as latent autoimmune diabetes in adults (LADA), is a heterogeneous disease that is often confused with type 1 and type 2 diabetes. As a result, there were few diagnostic criteria for this disorder until 2012, when the Japan Diabetes Society established criteria that could be used in clinical practice. A primary question is whether pathologic markers for type 1 or type 2 diabetes are present in the pancreas of patients with SPIDDM, because the phenotype of SPIDDM is similar to both type 1 and type 2 diabetes. Recent studies clarified pathologic findings in the pancreas of patients with SPIDDM, which included T-cell-mediated insulitis, a marker of type 1 diabetes; pseudoatrophic islets (islets specifically devoid of beta cells), another hallmark of type 1 diabetes; and a lack of amylin (ie, islet amyloid polypeptide) deposition to the islet cells, a pathologic marker of type 2 diabetes. In terms of preventing the loss of beta-cell function in patients with SPIDDM, several studies have shown that some drugs, including dipeptidyl peptidase-4 inhibitors, are effective. There is an increased need for early diagnosis of SPIDDM to preserve beta-cell function. This review presents updated findings on the pathogenesis and immunologic findings of the affected pancreas, diagnostic markers, risk factors for progression of beta-cell dysfunction, epidemiology, clinical features, diagnostic strategies, prevention strategies, and clinical options for patients with SPIDDM.

Latent autoimmune diabetes in adults (LADA) is characterized as a slow-progressing form of autoimmune diabetes. LADA resembles some phenotypes of type 1 diabetes (T1D) and type 2 diabetes (T2D), frequently leading to misdiagnosis and inappropriate therapeutic strategies. Understanding its transcriptome profiles aids in revealing the detailed molecular mechanisms of LADA and its therapy. In the present study, we performed RNA-seq analysis of LADA patients from Eastern China and showed that LADA exhibited 277 differentially expressed genes (DEGs) with 199 upregulated and 78 downregulated. Gene ontology and KEGG pathway enrichment analysis revealed that these DEGs were mainly related to immune function and cell death and growth. Furthermore, a comparison of DEGs in LADA with those in T1D and T2D identified from the online databases showed that there are very few overlapped genes between LADA and T1D or T2D, confirming LADA to be a distinct type of diabetes from T1D or T2D. In summary, our comprehensive analysis may aid in the understanding and treatment of LADA patients in Eastern China.

Latent autoimmune diabetes in adults (LADA) is a heterogeneous disease characterized by a less intensive autoimmune process and a broad clinical phenotype compared to classical type 1 diabetes mellitus (T1DM), sharing features with both type 2 diabetes mellitus (T2DM) and T1DM. Since patients affected by LADA are initially insulin independent and recognizable only by testing for islet-cell autoantibodies, it could be difficult to identify LADA in clinical setting and a high misdiagnosis rate still remains among patients with T2DM. Ideally, islet-cell autoantibodies screening should be performed in subjects with newly diagnosed T2DM, ensuring a closer monitoring of those resulted positive and avoiding treatment of hyperglycaemia which might increase the rate of β-cells loss. Thus, since the autoimmune process in LADA seems to be slower than in classical T1DM, there is a wider window for new therapeutic interventions that may slow down β-cell failure. This review summarizes the current understanding of LADA, by evaluating data from most recent studies, the actual gaps in diagnosis and management. Finally, we critically highlight and discuss novel findings and future perspectives on the therapeutic approach in LADA.

Latent autoimmune diabetes in adults (LADA) is characterized by the presence of islet autoantibodies and initial insulin independence, which can lead to misdiagnosis of type 2 diabetes (T2D). As such, understanding the genetic etiology of LADA could aid in more accurate diagnosis. However, there is ongoing debate regarding the exact definition of LADA, so understanding its impact in different populations when contrasted with type 1 diabetes (T1D) and T2D is one potential strategy to gain insight into its etiology. Unfortunately, the lack of consistent and thorough autoantibody screening around the world has hampered well-powered genetic studies of LADA. This review highlights recent genetic and epidemiological studies of LADA in diverse populations as well as the importance of autoantibody screening in facilitating future research.

Owing to the worldwide increase in life expectancy, the high incidence of diabetes in older individuals and the improved survival of people with diabetes, about one-third of all individuals with diabetes are now older than 65 years. Evidence is accumulating that type 2 diabetes is associated with cognitive impairment, dementia and frailty. Older people with diabetes have significantly more comorbidities, such as myocardial infarction, stroke, peripheral arterial disease and renal impairment, compared with those without diabetes. However, as a consequence of the increased use of multifactorial risk factor intervention, a considerable number of older individuals can now survive for many years without any vascular complications. Given the heterogeneity of older individuals with type 2 diabetes, an individualised approach is warranted, which must take into account the health status, presence or absence of complications, and life expectancy. In doing so, undertreatment of otherwise healthy older individuals and overtreatment of those who are frail may be avoided. Specifically, overtreatment of hyperglycaemia in older patients is potentially harmful; in particular, insulin and sulfonylureas should be avoided or, if necessary, used with caution. Instead, glucose-dependent drugs that do not induce hypoglycaemia are preferable since older patients with diabetes and impaired kidney function are especially vulnerable to this adverse event.

Excessive weight is a risk factor for type 2 diabetes, but its role in the promotion of autoimmune diabetes is not clear. We investigated the risk of latent autoimmune diabetes in adults (LADA) in relation to overweight/obesity in two large population-based studies.

Analyses were based on incident cases of LADA (n = 425) and type 2 diabetes (n = 1420), and 1704 randomly selected control participants from a Swedish case-control study and prospective data from the Norwegian HUNT Study including 147 people with LADA and 1,012,957 person-years of follow-up (1984-2008). We present adjusted ORs and HRs with 95% CI.

In the Swedish data, obesity was associated with an increased risk of LADA (OR 2.93, 95% CI 2.17, 3.97), which was even stronger for type 2 diabetes (OR 18.88, 95% CI 14.29, 24.94). The association was stronger in LADA with low GAD antibody (GADA; <median) (OR 4.25; 95% CI 2.76, 6.52) but present also in LADA with high GADA (OR 2.14; 95% CI 1.42, 3.24). In the Swedish data, obese vs normal weight LADA patients had lower GADA levels, better beta cell function, and were more likely to have low-risk HLA-genotypes. The combination of overweight and family history of diabetes (FHD) conferred an OR of 4.57 (95% CI 3.27, 6.39) for LADA and 24.51 (95% CI 17.82, 33.71) for type 2 diabetes. Prospective data from HUNT indicated even stronger associations; HR for LADA was 6.07 (95% CI 3.76, 9.78) for obesity and 7.45 (95% CI 4.02, 13.82) for overweight and FHD.

Overweight/obesity is associated with increased risk of LADA, particularly when in combination with FHD. These findings support the hypothesis that, even in the presence of autoimmunity, factors linked to insulin resistance, such as excessive weight, could promote onset of diabetes.

Patients with a type-2-diabetes (T2D) phenotype positive for glutamic acid decarboxylase antibodies (GADA) represent the majority of cases of latent autoimmune diabetes of the adult (LADA). The GLP-1 receptor agonist dulaglutide, recently introduced for treatment of T2D, has yet to be evaluated in LADA patients. Our primary objective was to evaluate the effect of dulaglutide on glycaemic control (HbA1c) in GADA-positive LADA vs GADA-negative T2D patients.

A post-hoc analysis was performed using data from 3 randomized phase 3 trials (AWARD-2,-4,-5; patients with GADA assessment) which were part of the dulaglutide clinical development programme in T2D. LADA patients were identified by GADA ≥5 IU/mL (ELISA). Changes in HbA1c during 12 months of treatment with dulaglutide or comparator were analysed using mixed-effect model repeated measures.

Of 2466 adults tested for GADA (dulaglutide, 1710; glargine, 298; sitagliptin, 294; placebo, 164), 2278 (92.4%) were GADA-negative and 188 (7.6%) were GADA-positive, including 58 GADA-high patients (> 200 IU/mL) and 130 GADA-low patients (≤200 and ≥5 IU/mL). Overall, baseline parameters were comparable between the groups. Dulaglutide resulted in comparable HbA1c reductions in GADA-negative (LS mean change [95%CI], -1.09% [-1.15, -1.03]) and GADA-positive patients (-0.94% [-1.15, -0.72]) at 12 months. HbA1c reductions were numerically, but not statistically, significantly larger in GADA-low patients (-1.02% [-1.26, -0.78]) vs GADA-high patients (-0.72% [-1.21,-0.24]) at 12 months. Similar outcomes were observed at 3 and 6 months.

These data are the first to indicate that dulaglutide was effective in reducing HbA1c in LADA patients.

Autoimmune diabetes is a heterogeneous disease which can arise at any age. Subjects with adult-onset autoimmune diabetes who do not necessitate insulin-therapy for at least 6 months after diagnosis are demarcated as having latent autoimmune diabetes in adults (LADA). This condition is more heterogeneous than young-onset autoimmune diabetes and shares clinical and metabolic characteristics with both type 2 and type 1 diabetes. Patients with LADA are considered by having highly variable β-cell destruction, different degrees of insulin resistance and heterogeneous titre and pattern of islet autoantibody, suggesting different pathophysiological pathways partially explaining the heterogeneous phenotypes of LADA. To date the heterogeneity of LADA does not allow to establish a priori treatment algorithm and no specific guidelines for LADA therapy are available. These subjects are mostly treated as affected by type 2 diabetes, a factor that might lead to the progression to insulin-dependency quickly. A personalised medicine approach is necessary to attain optimal metabolic control and preserve β-cell function to decrease the risk of long-term diabetes complications. Recent data concerning the use of oral antidiabetic agents as dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists indicate up-and-coming results in term of protect C-peptide levels and improving glycaemic control. This review summarises current knowledge on LADA, emphasising controversies regarding its pathophysiology and clinical features. Moreover, we discuss data available about novel therapeutic approaches that can be considered for prevention of β-cell loss in LADA.

Latent Autoimmune Diabetes in Adults (LADA) is the second most common form of diabetes, but data on its clinical course and prognosis are scarce. We compared long-term risk of mortality and cardiovascular outcomes in patients with LADA, type 2 diabetes mellitus (T2D), and insulin deficient diabetes (IDD).

We conducted a cohort study of 4368 adults with diabetes referred to the Department of Endocrinology, Odense University Hospital, Denmark, between 1997 and 2012. Data on comorbidity, cardiovascular outcomes and death were obtained from prospective medical databases. We compared adjusted hazard ratios (HRs) of mortality and cardiovascular outcomes for patients with LADA, T2D and IDD, respectively.

We included 327 patients with LADA, 3539 with T2D and 502 with IDD. At diagnosis, patients with LADA were older (50 years (IQR 37-59)) than IDD patients (40 years (IQR 28-52)), but younger than patients with T2D (55 years (IQR 45-64)). During a median follow-up period of 6.6 years (IQR 3.4-9.4), patients with IDD had higher mortality than patients with LADA, age- and gender-adjusted HR 2.2 (95% CI, 1.5-3.2). T2D also conferred higher mortality than LADA, HR 1.4 (95% CI, 1.0-1.9). Compared with LADA patients, cardiovascular outcome rates were increased both with IDD, HR 1.2 (95% CI, 0.7-2.0) and T2D, HR 1.2 (95% CI, 0.8-1.8), with the strongest association observed for T2D vs. LADA and acute myocardial infarction HR 1.7 (95% CI, 0.8-3.5).

LADA seems to be associated with lower mortality and lower risk of cardiovascular events, compared with both T2D and IDD.

Type 1 diabetes (T1D) results from immune-mediated loss of pancreatic beta cells leading to insulin deficiency. It is the most common form of diabetes in children, and its incidence is on the rise. This article reviews the current knowledge on the genetics of T1D. In particular, we discuss the influence of HLA and non-HLA genes on T1D risk and disease progression through the preclinical stages of the disease, and the development of genetic scores that can be applied to disease prediction. Racial/ethnic differences, challenges and future directions in the genetics of T1D are also discussed.

Bone formation is impaired in both type 1 diabetes and type 2 diabetes (T2D), whereas sclerostin, an antagonist of bone formation, is increased in T2D only. No data are available on latent autoimmune diabetes in adults (LADA), an autoimmune type of diabetes that may clinically resemble T2D at diagnosis. We evaluated serum sclerostin and bone turnover markers in LADA compared with those in T2D and whether metabolic syndrome (MetS) affects sclerostin in T2D or LADA.

This cross-sectional study included 98 patients with T2D and 89 with LADA from the Action LADA and Non Insulin Requiring Autoimmune Diabetes cohorts. Patients were further divided according to MetS status. Nondiabetic participants (n = 53) were used as controls. Serum sclerostin, bone formation (pro-collagen type 1 N-terminal propeptide [P1NP]), and bone resorption (C-terminal telopeptide of type I collagen [CTX]) were analyzed.

Patients with T2D had higher sclerostin than did those with LADA [P = 0.0008, adjusted for sex and body mass index (BMI)], even when analysis was restricted to patients with MetS (adjusted P = 0.03). Analysis of T2D and LADA groups separately showed that sclerostin was similar between those with and those without MetS. However, a positive trend between sclerostin and number of MetS features was seen with T2D (P for trend = 0.001) but not with LADA. Patients with T2D or LADA had lower CTX than did controls (P = 0.0003) and did not have significantly reduced P1NP. Sclerostin was unrelated to age or hemoglobin A1c but was correlated with BMI (ρ = 0.29; P = 0.0001), high-density lipoprotein (ρ = -0.23; P = 0.003), triglycerides (ρ = 0.19; P = 0.002), and time since diagnosis (ρ = 0.32; P < 0.0001).

Patients with LADA presented lower bone resorption than did controls, similar to patients with T2D. Sclerostin is increased in T2D but not in LADA, suggesting possible roles on bone metabolism in T2D only.

Depressive disorders represent a frequent comorbidity of type 1 diabetes (T1D) and type 2 diabetes (T2D). Subclinical inflammation increases the risk of depressive symptoms in the general population, but the relationship appears complex and bidirectional, and longitudinal data from patients with diabetes are lacking. Therefore, this study aimed to analyse associations between changes in depressive symptoms and changes in biomarkers of inflammation in patients with T1D and T2D and to investigate the hypothesis that higher baseline levels of biomarkers of inflammation are related to a less pronounced reduction of depressive symptoms over time.

Depressive symptoms and systemic levels of six biomarkers of inflammation were assessed in 168 individuals with T1D and 103 individuals with T2D who participated in baseline and 1-year follow-up examinations. Data were obtained from two matching randomised controlled trials addressing diabetes distress and depressive symptoms. Longitudinal associations between biomarkers and depressive symptoms were estimated using linear regression models adjusting for multiple confounders.

In patients with T2D, reductions in depressive symptoms were associated with reductions in high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-18 and IL-1 receptor antagonist (IL-1RA) (P ≤ 0.016), whereas no associations were seen for IL-6, CCL2 and adiponectin. Higher CCL2 levels at baseline were associated with lower subsequent reduction in depressive symptoms (P = 0.018). Neither baseline levels nor changes in biomarkers in subclinical inflammation were associated with changes in depressive symptoms in patients with T1D.

Reductions of depressive symptoms were longitudinally associated with reductions in biomarkers of inflammation in patients with T2D. Higher baseline CCL2 levels were related with lower reduction of depressive symptoms in this group. No such associations were observed in patients with T1D, suggesting that risk factors and pathomechanisms linking inflammation and depression may differ between diabetes types.

Individuals with diabetes are at increased risk for complications, including gastroparesis. Type 1 diabetes mellitus (T1DM) is an autoimmune disorder resulting in decreased beta-cell function. Glutamic acid decarboxylase-65 antibody (GADA) is the most commonly used test to assess autoimmunity while C-peptide level is used to assess beta-cell function. Patients with type 2 diabetes mellitus (T2DM), who are GADA positive, are labeled latent autoimmune diabetes in adults (LADA).

To characterize patients with T1 and T2DM who have symptoms of gastroparesis using GADA and C-peptide levels and to look for association with the presence of gastroparesis and its symptom severity.

113 T1DM and 90 T2DM patients with symptoms suggestive of gastroparesis were studied. Symptom severity was assessed using Gastroparesis Cardinal Symptom Index (GCSI). Serum samples were analyzed for GADA and C-peptide.

Delayed gastric emptying was present in 91 (81%) of T1DM and 60 (67%) of T2DM patients (p = 0.04). GADA was present in 13% of T2DM subjects [10% in delayed gastric emptying and 20% in normal gastric emptying (p = 0.2)]. Gastric retention and GCSI scores were mostly similar in GADA positive and negative T2DM patients. GADA was present in 45% of T1DM subjects [46% in delayed gastric emptying and 41% in normal gastric emptying (p = 0.81)]. Low C-peptide levels were seen in 79% T1DM patients and 8% T2DM. All seven T2DM patients with low C-peptide were taking insulin compared to 52% of T2DM with normal C-peptide.

GADA was present in 13% while low C-peptide was seen in 8% of our T2DM patients with symptoms of gastroparesis. Neither did correlate with degree of delayed gastric emptying or symptom severity.

NCT01696747.

Islet autoimmunity, age at onset and time to insulin treatment are often used to define subgroups of diabetes. However, the latter criterion is not clinical useful. Here, we examined whether an unbiased stratification of diabetes according to age at onset, fasting C-peptide and GAD autoantibodies (GADab) defines groups with differences in glycaemic control and markers of cardiometabolic risk.

A cohort of 4374 adults with relatively newly diagnosed diabetes referred to a Danish hospital during 1997-2012 was stratified according to age at onset above or below 30 years, fasting C-peptide above or below 300 pmol/l (CPEP_high or CPEP_low), and presence or absence of GADab (GAD_pos or GAD_neg). HbA_1c, BMI, blood pressure (BP), lipid profile, alanine aminotransferase (ALT) and creatinine were evaluated.

GADab were present in 13% of the cohort. Age at onset was not associated with major differences between groups. Patients with insulin deficient diabetes (CPEP_low; n = 503) had higher HbA_1c but otherwise lower cardiometabolic risk (lower BMI, BP, LDL, triacylglycerol, and ALT, and higher HDL) than both patients with latent autoimmune diabetes of adults (LADA defined as GAD_posCPEP_high; n = 327) and patients with type 2 diabetes (GAD_negCPEP_high; n = 3544). Patients with LADA defined an intermediate group with higher HbA_1c but otherwise lower cardiometabolic risk than patients with type 2 diabetes.

Our results demonstrate that fasting C-peptide and GADab status, but not age at onset, define groups of patients with diabetes with clinically relevant differences in glycaemic control and cardiometabolic risk.

We undertook a study to assess β-cell function, metabolic and immunological features of patients with latent autoimmune diabetes in adults (LADA) and investigate heterogeneity within LADA based on low and high glutamic acid decarboxylase autoantibodies (GADA) titers.

A total of 139 patients with adult-onset diabetes were examined cross-sectionally in the National capital region of Northern India. Medical history of all subjects was reviewed with the aim of collecting clinical data. Glucose, glycosylated hemoglobin, lipid profile, creatinine, C-peptide, and GADA were measured in 10-12 hrs fasting blood sample.

Assessment of metabolic features revealed lower mean systolic blood pressure in subjects with LADA than in those with type 2 diabetes (DM2). Mean triglyceride levels were lower in LADA subjects compared to DM2 subjects. Compared to DM2 subjects, prevalence of metabolic syndrome (MS) was also lower in LADA subjects. Compared to GADA-low, all GADA-high patients were male, had lower waist circumference, fasting C-peptide (FCP), and prevalence of MS. Compared to DM2 patients, GADA-high patients were younger, had lower age at onset, body mass index, waist circumference, systolic blood pressure, triglycerides, FCP, and prevalence of MS. The rate of patients on insulin was higher in GADA-high compared to DM2. There were no significant differences between characteristics of DM2 and GADA-low patients.

Our results indicate that LADA patients have distinct metabolic features with lower residual β-cell function than DM2 patients. GADA titer is important parameter in defining the severity of the disease as patients with high GADA titer tend to have significant β-cell impairment.

Our main aim was to assess the quality of life (QoL) and treatment satisfaction (TS) of subjects with LADA (latent autoimmune diabetes of the adult) and compare these measures with those of patients with other diabetes types, i.e., type 1 (T1DM) and type 2 diabetes mellitus (T2DM).

This was a cross-sectional study with a total of 48 patients with LADA, 297 patients with T2DM and 124 with T1DM. The Audit of Diabetes-Dependent Quality of Life (ADDQoL-19) questionnaire and the Diabetes Treatment Satisfaction Questionnaire (DTSQ) were administered. Relevant clinical variables were also assessed. The data analysis included comparisons between groups and multivariate linear models.

The LADA patients presented lower diabetes-specific QoL (p = 0.045) and average weighted impact scores (p = 0.007) than the T2DM patients. The subgroup of LADA patients with diabetic retinopathy (DR) who were treated with insulin had a lower ADDQoL average weighted impact score than the other diabetic groups. Although the overall measure of TS was not different between the LADA and T2DM (p = 0.389) and T1DM (p = 0.091) groups, the patients with LADA showed a poorer hyperglycemic frequency perception than the T2DM patients (p < 0.001) and an improved frequency of hypoglycemic perception compared with the T1DM patients (p = 0.021).

The current findings suggest a poorer quality of life, especially in terms of DR and insulin treatment, among patients with LADA compared with those with T1DM and T2DM. Hyperglycemia frequency perception was also poorer in the LADA patients than in the T1DM and T2DM patients. Further research with prospective studies and a large number of patients is necessary.

Microparticles (MPs) are a type of extracellular vesicles (EVs) shed from the outward budding of plasma membranes during cell apoptosis and/or activation. These microsized particles then release specific contents (e.g., lipids, proteins, microRNAs) which are active participants in a wide range of both physiological and pathological processes at the molecular level, e.g., coagulation and angiogenesis, inflammation, immune responses. Research limitations, such as confusing nomenclature and overlapping classification, have impeded our comprehension of these tiny molecules. Diabetic nephropathy (DN) is currently the greatest contributor to end-stage renal diseases (ESRD) worldwide, and its public health impact will continue to grow due to the persistent increase in the prevalence of diabetes mellitus (DM). MPs have recently been considered as potentially involved in DN onset and progression, and this review juxtaposes some of the research updates about the possible mechanisms from several relevant aspects and insights into the therapeutic perspectives of MPs in clinical management and pharmacological treatment of DN patients.

NLRP3 and NLRP1 inflammasomes signaling pathways may play an important role in the development and progression of type 1 diabetes mellitus (T1DM). However, relative research is rare.

The blood mononuclear cells (PBMCs) and granulocytes (GCs) were collected from T1DM patients. The mRNA and protein expression levels were detected by qRT-PCR and Western blotting, respectively. The NLRP3/NLRP1was knocked down by transfected with siRNA, or ovexpressed by infected with lentiviral vectors in PBMCs and GCs from non obese diabetic (NOD) mice, respectively. The occurrence of diabetes was evaluated and the intraperitoneal glucose tolerance was tested in NOD mice with IL-1 receptor-associated kinase-M deficiency (IRAK-M^-/-). The pancreas and lymphonodus of IRAK-M^-/- NOD mice were also collected for detection of NLRP3/NLRP1 expression.

NLRP3, NLRP1, Caspase-1and IL-1β were significantly downregulated in the PBMCs and GCs of patients with T1DM, and NLRP3 and NLRP1 were markedly downregulated in T1DM patients with DKA compared to that with ND and CC. Further study indicated that IL-1β mRNA expression level was positively correlated with the expression levels of NLRP3, NLRP1 and Caspase-1. Besides, NLRP3/NLRP1 knockdown decreased the expression levels of Caspase-1 and IL-1β; whereas NLRP3/NLRP1 overexpression increased the expression levels of Caspase-1 and IL-1β in vitro. IRAK-M^-/- NOD mice had early onset and rapid progression of T1DM, and weak glucose tolerance, which was regarded as an early T1D mouse model. The mRNA expression levels of NLRP3, NLRP1, Caspase-1and IL-1β in the pancreas and lymphonodus of IRAK-M^-/- NOD mice were significantly higher compared to that of IRAK-M^+/+ NOD mice.

NLRP3 and NLRP1 inflammasomes signaling pathways were associated with the development and progression of T1DM, which response as protective factors in the early stage of T1DM.

LADA is probably the most prevalent form of autoimmune diabetes. Nevertheless, there are few data about cardiovascular disease in this group of patients. The aim of this study was to investigate the frequency of carotid atherosclerotic plaques in patients with LADA as compared with patients with classic type 1 diabetes and type 2 diabetes.

Patients with LADA were matched for age and gender in different proportions to patients with type 2 diabetes, and classic type 1 diabetes. None of the patients had clinical cardiovascular disease. All subjects underwent B-mode carotid ultrasound to detect atheroma plaques. Demographics were obtained from all subjects.

We included 71 patients with LADA, 191 patients with type 2 diabetes and 116 patients with type 1 diabetes. Carotid atherosclerosis was more frequent in patients with LADA compared with type 2 diabetes (73.2% vs. 56.9%, P = 0.0018) and classic type 1 diabetes (57.1%, P = 0.026); these changes occurred despite healthier macrovascular risk profiles in the former. Age (P < 0.001), smoking (P = 0.003) and hypertension (P = 0.019) were independently associated with carotid atherosclerosis. Multiple plaques were also more frequent in patients with LADA as compared with classic type 1 diabetes and type 2 diabetes (45.1% and 33.6% vs. 27.2%, respectively, P = 0.022). The frequency of carotid plaques increased with increasing diabetes duration in LADA patients compared with type 2 diabetes (85.7% vs. 58.8%, inverse OR 5.72 [1.5-21.8]; P = 0.009).

LADA patients do not present with less carotid atherosclerosis than patients with type 1 and type 2 diabetes. Their macrovascular risk occurs despite a healthier macrovascular risk profile than those patients with type 2 diabetes.

Diabetes mellitus is a chronic disorder caused by relative or absolute insulin deficiency and characterized by chronic hyperglycaemia. It is expected that by year 2025, 80% of all type 2 diabetic patients will be living in developing or low- and middle-income countries. Among Asians, there has been an overall increase in abdominal obesity; however, the risk of diabetes in these populations starts at much lower body mass index as compared to Caucasians. A significant proportion of diabetic patients with adult-onset, initially nonrequiring insulin treatment, have diabetes-associated autoantibodies in their sera. A new subclass of diabetes with the designation of latent autoimmune diabetes of adult-onset (LADA) has been proposed for this category of subjects. Studies have demonstrated that patients with autoimmune diabetes, characterized by the presence of glutamic decarboxylase autoantibodies display a different clinical phenotype from classical type 2 diabetes without glutamic decarboxylase autoantibodies. This subset of phenotypic type 2 diabetes subjects with islet autoantibodies tend to have sulphonylurea failure and need insulin treatment earlier in the disease process. Diagnosing LADA at an initial stage will be important so that insulin can be initiated earlier, facilitating improved glycemic control sooner as well as the preservation of residual beta-cell function in adult-onset autoimmune diabetes. Because of differences in dietary habits, environmental factors, and phenotypic characteristics between European and Asian populations, there may be heterogeneity in the prevalence and other characteristics of LADA in these two populations.

Type-1 diabetes mellitus (T1DM) and latent autoimmune diabetes in adults (LADA) share similar pathological features but differ in age of onset and progression. There is a scarcity of information on differences in CD4+ T-cell responses, particularly, cytokine secretion, between the two forms of autoimmune diabetes. Here proliferative potential and concentration of pro- and anti-inflammatory cytokines secreted by peripheral blood mononuclear cells (PBMCs) of T1DM and LADA patients were compared, after in vitro stimulation with β-cell autoantigens.

A total of 19 patients with LADA, 37 with T1DM and 20 healthy controls were compared on the basis of lymphocyte proliferation and secretion of pro- and anti-inflammatory cytokines belonging to different T-helper types after in vitro stimulation of PBMCs with insulin and glutamic acid decarboxylase 65 (GAD65).

Following insulin stimulation, LADA group secreted higher concentration of interleukin-17 (IL-17) (P=0.02) and had higher proportion of interferon gamma (IFN-γ) secretors (P<0.001) than T1DM group. Post-GAD65 stimulation, higher proportion of LADA patients secreted IL-23 than T1DM group (P=0.02). Proportion of responders , as well as levels of secreted IL-10, were significantly higher in LADA than T1DM group, following stimulation with both insulin (P=0.01) and GAD65 (P=0.03). A significant positive correlation was observed between body mass index and IL-17 levels (r=0.41, P=0.04) and fasting plasma C-peptide with IL-10 levels (r=0.37, P=0.04).

There are differences in the portfolio of cytokine secretion in diabetic subjects with varying rates of β-cell destruction as LADA subjects secrete higher levels of both pro- and anti-inflammatory cytokines on exposure to β-cell autoantigens, thus highlighting another distinguishing feature in the pathophysiology of the two forms of autoimmune diabetes.

The characterization of diverse subtypes of diabetes is a dynamic field of clinical research and an active area of discussion. The objective of this study was to identify new antigenic determinants in the neuroendocrine autoantigen IA-2 (ICA512) and assess whether circulating autoantibodies directed to new IA-2 epitopes identify autoimmune diabetes in young and adult populations with diabetes.

Clinically diagnosed patients with type 2 diabetes (n = 258; diabetes duration: 0.01-31 years) were evaluated using a new biomarker detecting autoantibodies directed to the extracellular domain of the neuroendocrine autoantigen IA-2 (IA-2ec). The proportion of IA-2ec autoantibodies was also evaluated in newly diagnosed patients with type 1 diabetes (n = 150; diabetes duration: 0.04-0.49 years). In addition, IA-2 (intracellular domain), GAD65, and zinc transporter 8 autoantibodies were assayed.

IA-2ec autoantibodies were detected in patients with type 1 diabetes and, surprisingly, in 5% of patients with type 2 diabetes without serologic responses to other IA-2 antigenic epitopes or other islet autoantigens. We also assessed the ability of IA-2ec-derived peptides to elicit CD4⁺ T-cell responses by stimulating peripheral blood mononuclear cells from patients with type 1 diabetes (n = 18) and HLA-matched healthy subjects (n = 13) with peptides and staining with the peptide/DQ8-specific tetramers, observing disease-associated responses to previously unreported epitopes within IA-2ec.

We developed a new antibody biomarker identifying novel antigenic determinants within the N terminus of IA-2. IA-2ec autoantibodies can be detected in patients with type 1 diabetes and in a subgroup of adult autoimmune patients with type 2 diabetes phenotype negative for conventional islet autoantibody testing. These observations suggest that islet autoimmunity may be more common in clinically diagnosed type 2 diabetes than previously observed.

Depressive disorders represent a frequent comorbidity of both type 1 (T1D) and type 2 diabetes (T2D). Inflammation-related processes have been implicated in the development of both diabetes and depression. This study aimed to investigate whether biomarkers of subclinical inflammation were associated with depressive symptoms in individuals with recently diagnosed diabetes and if such associations differed by diabetes type. This cross-sectional study was based on 295 individuals with T2D (67% men, mean age 53years) and 139 individuals with T1D (60% men, mean age 36years) of the German Diabetes Study. The main inclusion criterion was a known disease duration of <1year. Depressive symptoms were assessed with the Allgemeine Depressionsskala, Langversion (ADS-L) questionnaire, the German version of the Center for Epidemiological Studies Depression scale (CES-D) questionnaire. Associations between biomarkers of subclinical inflammation and the ADS-L as continuous score were assessed using multiple linear regression models adjusting for age, sex, body mass index, HbA1c, lipids, hypertension, medication and comorbidities. Serum high-sensitivity C-reactive protein (hsCRP) and the ratio of high-molecular-weight (HMW)/total adiponectin were positively associated with ADS-L in T2D (both P<0.01), but not in T1D. In contrast, serum levels of soluble intercellular adhesion molecule (sICAM)-1 were positively associated with ADS-L only in T1D (P=0.035). The latter association was significantly different between both diabetes types (P_interaction=0.036). No associations were observed for interleukin (IL)-6, IL-18 and soluble E-selectin. Only the association between HMW/total adiponectin and ADS-L in T2D remained significant after correction for multiple testing. In conclusion, our study shows that the ratio HMW/total adiponectin is associated with depressive symptoms in individuals with recently diagnosed T2D. It also provides suggestive evidence that further biomarkers of subclinical inflammation and endothelial activation may be associated with depressive symptoms in individuals with recently diagnosed T1D and T2D.

We related organ-specific autoantibodies, including diabetes-associated autoantibodies (DAAs) and non-DAAs to systemic cytokines/chemokines in type 1 and type 2 diabetes.

From the European Action LADA (latent autoimmune diabetes in adults) cohort, patients with adult-onset type 1 diabetes (n = 80, of whom 50 had LADA and 30 had classic type 1 diabetes) and type 2 diabetes (n = 626) were analyzed for DAAs (GAD antibody [GADA], IA-2 antigen, islet cell antibody, and zinc transporter T8), non-DAAs (transglutaminase, thyroid peroxide autoantibodies, parietal cell antibodies), and 10 immune mediator concentrations (measured by LUMINEX).

Type 1 diabetes patients (whether having classic type 1 diabetes or LADA), apart from their clinical phenotype, could not be distinguished by either autoantibodies (both DAAs and non-DAAs) or immune mediators. In type 1 diabetes, most immune mediators (9 of 10) were negatively correlated with DAA titers. Type 2 diabetes patients, who by definition were without DAAs, had fewer non-DAAs (P < 0.0005), but had higher levels of proinflammatory immune mediators, especially compared with patients with type 1 diabetes who had high GADA titers (interleukin [IL]-6 [P < 0.001], soluble E-selectin [P < 0.01], and IL-1 receptor antagonist [P = 0.052], for trend).

Patients with type 1 diabetes had more DAAs and non-DAAs than did those with type 2 diabetes, whereas the frequency and nature of these autoantibodies was broadly similar in classic type 1 diabetes and LADA. Systemic immune mediator levels, in the main, were negatively correlated with DAA titers, and, for some, were higher in patients with type 2 diabetes, especially when compared with patients who had high GADA titers. Differences in the clinical classification of diabetes are associated with graded differences in adaptive and innate immune reactivity.