Critical Amino Acid Variants in HLA-DRB1 and -DQB1 Allotypes in the Development of Classical Type 1 Diabetes and Latent Autoimmune Diabetes in Adults in the Japanese Population.

The effects of amino acid variants encoded by the human leukocyte antigen (HLA) class II on the development of classical type 1 diabetes (T1D) and latent autoimmune diabetes in adults (LADA) have not been fully elucidated. We retrospectively investigated the HLA-DRB1 and -DQB1 genes of 72 patients with classical T1D and 102 patients with LADA in the Japanese population and compared the frequencies of HLA-DRB1 and -DQB1 alleles between these patients and the Japanese populations previously reported by another institution. We also performed a blind association analysis with all amino acid positions in classical T1D and LADA, and compared the associations of HLA-DRB1 and -DQB1 amino acid positions in classical T1D and LADA. The frequency of DRß-Phe-13 was significantly higher and those of DRß-Arg-13 and DQß-Gly-70 were significantly lower in patients with classical T1D and LADA than in controls. The frequencies of DRß-His-13 and DQß-Glu-70 were significantly higher in classical T1D patients than in controls. The frequency of DRß-Ser-13 was significantly lower and that of DQß-Arg-70 was significantly higher in LADA patients than in controls. HLA-DRß1 position 13 and HLA-DQß1 position 70 could be critical amino acid positions in the development of classical T1D and LADA.

Associated autoimmunity in Type 1 Diabetes and latent autoimmune diabetes of adults: The role of glutamic-acid decarboxylase autoantibodies.

AIMS: To determine the prevalence of Associated Autoimmune Diseases (AADs) in Latent Autoimmune Diabetes of Adults (LADA) versus autoimmune Type 1 Diabetes (T1D) and the role of glutamic-acid decarboxylase antibodies (GADA) and other factors. METHODS: Adults with autoimmune diabetes mellitus (DM) were recruited from the Diabetes Center of Nikaia-Piraeus Hospital. Demographic and clinical parameters were recorded and anti-pancreatic and organ-specific antibodies were measured. RESULTS: Of 160 patients, 33.75% had one AAD and 24.37% had two or more. Patients with LADA had higher overall prevalence of AADs, mainly autoimmune thyroiditis and gastritis. Celiac disease was present only in T1D. GADA positive patients had higher prevalence of AADs and multiple autoimmunity, especially thyroiditis and gastritis. Patients with LADA had higher rates of positive GADA or islet-cell antibodies (ICA). After controlling for LADA, GADA remained a significant predictor of AADs. Female gender and chronological age were also significant predictors of AADs. CONCLUSIONS: AADs were present in 58.13% of patients. Patients with LADA were more prone to a generalized autoimmune disorder than those with T1D. AADs development was significantly associated with female sex, older age and positive GADA, which proved an independent marker of associated autoimmunity.

Autoantibodies against zinc transporter 8 further stratify the autoantibody-defined risk for type 1 diabetes in a general population of schoolchildren and have distinctive isoform binding patterns in different forms of autoimmune diabetes: results from the Karlsburg Type 1 Diabetes Risk Study.

AIMS: To evaluate the diagnostic relevance of autoantibodies against zinc transporter 8 (ZnT8) in schoolchildren from the general population as well as in people with autoimmune diabetes. METHODS: A total of 137 schoolchildren positive for at least one of the three major diabetes-associated autoantibodies, without diabetes heredity or preselection on HLA typing, from the Karlsburg Type 1 Diabetes Risk Study, as well as 102 people at type 1 diabetes onset, 88 people with latent autoimmune diabetes in adults and 119 people with type 2 diabetes, were analysed for different ZnT8 autoantibody variants. RESULTS: Zinc transporter 8 autoantibody positivity was found in 18% of autoantibody-positive schoolchildren, with a noticeable association with other autoantibodies associated with type 1 diabetes and disease progression. Furthermore, ZnT8 autoantibody positivity was associated with diabetes progression in schoolchildren positive for autoantibodies against insulinoma-associated antigen-2 (IA-2) and, importantly, in seven IA-2 autoantibody-negative schoolchildren. Additionally, ZnT8 autoantibodies were found in 56% of people with type 1 diabetes, predominantly directed against all three ZnT8 variants and comparable to schoolchildren with multiple autoantibodies. In contrast, ZnT8 autoantibodies were detected in 10% of people with latent autoimmune diabetes in adults, none of them with reactivity to all three isoforms. CONCLUSION: Zinc transporter 8 autoantibodies are useful markers for prediction of type 1 diabetes in a general population, further stratifying the risk of progression in autoantibody-positive children. ZnT8 autoantibodies are also important markers in adult-onset diabetes, with a completely different reaction pattern in type 1 diabetes in comparison to latent autoimmune diabetes in adults, and may therefore help to differentiate between the two forms.

The clinical consequences of heterogeneity within and between different diabetes types.

Advances in molecular methods and the ability to share large population-based datasets are uncovering heterogeneity within diabetes types, and some commonalities between types. Within type 1 diabetes, endotypes have been discovered based on demographic (e.g. age at diagnosis, race/ethnicity), genetic, immunological, histopathological, metabolic and/or clinical course characteristics, with implications for disease prediction, prevention, diagnosis and treatment. In type 2 diabetes, the relative contributions of insulin resistance and beta cell dysfunction are heterogeneous and relate to demographics, genetics and clinical characteristics, with substantial interaction from environmental exposures. Investigators have proposed approaches that vary from simple to complex in combining these data to identify type 2 diabetes clusters relevant to prognosis and treatment. Advances in pharmacogenetics and pharmacodynamics are also improving treatment. Monogenic diabetes is a prime example of how understanding heterogeneity within diabetes types can lead to precision medicine, since phenotype and treatment are affected by which gene is mutated. Heterogeneity also blurs the classic distinctions between diabetes types, and has led to the definition of additional categories, such as latent autoimmune diabetes in adults, type 1.5 diabetes and ketosis-prone diabetes. Furthermore, monogenic diabetes shares many features with type 1 and type 2 diabetes, which make diagnosis difficult. These challenges to the current classification framework in adult and paediatric diabetes require new approaches. The 'palette model' and the 'threshold hypothesis' can be combined to help explain the heterogeneity within and between diabetes types. Leveraging such approaches for therapeutic benefit will be an important next step for precision medicine in diabetes. Graphical abstract.

Decline Pattern of Beta-cell Function in Adult-onset Latent Autoimmune Diabetes: an 8-year Prospective Study.

OBJECTIVE: To explore the decline pattern and possible determinants of beta-cell function progression in patients with latent-onset autoimmune diabetes in adults (LADA). RESEARCH DESIGN AND METHODS: In this 8-year prospective study, 106 LADA individuals underwent annual follow-up and their pattern of beta-cell function progression was assessed. Beta-cell function failure was defined by fasting C-peptide (FCP) < 75 pmol/L. Other clinical characteristics, including age of onset, body mass index (BMI), and glutamic acid decarboxylase autoantibody (GADA) titer, were analyzed to find out possible determinants of beta-cell function progression. RESULTS: The dropout rate was 4.7%. During the 8-year follow-up period, 29 (28.7%) of the 101 subjects developed beta-cell function failure. The decline pattern of C-peptide in LADA was biphasic, showing an initial rapid linear progression and then followed by a stable mode. The declination speed of FCP was 55.19 pmol/L/year (95% CI, -62.54 to -47.84, P < 0.001) during the first 5 years and 4.62 pmol/L/year (95% CI, -69.83 to 60.60, P = 0.790) thereafter. Further analysis showed that GADA titer was the most valuable discriminatory parameter related to a higher risk of development of beta-cell function failure (GADA titer of 173.5 WHO units/mL; area under the curve [AUC], 0.824). Beta-cell function failure occurred in 71.3% of high-GADA titer patients while only 6.2% of low-titer patients. CONCLUSIONS: The decline pattern of C-peptide was a fast-followed-by-slow biphasic mode, with about a quarter of LADA patients developing beta-cell function failure during the first 8 years. GADA titer less than 173.5 WHO units /mL was propitious for the preservation of beta-cell function.

Beware Ketoacidosis with SGLT2 Inhibitors in Latent Autoimmune Diabetes of the Adult.

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are increasingly used for the treatment of type 2 diabetes, but have been associated with ketoacidosis. METHODS/RESULTS: We report a case series of three patients with latent autoimmune diabetes of the adult who presented with ketoacidosis, including one case with normal blood glucose levels, in the context of SGLT2 inhibitor use. CONCLUSIONS: Sodium-glucose co-transporter-2 inhibitors should be used with caution and close clinical monitoring in patients with latent autoimmune diabetes of the adult. A clinical risk score permits targeted autoantibody testing and should be undertaken prior to commencement of SGLT2 inhibitors or cessation of insulin.

Glutamic Acid Decarboxylase Autoantibody Detection by Electrochemiluminescence Assay Identifies Latent Autoimmune Diabetes in Adults with Poor Islet Function.

BACKGROUND: The detection of glutamic acid decarboxylase 65 (GAD65) autoantibodies is essential for the prediction and diagnosis of latent autoimmune diabetes in adults (LADA). The aim of the current study was to compare a newly developed electrochemiluminescence (ECL)-GAD65 antibody assay with the established radiobinding assay, and to explore whether the new assay could be used to define LADA more precisely. METHODS: Serum samples were harvested from 141 patients with LADA, 95 with type 1 diabetes mellitus, and 99 with type 2 diabetes mellitus, and tested for GAD65 autoantibodies using both the radiobinding assay and ECL assay. A glutamic acid decarboxylase antibodies (GADA) competition assay was also performed to assess antibody affinity. Furthermore, the clinical features of these patients were compared. RESULTS: Eighty-eight out of 141 serum samples (62.4%) from LADA patients were GAD65 antibody-positive by ECL assay. Compared with ECL-GAD65 antibody-negative patients, ECL-GAD65 antibody-positive patients were leaner (P<0.0001), had poorer ß-cell function (P<0.05), and were more likely to have other diabetes-associated autoantibodies. The ß-cell function of ECL-GAD65 antibody-positive patients was similar to that of type 1 diabetes mellitus patients, whereas ECL-GAD65 antibody-negative patients were more similar to type 2 diabetes mellitus patients. CONCLUSION: Patients with ECL-GAD65 antibody-negative share a similar phenotype with type 2 diabetes mellitus patients, whereas patients with ECL-GAD65 antibody-positive resemble those with type 1 diabetes mellitus. Thus, the detection of GADA using ECL may help to identify the subtype of LADA.

Interleukin-6 and Interleukin-15 as Possible Biomarkers of the Risk of Autoimmune Diabetes Development.

AIM: The aim of our study was to assay circulating interleukin-15 (IL-15) and interleukin-6 (IL-6) levels and insulin resistance measured by two different methods in newly diagnosed autoimmune diabetes (AD) patients, their I° relatives, and healthy controls. MATERIAL AND METHODS: The group studied consisted of 54 patients with AD (28 with Latent Autoimmune Diabetes in Adults (LADA) and 26 with type 1 diabetes (T1D)), 70 first-degree relatives, and 60 controls. IL-6, IL-15, and anti-islet antibodies concentrations were measured by ELISA method. Homeostatic model assessment-insulin resistance (HOMAIR) and estimated glucose disposal rate (eGDR) were calculated. RESULTS: The patients with AD had significantly higher IL-15, IL-6, and HOMAIR and lower eGDR than the controls (p < 0.001, respectively) and first-degree relatives (p < 0.001, respectively). Significantly higher IL-15 and IL-6 were shown in the relatives with positive Ab as compared to the relatives without antibodies (p < 0.001, respectively) and the controls (p < 0.001, respectively). IL-15 negatively correlated with eGDR (r = -0.436, p = 0.021) in LADA and positively with HOMAIR in LADA and T1D (r = 0.507, p < 0.001; r = 0.4209, p < 0.001). CONCLUSIONS: Significantly higher IL-15 and IL-6 concentrations, HOMAIR, and markedly lower eGDR in newly diagnosed AD patients and first-degree relatives with positive anti-islet antibodies might suggest the role of these pro-inflammatory cytokines and insulin resistance in the pathogenesis of autoimmune diabetes. IL-15 and IL-6 might be used as biomarkers of the risk of autoimmune diabetes development, in particular IL-15 for LADA. Both methods of IR measurement appear equally useful for calculating insulin resistance in autoimmune diabetes.

[Features of the development of latent autoimmune diabetes in adults (LADA)]. / Osobennosti razvitiia latentnogo diabeta vzroslykh (LADA).

The study of the sociomedical problems of diabetes mellitus led to the discovery of latent autoimmune diabetes in adults (LADA), a special form of the disease. The slow onset of the disease, the clinical signs of type 2 diabetes mellitus concurrent with the autoantibody pancreatic ß-cell destruction mechanism that is characteristic of type 1 diabetes. Genetic factors play an important role in the genesis of the disease. Insulitis concurrent with intact or hypertrophic islets of the gland originally develops morphologically. Subsequently, the phenomena of islet atrophy and sclerosis are progressive. The disease is typical for young people (generally those aged 25-35 years) with normal body mass index, low blood C-peptide levels, with antibodies against ß-cells, primarily to glutamate decarboxylase, being detected. Insulin preparations should be used to treat these patients.

Clinical manifestation and islet ß-cell function of a subtype of latent autoimmune diabetes in adults (LADA): positive for T cell responses in phenotypic type 2 diabetes.

AIMS: To investigate the possibility of identifying a subtype of latent autoimmune diabetes in adults (LADA), T-LADA (T cell responses-positive and autoantibody-negative) from patients with phenotypic type 2 diabetes (T2D) by enzyme-linked immunospot (ELISPOT). METHODS: Eighty-two patients with phenotypic T2D were studied. Autoantibodies against glutamic acid decarboxylase (GAD), insulinoma-associated protein-2 and zinc transporter 8 were measured by radioligand assay. Thirty-nine Ab+ and 43 Ab- patients with phenotypic T2D were enrolled for T cell assay of responses to GAD65 and C-peptide antigen by ELISPOT. RESULTS: (1) Eleven of 43 Ab- participants with phenotypic T2D were demonstrated interferon (IFN)-γ secreting T cells by ELISPOT, while 13 of 39 Ab+ patients with phenotypic T2D were positive for T cells responses to islet antigens. (2) The onset ages of T cell+ people with phenotypic T2D were younger than that of T cell- individuals (42.7 ± 9.3 vs. 48.2 ± 10.2 years, P = 0.025). Moreover, T cell+ patients with T2D displayed a significantly lower fasting C-peptide (FCP) compared with T cell- participants [0.28 (0.02-0.84) vs. 0.42 (0.05-1.26) nmol/L, P = 0.013]. (3) Ab-T+ group had a significantly lower FCP compared with Ab-T- group [0.31 (0.13-0.84) vs. 0.51 (0.07-1.26) nmol/L, P = 0.023]. CONCLUSIONS: By measuring T cell responses to islet antigens in patients with phenotypic T2D, we identified a specific subtype of LADA who may be associated with worse basal ß-cell function than classic T2D (Ab-T-).

Long-term risk of cardiovascular disease in individuals with latent autoimmune diabetes in adults (UKPDS 85).

AIMS: 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. MATERIALS AND METHODS: 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). RESULTS: 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 (HRadj , 0.90; 95% CI, 0.76-1.07; P = 0.22). CONCLUSIONS: 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.

Cellular immunological changes in patients with LADA are a mixture of those seen in patients with type 1 and type 2 diabetes.

There is currently scarce knowledge of the immunological profile of patients with latent autoimmune diabetes mellitus in the adult (LADA) when compared with healthy controls (HC) and patients with classical type 1 diabetes (T1D) and type 2 diabetes (T2D). The objective of this study was to investigate the cellular immunological profile of LADA patients and compare to HC and patients with T1D and T2D. All patients and age-matched HC were recruited from Uppsala County. Peripheral blood mononuclear cells were isolated from freshly collected blood to determine the proportions of immune cells by flow cytometry. Plasma concentrations of the cytokine interleukin (IL)-35 were measured by enzyme-linked immunosorbent assay (ELISA). The proportion of CD11c+ CD123- antigen-presenting cells (APCs) was lower, while the proportions of CD11c+ CD123+ APCs and IL-35+ tolerogenic APCs were higher in LADA patients than in T1D patients. The proportion of CD3- CD56high CD16+ natural killer (NK) cells was higher in LADA patients than in both HC and T2D patients. The frequency of IL-35+ regulatory T cells and plasma IL-35 concentrations in LADA patients were similar to those in T1D and T2D patients, but lower than in HC. The proportion of regulatory B cells in LADA patients was higher than in healthy controls, T1D and T2D patients, and the frequency of IL-35+ regulatory B cells was higher than in T1D patients. LADA presents a mixed cellular immunological pattern with features overlapping with both T1D and T2D.

Immunological and clinical characteristics of latent autoimmune diabetes in the elderly.

BACKGROUND: Latent autoimmune diabetes in adults (LADA) is determined by both a noninsulin-dependent clinical presentation and an autoimmune pathogenic process. Glutamic acid decarboxylase antibody (GADA) constitutes the most important marker, although IA-2A and ZnT8A also define LADA presentation. Type 2 diabetes mellitus (T2DM) is the most prevalent type particularly over 65 years old. Studies about autoimmunity in this age group are scarce. OBJECTIVE: The aim of this work was to determine whether three autoantibodies for diabetes autoimmunity were present in elderly T2DM patients, and to assess the distinctive clinical features of autoantibody-positive patients. RESEARCH DESIGN AND METHODS: We recruited 153 patients with diabetes with onset of diabetes after 65 years of age and a BMI under 30 kg/m2 . RESULTS: The prevalence of at least one of the autoantibodies was 15.68% (24/153). The most prevalent autoantibody was GADA with 8.49% (13/153), followed by ZnT8A with 6.50% (10/153) and IA2A with 1.96% (3/153). The autoimmunity-positive group presented higher HbA1c (7.01 ± 1.98 vs 6.35 ± 1.01; P = 0.007) and more prevalent insulin therapy (25% vs 10.85%; P = 0.047). GADA-positive patients with diabetes presented higher FPG (7.79 ± 3.79 mmol/L vs 6.43 ± 1.6 mmol/L; P = 0.014) and insulin therapy more frequently (46% vs 10.71%; p = 0.015). GADA titre levels in the individuals with BMI under 27 kg/m2 were higher (35.00 ± 4.20) than those in the group with BMI over 27 kg/m2 (8.83 ± 3.041; P = 0.0005). CONCLUSION: Autoantibodies GADA and Znt8A may be useful markers in identifying a subgroup of older patients with a clinical presentation of diabetes which could be characterized as latent autoimmune diabetes in the elderly.

Altered T-cell subsets and transcription factors in latent autoimmune diabetes in adults taking sitagliptin, a dipeptidyl peptidase-4 inhibitor: A 1-year open-label randomized controlled trial.

AIMS/INTRODUCTION: Dipeptidyl peptidase-4 inhibitor has been proven to improve glycemic control and ß-cell function in latent autoimmune diabetes in adults (LADA). The potential immune modulation mechanism is still unknown. Thus, we tested T-lymphocyte subsets and expression of relevant transcription factors in LADA patients with sitagliptin intervention for up to 1-year. MATERIALS AND METHODS: A total of 40 LADA patients were randomly assigned to sitagliptin and/or insulin treatment (SITA group; n = 20) or insulin alone treatment (CONT group; n = 20). Peripheral blood mononuclear cells were isolated at baseline, 6 months and 12 months. The percentage of T-lymphocyte subsets (T helper 1, T helper 2, T helper 17 and regulatory T cells) tested by flow cytometry, and the messenger ribonucleic acid expression (T box expressed in T cells [T-BET], GATA binding protein 3 [GATA3], forkhead box protein 3 [FOXP3] and related orphan receptor C [RORC]) tested by real-time polymerase chain reaction were determined at baseline, 6 months and 12 months. RESULTS: The percentage of regulatory T cells in the SITA group was significantly lower than that of the CONT group at baseline. The percentage of T helper 2 cells was higher than that of the CONT group at 6 months and 12 months. At 12 months, the percentage of T helper 17 cells was lower in the SITA group than that of the CONT group. After a 1-year visit, the messenger ribonucleic acid expression levels of T-BET expressed in T cells and RORC in the SITA group were significantly lower than at baseline. Whereas that of RORC in the CONT group were significantly lower than that at baseline. CONCLUSIONS: The data confirmed that sitagliptin altered the phenotype of T cells and downregulated the expression of T-BET and RORC in LADA patients, and ameliorated glycemic control in LADA patients.

Tetraspanin 7 autoantibodies predict progressive decline of beta cell function in individuals with LADA.

AIMS/HYPOTHESIS: The aim of this work was to investigate whether tetraspanin 7 autoantibodies (TSPAN7A) are valuable in predicting poor beta cell function in individuals with latent autoimmune diabetes in adults (LADA). METHODS: The cross-sectional study involved participants with LADA (n = 173), type 1 diabetes (n = 158), type 2 diabetes (n = 204) and healthy control participants (n = 170). The longitudinal study involved 53 participants with LADA, with a 3-year follow-up. In both cohorts, TSPAN7A in the sera were measured by a luciferase immunoprecipitation system assay, and physical and clinical characteristics were recorded. RESULTS: The prevalence of TSPAN7A in LADA, type 1 diabetes, type 2 diabetes and healthy control participants was 21.4% (37/173), 26% (41/158), 0.5% (1/204) and 1.2% (2/170), respectively. Importantly, measurement of TSPAN7A significantly increased the number of individuals with LADA found to be positive for multiple antibodies (32.4% vs 22%; p < 0.001). Further logistic regression analysis demonstrated that positivity for TSPAN7A (OR 2.87, p = 0.034), disease duration (OR 1.83, p = 0.019) and GAD antibody titre (OR 2.67, p = 0.009) were risk factors for beta cell function in LADA, while BMI (OR 0.34, p = 0.001) was a protective factor. In the prospective study in individuals with LADA, the median annual decrease in rates of fasting C-peptide and 2 h postprandial C-peptide in individuals who were positive for TSPAN7A was significantly higher when compared with the decrease in those who were negative for TSPAN7A (34.6% vs 7.9%, p = 0.043 and 33.2% vs 11%, p = 0.041, respectively). CONCLUSIONS/INTERPRETATION: TSPAN7A are valid islet autoantibodies for use in East Asian populations with autoimmune diabetes and can discriminate individuals with LADA who have lower beta cell function after disease progression.

First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes.

OBJECTIVE: Latent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype. RESEARCH DESIGN AND METHODS: We performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10,396). RESULTS: The leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes. CONCLUSIONS: Our results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.

A Global Perspective of Latent Autoimmune Diabetes in Adults.

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.

Autoimmunity-Associated PTPN22 Polymorphisms in Latent Autoimmune Diabetes of the Adult Differ from Those of Type 1 Diabetes Patients.

BACKGROUND: A portion of adults with humoral immune changes have clinical diabetes that is initially not insulin-requiring (latent autoimmune diabetes of the adult, LADA). One of the genes strongly associated with autoimmune diabetes is PTPN22. We hypothesized that the manifestation and clinical features of LADA are linked to functional variants of PTPN22. METHODS: We genotyped allelic frequencies of 1 protective and 3 risk-associated PTPN22 variants in 156 Czech LADA patients, 194 type 2 diabetes mellitus patients with LADA-like progression to insulinotherapy and 324 type 1 diabetes mellitus patients, and subsequently examined the associations of PTPN22 variants with the expression of autoantibodies and other clinical features of LADA. RESULTS: We challenged the paradigm that stated that the PTPN22 c.1858T allele serves as a risk allele for LADA, although we confirmed its risk status in the geographically matched T1DM cohort. In contrast, the frequencies of other PTPN22 alleles (c.-1123C, c.788A and c.1970-852C) differed significantly from the healthy controls. We confirmed gender-related differences in the frequency of some PTPN22 polymorphisms (but not c.1858C>T) in LADA. The particular PTPN22 alleles and genotypes were associated with specific clinical features of the examined patients (autoantibodies, HbA1c and age at diagnosis of diabetes). CONCLUSIONS: The variability in PTPN22 haplotypes suggests that the genetic signature of LADA is independent and should not be considered a hybrid form of T1DM and T2DM. Further studies should elucidate the associations with clinical characteristics of the LADA patients and focus on the newly emerging types of diabetes with the disease onset in early to mid-adulthood.

Leptin Levels and Insulin Dependence in Latent Autoimmune Diabetes in Adults.

Latent autoimmune diabetes in adults (LADA) is an autoimmune type of diabetes accounting for up to 10% of all cases of diabetes initially diagnosed as type 2 diabetes mellitus. It has been demonstrated that LADA patients with a lower body mass index (BMI) undergo a faster depletion of beta cell function and require insulin therapy earlier. In this study, we assayed a panel of adipokines (leptin, adiponectin, omentin, resistin, visfatin) and proinflammatory cytokines (interleukin 2, interleukin 6, tumor necrosis factor-α) in 71 LADA patients and tested the association with a number of clinical and immunological features. Among men, leptin was positively and significantly correlated with BMI and fat mass (r = 0.487 and r = 0.664, respectively), resistin was positively and significantly correlated with total and low-density lipoprotein cholesterol (r = 0.644 and r = 0.746, P < 0.0001) and with interleukin 2 (r = 0.688, P < 0.01). Omentin showed an inverse correlation with systolic blood pressure in women (r = -0.359, P < 0.001) and a positive correlation with interleukin 2 in both genders (r = 0.395, P < 0.01). The Cox regression analysis showed that leptin levels were inversely and significantly related with the risk of early insulin dependence. Higher leptin secretion may exert a direct effect on beta cell function leading to more insulin sensitivity.