Adult-onset Autoimmune Diabetes Research Articles

227-LB: Kynurenine Pathway Is Associated with Preservation of Beta-Cell Function in Autoimmune Diabetes

Background: Autoimmune diabetes (AD) results from a loss of immune tolerance leading to the destruction of β-cells in the pancreas. Heterogeneity in severity of β-cell damage among people with AD is well-recognized, with some patients retaining a certain amount of insulin-producing cells for years despite the presence of pancreatic autoimmunity. Cellular and molecular mechanisms driving the preservation of β-cell function in AD remain unclear. Aim & Methods: To identify metabolic pathways associated with preservation of β-cell function we conducted a metabolomic study using gas and liquid chromatography-mass spectrometry (GC- and LC-MS) based platform on plasma samples collected from 32 subjects with adult-onset AD (median [Q1-Q3] age: 57 [52-62]; disease duration: 4.5 [3.0-9.0] years) with different severity of β-cell dysfunction, compared with data from people with rheumatoid arthritis (RA, n=28). Metabolome profiles of pancreatic islets from healthy donors after in vitro treatment with proinflammatory cytokines was also evaluated. Results: Metabolomic analyses showed decreased plasma Kynurenine/Tryptophan ratio (KynTr), a marker of indoleamine 2,3 dioxygenase-1 (IDO1) activity, in people with AD compared to RA (0.023 vs 0.027, p=0.03). Among people with AD, KynTr was directly associated with fasting C-peptide levels (rho=0.365), independently of age, gender, body mass index, diabetes duration and Hba1c (p-value after adjustments= 0.003). Lower concentrations of Tryptophan was observed in pancreatic islets from healthy donors after treatment with proinflammatory cytokines. Conclusions: While confirming that IDO1 impairment is involved in the pathogenesis of AD and in the regulation of inflammatory response of pancreatic islets, our results show that KynTr is a marker of beta-cell damage in AD. Overall, this suggests that the kynurenine pathway may be studied as a possible target for therapies aimed at preserving beta-cell function also after a diagnosis of AD Disclosure E. Maddaloni: Consultant; Abbott, Merck KGaA, PIKDARE S. p. A., Speaker's Bureau; Medical Technology & Devices. F. Dotta: None. P. Marchetti: None. R. Buzzetti: None. A. Gastaldelli: Advisory Panel; Pfizer Inc., Novo Nordisk, Merck Sharp & Dohme Corp., Boehringer Ingelheim International GmbH, Consultant; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Fractyl Health, Inc., Merck Sharp & Dohme Corp., Other Relationship; Pfizer Inc., Speaker's Bureau; Eli Lilly and Company. L. Navarini: Consultant; AbbVie Inc., Pfizer Inc., Bristol Myers, Celgene, MSD Life Science Foundation, Eli Lilly and Company, Novartis, Janssen Global Services, LLC. R. Amendolara: None. S. Fenizia: None. S. Pezzica: None. M. Tesi: None. L. D'onofrio: None. E. Bosi: None. Funding Italian Ministry of University and Research (PRIN 2017: 20175L9H7H)

Co-Occurring NMDA-Receptor and Anti-GAD65 Antibodies in the CSF of a Patient With Encephalitis: Case Report

Objective We describe a 58-year-old woman who presented with rapid cognitive changes and was found to have concurrent CSF NMDA and GAD65 receptor antibodies. Background Antibodies against NMDA and GAD65 receptors are associated with highly morbid autoimmune encephalitides. One case of co-occurring NMDA-R and anti-GAD65 antibodies in a patient with progressive cognitive changes and type I diabetes has previously been described. Herein, we describe a case of a previously high-functioning woman who experienced rapidly progressive cognitive changes secondary to autoimmune encephalitis (AE) with co-existent NMDAR and GAD65 antibodies. Design/Methods NA. Results A 58-year-old woman with adult-onset insulin-dependent diabetes mellitus, hypertension, and prior left-sided Bell's palsy presented to medical care for subacute cognitive decline characterized initially by inattention and difficulty with activities of daily living, progressing to profound global aphasia and seizures. Diagnostic testing revealed GAD65 antibody positivity in serum (33 nmol/L) and CSF (17.3 nmol/L) and negative serum but positive CSF NMDAR antibody. CSF showed pleocytosis (37 nucleated cells, 97% lymphocytes), elevated glucose (109 mg/dL), and normal protein (41 mg/dL). EEG showed right temporal epileptiform discharges. MRI was unrevealing. She was treated with IV steroids, IVIg, and rituximab, and has slowly improved on follow-up. Conclusions Co-existent CSF anti-NMDAR and anti-GAD65 AE is not well-described in the literature. While this patient's serum GAD65 titer was in a range that correlates with neurologic autoimmunity, it was not as high as is typically reported in AE, and could simply be a marker of her insulin-dependent diabetes. However, it was also definitively positive from the CSF, which usually correlates well with GAD65-associated AE. Clinically, the patient had AE features that can be seen associated with either NMDAR and/or GAD65 antibodies. It is interesting to consider whether the GAD65 positivity is most likely to correlate with the patient's adult-onset diabetes, her AE, or both.

Adult-onset autoimmune diabetes.

Adult-onset autoimmune (AOA) diabetes pathophysiology starts with immune changes, followed by dysglycaemia and overt disease. AOA diabetes can occur as classic type 1 diabetes when associated with severe loss of insulin secretion. More frequently, it is diagnosed as latent autoimmune diabetes in adults, a slowly progressing form with late onset, a long period not requiring insulin, and it is often misdiagnosed as type 2 diabetes. As its clinical presentation varies remarkably and immune markers often lack specificity, it is challenging to classify each case ad hoc, especially when insulin treatment is not required at diagnosis. Proper care of AOA diabetes aims to prevent complications and to improve quality of life and life expectancy. To achieve these goals, attention should be paid to lifestyle factors, with the aid of pharmacological therapies properly tailored to each individual clinical setting. Given the heterogeneity of the disease, choosing the right therapy for AOA diabetes is challenging. Most of the trials testing disease-modifying therapies for autoimmune diabetes are conducted in people with childhood onset, whereas non-insulin diabetes therapies have mostly been studied in the larger population with type 2 diabetes. More randomized controlled trials of therapeutic agents in AOA diabetes are needed.

Abstract #1185216: Adult-onset autoimmune diabetes revealed in a postpartum female with gestational diabetes

Latent autoimmune diabetes of adulthood (LADA) is an autoimmune disease characterized by adult onset of diabetes due to the presence of circulating autoantibodies. This disease is often challenging to diagnose due to the atypical age of onset. A known risk factor for LADA is a form of gestational diabetes (GDM) known as autoimmune gestational diabetes (AGD). AGD accounts for only 10% of GDM and carries a high risk for the development of LADA after pregnancy as its causative factor is islet cell autoantibodies that lead to the destruction of beta cells in the pancreas.

Adult-onset autoimmune diabetes identified by glutamic acid decarboxylase autoantibodies: a retrospective cohort study.

Patients with GAD antibodies (GADAb) showing clinical features of type 2 diabetes typically exhibit progression to an insulin-dependent state in several months or years. This condition is diagnosed as slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) or latent autoimmune diabetes in adults, a subtype of adult-onset autoimmune diabetes. However, some patients diagnosed with adult-onset autoimmune diabetes do not progress to an insulin-dependent state. We conducted a retrospective cohort study to identify patients with non-insulin-dependent diabetes among those diagnosed with adult-onset autoimmune diabetes using measurable indicators in routine clinical practice. We surveyed data from the electronic medical records of all patients with GADAb from eight medical centres in Japan for selecting and analysing patients who matched the diagnostic criteria of SPIDDM. Overall, 345 patients were analysed; of these, 162 initiated insulin therapy (insulin therapy group), whereas 183 did not (non-insulin therapy group) during the follow-up period (median 3.0years). Patients in the non-insulin therapy group were more likely to be male and presented a later diabetes onset, shorter duration of diabetes, higher BMI, higher blood pressure levels, lower HbA1c levels, lower GADAb levels and lesser antidiabetic agent use than those in the insulin therapy group when GADAb was first identified as positive. A Cox proportional hazards model showed that BMI, HbA1c levels and GADAb levels were independent factors for progression to insulin therapy. Kaplan-Meier analyses revealed that 86.0% of the patients with diabetes having GADAb who presented all three factors (BMI ≥ 22kg/m2, HbA1c < 75mmol/mol [9.0%] and GADAb <10.0U/ml) did not require insulin therapy for 4years. Higher BMI (≥22kg/m2), lower HbA1c (<75mmol/mol [9.0%]) and lower GADAb levels (<10.0U/ml) can predict a non-insulin-dependent state for at least several years in Japanese patients with diabetes having GADAb.

168-LB: Latent Autoimmune Diabetes in Youth (15–29 Years Old): The Heavier End of an Autoimmune Disease Spectrum

Context: Latent autoimmune diabetes in youth (LADY) falls in a grey zone of the current diabetes scheme due to the lack of established definition and diagnosis criteria. Objective: To investigate the prevalence and clinical features of LADY patients between 15-29 years old as a component of an age-related continuous diabetes spectrum. Methods: This nationwide, multi-center, cross-sectional study included 1803 newly diagnosed diabetic youth of 15-29 years old across China from April 2015 to October 2017. Glutamic acid decarboxylase autoantibody (GADA) was screened in 1508 phenotypic T2DM subjects and those with positive GADA were defined as LADY. Metabolic status, insulin resistance and residual β-cell function of LADY were investigated and compared with other 658 adult-onset latent autoimmune diabetes (LADA) patients enrolled at the same time. The age-related characteristics of the latent autoimmune diabetes spectrum were explored. Results: LADY accounted for 7.9% (119/1508) of the phenotypic T2DM youth. Compared with GADA-negative T2DM youth, LADY patients had better metabolic control, less insulin resistance, and lower levels of β-cell function, which were closely related to their GADA levels (all P &amp;lt; 0.05). After stratifying LADA patients according to their age of onset, the GADA level decreased across the LADY, ‘Y-LADA’ (young LADA, age of onset &amp;lt;60 years old) and ‘E-LADA’ (elderly LADA, age of onset ≥60 years old) groups, with the prevalence of metabolic syndrome, levels of insulin resistance and residual β-cell function presenting an increasing trend (all P &amp;lt;0.05). Conclusions: A high prevalence of LADY exist in phenotypic T2DM youth. The latent autoimmune diabetes occurred at different ages formed a continuous clinical spectrum from LADY to LADA, in which the LADY patients carried heavier autoimmune load. Disclosure J. Cheng: None. X. Tang: None. X. Yan: None. S. Luo: None. X. Li: None. Z. Zhou: None. Funding National Science and Technology Infrastructure Program (2013BAI09B12, 2015BAI12B13); National Key R&amp;D Program of China (2016YFC1305000, 2017YFC1309604)

Late-onset type 1 diabetes mellitus or latent autoimmune diabetes in adults: a teachable moment

Adult-onset autoimmune diabetes (AOAD) is clinical form of diabetes with a wide spectrum of genotypical and phenotypical manifestations, which has risen in prominence in recent decades, probably due to greater interest in its pathogenic mechanisms, and increased identification of autoimmune markers. The clinical presentation may vary from type 1 diabetes mellitus to latent autoimmune diabetes in adults, which although clearly distinct from a theoretical viewpoint, may pose various clinical pitfalls in practice. We present the case of a patient with AOAD which featured several diagnostic challenges during follow-up.

1076-P: A 12-Week Treatment with Ciclosporin A Improves Insulin Secretion in Patients with Adult-Onset Autoimmune Diabetes: An Open-Label, Single-Arm, Pilot Study

Objectives: Adult-onset autoimmune diabetes, defined as having latent autoimmune diabetes in adults (LADA), is characterized by a less intensive autoimmune process, in which a lymphocytic infiltration of the exocrine pancreas is involved. immunosuppressive agents may have potential therapeutic benefit. This is a pilot study examining the therapeutic effects of ciclosporin A on insulin secretion in patients with LADA. Methods: The study was an open label, single arm, pilot trial. A total of 18 patients (12 men and 6 women with mean age of 40.6 yrs old) diagnosed with LADA were prospectively evaluated. All patients underwent insulin treatment at least for 3 months without any oral anti-hyperglycemic agent. All patients were prescribed ciclosporin A (50mg/day) for 12 weeks. Serum C-peptide concentrations were measured at baseline and 3 months after ciclosporin A intervention. We also evaluated total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine (Cre) before and after ciclosporin A treatment. The primary outcome of the study was the change in serum C-peptide concentrations. Results: A total of 17 patients completed the study. One patient was withdrawn at day 32 due to discontinuation of medication. Serum fasting C-peptide concentrations significantly increased from 0.12 ng/ml up to 0.32 ng/ml (P&amp;lt;0.001). After 12-week ciclosporin A intervention, there was no significant difference on TBIL (14.65 vs. 12.83umol/L, P&amp;gt;0.05), DBIL (4.70 vs. 4.65 umol/L, P&amp;gt;0.05), AST (17.41 vs. 17.82 U/L, p&amp;gt;0.05), ALT (18.19 vs. 18.08 U/L, p&amp;gt;0.05), or Cre (67.40 vs. 67.53 umol/L, P&amp;gt;0.05) compared with the corresponding baseline levels. Conclusions: This pilot study demonstrates the potential therapeutic effects of oral administration of ciclosporin A for patients with LADA. Larger, controlled studies are needed to verify the findings. Disclosure L. Zhang: None. W. Meng: None. S. Chen: None. Y. Yang: None. J. Wang: None. Y. Dong: None.

A convenient diagnostic tool for discriminating adult-onset glutamic acid decarboxylase antibody-positive autoimmune diabetes from type 2 diabetes: a retrospective study.

BackgroundThe glutamic acid decarboxylase antibody (GADA) test, commonly used to diagnose autoimmune diabetes, is not cost-effective in areas of low prevalence. The aim of this study was to develop a convenient tool to discriminate adult-onset GADA-positive autoimmune diabetes from type 2 diabetes (T2DM) in patients with newly diagnosed diabetes.MethodsThis retrospective cross-sectional study, conducted at Changhua Christian Hospital in Taiwan, collected electronic medical record data from January 2009 to December 2018. Patients were divided into a case group (GADA+, n = 152) and a reference group (T2DM, n = 358). Variables that differed significantly between the groups were subjected to receiver operator characteristic analysis to establish cutoff values. Discriminant function analysis was then employed to discriminate the two groups.ResultsAt the onset of diabetes, the GADA+ group was younger, with lower body mass index (BMI), higher hemoglobin A1c (HbA1c), higher high-density lipoprotein cholesterol (HDL-C), and lower total cholesterol and triglycerides (TG). Five major factors were identified to form the linear discriminant functions: BMI, age at onset, TG, HDL-C, and HbA1c. BMI < 23 kg/m2 was the most important factor, followed by TG < 98 mg/dL, HDL-C ≥ 46 mg/dL, age at onset < 30 years, and HbA1c ≥ 8.6%. The overall accuracy of the linear discriminant functions was 87.1%, with 84.2% sensitivity and 88.3% specificity.ConclusionsRoutine tests in diabetes care were used to establish a convenient, low-cost tool that may assist in the early identification of adult-onset GAD+ autoimmune diabetes in clinical practice.

Latent autoimmune diabetes in adults (LADA)

Autoimmune diabetes is a heterogeneous disease which can appear at any age. Patients with adult-onset autoimmune diabetes who do not necessitate insulin therapy for at least 6 months after diagnosis are classified as having latent autoimmune diabetes in adults (LADA).

HLA-DQB1 and HLA-DRB1 Variants Confer Susceptibility to Latent Autoimmune Diabetes in Adults: Relative Predispositional Effects among Allele Groups.

Latent autoimmune diabetes in adults (LADA) was recently demonstrated to be the most frequent form of adult-onset autoimmune diabetes mellitus. Case–control studies have investigated the relationship between human leukocyte antigen (HLA)-DQB1 and HLA-DRB1 polymorphisms and LADA risk, but their conclusions are inconsistent. This study aimed to more precisely explore the correlation between these HLA gene variants and LADA development. Eight databases, including PubMed, Embase, and Medline, were systematically searched for relevant studies up to September 15, 2018. We performed this retrospective study using meta-analysis and relative predispositional effect (RPE) methods. The meta-analysis results indicated that DQB1*02 (odds ratio (OR) = 1.685, pc < 0.005) and DQB1*06 (OR = 0.604, pc = 0.010) have opposite effects on susceptibility to LADA, while a significant decrease in LADA risk caused by DQB1*05 (OR = 0.764, pc = 0.100) disappeared upon Bonferroni correction. The RPE method confirmed the roles of DQB1*02 (χ² = 46.475, p < 0.001) and DQB1*06 (χ² = 17.883, p < 0.001) and further suggested protective effects of DQB1*05 (χ² = 16.496, p < 0.001). Additionally, the meta-analysis results showed that DRB1*03 (OR = 2.685, pc < 0.013), DRB1*04 (OR = 1.954, pc < 0.013), and DRB1*09 (OR = 1.346, pc < 0.013) are associated with increased LADA risk, while DRB1*12 (OR = 0.600, pc < 0.013) and DRB1*13 (OR = 0.583, pc < 0.013) carriers have a decreased risk of developing LADA. Furthermore, the RPE method revealed that DRB1*03 (χ² = 98.754, p < 0.001), DRB1*04 (χ² = 94.685, p < 0.001), DRB1*09 (χ² = 40.489, p < 0.001), DRB1*01 (χ² = 12.181, p < 0.001), DRB1*07 (χ² = 10.882, p = 0.001), and DRB1*08 (χ² = 5.000, p = 0.025) play protective roles against LADA. LADA showed a close relationship with genetic polymorphisms of HLA-DQB1 and WHLA-DRB1, which could contribute to a better understanding of disease pathogenesis and the identification of predisposing loci in the diagnosis and treatment of LADA.

1147-P: Effect of Short-Term Ciclosporin A Treatment on Insulin Secretion in Patients with Adult-Onset Autoimmune Diabetes: An Open-Label, Single-Arm, Pilot Study in China

Adult-onset autoimmune diabetes, defined as having latent autoimmune diabetes in adults (LADA), is characterized by a less intensive autoimmune process, in which a lymphocytic infiltration of the exocrine pancreas is involved. Immunosuppressive agents may have potential therapeutic benefit. This is a pilot study examining the therapeutic effects of oral administration of ciclosporin A on insulin secretion in patients with LADA. The study was an open label, single arm, pilot trial. A total of 12 patients (8 men and 4 women with mean age of 40.2 years old) diagnosed with LADA were prospectively evaluated. All patients underwent insulin treatment at least for 3 months without any oral anti-hyperglycemic agent. Serum C-peptide concentrations were measured at baseline and after ciclosporin A intervention. We also evaluated clinical parameters including total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine (Cre) before and after ciclosporin A treatment. The primary outcome of the study was the change in serum C-peptide concentrations. A total of 12 patients completed the study. No patient was withdrawn. Serum fasting C-peptide concentrations significantly increased from 0.10 ng/ml up to 0.32 ng/ml, following treatment with ciclosporin A (50mg/day) for 4 weeks (P&amp;lt;0.001). After 4-week ciclosporin A intervention, there was no significant difference on TBIL (14.33 vs. 13.70 umol/L, P=0.59), DBIL(4.31 vs. 4.63 umol/L, P=0.48), AST(16.83 vs. 18.50 U/L, p=0.09), ALT(17.17 vs. 18.16 U/L, p=0.35), or Cre (67.17 vs. 66.01 umol/L, P=0.25) compared with the corresponding baseline levels. This pilot study demonstrates the potential therapeutic effects of oral administration of ciclosporin A for patients with LADA. No significant adverse effects of the drug were observed. Larger, controlled studies are needed to verify the results. Disclosure L. Zhang: None. J. Wang: None. N. Wang: None. Y. Yang: None. X. Yin: None. Y. Dong: None.

Type 1 Diabetes-related Autoantibodies in Different Forms of Diabetes.

Autoantibodies against Glutamic Acid Decarboxylase (GADA), insulinoma antigen-2 (IA- 2A), insulin (IAA) and the most recently Zinc Transporter 8 (ZnT8A) are one of the most reliable biomarkers for autoimmune diabetes in both children and adults. They are today the only biomarkers that can distinguish Latent Autoimmune Diabetes in Adults (LADA) from phenotypically type 2 diabetes. As the frequency of autoantibodies at diagnosis in childhood type 1 diabetes depends on age, GADA is by far the most common in adult onset autoimmune diabetes, especially LADA. Being multiple autoantibody positive have also shown to be more common in childhood diabetes compared to adult onset diabetes, and multiple autoantibody positivity have a high predictive value of childhood type 1 diabetes. Autoantibodies have shown inconsistent results to predict diabetes in adults. Levels of autoantibodies are reported to cause heterogeneity in LADA. Reports indicate that individuals with high levels of autoantibodies have a more type 1 diabetes like phenotype and individuals with low levels of autoantibody positivity have a more type 2 diabetes like phenotype. It is also well known that autoantibody levels can fluctuate and transient autoantibody positivity in adult onset autoimmune diabetes have been reported to affect the phenotype.

Identification of autoimmune type 1 diabetes and multiple organ-specific autoantibodies in adult-onset non-insulin-requiring diabetes in China: A population-based multicentre nationwide survey.

To investigate the prevalence of adult-onset autoimmune diabetes (ADM) and predisposition to autoimmune diseases by quantifying serum organ-specific autoantibodies in people with phenotype of type 2 diabetes (T2D). We included a nationally representative sample of 46 239 adults aged ≥20 years from 14 provinces, of whom 4671 had diabetes, plus 1000 control subjects with normal glucose tolerance (NGT). Participants were screened centrally for autoantibodies to glutamic acid decarboxylase (GAD), islet antigen 2 (IA2) and zinc transporter isoform-8 (Znt8) and were defined as having ADM where positive for these antibodies. We then assayed thyroid peroxidase (TPO), tissue transglutaminase (tTG) and 21-hydroxylase (21-OH) autoantibodies in randomly selected participants with ADM and in age-matched, sex-matched and non-ADM controls with T2D plus controls with NGT. Post-normalization, the standardized prevalence rate of ADM was 6.0% (95% confidence interval [CI] 5.3-6.8) in initially non-insulin-requiring participants with ADM, corresponding to six million adults in China, in whom adjusted antibody positivity was: TPO autoantibodies 16.3% (95% CI 10.8-21.8), tTG autoantibodies 2.1% (95% CI 0.0-4.2), and 21-OH autoantibodies 1.8% (95% CI -0.2 to 3.8). Those participants with ADM who were GAD autoantibody-positive had high risk of TPO autoantibody positivity (odds ratio [OR] 2.39, P = 0.0031) and tTG autoantibody positivity (OR 6.98, P = 0.027), while those positive for IA2 autoantibodies had a high risk of tTG autoantibody positivity (OR 19.05, P = 0.001). A proportion of people with phenotype of T2D in China have ADM, with diabetes-associated autoantibodies, and may be at risk of developing other organ-specific autoimmune diseases; therefore, it may be clinically relevant to consider screening such Chinese populations.

Results of the First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults further highlight the need for a novel diabetes classification system

Latent autoimmune diabetes of the adults (LADA) is a type of autoimmune diabetes characterized by adult-onset, presence of autoantibodies and no need for insulin treatment for a period following diagnosis. Epidemiological data suggest that LADA is the most common cluster of adult-onset autoimmune diabetes, but also the predominant form of autoimmune etiology diabetes, in general (1). LADA shares common genetic, clinical and pathophysiological features with both type 1 (T1D) and type 2 (T2D) diabetes, and for this reason it is often referred to medical literature as type 1.5 diabetes.

Latent autoimmune diabetes in adults in China: clinical features and epidemiology

Latent autoimmune diabetes in adults (LADA) is a type of adult-onset autoimmune diabetes with the autoimmune attack against islet beta cells similar to classic type 1 diabetes (T1DM) while manifesting as the slow progressing T2DM. Understanding more about the clinical and immunological features of LADA could help in avoiding misdiagnosis. Epidemiology studies of LADA in Europe, North America, and other Asia countries have revealed the clinical characteristics and disease progression of LADA to a certain extent. The LADA China Study and other studies in China provided further evidence for the prevalence of LADA in the Chinese population.

Latent Autoimmune Diabetes in Adults: Current Status and New Horizons.

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.

Metabolic Characteristics of Recently Diagnosed Adult-Onset Autoimmune Diabetes Mellitus.

Among patients diagnosed with type 2 diabetes, autoimmune diabetes often remains undetected. Metabolic features of these patients are insufficiently characterized at present. This study compared age- and sex-matched adult (aged 41 to 62 years) humans with recent-onset diabetes: patients positive for antibodies against glutamic acid decarboxylase (GAD) and/or cytoplasmic islet-cell antigen with an insulin-free period of >6 months [antibody positive/insulin negative (ab+/ins-); previously termed latent autoimmune diabetes of adults], type 1 diabetes [antibody positive/insulin positive (ab+/ins+)], and type 2 diabetes [antibody negative/insulin negative (ab-/ins-)], as well as glucose-tolerant humans (controls) of the German Diabetes Study (n = 41/group). β-Cell function was assessed from glucagon tests and intravenous glucose tolerance tests (IVGTTs), and insulin sensitivity was determined from hyperinsulinemic-euglycemic clamps. Of the ab+/ins- patients, 33 (81%) were initially diagnosed as having type 2 diabetes. In ab+/ins-, body mass index (BMI) was higher than in ab+/ins+ (27.8 ± 5.3 kg/m2 vs 25.0 ± 3.5 kg/m2, P < 0.05), lower than in ab-/ins- (31.9 ± 5.8 kg/m2, P < 0.05), and similar to controls (29.4 ± 6.6 kg/m2). In ab+/ins-, GAD antibody titers correlated negatively with BMI (r = -0.40, P < 0.05) and with C-peptide secretion in glucagon stimulation tests (r = -0.33, P < 0.05). β-Cell function from IVGTT was 228% higher in ab+/ins- than in ab+/ins+ but 35% lower than in ab-/ins- and 61% lower than in controls (all P < 0.05). Insulin sensitivity in ab+/ins- was comparable to ab+/ins+ and controls but 41% higher than in ab-/ins- (P < 0.05) after adjustment for BMI and fasting blood glucose or hemoglobin A1c. Even shortly after diagnosis, ab+/ins- patients feature partly preserved β-cell function and chronic hyperglycemia, which possibly contributes to the observed impairment of whole-body insulin sensitivity.

Adult-onset autoimmune diabetes: current knowledge and implications for management.

Adult-onset autoimmune diabetes is a heterogeneous disease that is characterized by a reduced genetic load, a less intensive autoimmune process and a mild metabolic decompensation at onset compared with young-onset type 1 diabetes mellitus (T1DM). The majority of patients with adult-onset autoimmune diabetes do not require insulin treatment for at least 6 months after diagnosis. Such patients are defined as having latent autoimmune diabetes in adults (LADA), which is distinct from classic adult-onset T1DM. The extensive heterogeneity of adult-onset autoimmune diabetes is apparent beyond the distinction between classic adult-onset T1DM and LADA. LADA is characterized by genetic, phenotypic and humoral heterogeneity, encompassing different degrees of insulin resistance and autoimmunity; this heterogeneity is probably a result of different pathological mechanisms, which have implications for treatment. The existence of heterogeneous phenotypes in LADA makes it difficult to establish an a priori treatment algorithm, and therefore, a personalized medicine approach is required. In this Review, we discuss the current understanding and gaps in knowledge regarding the pathophysiology and clinical features of adult-onset autoimmune diabetes and highlight the similarities and differences with classic T1DM and type 2 diabetes mellitus.

Latent autoimmune diabetes in adults (LADA) in Asian and European populations.

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.