Latent Autoimmune Diabetes Research Articles

Abstract 15063: Incidence and Risk Factors for Heart Failure in 20 000 Newly Diagnosed Diabetes Patients

Introduction: Heart Failure (HF) is a diabetes complication causing high mortality and morbidity but has received relatively limited attention compared to other complications such as acute myocardial infarction (AMI). Substantial residual HF risk remains after achieving current treatment targets, suggesting important additional pathophysiological mechanisms beyond conventional risk factors. Aim: to study the incidence and risk factors for HF in newly diagnosed diabetes patients. Methods: We used a contemporary, regional inception cohort (n=19,938) from Scania County in Sweden, to study the incidence and risk factors for HF from initial diabetes diagnosis. Biochemical and questionnaire data were collected within 1 year from initial diagnosis in newly diagnosed diabetes patients (>90% participation rate). We combined baseline data with information on incident HF and AMI diagnoses from a nationwide patient register, and applied Cox-regression models for analysis. Results: A total of 819 patients (4%) had been diagnosed with HF before diabetes diagnosis (median 3 years earlier) and 1245 (6%) with AMI. The cumulative incidence of HF in patients free from HF at diabetes diagnosis was 5%, similar to AMI (3%), during up to 13 years follow-up (median 5 years). Of patients with incident HF, 27% had a prior AMI. No type 1 diabetes (T1D) patient had incident HF, while HF risk was similar in type 2 diabetes, latent autoimmune diabetes in adults (LADA) and secondary diabetes. In non-T1D diabetes patients, male sex (HR 1.52) and higher age at onset (HR 1.08), BMI (HR 1.04), and insulin resistance (HR 1.17) were independently associated with higher incidence of all-cause HF and HF without prior AMI (p<0.05). Baseline fasting glucose, HbA1c and autoantibodies were not associated with HF. Conclusions: Our findings demonstrate high incidence of HF over the decade after initial diabetes diagnosis, comparable to AMI. We further identify insulin resistance, but not hyperglycemia or autoantibodies, as risk factor for HF.

A Review on Latent Autoimmune Diabetes in Adults.

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 becausethere isdelayinpresenting featuresand 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.

L’eterogeneità del diabete autoimmune

Autoimmune diabetes is a heterogeneous disease, encompassing both type 1 diabetes, characterized by fast progression towards an insulin-dependent state, and latent autoimmune diabetes in adults (LADA), considered a less severe form of autoimmune diabetes with a mild metabolic decompensation. An extensive genetic, phenotypic, and humoral heterogeneity is recognized even within the group of people with LADA. In this review, we discuss the pathological and clinical heterogeneity of autoimmune diabetes, highlighting the current understanding and gaps in knowledge.

Diagnosis of latent autoimmune diabetes after SARS–Cov2 vaccination in adult patients previously diagnosed with type 2 diabetes mellitus

Diagnosis of latent autoimmune diabetes after SARS–Cov2 vaccination in adult patients previously diagnosed with type 2 diabetes mellitus

FRI616 Combined Elf5a And Notch Inhibition Reprograms The Effector T Cell Fate Decisions Towards Treg Phenotype Without Any Off Target Effect

Abstract Disclosure: S. Rafiqi: None. A. Aldasouqi: None. S. faisal: None. S. Qureshi: None. A. Mahmood: None. J.C. Jaume: None. S. Imam: None. We explored immune resetting and plasticity of T effector cells towards T regulatory cells (CD4+CD25+FOXP3+) by elF5A and Notch inhibition. We validated our approach for plasticizing human T effector cells into Treg cells conducted on recent onset latent autoimmune diabetes of adult (LADA) patients (n=3), and nondiabetic patients (n=4) with simultaneous use of GC7 (100 μM) and anti-DLL4 (10 μg/ml). We also investigated the functional stability of plasticized Tregs and compared it with freshly isolated naïve Tregs from the same patient. Tregs were co-cultured with T effector cells and suppression/proliferation was accessed after 5 days. To create an ex-vivo Treg deficient environment, we sorted out CD4+ cells from the PBMCs. CD4+ deficient PBMCs and sorted single positive CD4+CD25- cells were treated with anti-DLL4+GC7+rhGAD65 with and without IL-2 supplementation and were compared with conventional anti-(CD3+CD28) stimulation and absolute control (20%FCS+RPMI). The presence of Treg cells was confirmed by flow cytometry. 30.5±5.1% of CD4 cells were plasticized into Tregs in the treatment group supplemented with IL-2 while only 18.8±4.6 % were plasticized in treatment group without IL-2 supplementation. Also, 11.2±3.1% plasticized to Tregs in treatment group in presence of CD3/CD28 microbeads compared to 6.19±2.4% in absolute control group. Similarly, 13±4.3% of CD8 cells had plasticized into Tregs in treatment group supplemented with IL-2 while only 11.5±6.7% plasticized in treatment group without IL-2 supplementation. 14.3±5.8% plasticized to Tregs in treatment group in presence of CD3/CD28 microbeads compared to 12.4±6.3% in absolute control group. Interestingly, the plasticized Tregs from LADA patients were more robust than those of non-diabetic patients at a 1:2 ratio (Treg:Tresp). Furthermore, the plasticized Tregs had comparable suppressive capacity over Tresp (CD4+CD25-) cells as that of freshly isolated naïve human Tregs. To investigate any off-target effects of (GC7 and anti-DLL4), live, dead, and apoptotic cell count at 24, 48, 96 hours, and 7 days post-treatment using dead cell apoptosis kit (Invitrogen). In our study, there was no significant difference between treatment and control groups in terms of live, dead, and apoptotic cells at different time intervals. On the 7th day of culture 64.06±8.66% and 68.88±6.15% of cells were live in treatment and absolute control groups respectively while 7.24±1.59% and 10.0±2.02% cells were found apoptotic respectively. Therefore, we define the reprogramming of T effector cells towards Treg cells with functional suppressive capacity using GC7 and anti-DLL4 without any off-target effect (toxicity). The present study expands the concept of T cell plasticity and establishes the functional stability of plasticized T cells that can accelerate pre-clinical trials for therapeutic use in T1D and as an adjunct to immunotherapies. Presentation: Friday, June 16, 2023

THU296 Effect Of Tirzepatide In GADA-positive Individuals With T2D: A Post Hoc Analysis Of The SURPASS 2-5 Trials

Abstract Disclosure: A.L. Peters: Advisory Board Member; Self; Abbott Diabetes Care, Eli Lilly & Company, Medscape, Novo Nordisk, Zealand. Grant Recipient; Self; Dexcom, Insulet Corporation. Stock Owner; Self; Omada Health, Teladoc. Other; Self; Abbott Diabetes Care. R. Buzzetti: Consulting Fee; Self; Sanofi, Novo Nordisk, Eli Lilly & Company. Speaker; Self; AstraZeneca, Abbott Laboratories. C.J. Lee: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. I. Pavo: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. M. Liu: Other; Self; Eli Lilly & Company. J.S. Paik: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. Tirzepatide, a novel once weekly GIP and GLP-1 receptor agonist, is approved for treatment of type 2 diabetes (T2D). People with T2D and positive glutamic acid decarboxylase autoantibodies (GADA), which is also referred to as latent autoimmune diabetes in adults (LADA), may often remain undetected and may be associated with more rapid progression to insulin therapy. The diagnosis is primarily made by the presence of GADA in patients previously diagnosed with T2D. The aim of this post hoc analysis was to evaluate the effect of tirzepatide on hemoglobin A1c (HbA1c) levels in people with T2D who were GADA-positive versus GADA-negative from the Phase 3 SURPASS clinical trial program. Tirzepatide-treated patients from SURPASS 2-5 studies were included in this analysis. Patients who had GADA concentrations ≥5 IU/mL were categorized as GADA-positive (ELISA, RSR Ltd., Cardiff, UK). Change from baseline in HbA1c at 40/42 weeks was assessed in GADA-positive vs GADA-negative patients using mixed model repeated measures from the efficacy analysis set, adjusting for baseline covariates including study, sex, HbA1c, and body mass index (BMI). All randomized patients who took at least one dose of study drug, excluding patients who discontinued study drug due to inadvertent enrollment and excluding data after initiation of rescue medication or premature discontinuation of study drug, were included in this analysis. Of the 3827 tirzepatide-treated patients who were tested for GADA, 3671 (95.9%) were GADA-negative, 120 (3.2%) were GADA-positive, and 36 (0.9%) were “no GADA status”. Baseline parameters were similar between the groups, except for baseline BMI and serum triglyceride concentration which were slightly lower in GADA-positive patients compared to GADA-negative patients (mean baseline BMI [SD] 32.2 [6.1] vs 33.6 [6.3] kg/m2, mean triglycerides 169.2 [101.3] vs 188.1 [131.4] mg/dL). At 40/42 weeks, both groups achieved significant reductions in HbA1c (-2.11% vs -2.32%; p<0.001 for both groups) and body weight (-9.2 kg vs -9.6 kg; p<0.001 for both groups), for GADA-positive vs. GADA-negative patients, respectively. Reductions in HbA1c were slightly greater in GADA-negative patients (estimated treatment differences [95% confidence interval]: 0.21% [0.03, 0.39]; p=0.024), whereas reductions in body weight did not significantly differ between groups (0.38 kg [-0.99, 1.75]; p=0.588). These data demonstrate that tirzepatide was effective in reducing HbA1c and body weight, irrespective of GADA status in adults with T2D, thus suggesting that tirzepatide may be effective to improve glycemic control in GADA-positive individuals. Future studies could help elucidate the long-term impact of GADA positivity on the progression of diabetes. Presentation: Thursday, June 15, 2023

SAT087 Maternally Inherited Diabetes And Deafness: Support For SGLT2 Inhibitor Use

Abstract Disclosure: S. Pandya: None. K. Selk: None. Introduction: Maternally inherited diabetes and deafness (MIDD) is a rare genetic disease resulting from a mitochondrial mutation. There is a wide phenotypic expression secondary to heteroplasmy. The clinical manifestations of MIDD are hyperglycemia, sensorineural hearing loss, maculopathy, cardiac conduction defects, myopathy/poor exercise tolerance, and neuropathy. Diabetes mellitus generally occurs during the third decade of life, and there tends to be rapid progression to insulin therapy with reported earlier onset of microvascular complications. Here we present a case of MIDD successfully treated long-term with empagliflozin and linagliptin. Clinical Case: A 36-year-old male with sensorineural hearing loss presented with a 20-pound unintentional weight loss, polyphagia, and polydipsia. His blood glucose level was 300 mg/dL and HbA1c was 14.3%. His mother carried a diagnosis of type 2 diabetes mellitus and his grandmother had latent autoimmune diabetes of adulthood. Prior to presenting to endocrinology, he had been started on metformin, glipizide, and linagliptin with ongoing poor glycemic control. Given his presentation, family history, and lean habitus with BMI of 20, he was assessed for possible autoimmune diabetes. Testing for glutamic acid decarboxylase 65-kilodalton isoform antibody (GAD65), islet cell antibody, tyrosine phosphatase-related islet antigen 2 (IA2), and zinc transporter 8 antibody (ZNT8) was unrevealing. A C-peptide level was detectable but <1 ng/mL. His sulfonylurea was discontinued, and he was started on basal insulin with a dramatic improvement in his glycemic control. He was later able to discontinue insulin therapy. However, given poor exercise tolerance and his known hearing loss, he was seen by genetics where he underwent testing and was found to have a m.3243 A>G mutation in MT-TL1 gene making the diagnosis of MIDD. Metformin was discontinued due to a possible risk of lactic acidosis and sitagliptin was initiated. Due to hyperglycemia, empagliflozin was added and he was later transitioned to empagliflozin-linagliptin to reduce his pill burden. He has continued to have a1c levels of 6.5% or less for the last 3 years and periodic C-peptide measurements have been >1 ng/mL. Conclusion: Given MIDD is a rare form of monogenic diabetes, treatment tends to be individualized with many transitioning to insulin early in their disease course. Given the reported increased risk for microvascular complications, sodium-glucose cotransporter-2 (SGLT2) inhibitors are an attractive therapeutic agent. However, there is little literature on the use of these agents in MIDD and there is concern about the risk for diabetic ketoacidosis given insulin use is required by many afflicted individuals. This case highlights the safety of long-term empagliflozin in a patient with MIDD. Presentation: Saturday, June 17, 2023

THU278 Hidden In The Immune System: Exogenous Insulin Antibody Syndrome In A Patient With Latent Autoimmune Diabetes In Adults

Abstract Disclosure: H.L. King: None. R. Nagappan: None. A. Sliwinska: None. Hidden in the Immune System: Exogenous Insulin Antibody Syndrome in a Patient with Latent Autoimmune Diabetes in Adults Background: Exogenous insulin antibody syndrome (EIAS) is a rare syndrome associated with insulin antibodies induced by exogenous insulin, found predominantly in patients with type 2 diabetes using various insulin formulations. Here, we present a case of young man previously diagnosed with type 2 diabetes, who was found to have severe refractory diabetic ketoacidosis (DKA) due to EIAS. Clinical Case: A 46-year-old man with a history of type 2 diabetes presented to an outside hospital for one week of fever and malaise. Laboratory studies were notable for serum glucose of 600 mg/dL (70-90mg/dL), HCO3 3 mmol/L (22-28mmol/L), and creatinine of 3.9 mg/dL (0.7-1.3mg/dL). He was diagnosed with DKA, shock and renal failure. During hospital stay, he remained on an insulin drip due to multiple unsuccessful attempts of transitioning to subcutaneous insulin, requiring over 1000 Units of insulin daily. This prompted insulin antibody testing that resulted elevated at >50U/mL (0-0.4U/mL), concerning for EIAS. Treatment was initiated with 5 days of IVIG and mycophenolate mofetil. During this treatment, his baseline insulin infusion rate of 30 Units/hr declined to 18 Units/hr, however at day 3, insulin requirements again increased. For better evaluation, quantitative insulin antibody values were requested and resulted as 362.5U/mL, followed by 350.9U/mL post IVIG treatment. After no significant improvement, patient was transferred to our hospital for further management of EIAS. Plasmapheresis was initiated followed by rituximab with plans for long term maintenance therapy. Dexamethasone was trialed but shortly after discontinued due concern of increased insulin resistance and hyperglycemia. Metformin was also started but discontinued due to concern of worsening acidosis in the setting of acute renal failure requiring CRRT. Ultimately, the patient was transitioned to subcutaneous U500 BID 75-150 Units based on scale. At discharge, metformin and pioglitazone were started. Due to the history of early onset insulin-dependent diabetes at age 30, he was tested for GAD-65 which resulted as positive at 0.28 nmol/L (<=0.02 nmol/L) and C peptide of 0.9ng/mL (0.8 - 3.9 ng/mL) consistent with LADA. Conclusion: EIAS is a rare and very challenging entity, increasing risks of severe ketoacidosis, hypoglycemic episodes and numerous other complications. Although mostly reported in type 2 diabetes, EIAS can occur in patients with LADA suggesting that autoimmunity may play a role. There is no FDA approved treatment, however attempts focus on eliminating antibodies by plasmapheresis, IVIG and immunotherapeutic agents. Presentation: Thursday, June 15, 2023

THU363 Misdiagnosing Latent Autoimmune Diabetes Mellitus In Adults: A Case Report

Abstract Disclosure: U. Rafat: None. W. Akhter: None. R. Alshantti: None. J.L. Gilden: None. Background: Latent Autoimmune Diabetes Mellitus (DM) in Adults (LADA) is often misdiagnosed as Type 2 DM. This can lead to increased risk of complications. Therefore, knowledge and awareness of LADA is essential. LADA is diagnosed based on three features, age greater than 35 years, presence of antibodies to pancreatic islet cell antigens (Glutamic Acid Decarboxylase GAD, Insulinoma antigen-2 IA-2A, Zinc Transporter 8 ZnT8A) and lack of insulin requirement for at least 6 months after diagnosis. It is important to diagnose LADA early, so that patients can be started on insulin earlier, thereby achieving better glycemic control and preserving residual beta cell function. Case Presentation: We present the case of a 44-year-old female of mixed African American and Greek ethnicity with a history of DM complicated by nephropathy, hypertension, obesity, acne and uterine fibroids. She was diagnosed with Type 2 DM at age 36 from routine screening with a HbA1c of 6.9% and started on Metformin by primary care provider. Family history was significant for transient postpartum hypothyroidism in her mother, and DM in both maternal and paternal grandparents. She was unable to tolerate Metformin due to gastrointestinal side effects and was switched to Insulin Detemir therapy one year later. She first presented to the endocrine clinic for evaluation and management of abnormal thyroid function tests with symptoms of weight loss, excessive hair fall, anxiety, and palpitations. Vital signs: Blood pressure 146/65 mmHg, Heart rate 89 bpm, Respiration 14 breaths/min, BMI 31 kg/m2. Physical examination was significant for marked edema of eyelids, but no thyromegaly or tremors, and marked acanthosis nigricans. Laboratory tests were consistent with Grave’s disease with TSH less than 0.005 uIU/mL (n= 0.358-3.74), free T3 22.93 pg/mL (n=2.18-3.98), free T4 4.63 ng/dL (n=0.76-1.46) and positive TSI of 291%. (n<140). The patient was started with methimazole therapy. GAD 65 was found to be positive >250 IU/mL (n<5) and islet cell antibodies were negative. A revised diagnosis of LADA was made. The co-existence of Grave’s disease enabled reclassifying the type of her DM. Conclusion: Type 1 diabetes mellitus or autoimmune diabetes mellitus should always be ruled out if the clinical picture does not match with type 2 Diabetes Mellitus or in a relatively young patient. Our case aims to increase awareness of Autoimmune Polyendocrine syndrome, which occurs as a result of loss of immune tolerance, leading to impairment of multiple endocrine glands.

Association between a high triglyceride–glucose index and chronic kidney disease in adult patients with latent autoimmune diabetes

BackgroundInsulin resistance (IR) is one of the risk factors for chronic kidney disease (CKD) and diabetes. The triglyceride–glucose (TyG) index is considered a reliable alternative marker of IR. We investigated the correlation between the TyG index and the severity of CKD in patients with latent autoimmune diabetes in adults (LADA).MethodsThis cross-sectional study included 288 patients with LADA in the department of endocrinology at our hospital between January 2018 and January 2022. The TyG index was calculated as Ln [TG (mg/dl) × fasting blood glucose (FBG) (mg/dl) / 2]. All individuals were divided into either a LADA + CKD group or a LADA + non-CKD group according to the presence or absence of CKD. A correlation analysis, logistic regression analysis and receiver operating characteristics curve analysis were performed.ResultsA total of 130 (45.1%) participants were identified as having CKD. Compared with the non-CKD group, the CKD group had a longer disease duration and a higher proportion of smokers; patients were more likely to have hypertension and higher serum creatinine, triglyceride, cholesterol, low-density lipoprotein cholesterol, FBG, uric acid estimated glomerular filtration rates (eGFR) and TyG levels as well as lower high-density lipoprotein cholesterol levels (all P < 0.05). The positive relationship between the TyG index and the urinary albumin/creatinine ratio was significant (r = 0.249, P = 0.010). There was also a significant correlation between the TyG index and the eGFR (r = − 0.211, P = 0.034) after adjusting for confounding factors. The area-under-the-curve value of the TyG index was 0.708 (95% confidence interval: 0.61–0.81, P < 0.001).ConclusionsThe TyG index is significantly associated with the severity of CKD in patients with LADA. This conclusion supports the clinical application of the TyG index for the assessment of kidney disease in patients with LADA.

Changes of B cell subsets in different types of diabetes and its effect on the progression of latent autoimmune diabetes in adults.

Developmental abnormalities in B cells is one of the key players in autoimmune diabetes, but little is known about its role in latent autoimmune diabetes in adults (LADA). This study aimed to investigate the distribution of B cell subsets in different types of diabetes and to analyze their correlations with other biochemical parameters. A total of 140 participants were prospectively enrolled from January 2021 to December 2022. Diabetes-related autoantibodies and laboratory indicators were tested. Flow cytometry was used to analyze the percentage of circulating B cell subsets and T follicular cells. The correlation of B cell subsets with different indicators was assessed by Spearman's correlation method. We observed that the Naïve phenotype cells tended to be less frequent in patients with diabetes than in healthy controls. The frequency of plasmablasts (PB) and Breg cell-related phenotype (B10) were significantly higher in LADA. Notably, the percentage of PB was positively associated with levels of islet cell antibody (ICA) and insulin autoantibody (IAA), but inversely associated with fasting C-peptide (FCP), further indicating that PB may promote the destruction of β-cell in patients with diabetes. This study showed that patients with LADA had significantly altered frequencies of B cell subsets, particularly in the naïve to memory B cell ratio. Our study provided valuable information on the distribution characteristics of B cell subsets in LADA and suggested the feasibility of B-cell targeted therapy in LADA patients.

Relationship between β-Cell Autoantibodies and Their Combination with Anthropometric and Metabolic Components and Microvascular Complications in Latent Autoimmune Diabetes in Adults.

Our study aimed to investigate the relationship between three autoantibodies and their combination with anthropometric and metabolic components and microvascular complications in patients with latent autoimmune diabetes in adults (LADA). Our study included 189 LADA patients divided into four subgroups according to the autoantibodies present: glutamic acid decarboxylase autoantibodies (GADA) only; zinc transporter-8 autoantibodies (ZnT8A)+GADA; insulinoma-associated-2 autoantibodies (IA-2)+GADA; and ZnT8+IA-2+GADA. Compared to GADA positivity only, patients with ZnT8+GADA positivity and ZnT8+IA-2+GADA positivity had a shorter diabetes duration and lower body mass index (BMI); patients with ZnT8+GADA positivity were younger and showed an increase in glomerular filtration rate, while those with ZnT8+IA-2+GADA positivity had lower C-peptide and lower insulin resistance measured with HOMA2-IR. In a multiple regression analysis, ZnT8 positivity was associated with lower BMI (p = 0.0024), female sex (p = 0.0005), and shorter duration of disease (p = 0.0034), while IA-2 positivity was associated with lower C-peptide levels (p = 0.0034) and shorter diabetes duration (p = 0.02). No association between antibody positivity and microvascular complications of diabetes, including retinopathy, neuropathy, and microalbuminuria, as well as with variables of glucose control and β-cell function were found. The results of our study suggest that ZnT8 and IA-2 autoantibodies are present in a significant number of LADA patients and associated with clinical and metabolic characteristics resembling classic type 1 diabetes. Due to increased LADA prevalence, earlier identification of patients requiring frequent monitoring with the earlier intensification of insulin therapy might be of special clinical interest.

Exploration of Immune Targets for Type 1 Diabetes and Latent Autoimmune Disease Immunotherapy.

Type 1 diabetes (T1D) is an autoimmune disease that destroys pancreatic beta cells, which produce insulin in the islets of Langerhans. The risk of developing T1D is influenced by environmental factors, genetics, and autoantibodies. Latent autoimmune diabetes in adults (LADA) is a type of T1D that is genetically and phenotypically distinct from classic T1D. This review summarizes the accumulated information on the risk factors for T1D and LADA, and immunotherapy trials that offer insights into potential future combined therapeutic interventions for both T1D and LADA to slow the rate of islet cell loss and preserve beta cell function. Future research should also focus on improving intervention doses, conducting more thorough examinations of intervention responders, and/or combining minimally effective single-target immunotherapies to slow the rate of islet cell loss and preserve beta cell function.

Exploring the Landscape of Latent Autoimmune Diabetes and Maturity Onset Diabetes of the Young in Africa: A Scoping Review

Background: Latent autoimmune diabetes in adults (LADA) and maturity onset diabetes of the young (MODY) are two forms of diabetes with varied disease symptoms. The prevalence of LADA is higher in adults than MODY. Both diseases contribute to the general burden of diabetes globally. While LADA is a sporadic autoimmune disorder, MODY is a heritable genetic disorder. The prevalence of LADA and MODY has not been fully documented in Africa due to the lack of robust diagnostic tools and the exorbitantly high cost of the available diagnostic tools. Methods: To understand the prevalence landscape of LADA and MODY in Africa, we conducted an extensive scoping review and mapped the various studies performed in Africa. We adopted the Joanna Briggs Institute literature review framework to conduct the scoping review of literature. Results: Research articles were included in the review analysis following exhaustive inclusion criteria to ensure that only qualified articles were included in the final analysis. Overall, 16 research articles met the inclusion criteria and were critically analyzed. An in-house data extraction sheet was used for data extraction from all the shortlisted articles. Information about the sample size, inclusion criteria, age, gender, and study design extracted from all the articles and analyzed. Majority of the studies adopted cross-sectional study design. In terms of sample sizes, the studies used relatively smaller sample sizes due to the high cost of the diagnosis and nature of the diseases. The prevalence rates of LADA and MODY varied in various countries ranging from 1.8 to 18%. Conclusion: African countries are significantly under-represented. The scarcity of research on LADA and MODY research in Africa is evidence of the urgent need to invest more resources in this area. This would guide future research and shape the road towards understanding diabetes in Africa.

All-Cause Mortality and Cardiovascular and Microvascular Diseases in Latent Autoimmune Diabetes in Adults.

Latent autoimmune diabetes in adults (LADA) is a heterogenous, slowly progressing autoimmune diabetes. We aim to contribute new knowledge on the long-term prognosis of LADA with varying degrees of autoimmunity by comparing it to type 2 diabetes and adult-onset type 1 diabetes. This Swedish population-based study included newly diagnosed LADA (n = 550, stratified into LADAlow and LADAhigh by median autoimmunity level), type 2 diabetes (n = 2,001), adult-onset type 1 diabetes (n = 1,573), and control subjects without diabetes (n = 2,355) in 2007-2019. Register linkages provided information on all-cause mortality, cardiovascular diseases (CVDs), diabetic retinopathy, nephropathy, and clinical characteristics during follow-up. Mortality was higher in LADA (hazard ratio [HR] 1.44; 95% CI 1.03, 2.02), type 1 (2.31 [1.75, 3.05]), and type 2 diabetes (1.31 [1.03, 1.67]) than in control subjects. CVD incidence was elevated in LADAhigh (HR 1.67; 95% CI 1.04, 2.69) and type 2 diabetes (1.53 [1.17, 2.00]), but not in LADAlow or type 1 diabetes. Incidence of retinopathy but not nephropathy was higher in LADA (HR 2.25; 95% CI 1.64, 3.09), including LADAhigh and LADAlow than in type 2 diabetes (unavailable in type 1 diabetes). More favorable blood pressure and lipid profiles, but higher HbA1c levels, were seen in LADA than type 2 diabetes at baseline and throughout follow-up, especially in LADAhigh, which resembled type 1 diabetes in this respect. Despite having fewer metabolic risk factors than type 2 diabetes, LADA has equal to higher risks of death, CVD, and retinopathy. Poorer glycemic control, particularly in LADAhigh, highlights the need for improved LADA management.

The relationship between red blood cell distribution width and islet β-cell function indexes in patients with latent autoimmune diabetes in adults

AimsThe objective of this study is to explore the relationship between red blood cell distribution and islet β-cell function indexes in patients with Latent Autoimmune Diabetes in Adults.MethodsA total of 487 LADA patients were enrolled in this cross-sectional study. Patients were divided into three groups according to RDW tertiles. Clinical and laboratory measurements of age, height, weight, duration of diabetes, blood pressure, RDW, glycosylated hemoglobin A1c (HbA1c), C-peptide and blood lipids were performed. Homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of β-cell function (HOMA-β) were assessed using homeostasis model assessment (HOMA) based on fasting blood glucose (FBG) and fasting C-peptide index (FCP). Correlations and multiple linear regressions were implemented to determine the association of RDW and islet function indexes.ResultsAs the increase of serum RDW level, the presence of β-cell secretion increased(P < 0.05). Correlation analysis indicated that there were significant correlations between RDW and male sex, age, duration, TG, Cr, FCP, and HOMA-β in all subjects. Multiple linear regressions indicated that RDW was significantly correlated with HOMA-β in the total population in both unadjusted and adjusted analysis. This finding could be reproduced in the subgroup of low GAD titers for HOMA-β. RDW were significantly associated with HbA1c in LADA patients with high GAD titers, but the correlation was not found in subgroup with low GAD titers in either unadjusted analyses or adjusted analysis.ConclusionsRDW is associated with β-cell function assessed by HOMA-β after adjusting for covariates in LADA patients with low GAD titers.

Efficacy of Regimens in the Treatment of Latent Autoimmune Diabetes in Adults: A Network Meta-analysis.

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.

A 1-year pilot study of intralymphatic injections of GAD-alum in individuals with latent autoimmune diabetes in adults (LADA) with signs of high immunity: No safety concerns and resemblance to juvenile type 1 diabetes.

To test, for the first time in latent autoimmune diabetes in adults (LADA), the effects of autoantigen-specific immunotherapy by intralymphatic administration of aluminium-formulated recombinant human glutamic acid decarboxylase 65 (GAD-alum); specifically, to test if this treatment is safe, to test whether it induces a strong immunological response akin to a similar protocol in type 1 diabetes and to look for associations with preserved beta-cell function. Three GAD-alum injections, 4 μg each, were administered 1 month apart into an inguinal lymph node in 14 people with newly diagnosed LADA (age 30-62 years) presenting with high levels of antibodies against glutamic acid decarboxylase (GADA). Adverse effects, immunological variables and beta-cell function were monitored, with detailed measurements at 5 and 12 months from baseline. Clinical adverse effects were minor and transient and measured laboratory variables were unaffected. All participants completed the study. Treatment raised levels of GADA, elicited strong effects on reactivity of peripheral blood mononuclear cells to GAD and raised cytokine/chemokine levels. Beta-cell function appeared stable preferentially in the seven participants carrying human leukocyte antigen (HLA) haplotypes DR3DQ2, as assessed by C-peptide glucagon tests (P < 0.05 vs. seven non-carriers). Intralymphatic treatment with GAD-alum in LADA is without clinical or other safety concerns over a 12-month period. As in a similar protocol used in type 1 diabetes, treatment exerts a strong immunological impact and is compatible with protection of beta-cell function preferentially in HLA-DR3DQ2 LADA patients. These findings pave the way for a randomized controlled trial in this important subgroup of LADA patients.

Comparative characteristics of newly diagnosed adult diabetic patients: a pilot study.

Diabetes is one of the most common chronic diseases. Early and improved classification of the type of diabetes, whether autoimmune (type 1 diabetes mellitus, T1DM, and latent autoimmune diabetes, LADA) or type 2 diabetes mellitus (T2DM), is essential to determine appropriate therapy. We aimed to present the biochemical and immunological characteristics of adult patients with newly diagnosed diabetes without prior drug treatment. This pilot, a cross-sectional study assessed major phenotypic characteristics and antibody titers, including islet cell antibodies (ICA), insulin autoantibodies (IAA), tyrosine phosphatase antibodies (IA-2A), glutamic acid decarboxylase antibodies (GADA), zinc antibodies (ZnT8A), but also selected sphingolipids belongs to ceramides (Cer) and sphingomyelin (SM). A total of 59 participants were included: 21 with T1DM, 15 with T2DM, and 23 with LADA. Saturated fatty acids chain Cer such as Cer-C22:0 and Cer-C24:0 positively correlates with total cholesterol (TC), triglycerides (TC), and low-density lipoprotein cholesterol (LDL), particularly in autoimmune diabetes (LADA, T1DM) while in T2DM group we found a higher frequency of positive correlation only between Cer-C24:0 and TC. In LADA patients, SM-C18:1 and -C:20:4 values rise with increasing fasting and glucagon-stimulated C-peptide values. The prevalence of GADA in patients diagnosed with T1DM is higher in younger patients versus older ones. While patients with LADA were more likely to test positive for multiple (&gt;4) antibodies. In this relatively small cross-sectional study adult patients with newly diagnosed diabetes have fluctuating clinical and metabolic features with variable severity of immune dysfunction, making it easier to diagnose patients.

The role of cholecalciferol deficiency in the development of latent autoimmune diabetes in adults

Background. Recently, a lot of information has appeared on the role of cholecalciferol deficiency in the development of the mechanisms of classical types of diabetes mellitus (DM) and its complications. However, there are currently almost no data regarding latent autoimmune diabetes in adults (LADA). The purpose of this study was to determine the effect of vitamin D deficiency on the compensation of carbohydrate metabolism in LADA. Materials and methods. The study included 56 patients with DM: 34 with LADA and 22 with classical type 1 DM (DM1), as well as 20 practically healthy individuals of the control group. According to the main phenotypes, patients with LADA were divided into 2 groups: LADA1 and LADA2. Cholecalciferol status was determined by the immunochemiluminescence method. Results. The fasting blood glucose level in LADA and DM1 group was significantly higher than in the controls, by 63.9 and 91.1 % (p &lt; 0.001), respectively, and was also 16.6 % higher when comparing DM1/LADA groups (p &lt; 0.05). The level of HbA1c in 66.1 % of patients of the experimental groups was more than 7 %, which indicates insufficient compensation of the disease. The content of vitamin D was significantly lower in the experimental groups compared to the controls; when comparing LADA/DM1 — by 43.7 % lower in case of classical DM1 (p &lt; 0.05). Compensation of carbohydrate metabolism is worse in patients with LADA1 than in LADA2, and the lowest level of vitamin D was recorded in LADA1. According to the linear regression analysis of correlations in patients with LADA, negative correlations of medium strength were recorded between the level of cholecalciferol and fasting blood glucose (r = 0.487; p &lt; 0.05), HbA1c (r = –0.593; p &lt; 0.05); positive — between cholecalciferol and C-peptide (r = 0.412; p &lt; 0.05). Conclusions. In patients with autoimmune diabetes, there is an insufficient supply of cholecalciferol. Low cholecalciferol content is observed in both groups of patients with LADA regardless of the disease phenotype and is associated with worse compensation of DM.