Hsa_circRNA_405498 and hsa_circRNA_100033 Serve as Potential Biomarkers for Differential Diagnosis of Type 1 Diabetes.

CONTEXT: The role of circular RNAs (circRNAs) in type 1 diabetes (T1D) is largely unknown. OBJECTIVE: We aimed to identify some circRNAs as differential diagnostic biomarkers for T1D to distinguish between patients with latent autoimmune diabetes in adults (LADA) and type 2 diabetes (T2D). METHODS: The circRNA expression profiles were determined by Arraystar human circRNA microarray in T1D compared to controls (n = 6 each). The differentially expressed circRNAs were validated by real-time quantitative polymerase chain reaction using a validation cohort with 20 T1D and 20 controls. The diagnostic performances of the candidate circRNAs and the clinical parameters were assessed using the logistic least absolute shrinkage and selection operator (LASSO) regression model in a larger cohort with 457 individuals, including patients with T1D, T2D, and LADA, and controls. RESULTS: We identified 110 differentially expressed circular transcripts (53 upregulated and 57 downregulated) in T1D patients compared with controls. Further analysis showed that the levels of hsa_circRNA_405498 and hsa_circRNA_100033 were significantly downregulated in T1D compared to controls (both P < .05). Moreover, the expression levels of these 2 circRNAs showed sequential downregulation from controls, patients with T2D, LADA, to T1D (P < .05). The area under the curve (AUC) of receiver operating characteristic plots in logistic LASSO regression model showed high diagnostic accuracy for combination model with the 2 circRNAs and some clinical parameters in distinguishing T1D from LADA (AUC = 0.915), T2D (AUC = 0.993), and controls (AUC = 0.992). CONCLUSION: Our study demonstrated that hsa_circRNA_405498 and hsa_circRNA_100033 are promising novel differential diagnostic biomarkers for T1D.

The role of renal damage markers in the diagnosis of early stages of kidney injury in patients with latent autoimmune diabetes in adults.

Serum creatinine level begins to increase after a decrease in glomerular filtration rate (GFR) by 50% and more, so the question emerged about a more accurate method of determining GFR. The study aimed to determine the role of renal damage markers in the diagnosis of early-stage renal disease in patients with latent autoimmune diabetes in adults (LADA). We included 84 patients with diabetes mellitus (DM) and chronic kidney disease (CKD) caused by diabetic kidney disease (DKD), as well as 25 representatives of the control group. Patients were divided into three groups - 43 people with LADA, 21 with type 1 diabetes mellitus (T1DM), and 20 patients with type 2 diabetes mellitus (T2DM). GFR was assessed using six formulas after establishing the category of GFR and albuminuria. The GFR rate estimated by the CKD-EPI formula in patients with LADA and DKD did not significantly differ from that of CKD-EPI cysC, slightly different from MDRD GFR (10.6% higher, respectively) but 21.9% lower compared to CG formula. In patients with LADA and T1DM, GFR was higher in cases with existing albuminuria, regardless of the formulas used. Thus, the non albuminuria phenotype is accompanied by a greater degree of renal impairment, which indicates the need to determine serum cystatin C in the early stages of LADA. Cystatin C levels are the most accurate, early, and independent predictor of the development and progression of CKD in patients with DM, including LADA.

Case Report: A Rare Case of Coexisting of Autoimmune Polyglandular Syndrome Type 3 and Isolated Gonadotropin-Releasing Hormone Deficiency.

APS (autoimmune polyglandular syndrome) is defined as the coexistence of at least two kinds of endocrine autoimmune diseases. APS type 3 comprises autoimmune thyroid diseases and other autoimmune diseases but does not involve autoimmune Addison's disease. So far, APS-3 combined with isolated gonadotropin-releasing hormone (GnRH) reduction caused by the suspected autoimmune hypothalamic disease has not been reported. We recently received a 43-year-old woman with a one-year history of Graves' disease (GD) and a four-month history of type 1 diabetes presented with hyperthyroidism and hyperglycemia. After the GnRH stimulation test, she was diagnosed with secondary amenorrhea attributed to suspected autoimmune Hypothalamitis and APS type 3 associated with Graves' disease and Latent Autoimmune Diabetes (LADA). According to this case, the hypothalamus cannot be spared from the general autoimmune process. It is recommended to carry out the GnRH stimulation test when encountering APS patients combined with secondary amenorrhea.

Development and Validation of a Prevalence Model for Latent Autoimmune Diabetes in Adults (LADA) Among Patients First Diagnosed with Type 2 Diabetes Mellitus (T2DM).

BACKGROUND We designed this study to develop and validate a prevalence model for latent autoimmune diabetes in adults (LADA) among people initially diagnosed with type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS The study recruited 930 patients aged ≥18 years who were diagnosed with T2DM within the past year. Demographic information, medical history, and clinical biochemistry records were collected. Logistic regression was used to develop a regression model to distinguish LADA from T2DM. Predictors of LADA were identified in a subgroup of patients (n=632) by univariate logistic regression analysis. From this we developed a prediction model using multivariate logistic regression analysis and tested its sensitivity and specificity among the remaining patients (n=298). RESULTS Among 930 recruited patients, 880 had T2DM (96.4%) and 50 had LADA (5.4%). Compared to T2DM patients, LADA patients had fewer surviving b cells and reduced insulin production. We identified age, ketosis, history of tobacco smoking, 1-hour plasma glucose (1hPG-AUC), and 2-hour C-peptide (2hCP-AUC) as the main predictive factors for LADA (P<0.05). Based on this, we developed a multivariable logistic regression model: Y=-8.249-0.035(X1)+1.755(X2)+1.008(X3)+0.321(X4)-0.126(X5), where Y is diabetes status (0=T2DM, 1=LADA), X1 is age, X2 is ketosis (1=no, 2=yes), X3 is history of tobacco smoking (1=no, 2=yes), X4 is 1hPG-AUC, and X5 is 2hCP-AUC. The model has high sensitivity (78.57%) and selectivity (67.96%). CONCLUSIONS This model can be applied to people newly diagnosed with T2DM. When Y ≥0.0472, total autoantibody screening is recommended to assess LADA.

Comparing the bone mineral density among male patients with latent autoimmune diabetes and classical type 1 and type 2 diabetes, and exploring risk factors for osteoporosis.

AIMS: This study aimed to compare the bone mineral densities (BMDs) among male patients with latent autoimmune diabetes in adults (LADA), classical type 1 diabetes (T1DM), and type 2 diabetes (T2DM), and to examine the risk factors for developing low BMD in these patients. PATIENTS AND METHODS: Between January 2017 and October 2020, a total of 57, 67, and 223 male patients with LADA, classical T1DM, and T2DM, respectively, were recruited from the endocrinology department of Shanghai Tenth People's Hospital. Hormonal markers of bone metabolism, lipid profiles, uric acid, glycosylated hemoglobin A1c (HbA1c), and beta-cell function were measured using blood samples. BMD was measured at the lumbar spine, femoral neck, and right hip by dual-energy X-ray absorptiometry. RESULTS: The mean BMD values from all three skeletal sites in male patients with LADA were comparable to those with classical T1DM but were much lower than those with T2DM. After adjusting for confounding factors, multiple linear regression analysis demonstrated that in all male patients with diabetes, body mass index (BMI), uric acid, and fasting C-peptide showed significant positive associations with BMD at all three skeletal sites; however, osteocalcin showed a negative association at all three sites. CONCLUSIONS: Compared with male patients with T2DM, lower BMDs were observed in patients with LADA and T1DM. Low BMI, uric acid, C-peptide levels, and high osteocalcin levels are risk factors for developing low BMD in male patients with diabetes.

Exogenous Insulin Injection-Induced Stiff-Person Syndrome in a Patient With Latent Autoimmune Diabetes: A Case Report and Literature Review.

Stiff-person syndrome (SPS) is highly associated with anti-glutamic acid decarboxylase (GAD) antibody. However, GAD antibodies alone appear to be insufficient to cause SPS, and they possibly are involved in only part of its pathophysiology. It is suspected that the symptoms of SPS get precipitated by external stimuli. Here, we briefly introduce the case of a patient with latent autoimmune diabetes who developed SPS through the action of subcutaneously injected insulin. A 43-year-old man was diagnosed with diabetes and initially well-controlled with oral hypoglycemic agents but progressed to requiring insulin within 1 year of diagnosis. Two months after the initiation of basal insulin therapy, he presented with abdominal stiffness and painful muscle spasms, involving the lower limbs, which resulted in walking difficulty, and thus, he refused insulin injections thereafter. He had been treated with oral anti-diabetic agents instead of insulin for 10 years until premixed insulin twice daily was started again due to poor diabetes control. Immediately after insulin injection, abdominal muscle rigidity and spasms were noted. When insulin was not administered, frequent episodes of diabetic ketoacidosis occurred. Serum GAD antibody test was positive and there was no positivity for islet antigen-2 antibody. A glucagon stimulation test demonstrated relative insulin deficiency, indicative of latent autoimmune diabetes in adults (LADA). Tolerable muscle rigidity was achieved when the dosage of basal insulin was split into two separate daily injections with lower amounts of units per injection. This case highlights a different form of autoimmune diabetes in SPS. To our knowledge, this is the first report of SPS described shortly after the initiation of insulin therapy that required basal insulin to achieve tolerable muscle symptoms and better glucose control, without the development of diabetic ketoacidosis.

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.

Type of diabetes mellitus: Does it matter to the clinician?

The classification of diabetes mellitus in 2020 still starts with 2 major types, ie, type 1 and type 2, but each of these now includes a few uncommon variants. Understanding the many faces of the diabetes syndrome can make a difference in how clinicians select glucose-lowering therapy.

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.

Pathophysiological characteristics in patients with latent autoimmune diabetes in adults using clamp tests: evidence of a continuous disease spectrum of diabetes.

AIMS: This study aimed to assess islet insulin secretion and insulin resistance in Chinese patients with latent autoimmune diabetes in adults (LADA). METHODS: Twelve patients with LADA, 10 with type 1 diabetes mellitus (T1DM), 10 with type 2 diabetes mellitus (T2DM), and 10 nondiabetic healthy controls (HCs) were included. Patients with LADA were subtyped according to the glutamic acid decarboxylase antibody (GADA) titer (LADA1, GADA titer ≥ 180 U/mL; LADA2, GADA titer 18-180 U/mL). Insulin secretion and sensitivity were assessed using hyperglycemic and hyperinsulinemic-euglycemic clamp tests, respectively. RESULTS: The first-phase insulin secretion gradually increased in patients with T1DM, LADA1, LADA2, and T2DM to HCs (29.32 ± 6.00 mU/L vs. 68.71 ± 4.50 mU/L vs. 87.60 ± 11.60 mU/L vs. 138.27 ± 13.18 mU/L vs. 248.49 ± 21.97 mU/L; P < 0.05). The second-phase insulin secretion (2 ph) and maximum insulin secretion (MIS) were significantly lower in patients with LADA2 and T2DM than in HCs, but higher in those with LADA1 and T1DM. No significant differences in 2 ph and MIS were observed between patients with LADA1 and T1DM, and between those with LADA2 and T2DM. The levels of insulin sensitivity index (ISI) during hyperinsulinemic-euglycemic clamps were lower in patients with LADA and T2DM than in those with T1DM. Patients with T1DM displayed lower ISI compared with HCs. CONCLUSIONS: Chinese patients with LADA and T1DM had impaired insulin sensitivity and ß-cell function. Furthermore, the hypothesis that diabetes is a continuous spectrum from T1DM, LADA1, LADA2 to T2DM was confirmed in this study.

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.

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.

Distinct neutrophil counts and functions in newly diagnosed type 1 diabetes, latent autoimmune diabetes in adults, and type 2 diabetes.

BACKGROUND: Recent discoveries from animal models demonstrated that neutrophils can induce type 1 diabetes (T1D) through infiltrating into the islets. However, the evidence of their actions in T1D patients is relatively rare, and the change trend of neutrophil numbers and functions in different subtypes of diabetes has not been investigated. METHODS: Patients with newly diagnosed T1D (n = 189), latent autoimmune diabetes in adults (LADA) (n = 86), T2D (n = 235), and healthy controls (n = 709) were enrolled. Circulating neutrophil counts were measured, and their correlations with clinical parameters were analysed. Neutrophils were isolated by density gradient centrifugation and magnetic bead cell sorting method. Neutrophil migration rate and chemokine levels in the blood were explored by trans-well and ELISA, respectively. Neutrophil phagocytosis rate, adhesion molecules and chemokine receptors expression were investigated by flow cytometry. RESULTS: Compared with controls, neutrophil counts decreased in T1D patients but increased in T2D patients, with no change in LADA patients. The numbers showed a gradual increase trend from T1D, LADA to T2D. In autoimmune diabetes, neutrophil counts were associated with the number and titre of positive autoantibodies against ß-cell antigens. No difference was found in neutrophil phagocytosis rate, but neutrophil migration in T1D patients was impaired and associated with CD62L expression, which was related closely to the titre of autoantibody. CONCLUSIONS: Neutrophil numbers and migration abilities displayed distinct levels in different types of diabetes. In T1D, CD62L seems to play an important role in the migration of neutrophils and ß-cell autoimmunity.

Identification of a distinct phenotype of elderly latent autoimmune diabetes in adults: LADA China Study 8.

BACKGROUND: Latent autoimmune diabetes in adults (LADA) exhibits significant clinical heterogeneity, but the underlying causes remain unclear. The aim of this study was to investigate whether age of onset of LADA contributes to the observed clinical heterogeneity by comparing the clinical, metabolic, and immunogenetic characteristics between elderly and young LADA patients. METHODS: The cross-sectional study included a total of 579 patients with LADA which was further divided into elderly LADA (E-LADA) group (n = 135, age of onset ≥60 years) and young LADA (Y-LADA) group (n = 444, age of onset <60 years). Age-matched subjects with type 2 diabetes were served as control (E-T2D group, n = 622). Clinical characteristics, serum autoantibodies, and HLA-DQ haplotypes were compared among these groups. RESULTS: Compared with patients with Y-LADA, patients with E-LADA have better residual beta-cell function and higher level of insulin resistance (both P < .01), more metabolic syndrome characteristics, similar proportion of islet autoantibody positivity, and strikingly different HLA-DQ genetic background. In comparison with E-T2D patients, E-LADA patients tend to have similar metabolic syndrome prevalence, comparable C-peptide levels, and insulin resistance levels and share similar HLA-DQ genetic characteristics. CONCLUSIONS: Elderly LADA differs phenotypically and genetically from Y-LADA but has a clinical and genetic profile more similar to that of E-T2D. These distinct phenotypes could potentially help physicians better manage patients with E-LADA.

Serum Sclerostin and Bone Turnover in Latent Autoimmune Diabetes in Adults.

Purpose: Bone formation is impaired in both type 1 diabetes and type 2 diabetes (T2D), whereas sclerostin, an antagonist of bone formation, is increased in T2D only. No data are available on latent autoimmune diabetes in adults (LADA), an autoimmune type of diabetes that may clinically resemble T2D at diagnosis. We evaluated serum sclerostin and bone turnover markers in LADA compared with those in T2D and whether metabolic syndrome (MetS) affects sclerostin in T2D or LADA. Methods: This cross-sectional study included 98 patients with T2D and 89 with LADA from the Action LADA and Non Insulin Requiring Autoimmune Diabetes cohorts. Patients were further divided according to MetS status. Nondiabetic participants (n = 53) were used as controls. Serum sclerostin, bone formation (pro-collagen type 1 N-terminal propeptide [P1NP]), and bone resorption (C-terminal telopeptide of type I collagen [CTX]) were analyzed. Results: Patients with T2D had higher sclerostin than did those with LADA [P = 0.0008, adjusted for sex and body mass index (BMI)], even when analysis was restricted to patients with MetS (adjusted P = 0.03). Analysis of T2D and LADA groups separately showed that sclerostin was similar between those with and those without MetS. However, a positive trend between sclerostin and number of MetS features was seen with T2D (P for trend = 0.001) but not with LADA. Patients with T2D or LADA had lower CTX than did controls (P = 0.0003) and did not have significantly reduced P1NP. Sclerostin was unrelated to age or hemoglobin A1c but was correlated with BMI (ρ = 0.29; P = 0.0001), high-density lipoprotein (ρ = -0.23; P = 0.003), triglycerides (ρ = 0.19; P = 0.002), and time since diagnosis (ρ = 0.32; P < 0.0001). Conclusions: Patients with LADA presented lower bone resorption than did controls, similar to patients with T2D. Sclerostin is increased in T2D but not in LADA, suggesting possible roles on bone metabolism in T2D only.

Dulaglutide treatment results in effective glycaemic control in latent autoimmune diabetes in adults (LADA): A post-hoc analysis of the AWARD-2, -4 and -5 Trials.

AIMS: Patients with a type-2-diabetes (T2D) phenotype positive for glutamic acid decarboxylase antibodies (GADA) represent the majority of cases of latent autoimmune diabetes of the adult (LADA). The GLP-1 receptor agonist dulaglutide, recently introduced for treatment of T2D, has yet to be evaluated in LADA patients. Our primary objective was to evaluate the effect of dulaglutide on glycaemic control (HbA1c) in GADA-positive LADA vs GADA-negative T2D patients. METHODS: A post-hoc analysis was performed using data from 3 randomized phase 3 trials (AWARD-2,-4,-5; patients with GADA assessment) which were part of the dulaglutide clinical development programme in T2D. LADA patients were identified by GADA ≥5 IU/mL (ELISA). Changes in HbA1c during 12 months of treatment with dulaglutide or comparator were analysed using mixed-effect model repeated measures. RESULTS: Of 2466 adults tested for GADA (dulaglutide, 1710; glargine, 298; sitagliptin, 294; placebo, 164), 2278 (92.4%) were GADA-negative and 188 (7.6%) were GADA-positive, including 58 GADA-high patients (> 200 IU/mL) and 130 GADA-low patients (≤200 and ≥5 IU/mL). Overall, baseline parameters were comparable between the groups. Dulaglutide resulted in comparable HbA1c reductions in GADA-negative (LS mean change [95%CI], -1.09% [-1.15, -1.03]) and GADA-positive patients (-0.94% [-1.15, -0.72]) at 12 months. HbA1c reductions were numerically, but not statistically, significantly larger in GADA-low patients (-1.02% [-1.26, -0.78]) vs GADA-high patients (-0.72% [-1.21,-0.24]) at 12 months. Similar outcomes were observed at 3 and 6 months. CONCLUSIONS: These data are the first to indicate that dulaglutide was effective in reducing HbA1c in LADA patients.

Low-grade Inflammatory Marker Profile May Help to Differentiate Patients With LADA, Classic Adult-Onset Type 1 Diabetes, and Type 2 Diabetes.

OBJECTIVE: To test whether differences in serum concentrations of adiposity-related low-grade inflammatory mediators could help to differentiate patients with latent autoimmune diabetes in adults (LADA), classic adult-onset type 1 diabetes, and type 2 diabetes. RESEARCH DESIGN AND METHODS: This cross-sectional study involved 75 patients with LADA, 67 with classic adult-onset type 1 diabetes, and 390 with type 2 diabetes. Serum concentrations of adiponectin, soluble tumor necrosis factor-α receptor 2 (sTNFRII), interleukin-6, hs-CRP, and total leukocyte number were measured. To evaluate the differences of these markers among diabetes types, we performed logistic regression models and evaluated area under the receiver-operating characteristic curve (AUCROC) values. RESULTS: The profile of innate immunity-related inflammatory markers correlated with metabolic syndrome components. LADA versus classic adult-onset type 1 diabetes was independently related to sTNFRII (odds ratio [OR] 1.9 [95% CI 1.01-3.97]; P = 0.047) and hs-CRP levels (OR 0.78 [95% CI 0.62-0.96]; P = 0.019), and a higher number of total leukocytes lowered the risk of LADA compared with type 2 diabetes (OR 0.98 [95% CI 0.97-0.99]; P = 0.036). The logistic regression model including explanatory biomarkers explained 35% of the variation for LADA versus classic adult-onset type 1 diabetes (AUCROC 0.83 [95% CI 0.74-0.92]; P < 0.001) and 15% of the variation for LADA versus type 2 diabetes (AUCROC 0.73 [95% CI 0.70-0.80]; P < 0.001). CONCLUSIONS: Inflammatory, adiposity, and immune-related markers could help to differentiate a LADA diagnosis from that of classic adult-onset type 1 diabetes, and also LADA from that of type 2 diabetes, along with islet autoantibody positivity.