Ketosis-prone type 2 diabetes in Caucasian adults: a follow-up cohort analysis.

Objective: To investigate the relationship between non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) in patients with latent autoimmune diabetes in adults (LADA). Methods: A total of 223 hospitalized patients were recruited between January 2007 and June 2009 in Department of Endocrinology and Metabolism of the Sixth People's Hospital Affiliated to Shanghai Jiaotong University. Finally, 142 patients with complete clinical data and without history of drinking were included in this study. According to the Chinese Medical Association's Guidelines of NAFLD, based on the result of ultrasound, all subjects were divided into two groups including patients with LADA and NAFLD (n=37) and patients with LADA but without NAFLD (n=105). Clinical data including diabetes duration, history of smoking and medications, height, weight, blood pressure, blood lipids, blood glucose, C-peptide, and liver and kidney function were collected. The prevalence and components of MetS were compared between two groups. The association between MetS and NAFLD was also explored. Results: After adjusting for age and sex, compared with the subjects without NAFLD, the subjects with NAFLD were older and had higher percentage of hypertension, and had higher body mass index[(26.5±3.7) kg/m(2) vs (21.9±3.1) kg/m(2)], waist-hip ratio(0.92±0.06 vs 0.86±0.07), low density lipoprotein cholesterol[(3.26±0.72) mmol/L vs (2.70±0.87) mmol/L], C-reactive protein, fasting C-peptide, 2 h postprandial C-peptide, systolic blood pressure, diastolic blood pressure, alanine aminotransferase and triglyceride (all P<0.05). But they had lower high-density lipoprotein cholesterol[(1.17±0.43) mmol/L vs (1.35±0.40) mmol/L]and HbA1c[(8.83±2.14) % vs (10.02±2.79)%](both P<0.05). In addition, after adjusting for age and sex, compared with the patients with LADA but without NAFLD, the prevalence of MetS in the patients with LADA and NAFLD was obviously higher (97.3% vs 47.6%, P<0.001), and the proportion of the patients with four (32.4% vs 16.2%, P<0.001) and five (43.2% vs 5.7%, P<0.001) components of MetS in the patients with LADA and NAFLD was also significantly increased than that in the patients with LADA but without NAFLD. Binary regression analysis showed that NAFLD was an independent factor associated with MetS in the patients with LADA after correcting other confounding factors (P<0.001). Conclusions: Compared with the patients with LADA but without NAFLD, the prevalence of MetS was obviously higher, and had more serious metabolic disorder in the patients with LADA and NAFLD. The presence of NAFLD was an independent factor associated with MetS in the patients with LADA.

The aim of this study was to investigate the association of cytotoxic T-lymphocyte antigen-4 (CTLA-4) + 49A/G and CT60 polymorphisms with latent autoimmune diabetes in adults (LADA) and the genetic differences between LADA, type 1 diabetes (T1DM), and type 2 diabetes (T2DM) in a Chinese population. A total of 231 LADA, 402 T1DM, and 330 T2DM patients as well as 482 nondiabetic controls were recruited in the study. CTLA-4 + 49A/G and CT60 polymorphisms were analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The level of glutamic acid decarboxylase antibodies (GADAs) was detected by a radioligand binding assay. The CTLA-4 + 49A/G risk genotype GG was most frequent in T1DM patients (45.3%), followed by LADA patients (44.2%) and T2DM patients (38.8%). Significantly higher frequencies of the risk genotype GG were observed in the T1DM (OR = 1.532, 95% CI 1.168-2.010, P = 0.002) and LADA patients (OR = 1.464, 95% CI 1.063-2.017, P = 0.019). The frequencies of the CTLA-4 CT60 risk genotype GG were 65.2, 61.9, 58.5, and 56.4% in the T1DM, LADA, T2DM, and control groups, respectively. The CTLA-4 CT60 GG risk genotypes were only associated with T1DM (OR = 1.445, 95% CI 1.1-1.898, P = 0.008). Compared with controls, patients having a high titer of GADA (GADA ≥ 180 IU/ml) had higher frequencies of the GG risk genotype of CTLA-4 + 49 A/G (49.4% vs. 35.1% OR = 1.807, 95% CI 1.125-2.903, P = 0.014), but there was no difference between patients having a low titer of GADA and controls. The CTLA-4 + 49 A/G polymorphism confers genetic susceptibility to LADA and T1DM, while the CTLA-4 CT60 polymorphism is only associated with T1DM in Chinese population. The CTLA-4 + 49 A/G genotype distribution in LADA is associated with the GADA level.

IDF21-0243 Clinical characteristics and outcomes in adult patients with hyperglycemic crises based on WHO classification 2019

Prevalence of latent autoimmune diabetes in adults in China: a systematic review and meta-analysis

Objective To determine interleukin (IL)-23 and IL-17 level in latent autoimmune diabetes in adult (LADA) patients, and to explore the relationship of IL-23, IL-17and β-cell function in these patients. Methods Forty LADA patients from 2011 to 2016 in our hospital were selected as LADA group, and forty participants were as normal control group. Clinical and biochemical data was collected and the level of the IL-23 and IL-17 was measured with the enzyme linked immunosorbent assay (ELISA). The differences in interleukin levels among the two groups were compared. Pearson correlation analysis was used for investigating the relationship between the dependent of statistical significant interleukins and the independent data in the LADA patients, all closely related variables then were included in a stepwise multiple linear regression analysis. Results The levels of serum IL-23 , IL-17 and IL-23/IL-17 were significantly higher in LADA group than those in control groups [3.54(2.88~5.24)μg/L vs 1.98(1.62~2.18)μg/L, P<0.05], [22.42(17.71~26.07)ng/L vs 17.97(17.15~20.70)ng/L, P<0.05], (175.79±38.67 vs 105.22±19.08, P<0.01). IL-23 and IL-17 in the LADA group were negatively correlated with fasting C peptide (FCP) (r=-0.42, r=-0.48, P<0.05), and the ratio of IL-23/IL-17 was positively correlated with fasting plasma glucose (FPG) (r=0.44, P=0.00). Stepwise multiple liner regression analysis showed that serum IL-23 and IL-17 level were independently associated with the FCP in LADA group. Conclusions IL-23 and IL-17 were possibly important proinflammatory factor in LADA patients, and can provide the new immunodiagnosis markers for LADA. Key words: Interleukin-23; Interleukin-17; Latent autoimmune diabetes in adults; C-peptide

To investigate the clinical features of non-alcoholic fatty liver disease (NAFLD) and its relationship with serum C-peptide levels in patients with latent autoimmune diabetes in adults (LADA). A total of 155 patients with LADA who had no drinking history and were hospitalized in department of endocrinology and metabolism from January 2007 to June 2009 were divided into two groups, including patients with LADA but without NAFLD and patients with both LADA and NAFLD, according to Chinese medical association's guidelines of NAFLD and hepatic ultrasound result. Their clinical data and results of laboratory examinations were collected and analyzed, including medications, blood pressure, weight, height, waist circumference, hip circumference, fasting plasma glucose, 2 h postprandial plasma glucose, fasting C-peptide, 2 h postprandial C-peptide, hemoglobin A1c, renal function, liver function, blood lipid and C-reactive protein. The clinical features between two groups were compared and the relationship between serum C-peptide and NAFLD were also analyzed. Compared to the patients with LADA but without NAFLD, patients with both LADA and NAFLD had higher alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (γ-GT) (all P<0.01), but the serum total bilirubin (TBI) and direct bilirubin (DBI) level had no significant inter-group difference (P>0.05). The patients with both LADA and NAFLD had higher fasting C-peptide [0.62(0.33-0.93) vs 0.17 (0.05-0.50) nmol/L, P<0.001], 2 h postprandial C-peptide [1.57(0.78-1.88) vs 0.42(0.06-1.01) nmol/L, P<0.001] and more severe insulin resistance [0.8(1.0-2.5) vs 0.6(0.2-1.3), P<0.001]. Logistic regression analysis showed that there was a significant association between fasting C-peptide and the presence of NAFLD after controlling other confounding factors in patients with LADA. The patients with both LADA and NAFLD had more severe metabolic disorders and insulin resistance. Serum fasting C peptide was independently associated with the presence of NAFLD in patients with LADA.

Aims Few research was reported to explore oxidative stress in individuals with latent autoimmune diabetes in adults (LADA). Therefore, our goal is to study oxidative stress and related factors in LADA patients. Methods In this study, 250 Chinese inpatients were diagnosed with LADA (n = 110) and type 2 diabetes mellitus (n = 140) and 140 healthy volunteers were recruited. Moreover, individuals with LADA were followed for 6 months to evaluate whether short-term glycemic control during hospitalization can improve oxidative stress. Clinical and laboratory measurements of height, weight, blood pressure, glycosylated hemoglobin (HbA1c), blood lipids, 8-isoprostaglandin F2α (8-iso-PGF2α), and superoxide dismutase (SOD) were performed. Stepwise multiple regression analyses were used to assess factors that related to oxidative stress in individuals with LADA. Results Compared with patients with type 2 diabetes, individuals with LADA have better oxidative stress and worse oxidative stress than healthy volunteers. After multiple regression analyses, systolic blood pressure, HbA1c, duration of diabetes, and diabetic retinopathy were associated with 8-iso-PGF2α and HbA1c. Diabetic retinopathy and diabetic ketosis were associated with SOD in individuals with LADA. Our results also revealed that, after 6 months of follow-up, oxidative stress was improved to some extent in persons with LADA. Conclusions Our results show that compared with type 2 diabetes, LADA means less oxidative stress, and compared with healthy volunteers, it means more oxidative stress. Systolic blood pressure, HbA1c, duration of diabetes, diabetic retinopathy, and ketosis were associated with oxidative stress in individuals with LADA. Furthermore, short-term glycemic control can improve oxidative stress to some extent in individuals with LADA.

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.

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.

ABSTRACTObjective In this study, we aimed to determine the frequency of and the clinical and metabolic features of patients with latent autoimmune diabetes in adults (LADA) at a single center in Turkey.Subjects and methods Patients over 30 years of age diagnosed with type 2 diabetes who did not require insulin for a minimum of 6 months following diagnosis were included. Data from 324 patients (163 women; 161 men), with a mean age of 54.97 ± 7.53 years, were analyzed in the study. Levels of antibodies to glutamate decarboxylase (anti-GAD) were measured in all patients, and LADA was diagnosed in patients testing positive for anti-GAD antibodies.Results Anti-GAD positivity was identified in 5 patients (1.5%). Family history of diabetes, body mass index (BMI), age, sex distribution, insulin resistance, serum triglycerides, high-density lipoprotein, and low-density lipoprotein were similar in the LADA and type 2 diabetes patients. Median HbA1c was significantly higher (10.8% vs. 7.38%, p = 0.002) and fasting C-peptide was lower (0.75 ng/mL vs. 2.82 ng/mL, p = 0.009) in patients with LADA compared to in those with type 2 diabetes. Among the 5 patients with LADA, 4 were positive for antithyroid peroxidase antibodies. The median disease duration was relatively shorter among patients with LADA (4 years vs. 7 years, p = 0.105).Conclusion We observed a LADA frequency of 1.5% among Turkish patients followed for type 2 diabetes. The presence of obesity and metabolic syndrome did not exclude LADA, and patients with LADA had worse glycemic control than patients with type 2 diabetes did.

Backgrounds. Latent autoimmune diabetes in adults (LADA) is a slowly progressive form of autoimmune diabetes mellitus characterized by older age at diagnosis, presence of pancreatic autoantibodies, and lack of absolute insulin requirement at diagnosis. Patients with LADA had better β-cell function than patients with classic Type 1 DM (T1DM). Overtime, LADA tends to experience rapid and progressive loss of beta cell function that requires intensive insulin therapy. This case report aims to describe a case of Diabetic Ketoacidosis (DKA) in a patient with latent autoimmune diabetes in adult (LADA) induced by sepsis (urinary tract infection/UTI).&#x0D; Case Presentations. A woman, 28 years-old, came to the Emergency Department (ED) RSMH Palembang with chief complaints of decreased consciousness and shortness of breath. Patient had a history of frequent urination, pain when urinating, and fever. Urinalysis examination were glycosuria, proteinuria, hematuria. Hb-A1c level was 10.7%, C-Peptide 0.11 ng/dL, Anti GAD65 qualitative positive, and Islet cell antibody (ICA) negative. Patient was diagnosed with diabetic ketoacidosis (DKA), LADA, and sepsis due to urinary tract infection (UTI). Patients were managed with DKA and sepsis management algorithm.&#x0D; Conclusion. Diabetic ketoacidosis (DKA) in LADA caused by sepsis is an emergency in the metabolic endocrine and diabetes fields. Prompt and appropriate management can improve outcome prognosis in this case.

Few studies were performed to evaluate the prevalence of latent autoimmune diabetes in adults (LADA) and the difference of chronic complications between LADA, T1DM, and T2DM in Korean. The aim of this study is to establish the prevalence of LADA in a diabetic clinic of Soonchunhyang University hospital and to compare the phenotypic characteristics according to DM classification based on positivity of glutamic acid decarboxylase antibodies (GADA). Also, another important point concerns the occurrence of diabetes chronic microvascular complications in LADA. 323 patients who were checked GADA among diabetic patients admitted at Soonchunhyang University hospital were recruited. Twenty-eight patients (8.7%) were identified as positive for GADA. 11.5% (n=37) were diagnosed with T1DM and 5.3% (n=17) were diagnosed with LADA. GADA titer showed significant negative correlation with age of onset, total cholesterol (TC), triglyceride (TG), fasting C-peptide, stimulated C-peptide, BMI, and positive correlation with HbA1C and HDL-C. Compared with those that tested negative for GADA, patients with GADA positive had lower values of onset age, BMI, TC, TG, LDL-C, fasting, and stimulated C-peptide levels and higher values of HbA1C. A significant gradual increase of values was observed for the onset age, BMI, SBP, DBP, fasting, and stimulated C-peptide across the T1DM, LADA, and T2DM subgroups. Concerning the chronic complications there was no difference in prevalence of retinopathy, neuropathy and nephropathy between three groups. Of LADA patients, 12 patients were receiving insulin treatment and mean time to insulin initiation was about 37months. In conclusion, because our study suggests LADA subgroups in Korea appear to have a faster decline in C-peptide levels, it is worth detecting the patients with LADA early and effort to preserve beta cell function. Furthermore, our results showed that the prevalence of microvascular complication was comparable between the subgroups.

This study aimed to compare pancreatic volume and its clinical significance among patients with type 2 diabetes mellitus (DM), adult-onset type 1 DM and latent autoimmune diabetes in adults (LADA). This is a cross-sectional study. One hundred twenty-six outpatients (68 with LADA and 58 with type 1 DM) and 158 inpatients (71 with type 2 DM and 87 non-diabetic controls) were recruited during May-July 2013 in Shanghai Jiao Tong University Affiliated Sixth People's Hospital. All the patients underwent abdominal computerized tomography; pancreatic volume was then calculated. The mean pancreatic volume was highest in the controls, followed by those in patients with type 2 DM, LADA and type 1 DM. The pancreatic volume in LADA was comparable with that in type 2 DM but significantly greater than that in type 1 DM (p < 0.05). The pancreatic volume in patients with LADA was significantly correlated with sex, waist circumference, body surface area, body mass index, diastolic blood pressure and high-density lipoprotein cholesterol (all p < 0.05). The correlation between pancreatic volume and fasting C-peptide was high in patients with LADA (r = 0.643, p < 0.001) and moderate in patients with type 2 DM (r = 0.467, p < 0.001). The area under the receiver operating characteristic curve for pancreatic volume predictive of absolute insulin deficiency (FCP < 0.9ng/mL) was 0.85 (0.76-0.94) in LADA. Pancreatic atrophy in LADA was less marked than in type 1 DM. Pancreatic atrophy may suggest reduced level of fasting C-peptide in patients with LADA. Copyright © 2016 John Wiley & Sons, Ltd.

Coffee consumption is associated with a reduced risk of Type2 diabetes. Our aim was to investigate if coffee intake may also reduce the risk of latent autoimmune diabetes in adults, an autoimmune form of diabetes with features of Type2 diabetes. We used data from a population-based case-control study with incident cases of adult onset (≥35years) diabetes, including 245 cases of latent autoimmune diabetes in adults (glutamic acid decarboxylase antibody positive), 759 cases of Type2 diabetes (glutamic acid decarboxylase antibody negative), together with 990 control subjects without diabetes, randomly selected from the population. Using questionnaire information on coffee consumption, we estimated the odds ratio of latent autoimmune diabetes in adults and Type2 diabetes adjusted for age, sex, BMI, smoking, physical activity, alcohol, education and family history of diabetes. Coffee intake was inversely associated with Type2 diabetes (odds ratio0.92, 95%CI 0.87-0.98 per cup/day). With regard to latent autoimmune diabetes in adults, the general trend was weak (odds ratio1.04, 95%CI 0.96-1.13), but stratification by degree of autoimmunity (median glutamic acid decarboxylase antibody levels) suggested that coffee intake may be associated with an increased risk of high glutamic acid decarboxylase antibody latent autoimmune diabetes in adults (odds ratio1.11, 95%CI 1.00-1.23 per cup/day). Furthermore, for every additional cup of coffee consumed per day, there was a 15.2% (P=0.0268) increase in glutamic acid decarboxylase antibody levels. Our findings confirm that coffee consumption is associated with a reduced risk of Type2 diabetes. Interestingly, the findings suggest that coffee may be associated with development of autoimmunity and possibly an increased risk of more Type1-like latent autoimmune diabetes in adults.

Latent autoimmune diabetes in adults (LADA) prevails as a name in diabetes research although it was ranked as the second silliest name some years ago [1]. LADA describes a subgroup of patients who develop phenotypic type 2 diabetes but with markers of autoimmunity [2, 3]. In 2005, we tried to describe the background to LADA and establish a definition based on adult age at onset, presence of autoantibodies and lack of requirement for insulin at least 6 months after diagnosis [4]. Both the age and the insulin criteria were soon questioned [1, 5], but they also gained some support [6]. The question of how to define LADA has resulted in numerous articles and debates discussing whether LADA is a disease on its own or just a variant of type 1 diabetes [7–9]. Thus, it could be questioned whether the introduction of the term LADA has been an asset or an obstacle to our understanding of diabetes. The first question we should ask is: what good has the concept of LADA done for science and patients? In defence of LADA we may note that the categorisation has put the existence of autoimmune diabetes in adults on the scientific map. We know that by including LADA in type 1 diabetes, as recommended by the WHO [10], more adults than children are affected by autoimmune diabetes [11]. We know more about cellular and humoral responses [12–15], metabolic traits [16, 17] and genetic background [18] in adult patients with autoimmune diabetes. Thus, the LADA concept has been an efficient tool for studying and communicating different pathophysiological aspects of autoimmune diabetes in adults. Another reason for classifying diabetes is to facilitate studies on treatment and prevention where strict inclusion criteria are needed. It was concluded in a recent Cochrane Review [19] that there were few randomised controlled trials of good quality available to evaluate which treatment is optimal for LADA patients, but using sulfonylurea seemed unfavourable for beta cell function. The review also noted that the definition of LADA was imprecise, which hampered comparison between the studies. Taken together, the scientific use of LADA has up to now been better and more productive than its clinical use. So, what is the problem with the concept of LADA? The main problem is how to define LADA. This leads to futile discussion that does not take our understanding of autoimmune diabetes any further; it might even be an obstacle to our way of thinking. This could be exemplified by studies trying to subgroup LADA, which already is a subgroup. There are manuscripts proposing different kinds of LADA based on the antibody titre, with low-titre and high-titre LADA [20, 21]. We even will have patients who fulfil the age and treatment criteria with T cell reactivity to O. Rolandsson (*) Family Medicine, Department of Public Health and Clinical Medicine, Umea University, Umea, Sweden e-mail: olov.rolandsson@fammed.umu.se