Metabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population

Background. Type 2 diabetes (T2D) has a heterogeneous etiology which is increasingly recognized to influence the risk of complications and choice of treatment. A data driven cluster analysis in four separate European populations of patients with type 2 diabetes identified four subtypes of severe insulin dependent (SIDD), severe insulin resistant (SIRD), mild obesity-related (MOD), and mild age-related (MARD) (Ahlqvist et al., Lancet Diabetes Endocrinology, 2018). Our aim was to extend this classification to the Arab population of Qatar and characterize the biological processes that differentiate these subtypes in relation to metabolomic and proteomic signatures. Methods. The Ahlqvist et al. subtype clustering approach was applied to 631 individuals with T2D from the Qatar Biobank (QBB) and validated in an independent set of 420 participants from the same population. The association between blood metabolites (n=1,159) and protein levels (n=1,305) with each cluster were established. Findings. The four subtypes of T2D were reproduced and validated in the population of Qatar. Cluster-specific metabolomic and proteomic associations revealed subtype-specific molecular processes. Activation of the complement system with many features of autoimmune diabetes and reduced 1,5-anhydroglucitol (1,5-AG) characterized SIDD, with evidence of impaired insulin signaling in SIRD, elevated leptin and fatty acid binding protein in MOD, whilst MARD appeared to be the healthiest subgroup. Interpretation. We have replicated the four T2D clusters in an Arab population and identified distinct metabolic and proteomic signatures, providing insights into underlying etiology with the potential to deploy subtype-specific treatment options.

Prevalence of Latent Autoimmune Diabetes in Adult Based on the Presence of GAD 65 Antibodies in North-Eastern Uttar Pradesh, India

Objective The objective of this paper was (1) to study the prevalence of latent autoimmune diabetes in adult (LADA) in the region of north-eastern Uttar Pradesh, India, based on the positivity for glutamic acid decarboxylase 65 (GAD65) antibodies and (2) to compare the glycemic profile between GAD65-positive and GAD65-negative subjects. Materials and Methods The subjects were of more than 30 years of age, with either recently diagnosed pre-diabetes/diabetes presenting with the hemoglobin A1c (HbA1c) level of ≥5.7% or already diagnosed cases of type 2 diabetes mellitus (T2DM) who had no requirement of insulin therapy for at least 6 months from the time of their diagnosis. All the patients were natives of north-eastern Uttar Pradesh. The GAD65 test was done by the enzyme-linked immunosorbent assay. Further, the glycemic status of GAD-positive and GAD-negative subjects were compared on the basis of fasting blood sugar (FBS), fasting insulin (FI), and homeostatic model assessment for insulin resistance (HOMA-IR). Statistical Analysis The “unpaired t-test” was used to compare and assess the significance of differences between the glycemic profile of GAD65-positive and GAD65-negative subjects using the GraphPad Prism Scientific Software, San Diego, CA, United States. The p-value of <0.05 was considered to be significant. Results A total of 77 patients were included in the study, with the age group ranging from 30 to 75 years (47.81 ± 12.9 years) with the male–female ratio of 1:2.6. The prevalence of LADA was found to be 51.95%. On comparing GAD65-positive and GAD65-negative groups, a higher value of HbA1c levels and FBS were found in the former, whereas FI and HOMA-IR were found to be higher in the latter. On testing for significance of difference, only FI and HbA1c values were significant (p-value <0.0001). Conclusion LADA can no longer be considered a rare type of diabetes mellitus, with the present study showing a high prevalence of LADA in this north eastern region of Uttar Pradesh. Identification of adult-onset diabetics accurately as LADA or true T2DM is very crucial for the appropriate treatment, as LADA patients require insulin inevitably and much earlier than true T2DM patients, who can be managed mostly on oral hypoglycemic agents with seldom requirement of insulin.

The role of “latent autoimmune diabetes in adults” in the structure of diabetes mellitus in young people

In the clinical practice of an endocrinologist, verification of the type of diabetes mellitus (DM) in young people is of high clinical significance, since the prescription of treatment depends on this: from the correction of carbohydrate metabolism by a balanced diet to the prescription of oral hypoglycemic drugs and insulin therapy. In rare forms of diabetes mellitus, which include «latent autoimmune diabetes in adults» (LADA), it is not always possible to make a correct diagnosis. This form of diabetes mellitus occupies an intermediate position between type 1 diabetes mellitus and type 2 diabetes mellitus (DM 1 and DM 2) and is often not detected. In this regard, the study of the LADA flow is of great practical importance. Verification of the LADA diagnosis is based on three clinical criteria: adult onset of diabetes; the presence of circulating islet autoantibodies, which distinguishes LADA from T2DM; the absence of an absolute need for insulin when making a diagnosis, which distinguishes LADA from the classic type 1 diabetes mellitus. The main treatment tactics for patients with LADA should be aimed at preserving their own insulin secretion. This requires the timely appointment of insulin therapy. The question of the possibility of using drugs of peripheral action – biguanides and glitazones, which do not cause depletion of β-cells, is discussed, but their effectiveness has not yet been established. The appointment of any secretogens, including sulfonylurea preparations, is contraindicated Quite often, LADA is difficult to diagnose, and the wrong treatment tactics are prescribed. At the moment, there is little data on the effectiveness of different classes of drugs, which leads to further detailed study of this type of diabetes. Currently, there are no special algorithms for LADA treatment

Sepsis-Induced Diabetic Ketoacidosis (DKA) in Latent Autoimmune Diabetes in Adult (LADA)

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). 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. 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.

Characteristics of the Gut Microbiota and Metabolism in Patients With Latent Autoimmune Diabetes in Adults: A Case-Control Study

OBJECTIVE <p>Type 1 and type 2 diabetes are associated with gut dysbiosis. However, the relationship between the gut microbiota and latent autoimmune diabetes in adults (LADA), sharing clinical and metabolic features with classic type 1 and type 2 diabetes, remains unclear. Here, we identified the characteristics of the gut microbiota and metabolic profiles in patients with LADA using a multi-omics approach.</p> <p>RESEARCH DESIGN AND METHODS</p> <p>This age- and sex-matched case-control study included 30 patients with LADA, 31 patients with classic type 1 diabetes, 30 patients with type 2 diabetes, and 29 healthy individuals. The gut microbiota profiles were identified via the 16S rRNA gene, and fecal and serum metabolites were measured via untargeted liquid chromatography-mass spectrometry.</p> <p>RESULTS </p> <p>LADA patients had a significantly different structure and composition of the gut microbiota and their metabolites as well as a severe deficiency of short-chain fatty acid-producing bacteria. The gut microbiota structure of the LADA patients was more similar to that of patients with type 1 diabetes who were positive for GAD antibody. We identified seven serum metabolite modules and eight fecal metabolite modules that differed between the LADA group and the other groups.</p> <p>CONCLUSIONS </p> <p><a>The characteristic gut microbiota and related metabolites of patients with LADA are associated with autoantibodies, glucose metabolism, islet function, and inflammatory factors, which may contribute to the pathogenesis of LADA. </a>Future longitudinal studies should explore whether modulating the gut microbiota and related metabolites can alter the natural course of autoimmune diabetes, in the quest for new therapeutic.</p>

A novel diabetes typology: towards precision diabetology from pathogenesis to treatment

The current classification of diabetes, based on hyperglycaemia, islet-directed antibodies and some insufficiently defined clinical features, does not reflect differences in aetiological mechanisms and in the clinical course of people with diabetes. This review discusses evidence from recent studies addressing the complexity of diabetes by proposing novel subgroups (subtypes) of diabetes. The most widely replicated and validated approach identified, in addition to severe autoimmune diabetes, four subgroups designated severe insulin-deficient diabetes, severe insulin-resistant diabetes, mild obesity-related diabetes and mild age-related diabetes subgroups. These subgroups display distinct patterns of clinical features, disease progression and onset of comorbidities and complications, with severe insulin-resistant diabetes showing the highest risk for cardiovascular, kidney and fatty liver diseases. While it has been suggested that people in these subgroups would benefit from stratified treatments, RCTs are required to assess the clinical utility of any reclassification effort. Several methodological and practical issues also need further study: the statistical approach used to define subgroups and derive recommendations for diabetes care; the stability of subgroups over time; the optimal dataset (e.g. phenotypic vs genotypic) for reclassification; the transethnic generalisability of findings; and the applicability in clinical routine care. Despite these open questions, the concept of a new classification of diabetes has already allowed researchers to gain more insight into the colourful picture of diabetes and has stimulated progress in this field so that precision diabetology may become reality in the future. Graphical abstract

Clinical Peculiarities in a Cohort of Patients with Wolfram Syndrome 1

Wolfram syndrome 1 is a rare, autosomal recessive, neurodegenerative, progressive disorder. Insulin-dependent, non-autoimmune diabetes mellitus and bilateral progressive optic atrophy are both sensitive and specific criteria for clinical diagnosis. The leading cause of death is central respiratory failure resulting from brainstem atrophy. We describe the clinical features of fourteen patients from seven different families followed in our Diabetes Center. The mean age at Wolfram syndrome 1 diagnosis was 12.4 years. Diabetes mellitus was the first clinical manifestation, in all patients. Sensorineural hearing impairment and central diabetes insipidus were present in 85.7% of patients. Other endocrine findings included hypogonadotropic hypogonadism (7.1%), hypergonadotropic hypogonadism (7.1%), and Hashimoto’s thyroiditis (21.4%). Neuropsychiatric disorders were detected in 35.7% of patients, and urogenital tract abnormalities were present in 21.4%. Finally, heart diseases were found in 14.2% of patients. Eight patients (57.1%) died at the mean age of 27.3 years. The most common cause of death was respiratory failure which occurred in six patients. The remaining two died due to end-stage renal failure and myocardial infarction. Our data are superimposable with those reported in the literature in terms of mean age of onset, the clinical course of the disease, and causes of death. The frequency of deafness and diabetes insipidus was higher in our patients. The incidence of urogenital diseases was lower although it led to the death of one patient. Long-term follow-up studies including large patient cohorts are necessary to establish potential genotype-phenotype correlation in order to personalize the most suitable clinical approach for each patient.

Immune checkpoint inhibitors, endocrine adverse events, and outcomes of melanoma

Objective: Immune checkpoint inhibitors (ICI) can cause endocrine adverse events. However, endocrine AEs could be related to better treatment outcomes. Our aim was to investigate whether this holds true in a real-world setting of metastatic melanoma patients. Design: A retrospective single-institution study. Methods: We included 140 consecutive metastatic melanoma patients treated with ICI between January 2012 and May 2019. We assessed endocrine toxicity and best possible treatment outcomes from electronic patient records, including laboratory parameters, and radiological images. Results: Of the treated patients, 21 patients (15%) were treated with ipilimumab, 46 (33%) with nivolumab, 67 (48%) with pembrolizumab, and six (4%) with combination therapy (ipilimumab + nivolumab). Endocrine AEs appeared in 29% (41/140) patients. Three patients had two different endocrine AEs. Thyroid disorders were the most common: 26% (36/140), followed by hypophysitis: 4% (5/140). Three subjects (2%, 3/140) were diagnosed with autoimmune diabetes. Three patients had to terminate treatment due to endocrine toxicity. Radiological manifestations of endocrine AEs were found in 16 patients (39%, 16/41). Endocrine toxicity was associated with significantly better treatment outcomes. Median progression-free survival (8.1 months, range 5.1 – 11.1 months vs. 2.7 months, range 2.4 – 3.0 months, P < 0.001), and median overall survival (47.5 months, range 15.5 – 79.5 months vs. 23.7 months, range 15.3 – 32.1 months, P = 0.035) were longer for patients experiencing endocrine AEs. Conclusions: The higher number of endocrine AEs suggest regular laboratory monitoring aids in AE detection. Endocrine AEs in metastatic melanoma may correlate with better treatment outcomes.

Cepharanthine Blocks Presentation of Thyroid and Islet Peptides in a Novel Humanized Autoimmune Diabetes and Thyroiditis Mouse Model

Autoimmune polyglandular syndrome type 3 variant (APS3v) refers to an autoimmune condition in which both type 1 diabetes (T1D) and autoimmune thyroiditis (AITD) develop in the same individual. HLA-DR3 confers the strongest susceptibility to APS3v. Previously we reported a unique amino acid signature pocket that predisposes to APS3v. We found that this pocket is flexible and can trigger APS3v by presenting both thyroid (Tg.1571, TPO.758) and islet (GAD.492) peptides to induce autoimmune response. We hypothesized that blocking the specific APS3v-HLA-DR3 pocket from presenting thyroid/islet antigens can block the autoimmune response in APS3v. To test this hypothesis we performed a virtual screen of small molecules blocking APS3v-HLA-DR3, and identified 11 small molecules hits that were predicted to block APS3v-HLA-DR3. Using the baculovirus-produced recombinant APS3v-HLA-DR3 protein we tested the 11 small molecules in an in vitro binding assay. We validated 4 small molecule hits, S9, S5, S53 and S15, that could block the APS3v-HLA-DR3 pocket in vitro. We then developed a novel humanized APS3v mouse model induced by co-immunizing a peptide mix of Tg.1571, TPO.758 and GAD.492. The immunized mice developed strong T-cell and antibody responses to the thyroid/islet peptides, as well as mouse thyroglobulin. In addition, the mice showed significantly lower free T4 levels compared to controls. Using the APS3v mouse model, we showed that one of the 4 small molecules, Cepharanthine (S53), blocked T-cell activation by thyroid/islet peptides ex vivo and in vivo. These findings suggested Cepharanthine may have a therapeutic potential in APS3v patients carrying the specific APS3v-HLA-DR3 pocket.