Prevalence of Positivity for Diabetes-Associated Autoantibodies in Individuals with Type 2 Diabetes and Their Further Characterisation: Cross-sectional Study from Slovakia.

BACKGROUND: Individuals initially diagnosed with type 2 diabetes (T2D) might exhibit positivity for diabetes-associated autoantibodies (DAA +). We investigated the prevalence of DAA positivity in a group of individuals with T2D who were referred to a tertiary diabetes centre within a pre-specified period of time. We aimed to identify characteristics linked with DAA positivity by comparing DAA + individuals with their DAA-negative counterparts. METHODS: This was a cross-sectional study into which all T2D patients referred to the National Institute of Endocrinology and Diabetology, Lubochna, Slovakia, between 1 January and 30 June 2016 were included. Data on > 70 participants' characteristics, including antibodies against glutamic acid decarboxylase (anti-GAD65), insulinoma-associated antigen IA-2 (IA-2A) and insulin (IAA), were collected. RESULTS: Six hundred and ninety-two individuals (387, 55.6% female) with a median (range) age of 62 (24-83) years, HbA1c of 8.9 (5.0-15.7)% [74 (31-148 mmol/mol)] and diabetes duration of 13.0 (0-42) years were analysed. One hundred and forty-five (145/692, 21.0%) tested positive for at least one DAA; 136/692 (19.7%) were positive for anti-GAD65, 21/692 (3.0%) were positive for IA-2A and 9/692 (1.3%) were positive for IAA. Only 84.9% of the DAA + individuals aged > 30 years at the time of diabetes diagnosis met the current diagnostic criteria for latent autoimmune diabetes of adults (LADA). DAA + differed from DAA - individuals in multiple characteristics, including the incidence of hypoglycaemia. CONCLUSION: Several pathological processes linked with distinct types of diabetes can develop in parallel, including insulin resistance and autoimmune insulitis. In this single-centre cross-sectional study from Slovakia, we report a higher than previously published prevalence of DAA positivity in a group of individuals with a formal diagnosis of T2D.

Induced Pluripotent Stem Cell (iPSC)-Derived Extracellular Vesicles Are Safer and More Effective for Cardiac Repair Than iPSCs.

RATIONALE: Extracellular vesicles (EVs) are tiny membrane-enclosed droplets released by cells through membrane budding or exocytosis. The myocardial reparative abilities of EVs derived from induced pluripotent stem cells (iPSCs) have not been directly compared with the source iPSCs. OBJECTIVE: To examine whether iPSC-derived EVs can influence the biological functions of cardiac cells in vitro and to compare the safety and efficacy of iPSC-derived EVs (iPSC-EVs) and iPSCs for cardiac repair in vivo. METHODS AND RESULTS: Murine iPSCs were generated, and EVs isolated from culture supernatants by sequential centrifugation. Atomic force microscopy, high-resolution flow cytometry, real-time quantitative RT-PCR, and mass spectrometry were used to characterize EV morphology and contents. iPSC-EVs were enriched in miRNAs and proteins with proangiogenic and cytoprotective properties. iPSC-EVs enhanced angiogenic, migratory, and antiapoptotic properties of murine cardiac endothelial cells in vitro. To compare the cardiac reparative capacities in vivo, vehicle, iPSCs, and iPSC-EVs were injected intramyocardially at 48 hours after a reperfused myocardial infarction in mice. Compared with vehicle-injected mice, both iPSC- and iPSC-EV-treated mice exhibited improved left ventricular function at 35 d after myocardial infarction, albeit iPSC-EVs rendered greater improvement. iPSC-EV injection also resulted in reduction in left ventricular mass and superior perfusion in the infarct zone. Both iPSCs and iPSC-EVs preserved viable myocardium in the infarct zone, whereas reduction in apoptosis was significant with iPSC-EVs. iPSC injection resulted in teratoma formation, whereas iPSC-EV injection was safe. CONCLUSIONS: iPSC-derived EVs impart cytoprotective properties to cardiac cells in vitro and induce superior cardiac repair in vivo with regard to left ventricular function, vascularization, and amelioration of apoptosis and hypertrophy. Because of their acellular nature, iPSC-EVs represent a safer alternative for potential therapeutic applications in patients with ischemic myocardial damage.

[Autoimmune insulitis in patients with type 2 diabetes mellitus A randomized clinical trial in hospitalized patients]. / Autoimunitná inzulítída u pacientov s diabetes mellitus 2. typu. Randomizovaný klinický prieskum u hospitalizovaných pacientov.

BACKGROUND: It is not always easy to classify diabetes (DM) diagnosed in adults, with a significant group of patients initially classified and treated for type 2 diabetes mellitus (DM2T) presenting signs indicating the presence of autoimmune insulitis (AI), which is characteristic of type 1 diabetes mellitus (DM1T), or latent autoimmune diabetes mellitus in adults (LADA). GOAL: Identify the proportion of patients entered with DM2T who present AI signs, and the number of patients of that proportion, who at the same time present low insulin secretion, and what clinical and laboratory manifestations could be used to differentiate between these patients.Cohort and methods: A randomized clinical trial with a pre-determined set of assessed parameters for n = 625 patients, who were hospitalized during the first 6 months of 2016 at the National Endocrinology and Diabetology Institute (NEDU), Lubochna. Apart from the standard parameters, C-peptide (CP) and autoantibodies to glutamic acid decarboxylase (GADA) were examined for each patient. GADA positive (GADA+) patients were compared to GADA negative (GADA-) patients in the following parameters: gender, age, age at the time of dia-gnosing DM, duration of DM, HbA1c, incidence of hypoglycemia, lipidogram, fasting C-peptide levels, BMI, waist circumference, incidence of hypoglycemias, presence of microvascular and macrovascular complications, treatment of dia-betes and incidence of other endocrinopathies. GADA+ with low CP were subsequently compared to GADA+ patients with normal CP. RESULTS: Of 625 patients originally classified and treated as DM2T, 13 % were GADA+. 31 % of them had low CP (< 0.2 nmol/l) and 28 % had CP levels within the intermediary range (0.2-0.4 nmol/l). Females made up a larger proportion of GADA+ patients, with a lower BMI, smaller waist circumference, lower CP, higher HDL cholesterol levels, a greater incidence of hypoglycemias and lower total daily dose of insulin. GADA+ patients with low CP differed from GADA+ patients with normal CP in higher HDL cholesterol levels, lower triglyceride levels and earlier need of insulin thera-py. The testing for GADA and CP levels with regard to the other relevant characteristics led to re-classification, or more precisely adding of DM1T/LADA (as the main, or parallel cause of DM) for 2.9 % of all the patients included and a clinically significant proportion of AI could be assumed in 6.1 % of the patients. SUMMARY: The results of our study show that the pathogenesis of DM in patients initially diagnosed and registered with DM2T and with concurrent presence of GADA includes mechanisms characteristic of both DM2T (insulin resistance) and DM1T (autoimmune insulitis) acting in parallel, with different intensity, in differing proportions and time sequence as a fluid continuum, which also accounts for the differences between individual patients. The characteristics highlighting the presence and role of AI based on our results include high titre of GADA+, low CP levels, early need of insulin therapy, presence of thyroid disorder, higher HDL cholesterol levels and lower triglyceride levels. The characteristics highlighting the dominance of mechanisms characteristic of DM2T (insulin resistance) included higher BMI and waist circumference values, normal CP levels, low HDL cholesterol levels, higher triglyceride levels, higher blood pressure and borderline titre of GADA. KEY WORDS: autoimmune diabetes mellitus - C-peptide - GADA - HDL-cholesterol - classification.

Deletion of Interleukin-6 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy and Dysfunction.

RATIONALE: The role of interleukin (IL)-6 in the pathogenesis of cardiac myocyte hypertrophy remains controversial. OBJECTIVE: To conclusively determine whether IL-6 signaling is essential for the development of pressure overload-induced left ventricular (LV) hypertrophy and to elucidate the underlying molecular pathways. METHODS AND RESULTS: Wild-type and IL-6 knockout (IL-6(-/-)) mice underwent sham surgery or transverse aortic constriction (TAC) to induce pressure overload. Serial echocardiograms and terminal hemodynamic studies revealed attenuated LV hypertrophy and superior preservation of LV function in IL-6(-/-) mice after TAC. The extents of LV remodeling, fibrosis, and apoptosis were reduced in IL-6(-/-) hearts after TAC. Transcriptional and protein assays of myocardial tissue identified Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and signal transducer and activator of transcription 3 (STAT3) activation as important underlying mechanisms during cardiac hypertrophy induced by TAC. The involvement of these pathways in myocyte hypertrophy was verified in isolated cardiac myocytes from wild-type and IL-6(-/-) mice exposed to prohypertrophy agents. Furthermore, overexpression of CaMKII in H9c2 cells increased STAT3 phosphorylation, and exposure of H9c2 cells to IL-6 resulted in STAT3 activation that was attenuated by CaMKII inhibition. Together, these results identify the importance of CaMKII-dependent activation of STAT3 during cardiac myocyte hypertrophy via IL-6 signaling. CONCLUSIONS: Genetic deletion of IL-6 attenuates TAC-induced LV hypertrophy and dysfunction, indicating a critical role played by IL-6 in the pathogenesis of LV hypertrophy in response to pressure overload. CaMKII plays an important role in IL-6-induced STAT3 activation and consequent cardiac myocyte hypertrophy. These findings may have significant therapeutic implications for LV hypertrophy and failure in patients with hypertension.

Does Chemotherapy Change Expression of VEGF A&C and MVD in Acute Myeloid Leukemia?

INTRODUCTION: Acute Myeloid Leukemia is a malignant transformation of hematopoietic tissue, bone marrow infiltration of undifferentiated cells known as blasts that interfere with the production of normal cells. Vascular endothelial growth factor (VEGF) is persistently secreted from myeloid cells and high levels can be detected in patients' serum. METHODS: Twenty-one AML patients, who were chemotherapy candidates were evaluated in a clinical trial. Serum VEGF was measured by ELISA. VEGFA, VEGFC mRNA and bone marrow MVD were measured in all patients before and after chemotherapy and then all results were analyzed. RESULTS: There were 10 (48%) female and 11(52%) male patients ranged in age from 20 to 60 years, with an average age of 39.5 ±14.1 years. The mean amount of MVD was reduced from 10.8±3.6 before chemotherapy to7.6±3.3 after chemotherapy (P=0.008). VEGF was also reduced from 0.59±0.16 before chemotherapy to 0.24±0.03 after chemotherapy (P=0.005). Gene expression differences for VEGFA mRNA was 4.6±1.4, while it was 120.7±93.2 for VEGFC mRNA, showing the significance only for VEGA mRNA (P=0.02). CONCLUSION: Regarding reduced angiogenesis, we can conclude that anti-angiogenic preparations can be effective in treatment course of AML in combination with chemotherapy regimen.