One third of cases of new-onset diabetic ketosis in adults are associated with ketosis-prone type 2 diabetes-A systematic review and meta-analysis.

AIMS: Ketosis-prone type 2 diabetes was defined by the World Health Organization in 2019. According to the literature, the diagnosis is based on the presence of ketosis, islet autoantibody negativity and preserved insulin secretion. Our meta-analysis assessed the prevalence and clinical characteristics of ketosis-prone type 2 diabetes among patients hospitalised with diabetic ketoacidosis (DKA) or ketosis. METHODS: The systematic search was performed in five main databases as of 15 October 2021 without restrictions. We calculated the pooled prevalence of ketosis-prone type 2 diabetes (exposed group) within the diabetic population under examination, patients with ketoacidosis or ketosis, to identify the clinical characteristics, and we compared it to type 1 diabetes (the comparator group). The random effects model provided pooled estimates as prevalence, odds ratio and mean difference (MD) with 95% confidence intervals. RESULTS: Eleven articles were eligible for meta-analysis, thus incorporating 2010 patients of various ethnic backgrounds. Among patients presenting with DKA or ketosis at the onset of diabetes, 35% (95% CI: 24%-49%) had ketosis-prone type 2 diabetes. These patients were older (MD = 11.55 years; 95% CI: 5.5-17.6) and had a significantly higher body mass index (BMI) (MD = 5.48 kg/m2 ; 95% CI: 3.25-7.72) than those with type 1 diabetes. CONCLUSIONS: Ketosis-prone type 2 diabetes accounts for one third of DKA or ketosis at the onset of diabetes in adults. These patients are characterised by islet autoantibody negativity and preserved insulin secretion. They are older and have a higher BMI compared with type 1 diabetes. C-peptide and diabetes-related autoantibody measurement is essential to identify this subgroup among patients with ketosis at the onset of diabetes.

[Genetics of type 1 diabetes: present and future]. / Az 1-es típusú diabetes genetikája: jelen és jövo.

Over the past decades the majority of genetic research focused on common diseases, and remarkable results were obtained for exploring the genetic background of type 1 diabetes. The classic linkage analyses and the modern genome-wide association studies demonstrated that the genetic background is the primary risk factor for beta-cell autoimmunity while the progression to clinical onset could be triggered by the genetic factors, epigenetic modifications of gene expression and environmental factors together. The new system biology concept can help to understand the mechanisms underlying the immune-mediated beta-cell destruction by generating networks based on data from whole genome scans, fine mapping and gene expression studies to develop targeted prevention and therapeutic strategies. In this paper, we discuss the present understanding of genetic factors which could initiate beta-cell autoimmunity (i.e. define the aetiology) and the genetic and epigenetic factors which might contribute to the progression to clinical disease in individuals with autoantibodies (i.e. define the pathogenesis). Orv Hetil. 2017; 158(44): 1731-1740.

No Association between Gastrointestinal Rebleeding and DOAC Therapy Resumption: A Systematic Review and Meta-Analysis.

BACKGROUND: There are recommendations for anticoagulation resumption after gastrointestinal bleeding (GIB), although data addressing this topic by direct oral anticoagulants (DOACs)-treated patients is lacking. We aim to determine the safety and efficacy of restarting DOACs after GIB. METHODS: Studies that reported rebleeding, thromboembolic events, and mortality after restarting or withholding DOACs were selected. The systematic research was conducted in five databases (MEDLINE, EMBASE, CENTRAL, Web of Science, and Scopus). The random effect model was implemented to calculate the pooled odds ratio (OR). The ROBINS-I tool was used for risk of bias assessment, and the certainty of the evidence was evaluated with the GRADE approach. RESULTS: Four retrospective cohort studies (1722 patients) were included in the meta-analysis. We did not find a significant increase in the risk of rebleeding in patients restarting DOACs after index GIB (OR = 1.12; 95% CI: 0.74-1.68). The outcomes of thromboembolic events and mortality data were not suitable for meta-analytic calculations. Single studies did not show statistically significant differences. Data quality assessment showed a serious overall risk of bias and very low quality of evidence (GRADE D). CONCLUSION: DOAC resumption after a GIB episode may not elevate the risk of rebleeding. However, the need for high-quality randomized clinical trials is crucial.

Microscopic colitis is a risk factor for low bone density: a systematic review and meta-analysis.

Background: Microscopic colitis (MC) is a chronic inflammatory disease of the large bowel characterized by watery diarrhea, substantially decreasing the patient's quality of life. Scarce data suggest that MC is associated with low bone density (LBD). Objectives: We aimed to assess whether MC is a risk factor for LBD and the proportion of patients with MC having LBD. Design: A systematic review and meta-analysis of studies reporting bone density measurements in MC patients. Data Sources and Methods: We systematically searched five databases from inception to October 16, 2021 (Pubmed, Embase, Cochrane, Scopus, and Web of Science). We used the random-effect model to calculate pooled odds ratios (ORs) and pooled event rates with 95% confidence intervals (CIs). To ascertain the quality of evidence of our outcomes, we followed the recommendations of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group. Results: The systematic search yielded a total of 3046 articles. Four articles were eligible for quantitative synthesis. All of them used age- and sex-matched controls to evaluate LBD occurrence among patients with MC. The odds of having LBD were twofold increased (OR = 2.13, CI: 1.42-3.20) in the presence of MC, the odds of osteopenia occurrence were 2.4 (OR = 2.45, CI: 1.11-5.41), and of osteoporosis 1.4 (OR = 1.42, CI: 0.65-3.12). The proportion of LBD was 0.68 (CI: 0.56-0.78), osteopenia was 0.51 (CI: 0.43-0.58), and osteoporosis was 0.11 (CI: 0.07-0.16) among the MC population. Our findings' certainty of the evidence was very low following the GRADEPro guideline. Conclusion: Our data demonstrate that MC is associated with a twofold risk for LBD. Based on our findings, we suggest screening patients for bone mineral density upon diagnosis of MC. Further prospective studies with higher patient numbers and longer follow-up periods on this topic are needed. Registration: Our protocol was prospectively registered with PROSPERO (CRD42021283392).

Investigating microscopic colitis as a risk factor for having low bone density in a literature overview and statistical approach Microscopic colitis (MC) is an underdiagnosed chronic inflammatory large bowel disease, characterized by watery diarrhea, which substantially impacts the patient's quality of life. The etiology of MC is still unclear but is suspected to be multifactorial. Moreover, low bone density (LBD) has been associated with the disease. Scarce data investigate the relationship of MC with LBD, although they share common risk factors, like advanced age and female sex. LBD has two forms; the mild is osteopenia and the severe form is osteoporosis. The most severe complications of osteoporosis are osteoporotic fractures, which can culminate in a life-threatening state and amplify the hospital expenses burden. Our primary aim was to assess if MC increases the risk of LBD. Furthermore, we estimated the proportions of bone mineral changes in the MC population. Following a rigorous methodology, our data suggest that MC doubles the odds of LBD. Furthermore, we have shown that two-thirds of the MC population suffers from bone density decrease, half of them have osteopenia, and one in 10 MC patients has osteoporosis. In conclusion, we highly suggest screening patients with MC for bone mineral density at the moment of diagnosis.

One in four patients with gastrointestinal bleeding develops shock or hemodynamic instability: A systematic review and meta-analysis.

BACKGROUND: Hemodynamic instability and shock are associated with untoward outcomes in gastrointestinal bleeding. However, there are no studies in the existing literature on the proportion of patients who developed these outcomes after gastrointestinal bleeding. AIM: To determine the pooled event rates in the available literature and specify them based on the bleeding source. METHODS: The protocol was registered on PROSPERO in advance (CRD42021283258). A systematic search was performed in three databases (PubMed, EMBASE, and CENTRAL) on 14th October 2021. Pooled proportions with 95%CI were calculated with a random-effects model. A subgroup analysis was carried out based on the time of assessment (on admission or during hospital stay). Heterogeneity was assessed by Higgins and Thompson's I2 statistics. The Joanna Briggs Institute Prevalence Critical Appraisal Tool was used for the risk of bias assessment. The Reference Citation Analysis (https://www.referencecitationanalysis.com/) tool was applied to obtain the latest highlight articles. RESULTS: We identified 11589 records, of which 220 studies were eligible for data extraction. The overall proportion of shock and hemodynamic instability in general gastrointestinal bleeding patients was 0.25 (95%CI: 0.17-0.36, I2 = 100%). In non-variceal bleeding, the proportion was 0.22 (95%CI: 0.14-0.31, I2 = 100%), whereas it was 0.25 (95%CI: 0.19-0.32, I2 = 100%) in variceal bleeding. The proportion of patients with colonic diverticular bleeding who developed shock or hemodynamic instability was 0.12 (95%CI: 0.06-0.22, I2 = 90%). The risk of bias was low, and heterogeneity was high in all analyses. CONCLUSION: One in five, one in four, and one in eight patients develops shock or hemodynamic instability on admission or during hospitalization in the case of non-variceal, variceal, and colonic diverticular bleeding, respectively.

Risk factors for diabetes mellitus after acute pancreatitis: a systematic review and meta-analysis.

Introduction: Within 5 years of having acute pancreatitis (AP), approximately 20% of patients develop diabetes mellitus (DM), which later increases to approximately 40%. Some studies suggest that the prevalence of prediabetes (PD) and/or DM can grow as high as 59% over time. However, information on risk factors is limited. We aimed to identify risk factors for developing PD or DM following AP. Methods: We systematically searched three databases up to 4 September 2023 extracting direct, within-study comparisons of risk factors on the rate of new-onset PD and DM in AP patients. When PD and DM event rates could not be separated, we reported results for this composite outcome as PD/DM. Meta-analysis was performed using the random-effects model to calculate pooled odds ratios (OR) with 95% confidence intervals (CI). Results: Of the 61 studies identified, 50 were included in the meta-analysis, covering 76,797 participants. The studies reported on 79 risk factors, and meta-analysis was feasible for 34 risk factor and outcome pairs. The odds of developing PD/DM was significantly higher after severe and moderately severe AP (OR: 4.32; CI: 1.76-10.60) than mild AP. Hypertriglyceridemic AP etiology (OR: 3.27; CI: 0.17-63.91) and pancreatic necrosis (OR: 5.53; CI: 1.59-19.21) were associated with a higher risk of developing PD/DM. Alcoholic AP etiology (OR: 1.82; CI: 1.09-3.04), organ failure (OR: 3.19; CI: 0.55-18.64), recurrent AP (OR: 1.89; CI: 0.95-3.77), obesity (OR: 1.85; CI: 1.43-2.38), chronic kidney disease (OR: 2.10; CI: 1.85-2.38), liver cirrhosis (OR: 2.48; CI: 0.18-34.25), and dyslipidemia (OR: 1.82; CI: 0.68-4.84) were associated with a higher risk of developing DM. Discussion: Severe and moderately severe AP, alcoholic and hypertriglyceridemic etiologies, pancreatic necrosis, organ failure, recurrent acute pancreatitis and comorbidities of obesity, chronic kidney disease liver disease, and dyslipidemia are associated with a higher risk of developing PD or DM. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021281983.

Early prediction of acute necrotizing pancreatitis by artificial intelligence: a prospective cohort-analysis of 2387 cases.

Pancreatic necrosis is a consistent prognostic factor in acute pancreatitis (AP). However, the clinical scores currently in use are either too complicated or require data that are unavailable on admission or lack sufficient predictive value. We therefore aimed to develop a tool to aid in necrosis prediction. The XGBoost machine learning algorithm processed data from 2387 patients with AP. The confidence of the model was estimated by a bootstrapping method and interpreted via the 10th and the 90th percentiles of the prediction scores. Shapley Additive exPlanations (SHAP) values were calculated to quantify the contribution of each variable provided. Finally, the model was implemented as an online application using the Streamlit Python-based framework. The XGBoost classifier provided an AUC value of 0.757. Glucose, C-reactive protein, alkaline phosphatase, gender and total white blood cell count have the most impact on prediction based on the SHAP values. The relationship between the size of the training dataset and model performance shows that prediction performance can be improved. This study combines necrosis prediction and artificial intelligence. The predictive potential of this model is comparable to the current clinical scoring systems and has several advantages over them.

Environmental factors and epidemiology of childhood type 1 diabetes / Környezeti hatások a gyermekkori kezdetu, 1-es típusú diabetes epidemiológiai változásainak hátterében.

Összefoglaló. A Nemzetközi Diabetes Szövetség (International Diabetes Federation, IDF) legutóbbi becslése szerint napjainkban több mint 600 000, 15 év alatti 1-es típusú cukorbeteg gyermek él a világon, az új esetek száma pedig évi 98 200-ra teheto. Az elmúlt évtizedekben az 1-es típusú diabetes incidenciája világszerte jelentosen nott ebben a korosztályban: Európában az 1989 és 2013 közötti periódusban átlagosan évi 3,4%-kal, ami 20 éven belül a betegek számának duplázódását vetíti elore a kontinensen. Az epidemiológiai vizsgálatok kezdete óta nyilvánvaló, hogy a gyermekkori kezdetu, 1-es típusú diabetes elofordulási gyakorisága széles határok között ingadozik, amit egyaránt befolyásolnak geográfiai és klímaviszonyok, etnikai és demográfiai hatások. Bár az 1-es típusú cukorbetegség kialakulása során az autoimmunitás primer kockázati tényezoje a genetikai háttér, mégsem a genetikai terheltség populációszintu fokozódása okozza az incidencia robbanásszeru növekedését, hanem a környezeti tényezoknek a betegség penetranciáját megváltoztató hatása. A környezeti hatások oki tényezokként, akcelerátorokként és védofaktorokként is hozzájárulhatnak mindehhez, sot akár a betegség patogenezisében egyszerre több ponton, több mechanizmussal is részt vehetnek. Ugyanakkor a nemzetközi kutatások ellenére a legnépszerubb háttérelméletek (például vírusinfekció, higiéniahipotézis, bélmikrobiom, átereszto bél, D-vitamin-hiány) máig nem szolgálnak kielégíto magyarázattal az epidemiológiai észlelések többségére (például földrajzi régiónként jelentosen eltéro incidenciaértékek, geográfiai "forrópontok", az új esetek megjelenésének szezonális ingadozása, az incidenciacsúcsok ciklicitása). Összefoglalónk célja a gyermekkori 1-es típusú diabetes epidemiológiájára vonatkozó aktuális adatok és háttérelméletek áttekintése. Orv Hetil. 2021; 162(1): 13-22. Summary. According to the latest report of the IDF (International Diabetes Federation), more than 600 000 children under the age of 15 years are living with type 1 diabetes in the world and the number of new cases is estimated to be 98 200 annually. In recent decades, a significant increase in the incidence has been observed globally: during 1989-2013, the annual rate of increase was 3.4% in Europe, suggesting a doubling in the number of patients within approximately 20 years on the continent. The wide variation in incidence has been well documented by epidemiological studies and influenced by geographical and climatic conditions, ethnic and demographic factors. Although the genetic background is the primary risk factor for beta-cell autoimmunity, such dynamic changes in incidence are more likely to be associated with the higher environmental pressure than the increase in genetic load at population level. Environmental factors can also contribute to the pathogenesis of type 1 diabetes as accelerators, causal or protective factors, moreover may even be involved at several points and with several mechanisms at the same time. However, despite the extensive international research on environmental factors, the most popular hypotheses associated with them (e.g., virus infections, hygiene hypothesis, intestinal microbiota, leaky gut, lack of vitamin D) have not yet provided a satisfactory explanation for most epidemiological observations (e.g., geographically significant variability of incidence rates, geographical "hotspots", seasonal fluctuations in new cases, cyclical trends of incidence peaks). In this article, recent data and hypotheses about the epidemiology of childhood type 1 diabetes are summarized. Orv Hetil. 2021; 162(1): 13-22.

Clinical Considerations When Initiating and Titrating Insulin Degludec/Liraglutide (IDegLira) in People with Type 2 Diabetes.

Therapeutic inertia is a substantial obstacle to the initiation of insulin therapy in people with uncontrolled type 2 diabetes (T2D). This effect has in part been perpetuated by concerns over the impact of a burdensome regimen and the increased risk of hypoglycemia and body weight gain often associated with insulin use. An effective, yet simple, less burdensome regimen with a lower risk of body weight gain and hypoglycemia compared with an insulin-only regimen, may help to address these concerns more effectively. We review the available clinical and real-world data on IDegLira, a once-daily, injectable, fixed-ratio combination of insulin degludec (degludec) and the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide, in people with T2D. Evidence from the comprehensive DUAL clinical trial program suggests an advantage of IDegLira over traditional insulin therapies in a number of clinical outcomes, including maintenance of glycemic control, achievement of glycemic targets, reducing the risk of hypoglycemia, and body weight loss. These findings were demonstrated in participants with T2D irrespective of prior GLP-1RA and insulin use. Furthermore, the individual components of IDegLira have confirmed safety (degludec) or significant benefit in terms of improvement of cardiovascular risk (liraglutide). As an injectable therapy that is simple to titrate, IDegLira has the potential to optimize the ability to achieve relevant glycemic targets, and offers a suitable treatment option for people with T2D requiring insulin therapy who are at risk of hypoglycemia or weight gain.

Association of hypoxia inducible factor-1 alpha gene polymorphism with both type 1 and type 2 diabetes in a Caucasian (Hungarian) sample.

BACKGROUND: Hypoxia inducible factor-1 alpha (HIF-1alpha) is a transcription factor that plays an important role in neo-vascularisation, embryonic pancreas beta-cell mass development, and beta cell protection. Recently a non synonymous single nucleotide polymorphism (g.C45035T SNP, rs11549465) of HIF-1alpha gene, resulting in the p.P582S amino acid change has been shown to be associated with type 2 diabetes (T2DM) in a Japanese population. Our aim was to replicate these findings on a Caucasian (Hungarian) population, as well as to study whether this genetic effect is restricted to T2DM or can be expanded to diabetes in general. METHODS: A large Caucasian sample (N = 890) was recruited including 370 T2DM, 166 T1DM and 354 healthy subjects. Genotyping was validated by two independent methods: a restriction fragment analysis (RFLP) and a real time PCR using TaqMan probes. An overestimation of heterozygotes by RFLP was observed as a consequence of a nearby SNP (rs34005929). Therefore genotyping results of the justified TaqMan system were accepted. The measured genotype distribution corresponded to Hardy-Weinberg equilibrium (P = 0.740) RESULTS: As the TT genotype was extremely rare in the population (0.6% in clinical sample and 2.5% in controls), the genotypes were grouped as T absent (CC) and T present (CT and TT). Genotype-wise analysis showed a significant increase of T present group in controls (24.0%) as compared to patients (16.8%, P = 0.008). This genetic effect was demonstrated in the separated samples of type 1 (15.1%, P = 0.020), and also in type 2 (17.6%, P = 0.032) diabetes. Allele-wise analysis gave identical results showing a higher frequency of the T allele in the control sample (13.3%) than in the clinical sample (8.7%, P = 0.002) with similar results in type 1 (7.8%, P = 0.010) and type 2 (9.1%, P = 0.011) diabetes. The odds ratio for diabetes (either type 1 or 2) was 1.56 in the presence of the C allele. CONCLUSION: We confirmed the protective effect of a rare genetic variant of HIF-1alpha gene against type 2 diabetes in a Caucasian sample. Moreover we demonstrated a genetic contribution of the same polymorphism in type 1 diabetes as well, supporting a possible overlap in pathomechanism for T2DM and a T1DM.

A detailed investigation of maternally inherited diabetes and deafness (MIDD) including clinical characteristics, C-peptide secretion, HLA-DR and -DQ status and autoantibody pattern.

BACKGROUND: This article presents a clinically characterization of the mitochondrial DNA mutation (A3243G) associated with maternally inherited diabetes and deafness (MIDD) syndrome in two families. METHODS: Six patients with MIDD and one mutation-positive relative with normal glucose tolerance (NGT) were examined. Fasting serum C-peptide was measured in all subjects and compared with controls having NGT (n = 14). C-peptide response to an intravenous glucose tolerance test (IVGTT) was investigated in the diabetic patients not treated with insulin (n = 3) and in the mutation-positive healthy individual and compared with the controls. RESULTS: The A3243G heteroplasmy value varied between 5 and 30%. All A3243G carriers had HLA-DR1-DQ5 haplotype, and either the -DQ5 or the -DQ6 allele. The fasting and the serum C-peptide levels at 120 min during the IVGTT did not differ between the A3243G carriers and the controls. A missing first phase and a decreased total C-peptide response was detected in the mutation-positive diabetics compared with controls (p < 0.0001). The same abnormality was found in the A3243G carrier with NGT. Circulating islet cell antibody (ICA) was present in three patients with MIDD. Glutamic acid decarboxylase (GAD), tyrosine phosphatase-like protein IA-2 (IA-2) and mitochondrial antibodies were missing. The diagnosis of MIDD was delayed in each case. CONCLUSIONS: A missing first phase and a decreased total C-peptide response during an IVGTT was characteristic for the A3243G mutation. The fasting C-peptide level of the carriers did not differ from the controls. Circulating ICA was present in some patients, but GAD, IA-2 and mitochondrial antibodies were absent. All subjects had HLA-DR1-DQ5 haplotype, and either -DQ5 or -DQ6 alleles.

Decreased Ficolin-3-mediated Complement Lectin Pathway Activation and Alternative Pathway Amplification During Bacterial Infections in Patients With Type 2 Diabetes Mellitus.

Bacterial infections are frequent and severe in patients with diabetes mellitus. Whether diabetes per se induces functional alterations in the complement system hampering activation during infection is unknown. We investigated key elements of the complement system during bacterial infections in patients with type 2 diabetes mellitus (T2DM) and compared them to non-diabetic (ND) individuals. Using a prospective design, we included 197 T2DM, and 196 ND subjects, all with clinical diagnosis of acute community-acquired bacterial infections. Functional activities of the ficolin-3-mediated lectin (F3-LP), mannose binding lectin-mediated lectin- (MBL-LP), classical (CP), and alternative pathways (AP), as well as concentrations of complement activation products C4d and sC5b-9 were determined. Functional in vitro activities of F3-LP and AP were significantly higher in T2DM than in ND subjects, (median 64% vs. 45%, p = 0.0354 and 75 vs. 28%, p = 0.0013, respectively), indicating a decreased in vivo activation and lack of consumption of F3-LP and AP in T2DM patients, whereas no difference in functional capacities of CP and MBL-LP were observed between T2DM and ND subjects. Diminished F3-LP and AP activation was most pronounced in diabetic patients with urinary tract infections with positive microbiological culture results for Escherichia coli bacteria. In the T2DM group 3-months mortality significantly associated with diminished F3-LP and AP, but not with CP activation. Concentrations of C4d and sC5b-9 were significantly lower in the T2DM than in ND patients. In conclusion, we found impaired F3-LP activation and lack of AP amplification during bacterial infections in patients with type 2 diabetes, compared to non-diabetic subjects, suggesting a diminished complement mediated protection to bacterial infections in T2DM.

[Community-acquired bacterial infections among type 2 diabetic and non-diabetic patients hospitalized on a general medical ward: a clinical comparison]. / 2-es típusú diabetesesek és nem cukorbetegek területen szerzett, belgyógyászati osztályos felvételt igénylo bakteriális infekcióinak klinikai összehasonlítása.

Introduction: Previous data showed bacterial infections among diabetic patients to be more serious and frequent, with higher mortality rates in comparison with non-diabetics. Recent investigations, however, are contradictory. Aim: The goal of our prospective, observational study was to compare patients hospitalized on a general medical ward due to community-acquired bacterial infections with type 2 diabetes mellitus (T2DM) to those of non-diabetics (K) by 1) infection localization, 2) spectrum of pathogens, 3) three-month mortality rates. Method: Patients were consecutively involved (T2DM: n = 205, K: n = 202). We characterized the infections, clinical parameters, mortalities of the two groups, and matched them to international data. Results: No difference regarding clinical details of the groups were found except for glycemic parameters and BMI. In the T2DM group the skin- and soft tissue- (37.1%), in the K patients respiratory infections (37.1%) were the most common, followed by urinary ones (31.2% and 31.7%, respectively). Skin- and soft tissue infection incidence among T2DM subjects were higher compared to international results (37.1% vs. 16%). Co-presence of Gram positive and Gram negative bacteria in the skin- and soft tissue infections (23/76 vs. 5/46, p = 0.0149), and polymicrobial origin in the urinary tract infections (34.0% vs. 15.1%, p = 0.0335) were found to be more frequent in T2DM than in K. No difference regarding mortality rates were detected. In T2DM the skin- and soft tissue while in the K group the respiratory infections had the most death counts. Conclusions: We found higher rates of skin- and soft tissue infections among T2DM patients hospitalized on a general medical ward compared to international data. In total we did not find difference regarding three-month mortality between the groups. Our results highlight the importance of primary prevention and shows its inadequacy concerning skin and soft tissue infections among type 2 diabetics in Hungary. Orv Hetil. 2019; 160(41): 1623-1632.

Glutathione S-transferase enzyme polymorphisms in a Hungarian myelodysplasia study population.

GSTM1, GSTT1 and GSTP1 Ile105Val that are members of the GST gene family encode for Phase II drug/xenobiotic metabolizing enzymes, primarily with detoxifying function, and are polymorphic in humans. GSTM1 and GSTT1 homozygous deletion genotypes do not express the enzymes. It has been hypothesised that individuals with homozygous deletion of the GSTM1 and/or GSTT1 gene may have lower detoxification capacity towards genotoxic agents therefore those individuals may be at increased risk of myelodysplastic syndrome which is a preleukemic condition. Genetic polymorphism of GSTM1, GSTT1 and GSTP1 Ile105Val was investigated in a case-control study in a Hungarian patient population comprising 86 patients with myelodysplastic syndrome and 99 hospital-based controls. There were no statistically significant differences between cases and controls for the GSTM1, GSTT1 and GSTP1 Ile105Val genotype frequencies for any of the three genes separately and in various combinations. This suggests that these genetic polymorphisms may not be strong risk factors, if any, for myelodysplastic syndrome.

The HLA 8.1 ancestral haplotype is strongly linked to the C allele of -429T>C promoter polymorphism of receptor of the advanced glycation endproduct (RAGE) gene. Haplotype-independent association of the -429C allele with high hemoglobinA1C levels in diabetic patients.

Previously we reported on strong linkage disequilibrium (LD) between the mono-S-C4B-RCCX module (mono-S) and the TNF2 allele (both known constituents of the 8.1 ancestral haplotype (8.1 AH)) in two Caucasian populations. The gene for the receptor of advanced glycation endproducts (RAGE) is encoded between the RCCX module and the HLA class II genes in the central MHC region. In order to assess the relationship between the promoter polymorphisms of the RAGE gene and the 8.1 AH, we performed a family study in eight informative families affected with type 1 diabetes mellitus; haplotypes of a RAGE promoter SNP (-429T>C) with the HLA-DQ2, -DR-3(17) and TNF2 alleles, as well as the mono-S genotype were determined. A similar analysis was performed in 82 unrelated patients with type 1 diabetes mellitus, and in unrelated healthy individuals of three different Caucasian populations (Hungarians, Ohioian females, Icelandics). In the diabetic patients clinical correlations were also investigated. Out of the 32 paternal and maternal chromosome 6 from the eight families, 15 different MHC haplotypes were found. Haplotypes containing at least three of the known constituents of the 8.1 AH (HLA-DQ2, -DR17, mono-S, TNF2) were always linked to the RAGE -429C allele. The RAGE -429C allele exhibited highly significant (p<0.0001) LD coefficients to known constituents of the 8.1 AH both in healthy persons and patients with type 1 diabetes. In the group of patients with diabetes we found significantly (p=0.013) higher maximal hemoglobinA1C concentration in the carriers of the RAGE -429C allele, this trait, however was not linked to the 8.1 AH. Our present findings indicate that the RAGE -429C allele can be considered as a candidate member of the 8.1 AH. The results also reveal a spectrum of recombinant MHC haplotypes in addition to the conserved ancestral haplotypes.

[Effectiveness of cardiometabolic risk reduction in patients with type 1 diabetes mellitus]. / A kardiometabolikus kockázati tényezôk kezelésének eredményessége 1-es típusú diabetesben szenvedôk körében.

UNLABELLED: The attainment and maintenance of therapeutic goal of cardiovascular risk factors are of great clinical importance. The effectiveness of cardiovascular risk management is not well characterized during regular care of patients with type 1 diabetes mellitus. AIM: The aim of the study was to estimate the effectiveness of cardiovascular risk management in type 1 diabetic patients. METHODS: Adult patients with type 1 diabetes mellitus (n = 533; 256 men, 277 women; age: 35.6 +/- 11.6 years; duration of diabetes: 18.0 +/- 11.1 years; x +/- SD) were consecutively enrolled from 11 diabetes outpatient departments. Data on medical history, actual treatment, anthropometric and laboratory parameters as well as actual blood pressure were registered, while eating and smoking habits, education level and physical activity were evaluated by standardized questionnaires. The treating goal was set according to the national guideline which corresponds to the current international task force. RESULTS: Of 533 patients, the body mass index target level (< 25 kg/m 2 ) was achieved by 295 (55.5%) patients. Ideal waist circumference (< 80 cm for women and < 94 cm for men) was measured in 140 (50.5%) and in 165 (63.7%) patients, respectively. Optimal glycaemic control (HbA 1c level < 6.5%) was documented in 45 (8.4%) patients. Lipid lowering drugs (statins, fibrates or ezetimibe) were used by 130 patients, among which 53.1% reached the target triglyceride level, 71.5% the target HDL-cholesterol and 27.8% the target LDL-cholesterol levels. Taking the lipid target values together, only 23 (17.7%) patients were at goal. Antihypertensive drugs were used by 173 patients among which 29.5% reached the systolic and 34.8% the diastolic target values (< 130/80 mmHg). Regarding smoking habits, 94 (17.7%) patients were current smokers and 102 (19.2%) ex-smokers. CONCLUSIONS: The attainment of therapeutic goal of cardiovascular risk factors proved to be difficult in a substantial part of patients. Further efforts are needed for attaining and maintaining the established goal of cardiovascular risk management during regular care of adult patients with type 1 diabetes mellitus.

Similar genetic features and different islet cell autoantibody pattern of latent autoimmune diabetes in adults (LADA) compared with adult-onset type 1 diabetes with rapid progression.

OBJECTIVE: To compare the clinical parameters, C-peptide levels, pattern of islet cell-specific autoantibodies, and prevalence of predisposing genotypes in subjects with latent autoimmune diabetes in adults (LADA) and those with adult-onset type 1 diabetes with rapid progression. RESEARCH DESIGN AND METHODS: We evaluated the clinical parameters, C-peptide levels, and islet cell-specific autoantibodies in 54 LADA, 57 adult-onset type 1 diabetic, and 190 type 2 diabetic patients. Islet cell autoantibodies were also compared between subgroups of newly diagnosed patients with LADA and those with newly diagnosed adult-onset and childhood-onset type 1 diabetes. The genetic study was performed in subjects with LADA and those with adult-onset type 1 diabetes in comparison with a control population. RESULTS: There were no differences in the clinical parameters between LADA and adult-onset type 1 diabetes. Patients with LADA had lower BMI (P < 0.0001), waist-to-hip ratio (0.0029), total cholesterol (P = 0.001), and triglycerides (P = 0.001); higher HDL cholesterol levels (P < 0.0001); and lower prevalence of hypertension (P = 0.0028) compared with patients with type 2 diabetes. C-peptide levels were similar at onset (P = 0.403) but decreased less rapidly in LADA than in adult-onset type 1 diabetes (P = 0.0253). Single-autoantibody positivity was more often seen in LADA than in type 1 diabetes (P = 0.0001). The prevalence of predisposing HLA-DQB1*0302, -DR4, -DR3, and -DR3/DR4 genotypes and the DR4-DQB1*0302 haplotype were increased in both LADA and adult-onset type 1 diabetic subjects compared with the control population. There were no differences in the frequencies of these risk alleles and haplotypes between the two patient groups. CONCLUSIONS: Subjects with LADA had clinical characteristics similar to those with adult-onset type 1 diabetes with rapid progression. C-peptide levels did not differ at onset but decreased less rapidly in LADA. Patients with LADA rather had single islet cell-specific autoantibody positivity. The prevalence of HLA-DQB1*0302, -DR4, -DR3, and -DR3/DR4 risk alleles and the DR4-DQB1*0302 high-risk haplotype did not differ in the two forms of autoimmune diabetes.

Micro-RNA Binding Site Polymorphisms in the WFS1 Gene Are Risk Factors of Diabetes Mellitus.

The absolute or relative lack of insulin is the key factor in the pathogenesis of diabetes mellitus. Although the connection between loss of function mutations of the WFS1 gene and DIDMOAD-syndrome including diabetes mellitus underpins the significance of wolframin in the pathogenesis, exact role of WFS1 polymorphic variants in the development of type 1 and type 2 diabetes has not been discovered yet. In this analysis, 787 patients with diabetes and 900 healthy people participated. Genotyping of the 7 WFS1 SNPs was carried out by TaqMan assays. Association study was performed by χ2-test in combination with correction for multiple testing. For functional analysis, the entire 3' UTR of the WFS1 gene was subcloned in a pMIR-Report plasmid and relative luciferase activities were determined. Linkage disequilibrium analysis showed a generally high LD within the investigated region, however the rs1046322 locus was not in LD with the other SNPs. The two miR-SNPs, rs1046322 and rs9457 showed significant association with T1DM and T2DM, respectively. Haplotype analysis also confirmed the association between the 3' UTR loci and both disease types. In vitro experiments showed that miR-185 reduces the amount of the resulting protein, and rs9457 miRSNP significantly influences the rate of reduction in a luciferase reporter assay. Genetic variants of the WFS1 gene might contribute to the genetic risk of T1DM and T2DM. Furthermore demonstrating the effect of rs9457 in binding of miR-185, we suggest that the optimal level of wolframin protein, potentially influenced by miR-regulation, is crucial in normal beta cell function.

Differences in the genetic background of latent autoimmune diabetes in adults (LADA) and type 1 diabetes mellitus.

OBJECTIVES: According to the recent classification of diabetes mellitus the Latent Autoimmune Diabetes in Adults (LADA) belongs to the group of type 1 autoimmune diabetes, as a slowly progressive form. Our aim was to determine (i) the prevalence of HLA-DRB1 and DQB1 genotypes, and (ii) to determine the tumor necrosis factor (TNF) alpha promoter polymorphism at position -308 (the G-->A substitution, designated the TNF2 allele) in patients with type 1 diabetes and with LADA compared with the healthy population. METHODS: The major histocompatibility complex (MHC) II genotypes and the TNF alpha promoter polymorphism were determined by PCR method. We examined 69 type 1 diabetic and 42 LADA patients. As control samples of 336 cadaver kidney donors and 138 volunteers were used. RESULTS: Both type 1 diabetes mellitus and LADA were positively associated with the DRB1*04-DQB1*0302 (DR4/DQ8) haplotype (P=0.00001, and P=0.0005, respectively), and negatively associated with the DRB1*11-DQB1*0301 (DR11/DQ7) haplotype (P=0.00006, and P=0.007, respectively) compared with control population. There were differences between the two disease entities in the frequency of the DRB1*03-DQB1*02 (DR3/DQ2) haplotype (P=0.00008 vs. P=0.177) compared with control group. The presence of the TNF2 allele was significantly lower in LADA than type I diabetes (P=0.022) or control group (P=0.017). CONCLUSION: Our findings indicate that there are marked differences in the genetic background of type 1 diabetes and LADA. The low presence of TNF2 allele (known to be associated with high amount of TNF alpha production) in LADA could be one of the factors responsible for the relatively slow progression.

Serum semicarbazide-sensitive amine oxidase (SSAO) activity is an independent marker of carotid atherosclerosis.

BACKGROUND: Clinical and experimental studies suggest that increased activity of semicarbazide-sensitive amine oxidase (SSAO) and the production of cytotoxic metabolites (e.g., formaldehyde and hydrogen peroxide) may play an important role in the pathogenesis of atherosclerosis. The present study was designed to assess the relationship between the increased activity of the enzyme and the severity of atherosclerosis in diabetic and control subjects. METHODS: The study included 29 patients with type 2 diabetes mellitus and 25 control subjects. Human serum SSAO activity was determined by using 14C-benzylamine as substrate. Mean common carotid intima-media thickness (IMT), Crouse score and Bogousslawsky score was evaluated by color-coded, high-resolution duplex carotid sonography. RESULTS: Serum SSAO activity was significantly increased in patients with type 2 diabetes compared to controls. Carotid plaque score (Crouse score), total cholesterol level and age-corrected intima-media thickness showed positive correlation with enzyme activity in control subjects. In patients with diabetes, serum SSAO activity correlated with the severity of carotid stenosis (Bogousslawsky score) as well as the carotid plaque score. CONCLUSIONS: Determination of serum SSAO activity might be a candidate biochemical marker of early atherosclerosis and diabetic macrovascular complications.