Association of HLA Haplotypes with Autoimmune Pathogenesis in Newly Diagnosed Type 1 Romanian Diabetic Children: A Pilot, Single-Center Cross-Sectional Study.

BACKGROUND: The increasing incidence of autoimmune diseases in type 1 diabetes mellitus (T1DM) patients highlights the influence of human leukocyte antigen (HLA) haplotypes on their development. This study aims to determine genetic predisposition to autoimmune diseases in T1DM patients, including thyroid disease and celiac diseases, and explore its correlation with vitamin D deficiency. METHODS: A cross-sectional study involving thirty-six T1DM children was conducted. Typing was performed for the HLA A, B, C, DP, DR, and DQ loci. Regression analysis linked DR-DQ haplotypes to T1DM and the associated conditions. RESULTS: The most frequent predisposing alleles and haplotypes were HLA-DR3 (70.27%), DQ2 (70.27%), DR3-DQ2 (70.27%), DQB1*02:01 (70.27%), A02 (54.05%), whereas the most prevalent protecting allele was DPB1*04:01 (52.63%). Positive correlations were observed between positive anti-thyroid peroxidase antibodies and the absence of protective alleles (DPB1*04:02, p = 0.036; DPB1*04:01, p = 0.002). Associations were found between the absence of DPB1*04:01 and anti-thyroglobulin antibodies (p = 0.03). HLA allele DPB1*03:01 was linked with vitamin D deficiency (p = 0.021). Positive anti-transglutaminase antibodies correlated with C03:03 (p = 0.026) and DRB1*04:01-DQA1*03-DQB1*03:01 (p < 0.0001) and the lack of DQA1*01:03-DQB1*06:03-DRB1*13:01 (p < 0.0001). CONCLUSIONS: The predisposing T1DM haplotypes were associated with the presence of anti-transglutaminase and anti-thyroid antibodies, indicating a genetic predisposition to autoimmune diseases.

The role of sex on the prevalence of cardiovascular risk factors in children and adolescents with Type 1 diabetes: The SWEET international database.

OBJECTIVE: To assess the prevalence of cardiovascular risk factors (CVRFs) in children and adolescents with type 1 diabetes (T1D) in the International SWEET registry and the possible role of clinical variables in modifying the risk of having single or multiple CVRFs. STUDY DESIGN: The study is a cross-sectional study. Cut-off points for CVRFs were fixed according to International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines and WHO parameters: LDL cholesterol (LDL-C) > 100 mg/dL; Systolic Blood Pressure (BP-SDS) > 90th percentile for sex, age, and height; BMI-SDS > 2SD for sex and age. Logistic regression models were applied to evaluate variables associated with at least 1 or 2 CVRFs among registry children and adolescents. RESULTS: 29,649 individuals with T1D (6-18 years, T1D ≥ 2 years) participating in the SWEET prospective multicenter diabetes registry were included. In the cohort, 41 % had one or more CVRFs, and 10 % had two or more CVRFs. Thirty-five percent of enrolled individuals had LDL-C > 100 mg/dL, 26 % had BMI-SDS > 2SD, and 17 % had Systolic BP-SDS > 90th percentile. Females had higher frequency than males of having 1 or 2 CVRFs (45.1 % vs 37.4 %, 11.8 % vs 7.8 %; p < 0.001). Multivariable logistic regression models showed that sex (female), HbA1c category (>7.0 %), and age (>10 years) were associated with a higher chance of having at least 1 or 2 CVRFs (p < 0.001). CONCLUSIONS: In children and adolescents with T1D, female sex, in addition to HbA1c above 7 %, and older age (>10 years) was associated with a higher risk of having at least a CVRF (LDL-C, BMI-SDS, BP) according to internationally defined cut-offs.

Bone Mineral Density Trends During the First Year After Laparoscopic Sleeve Gastrectomy-a Cohort Study on 241 Patients.

PURPOSE: Laparoscopic sleeve gastrectomy (LSG) is an effective weight loss procedure, but detrimental effects on bone health have been described. We aimed to assess the dynamics of regional and total bone mineral density (BMD) in a cohort of patients undergoing LSG and to capture gender differences in terms of evolution. MATERIALS AND METHODS: We conducted a retrospective study on 241 patients who underwent LSG to determine the regional and total BMD changes at 6 and 12 months after the intervention. RESULTS: One hundred ten males and 140 females (97 pre-, 43 postmenopausal) were included. Mean baseline body mass index (BMI) was 44.16 ± 6.11 kg/m2 in males and 41.60 ± 5.54 kg/m2 in females, reaching 28.62 ± 4.26 kg/m2 and 27.39 ± 4.2 kg/m2, respectively, at 12 months. BMD showed a continuous decline, with significant loss from 6 months postoperatively. There was a positive correlation between BMD and BMI decline at 12 months (r = 0.134, p < 0.05). Total BMD loss at 12 months was significantly greater in males than premenopausal females, independent of BMI variation and age. During the first 6 months, men lost significantly more bone mass than premenopausal and postmenopausal women (BMD variation was 2.62%, 0.27%, 1.58%, respectively). The second period (6-12 months) was similar in all three groups, revealing a further steady (~ 1.4%) BMD decline. CONCLUSIONS: Our results are consistent with previous findings that LSG negatively impacts BMD, stressing the importance of bone health-oriented measures in postoperative care. Moreover, the impact that seems more significant in males warrants future exploration, as it might change clinical practice.

Stroke Mortality Rates and Trends in Romania, 1994-2017.

BACKGROUND AND AIM: Romanian national level stroke mortality data is relatively scarce. The current study investigated stroke mortality rates and trends in Romania. METHODS: All individual deaths registered in Romania during 1994-2017 were analyzed using an anonymized database, based on death certificates. Stroke crude mortality rates (CMR) and age-standardized mortality rates (ASMR) were calculated and expressed per 100,000 persons-year. RESULTS: Between 1994 and 2017, 6,281,873 persons died in Romania, stroke being registered as the underlying cause of death in 959,319 cases. The overall stroke CMR was 188.2 (199.3 for women and 176.5 for men). The CMR for hemorrhagic stroke (HEMS) was 32.4 and for ischemic stroke (ISCS) 10.9. There was a significant decrease in stroke ASMR from 344.4 (95% confidence interval [CI] 343.4-345.4) in 1994 to 192.1 (95% CI 191.5-192.7) in 2017, with an annual percent change (APC) of 2.53% per year (95% CI 2.50-2.55, P < .001). Although compared with men, women had higher CMRs, when those rates were age-standardized men had higher ASMR as compared with women. The decline in HEMS ASMR had an APC of 4.65% per year (95% CI 4.59-4.70, P < .001). ISCS ASMR showed an initial increase in ASMR during 1994-2005, with APC 6.39% per year (95% CI 6.09-6.70, P < .001), followed by a significant decrease until 2017, with APC 2.83% per year (95% CI 2.59-3.07, P < .001). CONCLUSION: There was a significant reduction in stroke ASMR during 1994-2017. The decline was slow until 2002 and became steeper after that, with significant differences in gender analysis.

Acute Myocardial Infarction Mortality Rates and Trends in Romania between 1994 and 2017.

Introduction: The current study aimed to assess recent acute myocardial infarction (AMI) mortality rates and trends in Romania between 1994 and 2017. This dataset is a necessity in the context of the current improvement of emergency protocols, medical addressability, and modernization of hospital infrastructure. Materials and Methods: The study is a retrospective analysis of an anonymized mortality database containing all deaths registered in Romania during 1994-2017. AMI crude mortality rates (CMR) and age-standardized mortality rates (ASMR) were calculated using the European Standard Population. Poisson regression was used for calculating the annual percentage change (APC) in mortality, subsequently used to make mortality predictions through the year 2030. Results: There were 197,152 AMI deaths in women (39.3% of total AMI), and 304,644 (60.7%) in men. Mortality rates were higher in men as compared with women for the entire time covered by the study. Based on the 1994-2017 ASMR dynamics, predictions for the year 2030 showed an overall AMI ASMR of 70.9 (95% CI 69.9-71.9), with gender analysis showing 46.8 (95% CI 45.8-47.9) in women and 104.1 (95% CI 102.3-105.8) in men. Conclusion: Acute myocardial infarction age-standardized mortality rates decreased significantly in Romania between 1994 and 2017 in close correlation to the implementation of national healthcare programs.

Rates and Causes of Death among Adult Diabetes Patients in Romania.

Aims: To study the age and sex-dependent mortality rates and causes of death in a large Romanian diabetes cohort as compared with the general population. Methods: All adult patients aged 20-64 years, receiving a free diabetes prescription in a major urban area during 2001-2008 were included and followed-up for death until December 31, 2011. Crude mortality rates and standardized mortality rate ratios (SMR) against general population (data from the National Institute of Statistics) were calculated. Years lost due to diabetes were computed assuming the general population mortality rates for ages below 20 and above 64 years. Results: During the 11 years study period, 49,328 diabetes patients (mean age at baseline 53.0 ± 8.8 years) contributed 297,370 person-years and 5,053 deaths. All cause mortality rates (per 1000 person years) increased with age and was 3.4 in 20-24 years age group and 25.7 in 60-64 year age group, while the corresponding SMR decreased from 6.0 to 1.5. Diabetes patients aged 20-24 years had a life expectancy of 48.6 years, which was 6.6 years less compared with the corresponding general population (55.2 years). The gap was 7.0 years in women and 5.8 years in men. Diabetes patients aged 20-24 years lost 196 minutes of life daily due to diabetes in women and 182 minutes in men. Conclusions: Mortality rates increased, while mortality rate ratios against general population decreased with age. Men had higher mortality rates, but women had higher mortality rate ratios in the gender analysis.

To diet or not to diet in neonatal diabetes responding to sulfonylurea treatment.

Background Neonatal diabetes mellitus (NDM) is defined as a monogenic form of diabetes that occurs in the first 6 months of life. As information on diet in NDM patients successfully treated with sulfonylurea is not yet available, we aimed to investigate the hypothesis that a carb-restricted diet is not needed in such cases. Case presentation In this case report, we present a successful implementation of a completely liberalized diet in a young patient with NDM, developmental delay and epilepsy (DEND syndrome), who was also switched to sulfonylurea treatment. The excellent metabolic control during follow-up despite completely ignoring any diet suggests that at least in some patients this approach might work. Conclusions If our proposed hypothesis is also confirmed by other reports, it might add significantly to the quality of life of these patients and broaden the knowledge in this medical field.

Recent diabetes-related mortality trends in Romania.

AIMS: As there are no published articles on country-level diabetes-related mortality in Romania, we aimed to investigate this aspect for the 1998-2015 period. METHODS: Anonymized demographic and diabetes-related mortality data (underlying or first secondary cause of death) were retrospectively obtained from the National Institute of Statistics/Eurostat microdata. Age-standardized mortality rates (ASMR) and their annual percentage change (APC) were analysed. RESULTS: During 1998-2015, 4,567,899 persons died in Romania, among whom, diabetes was responsible for 168,854 cases. The ASMR for diabetes was 39.34 per 100,000 person-years (p-y) (95% CI 39.32-39.35). There was an increase in ASMR from 27.10 per 100,000 p-y (95% CI 27.01-27.19) in women and 30.88 per 100,000 p-y (95% CI 30.77-30.99) in men in 1998 to 35.42 per 100,000 p-y (95% CI 35.34-35.51) in women and 48.41 per 100,000 p-y (95% CI 48.29-48.52) in men, in 2015. The mean APC in women was 3.8% per year (95% CI 3.5-4.0, p < 0.001) during 1998-2010 and - 1.9% per year (95% CI - 2.7 to - 1.1, p < 0.001) during 2010-2015. The mean APC in men was 5.3% per year (95% CI 5.0-5.5, p < 0.001) during 1998-2010 and - 1.5% per year (95% CI - 2.2 to - 0.8, p < 0.001) during 2010-2015. Diabetes-related mortality rates increased with age, with men experiencing higher mortality rates than women for most age groups and calendar years. CONCLUSIONS: Diabetes-related mortality rates increased significantly in Romania during 1998-2010, followed by a steady decline during 2010-2015.

All-cause and cardiovascular mortality associated with sulphonylurea and metformin therapy in type 2 diabetes.

PURPOSE: To test the hypothesis that cumulative exposure to sulphonylurea (SU) or metformin (MET) have different effects on mortality when taken as a replacement or add-on of one for the other. METHODS: All consecutive diabetes patients aged over 20 years were screened at their first diabetes outpatient visit between 2001 and 2008 (n = 79869). Only patients on MET (n = 11374) or SU (n = 18502) monotherapy were retained. All patients were followed up for death until December 31, 2011, but censored at first exposure to anything else besides MET/SU. Adjusted time-dependent Cox regression and competing risk regression analysis, with daily updates of treatment modalities were performed. RESULTS: Mean age was 62.1 ± 11.2 years and follow-up was 4.6 ± 3.2 years (138496 person-years). Adjusted all-cause and cardiovascular mortality rates were significantly higher in MET as compared with SU group. All-cause mortality hazard ratios (HR) for cumulative time exposure were as follows: HR 0.956 (95%CI 0.951-0.962, p < 0.001) for SU added to MET, HR 1.092 (95%CI 1.087-1.096, p < 0.001) for SU replacing MET, HR 0.979 (95%CI 0.975-0.983, p < 0.001) for MET added to SU, and HR 1.127 (95%CI 1.118-1.136, p < 0.001) for MET replacing SU. CONCLUSION(S): The effect on all-cause mortality was beneficial for MET+SU combined therapy, but deleterious for either SU replacing MET, or MET replacing SU. There were no major outcome differences when analyzing individual SU, or specific mortality.

First case of neonatal diabetes with KCNJ11 Q52R mutation successfully switched from insulin to sulphonylurea treatment.

In this report, we present the first known case of intermediate developmental delay, epilepsy and permanent neonatal diabetes (DEND) syndrome caused by a Q52R mutation in the KCNJ11 gene who was successfully switched (at age 1.3 years) to sulphonylurea monotherapy, namely glibenclamide. The most recent evaluation, after 2 years, showed a glycated hemoglobin level of 6.0% (42 mmol/mol). This mutation is so severe that none of the previously reported four cases were able to switch from insulin to sulphonylurea monotherapy. The Q52R mutation seems to have a chance of positive response to glibenclamide administered every 3-6 h instead of the classical 8-12 h, in doses around or above 2.5 mg/kg/day.

Cardiovascular Mortality in Type 2 Diabetes Patients with Incident Exposure to Insulin Glargine.

The study investigated the impact of insulin glargine exposure on cardiovascular mortality in type 2 diabetes patients with incident insulin initiation. All consecutive diabetes patients aged >40 years were screened at their first diabetes outpatient visit between 01/01/2001 and 12/31/2008 (n = 79869). Exclusion criteria restricted the cohort to 4990 incident insulin users, aged 40-79 years, who were followed up for death until 12/31/2011. Baseline was defined 6 months after insulin initiation. Adjusted time-dependent competing risk regression analysis was performed. Mean baseline age was 62 ± 9 years, with mean follow-up of 4.7 ± 1.9 years. During 23179 person-years of exposure time, there were 887 deaths (521 cardiovascular). Glargine cumulative time exposure significantly lowered overall cardiovascular, subhazard ratio (SHR) 0.963 (CI 95% 0.944-0.981, p < 0.001), and myocardial infarction mortality, SHR 0.945 (CI 95% 0.899-0.994, p = 0.028), but not stroke mortality. Glargine cumulative dose exposure (10,000 IU increments) significantly lowered cardiovascular mortality, SHR 0.977 (CI 95% 0.960-0.993, p = 0.006), but not for myocardial infarction and stroke. Both cumulative dose and time exposure to insulin glargine were associated with lower cardiovascular mortality. The effect was mostly driven by myocardial infarction end point, supporting the concept of macrovascular benefit for basal analogue insulin use in type 2 diabetes.

Long-Term Home Study on Nocturnal Hypoglycemic Alarms Using a New Fully Implantable Continuous Glucose Monitoring System in Type 1 Diabetes.

BACKGROUND: This study analyzed the overall nocturnal performance during home use of a long-term subcutaneous implantable continuous glucose monitoring (CGM) sensor. SUBJECTS AND METHODS: In this study, 12 subjects with type 1 diabetes mellitus (T1DM) (mean±SD age, 37±8 years; mean±SD disease duration, 11±6 years) were implanted with an investigational continuous glucose sensor in the upper arm for up to 90 days. All subjects received full access to real-time glucose display and user programmable hypo- and hyperglycemic alarms. Subjects calibrated the sensors with a self-monitoring of blood glucose (SMBG) meter and continued to rely on their regular SMBG measurements for their diabetes management. Accuracy of the sensors during the home-use study was calculated using SMBG as the reference. The nocturnal sensor attenuation (NSA) concept was tested. Sensitivity and specificity of the nocturnal hypoglycemic alarm were calculated. RESULTS: Mean±SD glucose sensor life span was 87±7 days. The mean±SE absolute relative difference over the range of 40-400 mg/dL for the sensors in this home-use study was 12.3±0.7% using SMBG as the reference. The hypoglycemia alarms were set to be triggered when the glucose level went below 70 mg/dL. Percentage of nights with hypoglycemic alarms triggered for at least 10 min was 13.6%. Recovery into euglycemia within 30 min from the timestamp of the immediate confirmatory SMBG testing was obtained in 74% of all episodes (n=20). The implanted continuous glucose sensor showed a hypoglycemia detection sensitivity and specificity of 77% and 96%, respectively. The NSA-associated high negative rate of change of at least -4 mg/dL/min was not encountered during night use of the system. CONCLUSIONS: This home-use study of a fully implantable, long-term continuous glucose sensor shows excellent performance in nocturnal hypoglycemia detection in T1DM patients. The apparent lack of NSA affecting the implanted sensor and the high specificity of the hypoglycemic alarm expedite the recovery from nighttime hypoglycemia.

Multisite Study of an Implanted Continuous Glucose Sensor Over 90 Days in Patients With Diabetes Mellitus.

BACKGROUND: Continuous glucose monitoring (CGM), which enables real-time glucose display and trend information as well as real-time alarms, can improve glycemic control and quality of life in patients with diabetes mellitus. Previous reports have described strategies to extend the useable lifetime of a single sensor from 1-2 weeks to 28 days. The present multisite study describes the characterization of a sensing platform achieving 90 days of continuous use for a single, fully implanted sensor. METHOD: The Senseonics CGM system is composed of a long-term implantable glucose sensor and a wearable smart transmitter. Study subjects underwent subcutaneous implantation of sensors in the upper arm. Eight-hour clinic sessions were performed every 14 days, during which sensor glucose values were compared against venous blood lab reference measurements collected every 15 minutes using mean absolute relative differences (MARDs). RESULTS: All subjects (mean ± standard deviation age: 43.5 ± 11.0 years; with 10 sensors inserted in men and 14 in women) had type 1 diabetes mellitus. Most (22 of 24) sensors reported glucose values for the entire 90 days. The MARD value was 11.4 ± 2.7% (range, 8.1-19.5%) for reference glucose values between 40-400 mg/dl. There was no significant difference in MARD throughout the 90-day study (P = .31). No serious adverse events were noted. CONCLUSIONS: The Senseonics CGM, composed of an implantable sensor, external smart transmitter, and smartphone app, is the first system that uses a single sensor for continuous display of accurate glucose values for 3 months.

Cancer specific mortality in insulin-treated type 2 diabetes patients.

AIMS: To test the hypothesis that cumulative exposure to insulin and long-acting insulin analogs might be associated with cancer mortality in diabetes patients. METHODS: All consecutive diabetes patients aged over 40 years, residing in a major urban area were screened at their first diabetes outpatient visit between 01/01/2001-12/31/2008 (n = 79869). Exclusion criteria were insulin treatment at screening, no insulin treatment until 12/31/2008, less than 6 months of glucose-lowering treatment alone before insulin initiation, insulin prescription before glargine became available, age <40/≥ 80 years at first insulin prescription, and <6 months of insulin exposure. A total 4990 subjects were followed-up for death based on death certificate, until 12/31/2011. Adjusted time-dependent competing risk regression analysis, with daily updates of treatment modalities was performed. Results are expressed for every 10,000 IU of cumulative dose or one year of cumulative time exposure to insulin. RESULTS: Mean baseline age was 62 ± 9 years, and follow-up 4.7 ± 1.9 years. Glargine cumulative dose was associated with lower cancer mortality risk (subhazard ratio, SHR: 0.94 (95%CI 0.89-0.99, p = 0.033)). Cumulative exposure limited to that attained one year prior to death revealed lower SHRs for cumulative time (0.94 (95%CI 0.89-0.99, p = 0.018)) and cumulative dose of glargine (0.92 (95%CI 0.86-0.98, p = 0.014)). Glargine cumulative time and cumulative dose were significant predictors for lower pancreatic and breast cancer mortality, but not for deaths from lung, colorectal, female genital, liver, and urinary tract cancer. No increased hazards were found for any other subtypes of insulins. CONCLUSIONS: The cumulative dose exposure to insulin glargine was associated with a lower risk of cancer mortality in general, and of breast and pancreatic cancer in particular. This effect remained even after additional "fixed" cohort or propensity score analyses.

Improvements in life expectancy in adult type 2 diabetes patients in the last six decades.

AIM: To investigate the historical changes in survival with diabetes in adult type 2 diabetes patients. METHODS: We analyzed 9066 deaths, 54.2% males, registered at "I. Pavel" Bucharest Diabetes Centre, aged 40-64 years and deceased between 1943 and 2009. We split the analysis in three time periods according to year of death: 1943-1965, 1966-1988 and 1989-2009. RESULTS: The mean age at diabetes onset was 55.5 ± 6.2 years, with mean disease duration at death 12.7 ± 8.2 years and mean age at death 68.2 ± 8.7 years. The mean disease duration at death was 9.9 ± 7.3 years in 1943-1965 period, followed by a significant (p<0.001) rise to 12.2 ± 8.2 years in 1966-1988, and 14 ± 8.1 years (p < 0.001) in 1989-2009. There was a significant increase for coronary heart diseases and cancer and a significant decrease for infections and end-stage renal disease as causes of death. CONCLUSION: We found a significant increase in age at onset and survival with diabetes leading to a significant increase in age at death.

Improvements in life expectancy in type 1 diabetes patients in the last six decades.

AIMS: To investigate the survival with diabetes in patients treated with insulin from diagnosis. SUBJECTS AND METHODS: We analyzed 845 subjects, 55.9% males, registered at "I. Pavel" Bucharest Diabetes Centre, insulin-treated from diagnosis, aged <40 years and deceased between 1946 and 2005. We divided the subjects in two groups by age at diagnosis: group A <18 years and group B 18-39.99 years. We used 20 years time periods for year of death: 1946-1965, 1966-1985 and 1986-2005. RESULTS: The mean age at diabetes onset was 30.36+/-8.04 years, disease duration at death 20.98+/-11.62 years and age at death 51.34+/-14.37 years. The mean increase in survival with diabetes was 19.3 years for group A and 15.9 years for group B. There was a significant decrease in infections in both groups. The increase in coronary heart diseases and stroke is evident only in group B. CONCLUSIONS: We found no changes in age at onset, which combined with an increase in survival with diabetes lead to a significant increase in age at death over the six decades analyzed.

A pathophysiological approach to metabolic syndrome using factor analysis in an adult Romanian population.

The aim of the study was to examine the role of insulin resistance in etiopathogenesis of metabolic syndrome in an adult Romanian population using exploratory factor analysis. We analyzed 228 non-diabetic subjects randomized in respect to the age and sex distribution of the general population. For each patient, age, sex, body mass index (BMI), systolic and diastolic blood pressure (SBP, DBP), HDL-cholesterol (HDL), plasma triglycerides (TG), fasting plasma glucose (FPG) and fasting insulin were obtained. Factor analysis was performed using principal component analysis, with Varimax rotation of the major determinants of metabolic syndrome. Mean age was 48.9 +/- 12.7 years; 107 (46.9%) were men and 121 (53.1%) women. We found three major factors, which are correlated with metabolic syndrome and may explain its variance. Factor 1 comprises SBP and DBP in men and SBP, DBP and BMI in women. Factor 2 comprises BMI, HDL, TG and FPG in men and BMI, TG and FPG in women. Factor 3 comprises fasting insulin in men and fasting insulin, TG and HDL in women. The finding of more than one factor suggests that insulin resistance is not the only pathophysiological mechanism involved. These factors appear to work independently of each other in men, but they intersect in women, suggesting that the pathophysiology of metabolic syndrome may be different in women compared with men.