Corrigendum: Diabetes as a risk factor of death in hospitalized COVID-19 patients - an analysis of a National Hospitalization Database from Poland, 2020.

[This corrects the article DOI: 10.3389/fendo.2023.1161637.].

Novel methods of continuous glucose monitoring and telehealth in the improvement of diabetes care: a narrative review.

Standard markers of glycaemic control, such as glycated haemoglobin (HbA1c) and self-measurement of blood glucose (SMBG), have proven insufficient. HbA1c is an averaged measurement that does not give information about glucose variability. SMBG provides limited, intermittent blood glucose (BG) values over the day and is associated with poor compliance because of the invasiveness of the method and social discomfort. In contrast to glucometers, continuous glucose monitoring (CGM) devices do not require finger-stick blood samples, but instead measure BG via percutaneous or subcutaneous sensors. The immediate benefits of CGM include prevention of hypoglycaemia or hyperglycaemia, and automated analysis of long-term glycaemic data enables reliable treatment adjustments. This review describes the principles of CGM and how CGM data have changed diabetes treatment standards by introducing new glycaemic control parameters. It also compares different CGM devices and examines how the convenience of sharing CGM data in telehealth applies to the current coronavirus-19 pandemic.

Diabetes as a risk factor of death in hospitalized COVID-19 patients - an analysis of a National Hospitalization Database from Poland, 2020.

Introduction: Diabetes is one of the comorbidities associated with poor prognosis in hospitalized COVID-19 patients. In this nationwide retrospective study, we evaluated the risk of in-hospital death attributed to diabetes. Methods: We analyzed data from discharge reports of patients hospitalized with COVID-19 in 2020 as submitted to the Polish National Health Fund. Several multivariate logistic regression models were used. In each model, in-hospital death was estimated with explanatory variables. Models were built either on the whole cohorts or cohorts matched with propensity score matching (PSM). The models examined either the main effects of diabetes itself or the interaction of diabetes with other variables. Results: We included 174,621 patients with COVID-19 who were hospitalized in the year 2020. Among them, there were 40,168 diabetic patients (DPs), and the proportion of DPs in this group was higher than in the general population (23.0% vs. 9.5%, p<0.001). In this group of COVID-19 hospitalizations, 17,438 in-hospital deaths were recorded, and the mortality was higher among DPs than non-diabetics (16.3% vs. 8.1%, p<0.001). Multivariate logistic regressions showed that diabetes was a risk factor of death, regardless of sex and age. In the main effect analysis, odds of in-hospital death were higher by 28.3% for DPs than for non-diabetic patients. Similarly, PSM analysis including 101,578 patients, of whom 19,050 had diabetes, showed that the risk of death was higher in DPs regardless of sex with odds higher by 34.9%. The impact of diabetes differed among age groups and was the highest for patients aged 60-69. Conclusions: This nationwide study confirmed that diabetes was an independent risk factor of in-hospital death in the course of COVID-19 infection. However, the relative risk differed across the age groups.

Characteristics, Mortality, and Clinical Outcomes of Hospitalized Patients with COVID-19 and Diabetes: A Reference Single-Center Cohort Study from Poland.

Background: Diabetes is a risk factor for a severe course of COVID-19. We evaluated the characteristics and risk factors associated with undesirable outcomes in diabetic patients (DPs) hospitalized due to COVID-19. Materials and Methods: The data analysis of patients admitted between March 6, 2020, and May 31, 2021, to the University Hospital in Krakow (Poland), a reference center for COVID-19, was performed. The data were gathered from their medical records. Results: A total number of 5191 patients were included, of which 2348 (45.2%) were women. The patients were at the median age of 64 (IQR: 51-74) years, and 1364 (26.3%) were DPs. DPs, compared to nondiabetics, were older (median age: 70 years, IQR: 62-77 vs. 62, IQR: 47-72, and p < 0.001) and had a similar gender distribution. The DP group had a higher mortality rate (26.2% vs. 15.7%, p < 0.001) and longer hospital stays (median: 15 days, IQR: 10-24 vs. 13, IQR: 9-20, and p < 0.001). DPs were admitted to the ICU more frequently (15.7% vs. 11.0%, p < 0.001) and required mechanical ventilation more often (15.5% vs. 11.3%, p < 0.001). In a multivariate logistic regression, factors associated with a higher risk of death were age >65 years, glycaemia >10 mmol/L, CRP and D-dimer level, prehospital insulin and loop diuretic use, presence of heart failure, and chronic kidney disease. Factors contributing to lower mortality were in-hospital use of statin, thiazide diuretic, and calcium channel blocker. Conclusion: In this large COVID-19 cohort, DPs constituted more than a quarter of hospitalized patients. The risk of death and other outcomes compared to nondiabetics was higher in this group. We identified a number of clinical, laboratory, and therapeutic variables associated with the risk of hospital death in DPs.

Type 1 diabetes outpatient care and treatment effectiveness during COVID-19: A single-center cohort study.

PURPOSE: COVID-19 has brought many challenges for providing quality healthcare for type 1 diabetes (T1DM). We evaluated the impact of the COVID-19 pandemic on the medical care, glycemic control, and selected outcomes in T1DM patients. METHODS: We retrospectively analyzed medical records from 357 T1DM adults enrolled in the Program of Comprehensive Outpatient Specialist Care at the University Hospital in Krakow, and assessed differences in patient data from before the COVID-19 period (March 2019-February 2020) and after it started COVID-19 (March 2020-February 2021). RESULTS: The median HbA1c levels and the percentage of patients within the HbA1c target of <7 % (53 mmol/mol) were similar in both periods: before and after the beginning of the pandemic (6.86 % [51.5 mmol/mol], IQR 6.23-7.58 % [44.6-59.3 mmol/mol] vs. 6.9 % [51.9 mmol/mol], IQR 6.2-7.61 % [44.3-59.7 mmol/mol]; p = 0.50 and 56.3 % vs. 57.1 %, p = 0.42, respectively). However, we observed a rise in BMI and body weight (median 24.25, IQR 21.97-27.05 vs. 24.82, IQR 22.17-27.87 and median weight 71.0 IQR 61-82 vs. 72.55, IQR 55-85; p < 0.001 for both comparisons). There was no reduction in the numbers of total diabetes-related visits (median 4, IQR 4-5 vs. 5, IQR 4-5; p = 0.065), but the frequency of other specialist consultations decreased (2, IQR 0-2 vs. 1, IQR 0-2). During the pandemic, telehealth visits constituted of 1191 out of 1609 (71.6 %) total visits. CONCLUSIONS: In this single-center observation, the COVID-19 pandemic did not have a negative impact on glycemic control in T1DM patients, but the patients' weight did increase. Telemedicine proved to be a valuable tool for T1DM care.

Higher scanning frequency is correlated with less fear of hypoglycemia in type 1 diabetes patients using isCGM.

Background: Frequent scanning of intermittently scanned continuous glucose monitoring (isCGM) devices is associated with improvements in glycemic indices. Limited data is available for its correlation with fear of hypoglycemia (FOH), an established factor affecting quality of life and glycemic control in type 1 diabetes (T1DM). Aim: The aim of the study was to analyze the association of sensor scanning frequency with FOH and glycemic indices in T1DM patients using isCGM. Subjects and methods: T1DM patients using isCGM were eligible. Clinical data and Ambulatory Glucose Profile (AGP) reports were obtained from medical records. At outpatient visits, AGP of last 14 days prior to visit were analyzed and FOH was assessed using Hypoglycemia Fear Survey II (HFS II). Results: We included 77 consecutive T1DM patients (58 females, 19 males). Mean age was 34.1 ± 10.2 years and mean T1DM duration was 14.7 ± 12.0 years. Baseline mean glycemic indices were as follows: mean glucose - 155.8 ± 29.8 mg/dL; GMI - 53.3 ± 7.5 mmol/mol; TIR - 66.4 ± 17.8%; TBR70 - 4.5 ± 4.1%; TBR54 - 0.6 ± 1.2%; TAR180 - 29.2 ± 17.9%; TAR250 - 9.6 ± 10.4%; %CV - 36.7 ± 8.3. Average scanning frequency was 13.8 ± 7.8 scans/day. Mean HFS II scores were 16.1 ± 7.2 and 18.7 ± 12.2 in behavior and worry subscale, respectively. Correlation was confirmed between scanning frequency and mean glucose, GMI, TIR, TBR70, TAR180, TAR250, %CV and HFS II total, and HFS II - B (p<0.05 for all statistics). Conclusions: For the first time, we report that higher scanning frequency is associated not only with better glycemic indices but also with less FOH in T1DM adult patients using isCGM.

Mutation search within monogenic diabetes genes in Polish patients with long-term type 1 diabetes and preserved kidney function.

INTRODUCTION: Some patients with type 1 diabetes (T1DM) are free from advanced complications despite long­standing disease. These patients may be carriers of gene mutations responsible for maturity­onset diabetes of the young and may have been misdiagnosed with T1DM. OBJECTIVES: We aimed to determine the clinical characteristics of patients with long­term T1DM, without advanced microvascular complications, and with well­preserved kidney function. A search for mutations in monogenic diabetes genes was performed. PATIENTS AND METHODS: Patients were recruited at 2 Polish university centers based on the following criteria: T1DM duration of 40 years or longer and absence of advanced complications defined as chronic kidney disease (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2 ), overt proteinuria, blindness, and diabetic foot syndrome. Mutations in the 7 most frequent monogenic diabetes genes were identified using next­generation sequencing. RESULTS: We enrolled 45 patients with T1DM (mean [SD] age at examination, 59.2 [8.0] years; mean [SD] age at T1DM diagnosis, 14.6 [6.7] years). Mean (SD) hemoglobin A1c levels were 7.6% (1.4%); daily insulin dose, 0.48 (0.17) U/kg; high­density lipoprotein (HDL) cholesterol levels, 1.9 (0.6) mmol/l; body mass index (BMI), 26.4 (5.0) kg/m2 ; and eGFR, 82.2 (12.1) ml/min/1.73 m2 . Albuminuria and retinopathy were reported in 7 and 39 patients, respectively. We were not able to assign a causative role to any of 10 genetic variants identified by next­generation sequencing in this cohort. CONCLUSIONS: Patients with long­term T1DM and preserved kidney function have good glycemic control, elevated HDL cholesterol levels, low insulin requirements, near ­normal BMI, and a rare occurrence of mutations in monogenic diabetes genes.

Neurological symptoms in hospitalised patients with COVID-19 and their association with in-hospital mortality.

OBJECTIVES: To evaluate the spectrum of neurological symptoms in patients with COVID-19 during the first 14 days of hospitalisation and its association with in-hospital mortality. MATERIAL AND METHODS: We included 200 patients with RT-PCR-confirmed COVID-19 admitted to University Hospital in Krakow, Poland. In 164 patients, a detailed questionnaire concerning neurological symptoms and signs was performed prospectively within 14 days of hospitalisation. In the remaining 36 patients, such questionnaires were completed retrospectively based on daily observations in the Department of Neurology. RESULTS: During hospitalisation, 169 patients (84.5%) experienced neurological symptoms; the most common were: fatigue (62.5%), decreased mood (45.5%), myalgia (43.5%), and muscle weakness (42.5%). Patients who died during hospitalisation compared to the remainder were older (79 [70.5-88.5] vs. 63.5 [51-77] years, p = 0.001), and more often had decreased level of consciousness (50.0% vs. 9.3%, p < 0.001), delirium (33.3% vs. 4.4%, p < 0.001), arterial hypotension (50.0% vs. 19.6%, p = 0.005) or stroke during (18.8% vs. 3.3%, p = 0.026) or before hospitalisation (50.0% vs. 7.1, p < 0.001), whereas those who survived more often suffered from headache (42.1% vs. 0%, p = 0.012) or decreased mood (51.7% vs. 0%, p = 0.003). CONCLUSIONS: Most hospitalised patients with COVID-19 experience neurological symptoms. Decreased level of consciousness, delirium, arterial hypotension, and stroke during or before hospitalisation increase the risk of in-hospital mortality.

Intermittently Scanned Continuous Glucose Monitoring Data of Polish Patients from Real-Life Conditions: More Scanning and Better Glycemic Control Compared to Worldwide Data.

Background: Randomized trials and observational studies have shown that the use of FreeStyle Libre® intermittently scanned continuous glucose monitoring system (isCGMS) is associated with improved glycemic indices and quality of life. Materials and Methods: In this retrospective, real-world data analysis, we described country-specific glucometrics among isCGMS users from Poland and compared them with international data. The analyzed time period for the Polish data ranged between August 2016 and August 2020, and the analyzed time period for the international data ranged from September 2014 to August 2020. Results: Data from the Polish population were collected from 10,679 readers and 92,627 sensors with 113 million automatically recorded glucose readings. The worldwide database included information from 981,876 readers and 11,179,229 sensors with 13.1 billion glucose readings. On average, the users of isCGMS from Poland performed substantially more scans/day (21.2 ± 14.2 vs. 13.2 ± 10.7), achieved lower eHbA1c (7.0% ± 1.2% vs. 7.5% ± 1.5%), and spent more time-in-range (TIR) (64.2% ± 17.3% vs. 58.1% ± 20.3%) and less time-above-range (TAR) (29.7% ± 18.0% vs. 36.6% ± 21.3%) (P < 0.0001 for all comparisons). Moreover, they were more likely to achieve TIR >70% (36.3% vs. 28.8%), but spent more time-below-range (TBR) (4.7% vs. 3.6%). Our results confirmed that analyzed glucometrics improve as the scan rate frequency increases. However, at a similar scanning frequency to the comparative group, users from Poland achieved lower eHbA1c, higher TIR, and lower TAR, but higher TBR. Conclusions: We report more scanning and better glycemic control in isCGMS users in Poland than worldwide. The cause of this observation remains unknown. Our data also show that in real-life practice, a large number of patients may be willing to perform scanning more frequently than it is usually assumed.

Physiological Characteristics of Type 1 Diabetes Patients during High Mountain Trekking.

In this study, the aim was to provide observational data from an ascent to the summit of Mount Damavand (5670 meters above sea level (m.a.s.l), Iran) by a group of people with type 1 diabetes (T1DM), with a focus on their physiological characteristics. After a 3-day expedition, 18 T1DM patients, all treated with personal insulin pumps, successfully climbed Mount Damavand. Information was collected on their physiological and dietary behaviors, as well as medical parameters, such as carbohydrate consumption, glucose patterns, insulin dosing, and the number of hypo- and hyperglycemic episodes during this time frame. The participants consumed significantly less carbohydrates on day 3 compared to day 1 (16.4 vs. 23.1 carbohydrate units; p = 0.037). Despite this, a gradual rise in the mean daily glucose concentration as measured with a glucometer was observed. Interestingly, the patients did not fully respond to higher insulin delivery as there was no significant difference in mean daily insulin dose during the expedition. There were more hyperglycemic episodes (≥180 mg/dL) per patient on day 3 vs. day 1 (p < 0.05) and more severe hyperglycemic episodes (>250 mg/dL) per patient on days 2 (p < 0.05) and 3 (p < 0.05) vs. day 1. In summary, high mountain trekking is feasible for T1DM patients with good glycemic control and no chronic complications. However, some changes in dietary preferences and an observable rise in glucose levels may occur. This requires an adequate therapeutic response.

Negative pressure wound therapy affects circulating plasma microRNAs in patients with diabetic foot ulceration.

AIMS: Negative pressure wound therapy (NPWT) is commonly used in diabetic foot ulceration (DFU). The molecular mechanisms of NPWT action, particularly outside of the wound site, have not been described. We assessed NPWT's effect on circulating miRNA expression levels in type 2 diabetes (T2DM) patients with DFU. METHODS: We examined 34 T2DM patients treated with either NPWT (n = 24) or standard therapy (ST, n = 10). The group assignment was based on clinical criteria and local practice. Next-generation sequencing-based microRNA expression was determined on the patient's plasma collected before therapy and after 8 days. RESULTS: NPWT patients were similar to the ST group in terms of age, BMI, and HbA1c level; however, they differed by mean wound area (12.6 cm2 vs. 1.1 cm2 p = 0.0005). First, we analyzed the change of miRNA after NPWT or ST and observed an upregulation of let-7f-2 only in the NPWT group. Then, we analyzed the differential expression between NPWT and ST groups, looking at possible wound size effects. We found 12 differentially expressed miRNAs in pre-treatment comparison, including let-7f-2, while in post-treatment analysis we identified 28 miRNAs. The pathway enrichment analysis suggests that identified miRNAs may be involved in wound healing, particularly through angiogenesis. CONCLUSION: We found initial evidence that NPWT in T2DM patients with DFU affects miRNA expression in plasma. Additionally, some differences in plasma miRNA expression may be related to wound size.

NPWT in diabetic foot wounds-a systematic review and meta-analysis of observational studies.

PURPOSE: Negative-pressure wound therapy (NPWT) is an adjunct modality in diabetic foot ulcerations (DFUs). Randomized controlled trials (RCTs) have shown its advantage over standard approaches; however, data from observational studies remain scarce.We performed a systematic review of observational non-RCTs evaluating NPWT efficacy and safety in patients with DFU. METHODS: Electronic databases were searched for observational studies involving NPWT. The results of single-arm studies were presented as percentages of patients with the outcome of interest. A meta-analysis of comparative studies provided point estimates of outcomes. Continuous outcomes were reported as either weighted or standardized mean differences and dichotomous data as relative risks (RR). RESULTS: The search identified 16 relevant observational studies, 12 single-arm, and 4 comparative, reporting on a total of 18,449 patients with DFU, of whom 1882 were managed with NPWT. In the NPWT-treated patients, ulcers were larger (average size range 6.6-27.9 cm2), as compared with controls (≤3 cm2). The pooled results showed healing and major amputation in 51% and 5% of NPWT patients, respectively. The meta-analysis of comparative studies revealed lower risk of major amputation [RR = 0.23 (0.07; 0.80)] in NPWT-treated patients. The pooled results for healing rate and risk of any amputation were inconclusive due to large between-study heterogeneity. Overall, 6 deaths out of 158 patients were reported, none of them related to NPWT. Serious adverse events occurred in 6% of patients on NPWT. CONCLUSIONS: This systematic review of observational studies provided supportive evidence that NWPT is an efficient and safe adjunct treatment in the management of DFUs.

Effects of Negative Pressure Wound Therapy on Levels of Angiopoetin-2 and Other Selected Circulating Signaling Molecules in Patients with Diabetic Foot Ulcer.

BACKGROUND AND AIMS: Diabetic foot ulcers (DFUs) are linked to amputations and premature deaths. Negative pressure wound therapy (NPWT) has been used for DFUs. The mechanism of NPWT's action may be associated with its influence on circulating molecules. We assessed NPWT's effect on the plasma levels of angiopoietin-2 (Ang2), a key regulator of angiogenesis, and its microvesicular receptors (Tie2) as well as the microvesicles (MVs) themselves in DFU patients. MATERIALS AND METHODS: We included 69 patients with type 2 diabetes mellitus (T2DM) and neuropathic, noninfected DFUs-49 were treated with NPWT and 20 were treated with standard therapy (ST). Assigning patients to the NPWT group was not random but based on DFU characteristics, especially wound area. Ang2 was measured by ELISA in the entire group, while in a subgroup of 19 individuals on NPWT and 10 on ST, flow cytometry was used to measure Tie2+ and the corresponding isotype control (Iso+) and annexin V (AnnV+) as well as total MVs. Measurements were performed at the beginning and after 8 ± 1 days of therapy. RESULTS: Treatment groups were similar for basic characteristics but differed by their median DFU areas (10.3 (4.2-18.9) vs. 1.3 (0.9-3.4) cm2, p = 0.0001). At day 0, no difference was observed in Ang2 levels, total MVs, MV Tie+, and MV AnnV+ between the groups. Ang2 decreased after 8 days in the NPWT group, unlike in the ST group (3.54 (2.40-5.40) vs. 3.32 (2.33-4.61), p = 0.02, and 3.19 ± 1.11 vs. 3.19 ± 1.29 ng/mL, p = 0.98, respectively). No other parameters were identified that may have been influenced by the NPWT treatment. CONCLUSION: NPWT in T2DM patients with neuropathic, noninfected DFU seems to lead to reduction of the Ang2 level. Influencing the level of Ang2 may constitute one of NPWT-related mechanisms to accelerate wound healing.

The utility of MODY Probability Calculator in probands of families with early-onset autosomal dominant diabetes from Poland.

BACKGROUND: Maturity-onset diabetes of the young (MODY) accounts for 1-2% of all diabetes cases. Unfortunately, circa 90% of MODY cases are misdiagnosed as type 1 or type 2 diabetes. A proper genetic diagnosis based on automatic sequencing is crucial for the use of a tailored treatment. However, this method is still expensive and, thus, patients' selection for testing should be performed precisely. In 2012, an easy-to-use tool was developed in Exeter, UK, to support genetic testing for MODY in the British population. The aim of the study was to assess the utility of MODY Probability Calculator in probands from Polish families with early-onset autosomal dominant diabetes. METHODS: We have performed a retrospective analysis of 155 probands who were qualified for genetic testing between 2006 and 2018. Probands were recruited for MODY testing based on the following criteria: 1) early age of diagnosis (≤35 years); 2) a positive, multigenerational family history of diabetes. Automatic sequencing, Sanger and, in case of initial negative results, new generation sequencing (NGS) of a set of 28 genes, were performed. MODY Probability was calculated on the website www.diabetesgenes.org. RESULTS: The group of probands consisted of 64 GCK-, 37 HNF1A-, and three HNF4A-MODY patients and 51 NGS-negative subjects. The median positive predictive value (PPV) was 75.5% (95% CI: 75.5-75.5%), 49.4% (95% CI: 24.4-75.5%), 45.5% (95% CI: 21.0-75.5%) and 49.4% (95% CI: 32.9-75.5%) for GCK-, HNF1A-, HNF4A-MODY and NGS-negative, respectively. The discriminative accuracy, as expressed by AUC, of PPV between MODY and NGS negative groups was 0.62 (95% CI: 0.52-0.71) with the corresponding sensitivity of 71.2% and specificity of 51.0%. CONCLUSIONS: In this highly pre-selected group of probands that were qualified for genetic testing based on clinical features, the use of MODY Probability Calculator would not substantially improve the patients' selection process for genetic testing. Further efforts to improve this tool are desirable.

Risk factors of hypoglycaemia in type 1 diabetes individuals during intensive sport exercise-Data from the SPORTGIVECHANCE event.

AIMS: Fear of hypoglycaemia seems to be one of the strongest barrier to physical activity for individuals with type 1 diabetes mellitus (T1DM).The aim of the study was to describe clinical characteristics of participants with T1DM in the intense sporting event of runs and bike rides"SPORTGIVECHANCE-Diabetic runners and cyclists for more sport for all in Europe", and investigate factors associated with self-reported hypoglycaemia episodes during the competition, in particular the use of continuous and flash glucose monitoring systems (CGM/FGM). METHODS: The sporting event took place in Spoleto, Italy from 30 August 2018 to 2 September 2018. An online survey was distributed among 150 participants with diabetes. Only T1DM patients were invited to complete the survey that included questions on baseline clinical characteristics as well as glucose control and meal related issues during the competition. Logistic regression was used to determine factors associated with reported hypoglycaemia. RESULTS: There were 35 T1DM individuals who completed the questionnaire: eight subjects were continuous glucose monitoring system (CGM) users, 10 used flash glucose monitoring systems (FGM), while the others performed self-measured blood glucose measurements (SMBG) on glucose meters. Mild hypoglycaemia episodes during the competition were reported by four CGM/FGM users and six non-users (OR: 0.73, CI: 0.34-1.53). No severe hypoglycaemic episode was reported. Body mass index (BMI) (OR: 1.47, CI: 1.01-2.13) and subjectively very hard or maximal intensity of the competition (OR: 4.90, CI: 1.51-15.89) were associated with a higher risk of hypoglycaemia. CONCLUSIONS: Data obtained from the self-selected sample of T1DM patients suggests that T1DM individuals can participate in intense sport competitions with moderate risk of mild hypoglycaemia regardless of CGM/FGM or SMBG use.

Predictors of neutrophil extracellular traps markers in type 2 diabetes mellitus: associations with a prothrombotic state and hypofibrinolysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with a hypercoagulable state and increased neutrophil extracellular traps formation (NETosis). We investigated predictors of NETosis and cell death markers in circulating blood and their association with a prothrombotic state in T2DM. METHODS: In a cross-sectional study involving 113 T2DM patients aged 63.7 ± 8.2 years, we investigated citrullinated histone H3 (H3Cit), cell-free deoxyribonucleic acid (cfDNA), myeloperoxidase, neutrophil elastase, and inflammation markers, along with thrombin generation (TG), plasma clot lysis time (CLT), clot permeability (Ks) and fibrinolysis inhibitors. RESULTS: On multivariate logistic regression analysis adjusted for age and gender, predictors of high H3Cit (≥ 7.36 ng/mL, upper quartile) were: glycated hemoglobin (HbA1c) ≥ 7.0% and interleukin-6. Interleukin-6 was also found to be a predictor of high cfDNA (≥ 2.84 µg/mL, upper quartile) along with glucose. Citrullinated histone H3 and cfDNA correlated positively with CLT and inversely with Ks, while TG associated solely with cfDNA. These associations were not seen with myeloperoxidase and neutrophil elastase. Patients with previous myocardial infarction (n = 21, 18.6%) had higher H3Cit (+108%, p < 0.001) and cfDNA (+45%, p = 0.022). On multivariable analysis adjusted for potential confounders, H3Cit and cfDNA, along with plasminogen activator inhibitor-1 and concomitant cardiovascular disease, were predictors of CLT. Citrullinated histone H3 alone was a predictor of Ks and only cfDNA was a predictor of peak thrombin generated. CONCLUSIONS: In T2DM, NETosis detectable in circulating blood is associated with inflammatory state and a prothrombotic state, especially hypofibrinolysis.

A decision algorithm to identify patients with high probability of monogenic diabetes due to HNF1A mutations.

PURPOSE: To investigate the utility of biomarkers of maturity-onset diabetes of the young (MODY), high-sensitivity C-reactive protein (hsCRP), and 1,5-anhydroglucitol (1,5-AG) in conjunction with other clinical and laboratory features to improve diagnostic accuracy and provide a diagnostic algorithm for HNF1A MODY. METHODS: We examined 77 patients with HNF1A MODY, 88 with GCK MODY mutations, 99 with type 1 diabetes, and 92 with type 2 diabetes. In addition to 1,5-AG and hsCRP, we considered body mass index (BMI), fasting glucose, and fasting serum C-peptide as potential biomarkers. Logistic regression and receiver operating characteristic curves were used in marker evaluation. RESULTS: Concentration of hsCRP was lowest in HNF1A MODY (0.51 mg/l) and highest in type 2 diabetes (1.33 mg/l). The level of 1,5-AG was lowest in type 1 diabetes and HNF1A MODY, 3.8 and 4.7 µg/ml, respectively, and highest (11.2 µg/ml) in GCK MODY. In the diagnostic algorithm, we first excluded patients with type 1 diabetes based on low C-peptide (C-statistic 0.98) before using high BMI and C-peptide to identify type 2 diabetes patients (C-statistic 0.92). Finally, 1,5-AG and hsCRP in conjunction yielded a C-statistic of 0.86 in discriminating HNF1A from GCK MODY. We correctly classified 92.9% of patients with type 1 diabetes, 84.8% with type 2 diabetes, 64.9% HNF1A MODY, and 52.3% GCK MODY patients. CONCLUSIONS: Plasma 1,5-AG and serum hsCRP do not discriminate sufficiently HNF1A MODY from common diabetes types, but could be potentially useful in prioritizing Sanger sequencing of HNF1A gene.

Negative pressure wound therapy use in diabetic foot syndrome-from mechanisms of action to clinical practice.

BACKGROUND: Diabetes and its complications constitute a rising medical challenge. Special attention should be given to diabetic foot syndrome (DFS) due to its high rate of associated amputation and mortality. Negative pressure wound therapy (NPWT) is a frequently used supportive modality in a diabetic foot with ulcerations (DFUs). DESIGN: Here, we reviewed the current knowledge concerning the tissue and molecular mechanisms of NPWT action with an emphasis on diabetes research followed by a summary of clinical DFU studies and practice guidelines. RESULTS: Negative pressure wound therapy action results in two types of tissue deformations-macrodeformation, such as wound contraction, and microdeformation occurring at microscopic level. Both of them stimulate a wound healing cascade including tissue granulation promotion, vessel proliferation, neoangiogenesis, epithelialization and excess extracellular fluid removal. On the molecular level, NPWT results in an alteration towards more pro-angiogenic and anti-inflammatory conditions. It increases expression of several key growth factors, including vascular endothelial growth factor and fibroblast growth factor 2, while expression of inflammatory cytokinesis reduced. The NPWT application also alters the presence and function of matrix metalloproteinases. Clinical studies in DFU patients showed a superiority of NPWT over standard therapy in terms of efficacy outcomes, primarily wound healing and amputation rate, without a rise in adverse events. International guidelines point to NPWT as an important adjuvant therapy in DFU whose use is expected to increase. CONCLUSIONS: This current knowledge improves our understanding of NPWT action and its tailoring for application in diabetic patients. It may inform the development of new treatments for DFU.

Plasma Protein Oxidation as a Determinant of Impaired Fibrinolysis in Type 2 Diabetes.

OBJECTIVE: We investigated clinical and laboratory determinants of plasma protein oxidation and its associations with clot fibrinolysis in type 2 diabetes patients. MATERIALS AND METHODS: Our cross-sectional study consisted of 246 type 2 diabetic patients, 143 (58%) with concomitant cardiovascular disease (CVD), including 41 (17%) with previous myocardial infarction (MI). We measured total protein carbonylation (PC), thiobarbituric acid reactive substances (TBARS) and total antioxidant capacity (TAC) along with clot lysis time (CLT) and clot permeation (Ks ), fibrinogen, plasminogen, α-2-antiplasmin, plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI) and thrombomodulin. RESULTS: Total PC correlated positively, while TAC correlated inversely with glycated haemoglobin and diabetes duration (all p < 0.05). Diabetic patients with CVD had higher total PC, TBARS and lower TAC compared with the remainder (all p < 0.001). Among correlations of total PC with Ks , PAI-1, thrombomodulin and TAFI, the strongest was with CLT (r = 0.687, all p < 0.01). High total PC, defined as ≥ 3.45 nmol/mg, was predicted by time since diabetes diagnosis ≥ 5 years (odds ratio [OR]: 3.0, 95% confidence interval [CI]: 1.36-6.63) and previous MI (OR: 11.31, 95% CI: 4.37-29.32). After adjustment for potential confounders, total PC accounted for 34.9% of the total variance in CLT. Total PC at a cut-off of 3.44 nmol/mg showed high discriminatory power for identifying patients with prolonged CLT (area under the curve: 0.845, 95% CI: 0.792-0.898, p < 0.001). CONCLUSION: Elevated plasma PC, largely driven by a long history of diabetes and concomitant CVD, is an important determinant of hypofibrinolysis in type 2 diabetes.