Insulin Can Delay Neutrophil Extracellular Trap Formation In Vitro-Implication for Diabetic Wound Care?

Diabetes is a worldwide evolving disease with many associated complications, one of which is delayed or impaired wound healing. Appropriate wound healing strongly relies on the inflammatory reaction directly after injury, which is often altered in diabetic wound healing. After an injury, neutrophils are the first cells to enter the wound site. They have a special defense mechanism, neutrophil extracellular traps (NETs), consisting of released DNA coated with antimicrobial proteins and histones. Despite being a powerful weapon against pathogens, NETs were shown to contribute to impaired wound healing in diabetic mice and are associated with amputations in diabetic foot ulcer patients. The anti-diabetic drugs metformin and liraglutide have already been shown to regulate NET formation. In this study, the effect of insulin was investigated. NET formation after stimulation with PMA (phorbol myristate acetate), LPS (lipopolysaccharide), or calcium ionophore (CI) in the presence/absence of insulin was analyzed. Insulin led to a robust delay of LPS- and PMA-induced NET formation but had no effect on CI-induced NET formation. Mechanistically, insulin induced reactive oxygen species, phosphorylated p38, and ERK, but reduced citrullination of histone H3. Instead, bacterial killing was induced. Insulin might therefore be a new tool for the regulation of NET formation during diabetic wound healing, either in a systemic or topical application.

Switching the basal insulin to insulin glargine 300 U/ml in people with type 2 diabetes under basal insulin supported oral therapy: Observational trial on effectiveness and safety.

AIMS: This study evaluated the effectiveness and safety of switching the basal insulin (BI) in a BI-supported oral therapy (BOT) to insulin glargine 300 U/ml (Gla-300) in adults with inadequately controlled type 2 diabetes (T2D). MATERIALS AND METHODS: This was a non-interventional, multicentre, prospective 12-month study, conducted in Germany, Austria and Switzerland. The study documented people with T2D with glycated haemoglobin (HbA1c) between 7.5% and 10.0%, currently treated by a non-Gla-300 BOT regimen, after the physician had decided to switch the BI to Gla-300. Primary endpoint was the proportion of patients achieving the fasting plasma glucose (FPG; ≤110 mg/dl) target. RESULTS: In total, 1194 participants comprised the full analysis set, of which 793 completed documentation of 12 months Gla-300 treatment (FAS-M12). The main previous BI was insulin glargine 100 U/ml (Gla-100; 47.2%). Twelve months after switching to Gla-300, 27.0% of FAS-M12 participants achieved the FPG target and 44.8% their individualized HbA1c target. The greatest FPG target achievements were seen in previous Gla-100 (29.3%), and greatest HbA1c target achievements in previous insulin detemir users (57.7%). The mean FPG decreased by -36.3 ± 51.2 mg/dl to 135.5 ± 36.9 mg/dl and mean HbA1c by -0.79 ± 1.01% to 7.45 ± 0.94%. Symptomatic and nocturnal hypoglycaemia incidence significantly decreased over 12 months of Gla-300 treatment. Body weight remained unchanged. CONCLUSIONS: Switching the BI to Gla-300 in a BOT regimen improved metabolic control and treatment satisfaction in a substantial proportion of patients with T2D and inadequate target achievement within 12 months in clinical practice with a decreased risk of symptomatic and nocturnal hypoglycaemia and without weight gain.

Effectiveness and safety of insulin glargine 300 U/mL in insulin-naïve patients with type 2 diabetes after failure of oral therapy in a real-world setting.

AIM: To evaluate the effectiveness and safety of initiating basal insulin-supported oral therapy (BOT) with insulin glargine 300 U/mL (Gla-300) in patients with type 2 diabetes inadequately controlled on oral antidiabetic drugs (OADs). MATERIALS AND METHODS: This non-interventional, multi-centre, prospective 52-week study, conducted in Germany and Switzerland, documented patients with type 2 diabetes with an HbA1c of between 7.5% and 10.0%, currently treated with OADs, after the physician had decided to start a BOT regimen with Gla-300. The primary endpoint was the rate of achievement of the individualized predefined HbA1c target. RESULTS: Of 1748 patients included, 1153 comprised the full analysis set, of whom 721 completed documentation of 12 months of Gla-300 treatment. Twelve months after starting Gla-300, 49.9% achieved their individualized HbA1c target, and 61.1% achieved either their HbA1c target or a fasting plasma glucose (FPG) of ≤110 mg/dL. Mean HbA1c decreased by -1.22% ± 1.05% to 7.28% ± 0.92% and mean FPG by -51.5 (±48.63) mg/dl to 132.9 ± 33.0 mg/dL. Median duration of HbA1c target achievement was 341 days and probability to remain on target after 6 months was 81%. Hypoglycaemia incidence and rates remained low after 12 months of Gla-300 treatment; no severe or severe nocturnal hypoglycaemia was observed. Body weight remained unchanged. CONCLUSIONS: Starting a BOT regimen with Gla-300 allowed about 60% of 721 German and Swiss patients with inadequately controlled type 2 diabetes to achieve glycaemic control within 12 months in daily clinical practice. Glycaemic control was achieved without weight gain or increased risk of nocturnal or severe hypoglycaemia.

Titration of insulin glargine 100 U/mL when added to oral antidiabetic drugs in patients with type 2 diabetes: results of the TOP-1 real-world study.

AIMS: Adequate insulin titration is crucial for optimal glycaemic control in type 2 diabetes (T2D). We aimed to explore the factors and outcomes associated with titration of glargine 100 U/mL (Gla-100) in patients uncontrolled on oral antidiabetic drugs (OAD) and initiating insulin therapy. METHODS: Patients from the Titration and Optimization (TOP)-1 registry were stratified by the magnitude of Gla-100 up-titration during the first month (no [< 1 Units (U)/day (d)], minimal [≥ 1 and < 5 U/d], moderate [≥ 5 and ≤ 8 U/d] and strong [> 8 U/d]). The primary endpoint was a fasting blood glucose (FBG) ≤ 110 mg/dL on ≥ 2 occasions and/or individual HbA1c target by 12 months. RESULTS: Of 2308 patients, 905, 715, 409 and 279 underwent no, minimal, moderate and strong titration, respectively. Age decreased across increasing titration groups (p = 0.02) while body mass index (BMI) (p < 0.0001), FBG (p < 0.0001), and HbA1c (p < 0.0001) increased. At 12 months, the proportions of patients achieving the primary endpoint were comparable across groups (66.1% overall), though a smaller proportion of no titration patients met both their individual HbA1c target and FBG ≤ 110 mg/dL compared to moderate and strong titration patients (20.1% vs. 27.2% and 26.2%, p = 0.033 and 0.023, respectively). HbA1c was also comparable, though FBG was higher in the no titration group (126.2 vs. 122.6, 121.5 and 120.9 mg/dL, p < 0.02). A similar, small reduction in body weight occurred in all groups; hypoglycaemia rates were comparable across groups. CONCLUSIONS: In real-world, titration of Gla-100 during the first month appears to coincide with a number of baseline factors. Insulin dose to meet HbA1c and FBG targets remains suboptimal in the majority of T2D patients.

HbA1c target achievement in the elderly: results of the Titration and Optimization trial for initiation of insulin glargine 100 U/mL in patients with type 2 diabetes poorly controlled on oral antidiabetic drugs.

Objectives: To identify real-world, age-related trends in the use of insulin glargine 100 U/mL (Gla-100) as part of basal-supported oral therapy (BOT). Research design and methods: The prospective, observational Titration and Optimization registry enrolled patients with poorly controlled type 2 diabetes mellitus initiated on Gla-100 BOT. The primary outcome was the proportion of patients with capillary fasting blood glucose (FBG) ≤110 mg/dL on ≥2 occasions and/or who met their individual HbA1c target within 12 months. Results: 2462 patients were analyzed (<65 years: n=1122; 65-74 years: n=771; ≥75 years: n=569). Diabetes duration (6.8, 8.9, and 11.2 years, p<0.0001) and proportion of women (40.7%, 47.9%, and 55.7%, p<0.0001) increased with age. Baseline HbA1c was highest in <65-year-olds (8.6% vs 8.4% and 8.5%, p<0.0001). Gla-100 up-titration until 12 months was highest in <65-year-olds (+11.6 U/day), compared with 65-74 (+10.2 U/day) and ≥75 years (+8.8; p<0.0001) but similar by units per kilogram, as was the decrease in FBG (<65: -64.1 mg/dL; 65-74: -56.1 mg/dL; ≥75: -53.4 mg/dL) and HbA1c (<65: -1.47%; 65-74: -1.31%; ≥75: -1.22%, p<0.0001). At 12 months, 65.9% of participants met the primary endpoint, with no significant difference between age groups. The proportion achieving their individual HbA1c target was lower for <65-year-olds (46.0% vs 54.3% and 54.7%; p<0.02). Symptomatic hypoglycemia incidence was more common in the ≥75-year-old group (3.4% vs 1.4% and 1.4%; p=0.0126). Conclusions: BOT with Gla-100 results in similar improvements of glycemic values with low risk of hypoglycemia across age groups. Given the link between HbA1c and long-term cardiovascular risk, ensuring appropriately stringent target-setting, intensification of basal insulin and making sure hypoglycemia is avoided is of paramount importance. Trial registration number: Database: https://awbdb.bfarm.de; Identifier: 1641; Date of registration: September 23, 2013.

Predictors of treatment response in type-2 diabetes patients initiating basal-supported oral therapy with insulin glargine 100 U/mL: A sub-analysis of the Titration and OPtimisation (TOP) registry.

The aim of this study was to identify predictors of long-term response to the initiation of basal-supported oral therapy (BOT) with insulin glargine (IGlar-100). Patients from the observational TOP registry were grouped based on those who had achieved (responders) and those who had not achieved (non-responders) their HBA1c target and/or FBG ≤110 mg/dL 12 months after IGlar-100 initiation. Independent predictors of treatment response were identified by regression analysis. Data for 2444 patients were analysed (responders, n = 1610; non-responders, n = 834). Although the IGlar-100 dose increase over 12 months was larger for non-responders (+12.83 vs +9.46 U/d; P < 0.0001), the corresponding decrease in HbA1c was smaller (-0.88% vs -1.57%). Independent predictors of response included lower BMI (OR, 0.97; 95% CI, 0.95-1.00), lower FBG (OR, 0.98; 95% CI, 0.97-0.98) and HbA1c values at baseline (OR, 0.24; 95% CI, 0.18-0.31), a less ambitious HbA1c target (OR, 5.07; 95% CI, 3.37-7.63) and bedtime administration of IGlar-100 (OR, 1.55; 95% CI, 1.12-2.14). In conclusion, HbA1c was the clinically most significant baseline characteristic predictive of response to BOT. This may suggest an advantage of IGlar-100 initiation prior to excessive hyperglycaemia escalation.

Time to Insulin Initiation in Type 2 Diabetes Patients in 2010/2011 and 2016/2017 in Germany.

BACKGROUND: The aim of the current study was to determine whether the time to insulin therapy initiation in patients with type 2 diabetes in primary care in Germany has changed in recent years. METHODS: Longitudinal data from general practices in Germany (Disease Analyzer) were analyzed. These data included information of 7128 patients (age: 68.5 [SD: 11.5] years; 54.4% male) receiving incident insulin therapy in 2010/2011 and 8216 patients (age: 69.1 [SD: 11.9] years; 54.9% male) receiving incident insulin therapy in 2016/2017. Changes in time to insulin initiation in the practices and the last HbA1c value before the start of insulin therapy were analyzed, stratified by index date. To analyze the impact of covariables on the time to insulin initiation, a multivariate regression analysis was performed, adjusted for age, sex, diabetologist care, and HbA1c as independent variables. RESULTS: Median time from T2D diagnosis to insulin therapy in the Disease Analyzer database increased from 1717 days in 2010/2011 to 1917 days in 2016/2017 (P < .001). The proportion of patients with a HbA1c value ≥9% before insulin initiation was high in both groups (2010/2011: 33.0%, 2016/2017: 34.2%, P = .347). The time to insulin initiation in DPP-4i patients was 112 days longer, and in SGLT2 patients 346 days longer than in patients treated with sulfonylurea. CONCLUSIONS: The present analysis confirms an increasing delay of the insulin therapy initiation as a consequence of the more frequent use of newer oral antidiabetics. However, the rather moderate increase of time to insulin might display insufficient long-term glycemic control using these agents. Still, more than one-third of patients receive insulin only when HbA1c levels exceed 9%.

Titration and optimization trial for the initiation of insulin glargine 100 U/mL in patients with inadequately controlled type 2 diabetes on oral antidiabetic drugs.

For patients with type 2 diabetes mellitus (T2DM) and inadequate glycaemic control, addition of basal insulin is recommended, but titration and optimization of basal insulin therapy in primary care is not well understood. We conducted an observational trial in 2470 patients with T2DM who initiated insulin glargine 100 U/L (Gla-100) on top of oral antidiabetic drugs. Physicians were free to choose either a "Davies," "Fritsche" or "individual" titration algorithm. We found that fasting blood glucose (FBG) and glycated haemoglobin (HbA1c) levels were effectively reduced by Gla-100; 65.9% of patients achieved the primary endpoint (FBG ≤6.1 mmol/L (110 mg/dL) or an individual HbA1c target). There were no significant differences in efficacy and safety between the algorithms used. The mean FBG decreased by 3.2 mmol/L (59 mg/dL) over 12 months, while the mean HbA1c decreased by 15.3 mmol/mol (1.4%)%. From a starting dose of 11.7 U/d, the Gla-100 dosage was 22.8 U/d at 12 months, with similar values in each group. Rates of hypoglycaemia were low and did not differ by titration algorithm. We conclude that Gla-100 was effective at reducing FBG and HbA1c, independent of the titration algorithm, but observed that algorithms were inconsistently applied in clinical practice.

Assessment of the Influence of Diabetes mellitus and Malnutrition on the Postoperative Complication Rate and Quality of Life of Patients in a Clinic Focused on Trauma Surgery. / Einschätzung der Auswirkungen eines Diabetes mellitus und einer Mangelernährung auf die postoperative Komplikationsrate und Lebensqualität von Patienten in einer unfallchirurgischen Schwerpunktklinik.

BACKGROUND: The prevalence of diabetes mellitus (DM) or malnutrition in hospitalised patients depends on the clinical domain, but is much higher than in the normal population. In trauma surgery, this increase is frequently associated with more postoperative complications and constantly rising costs. In addition, the quality of life of this target group is decreased, but there are only limited data from departments of traumatology and/or orthopaedics. Therefore, we aim to analyse the factors influencing the postoperative complication rate as well as the quality of life of orthopaedic and trauma patients. METHODS: Within this prospective trial in the period of 06/2014 to 02/2017, we analysed data of 1643 patients from traumatology - geriatric and septic traumatology - as well as endoprosthetics with regard to the clinical outcome, the complication rate and the quality of life (Short Form Health Survey 36, SF-36) associated with diabetes mellitus (DM) and the nutritional status (Nutritional Risk Screening 2002, NRS). RESULTS: Within our hospitalised group of trauma patients, the prevalence of diabetes mellitus was 12.4% and the risk for malnutrition (NRS ≥ 3) was 18.3%, which is much higher than in the normal population (DM 7.2%). Patients suffering from diabetes mellitus had significantly more complications than patients without diabetes mellitus. Similar results were found when comparing patients with a risk of malnutrition to the patients without. Furthermore, patients with DM evaluate their subjective quality of life lower than do patients without DM in the most domains of the SF-36, especially in the subjective-physical domains, while patients with NRS ≥ 3 assess their quality of life as being lower than do patients without a risk of malnutrition in all domains of the SF-36 (physical and mental). Additionally, we showed that reduced nutritional status has a greater influence on the decline in quality of life than did diabetes mellitus. CONCLUSION: Both diabetes mellitus and malnutrition seems to influence the subjective quality of life and the complication rate of hospitalised trauma patients. A nationwide data collection and targeted interventions within the frame of interdisciplinary cooperation are necessary. In this way, the postoperative complication rate as well as associated higher treatment costs could be reduced.

Changes in Glycemic Control and Body Weight After Initiation of Dapagliflozin or Basal Insulin Supported Oral Therapy in Type 2 Diabetes: A Primary Care Database Study.

BACKGROUND: The aim was to compare changes in HbA1c and body weight after initiation of dapagliflozin or basal insulin supported oral therapy (BOT) in type 2 diabetes patients in primary care practices. METHODS: Patients from 983 primary care practices who started dapagliflozin or BOT between December 2012 and July 2015 (index date, ID) were retrospectively analyzed (Disease Analyzer; Germany). Changes in HbA1c (%) and body weight (kg) were evaluated 90-270 days after ID. Propensity score (PS) matching (1:1) was used to adjust for differences in baseline clinical characteristics (180-0 days before ID: age, sex, health insurance, diabetologist care, glucose lowering therapy, HbA1c, body mass index) and duration (days) between start of therapies and last HbA1c or weight documentation after ID. RESULTS: After PS matching, 766 dapagliflozin (mean ± SD; age: 63 ± 10 years; HbA1c: 8.9 ± 1.2%) and 766 BOT (age: 63 ± 10 years; HbA1c: 8.7 ± 1.1%) patients were included. HbA1c decreased by mean (SD) of 1.0% (1.3) in dapagliflozin and by 1.0% (1.4) in BOT patients after 90-270 days (HbA1c reduction; dapagliflozin vs BOT: -0.01%; P = .79). In 440 dapagliflozin users with available data, body weight (97.4 ± 19.9 kg) decreased by 3.1 (5.8) kg after 90-270 days, whereas no significant weight change was observed in 440 matched BOT patients (97.5 ± 19.9 kg) (weight reduction; dapagliflozin vs BOT: -3.0 kg; P < .05). CONCLUSIONS: Initiation of dapagliflozin therapy reduced HbA1c similar to basal insulin with the additional benefit of weight reduction in type 2 diabetes patients treated in general practices.

BMP9 a possible alternative drug for the recently withdrawn BMP7? New perspectives for (re-)implementation by personalized medicine.

Promotion of rhBMP2 and rhBMP7 for the routine use to support fracture healing has been hampered by high costs, safety concerns and reasonable failure rates, imposing restrictions in its clinical use. Since there is little debate regarding its treatment potential, there is rising need for a better understanding of the mode of action of these BMPs to overcome its drawbacks and promote more efficacious treatment strategies for bone regeneration. Recently, BMP9, owing to its improved osteogenic potential, is gaining attention as a promising therapeutic alternative. Our study aimed at identifying specific gene expression patterns which may predict and explain individual responses to rhBMP7 and rhBMP9 treatments. Therefore, we investigated the effect of rhBMP7 and rhBMP9 on primary human osteoblasts from 110 donors and corresponding THP-1-derived osteoclasts. This was further compared with each other and our reported data on rhBMP2 response. Based on the individual donor response, we found three donor groups profiting from rhBMP treatment either directly via stimulation of osteoblast function or viability and/or indirectly via inhibition of osteoclasts. The response on rhBMP7 treatment correlated with expression levels of the genes BAMBI, SOST, Noggin, Smad4 and RANKL, while the response of rhBMP9 correlated to the expression levels of Alk6, Endoglin, Smurf1, Smurf2, SOST and RANKL in these donors. Noteworthy, rhBMP9 treatment showed significantly increased osteogenic activity (AP activity and Smad nuclear translocation) when compared to the two clinically used rhBMPs. Based on patient's respective expression profiles, clinical application of rhBMP9 either solely or in combination with rhBMP2 and/or rhBMP7 can become a promising new approach to fit the patient's needs to promote fracture healing.

Titration of basal insulin or immediate addition of rapid acting insulin in patients not at target using basal insulin supported oral antidiabetic treatment - A prospective observational study in 2202 patients.

AIM: Optimal treatment intensification strategies in patients with type-2 diabetes mellitus (T2DM) receiving basal insulin supported oral antidiabetic therapy (BOT) remain controversial. The objective of the present study was to compare outcomes of BOT-intensification by either the uptitration of long-acting insulin glargine or by the immediate addition of a rapid acting insulin analogue (RAIA). METHODS: This was a prospective, observational, 24-week study in T2DM patients with BOT using insulin glargine and baseline glycated hemoglobin (HbA1c) between 7.0 and 8.5%. Patients were stratified by their physicians to one of the following treatment intensification strategies: Basal insulin titration to target with discretionary subsequent addition of RAIA at weeks 12 or 24 (GLAR), or immediate addition of RAIA at baseline (GLARplus). RESULTS: A total of 3266 patients were prescreened of whom 2202 fulfilled the selection criteria. Of these, 1684 patients were documented in the GLAR group and 518 in the GLARplus group. In the GLAR group, in 91 (5.5%) and 21 patients (1.3%) RAIA was added at weeks 12 and 24, respectively. The groups displayed similar baseline characteristics; except, mean diabetes duration was slightly shorter in the GLAR group (8.7 vs. 9.4 years). During the study, insulin glargine dose was increased from 18.7 to 26.4U (plus 7.7U) in GLAR and from 24.9 to 27.3U (plus 2.4U) in GLARplus patients. Mean RAIA dose was 9.6±4.7U at the final visit. After 24 weeks, HbA1c was reduced by 0.8 and 0.9% in the GLAR and GLARplus groups, respectively (both p<0.001). An HbA1c of ≤7.0% was achieved in 49.2% of GLAR and 48.5% of GLARplus patients. In both groups, we observed improvements in cardiovascular risk factors such as lipids and blood pressure. The rates of symptomatic (1.6 vs. 1.7%) and severe (0.18 vs. 0.19%) hypoglycemic episodes were low and comparable in both groups. CONCLUSION: These findings provide evidence that treatment intensification in patients with type 2 diabetes not at glycemic target on BOT with insulin glargine is equally safe and effective using either long-acting insulin titration alone or the addition of a rapid-acting insulin analogue.

Distinct Gene Expression Patterns Defining Human Osteoblasts' Response to BMP2 Treatment: Is the Therapeutic Success All a Matter of Timing?

BACKGROUND: Bone morphogenetic proteins (BMPs) play a key role in bone formation. Local application of BMP2 (Dibotermin alfa) supports bone formation when applied to complex fractures. However, up to 33% of patients do not respond to this therapy. PURPOSE: Aiming to investigate whether inter-individual responses to BMP2 treatment can be predicted by gene expression patterns, we investigated the effect of BMP2 on primary human osteoblasts and THP-1 cell-derived osteoclasts from 110 donors. METHODS: Osteoblasts were obtained by collagenase digestion of spongy bone tissues. Osteoclasts were differentiated from THP-1 cells using the conditioned media of the osteoblasts. Viability was determined by resazurin conversion. As functional characteristics AP and Trap5B activity were measured. Gene expression levels were determined by RT-PCR in 21 of the 110 evaluated donors and visualized by electrophoresis. RESULTS: Based on our data, we could classify three response groups: (i) In 51.8% of all donors, BMP2 treatment induced osteoblast function. These donors strongly expressed the BMP2 inhibitor Noggin (NOG), the alternative BMP2 receptors repulsive guidance molecule B (RGMb) and activin receptor-like kinase 6 (Alk6), as well as the Wnt inhibitor sclerostin (SOST). (ii) In 17.3% of all donors, BMP2 treatment induced viability. In these donors, the initial high SOST expression significantly dropped with BMP2 treatment. (iii) 30.9% of all donors were not directly affected by BMP2 treatment. These donors expressed high levels of the pseudoreceptor BMP and activin membrane-bound inhibitor (BAMBI) and lacked SOST expression. In all donors, SOST expression correlated directly with receptor activator of NF-κB ligand (RANKL) expression, defining the cells' potential to stimulate osteoclastogenesis. CONCLUSIONS: Our data identified three donor groups profiting from BMP2 treatment either directly via stimulation of osteoblast function or viability and/or indirectly via inhibition of osteoclastogenesis, depending on their expression of BAMBI, SOST, NOG, and RANKL. On the basis of patients' respective expression profiles, the clinical application of BMP2 as well as its timing might be modified in order to better fit the patients' needs to promote bone formation or to inhibit bone resorption.

Diabetes treatment in people with type 2 diabetes and schizophrenia: Retrospective primary care database analyses.

AIMS: Aim of this study were to compare outcomes (HbA1c, BMI) and antidiabetic treatment of type 2 diabetes patients with and without schizophrenia under real-life conditions in primary care practices in Germany. METHODS: 1321 type 2 diabetes patients with and 1321 matched controls (age, sex, diabetes duration, diabetologist care, practice) without schizophrenia in 1072 general practices throughout Germany were retrospectively analyzed (Disease Analyser: 01/2009-12/2013). Antidiabetic treatment, HbA1c and BMI were compared using paired t-tests, McNemar tests and conditional logistic regression adjusting for macro- and microvascular comorbidity (ICD-10). RESULTS: Mean age (±SD) of patients and controls was 67.4±13.2 years (males: 38.9%). Diabetes duration was 5.7±4.3 years, 6% were in diabetologist care. Private health insurance was less often found among patients with schizophrenia than controls (2.2% vs 6.3%; p<0.0001). There was no difference in the mean HbA1c values (cases: 7.1±1.4%; controls: 7.2±1.5%) (54.1 vs. 55.2 mmol/mol) (p=0.8797) and in the average BMI (32.4±6.6 vs. 31.0±5.0 kg/m(2); p=0.2072) between the two groups. Novel cost-intensive antidiabetic agents (DPP-4- or SGLT2-inhibitors, GLP-1 receptor agonists) were less often prescribed in cases (15.3 vs. 18.3%; p=0.0423). However, in multivariable logistic regression, schizophrenia (odds ratio, 95%CI: 1.101; 0.923-1.317) was not associated with prescription use of novel antidiabetic agents (reference: other antidiabetic agents) after adjusting for private health insurance (OR: 2.139; 1.441-3.177) and comorbidity. CONCLUSIONS: There is no evidence that type 2 diabetes patients with schizophrenia have worse diabetes control than those without a severe mental illness in general practices.

Effectiveness and tolerability of treatment intensification to basal-bolus therapy in patients with type 2 diabetes on previous basal insulin-supported oral therapy with insulin glargine or supplementary insulin therapy with insulin glulisine: the PARTNER observational study.

BACKGROUND: Due to the progressive nature of type 2 diabetes mellitus (T2DM), antidiabetic treatment needs to be continuously intensified to avoid long-term complications. In T2DM patients on either basal insulin-supported oral therapy (BOT) or supplementary insulin therapy (SIT) presenting with HbA1c values above individual targets for 3-6 months, therapy should be intensified. This study investigated effectiveness and tolerability of an intensification of BOT or SIT to a basal-bolus therapy (BBT) regimen in T2DM patients in daily clinical practice. METHODS: This noninterventional, 8-month, prospective, multicenter study evaluated parameters of glucose control, occurrence of adverse events (eg, hypoglycemia), and acceptance of devices in daily clinical practice routine after 12 and 24 weeks of intensifying insulin therapy to a BBT regimen starting from either preexisting BOT with insulin glargine (pre-BOT) or preexisting SIT with ≥3 daily injections of insulin glulisine (pre-SIT). RESULTS: A total of 1,530 patients were documented in 258 German medical practices. A total of 1,301 patients were included in the full analysis set (55% male, 45% female; age median 64 years; body mass index median 30.8 kg/m(2); pre-BOT: n=1,072; pre-SIT: n=229), and 1,515 patients were evaluated for safety. After 12 weeks, HbA1c decreased versus baseline (pre-BOT 8.67%; pre-SIT 8.46%) to 7.73% and 7.66%, respectively (Δ mean -0.94% and -0.80%; P<0.0001). At week 24, HbA1c was further reduced to 7.38% and 7.30%, respectively (Δ mean -1.29% and -1.15%; P<0.0001), with a mean reduction of fasting blood glucose values in both treatment groups by more than 46 mg/dL. An HbA1c goal of ≤6.5% was reached by 17.9% (pre-BOT) and 18.6% (pre-SIT), and an HbA1c ≤7.0% by 46.1% (pre-BOT) and 43.0% (pre-SIT) of patients. During 24 weeks, severe as well as serious hypoglycemic events were rare (pre-BOT: n=5; pre-SIT: n=2; pretreated with both insulins: n=1). CONCLUSION: Intensifying glargine-based BOT or glulisine-based SIT to a BBT regimen in poorly controlled T2DM patients in daily routine care led to marked improvements of glycemic control and was well tolerated.

Treatment persistence after initiating basal insulin in type 2 diabetes patients: A primary care database analysis.

AIMS: To compare persistence and its predictors in type 2 diabetes patients in primary care, initiating either basal supported oral therapy (BOT) or intensified conventional therapy (ICT) with glargine, detemir, or NPH insulin. METHODS: In the BOT cohort, 1398 glargine (mean age: 68 years), 292 detemir (66 years), and 874 NPH (65 years) users from 918 practices were retrospectively analyzed (Disease Analyzer, Germany: 2008-2012). The ICT group incorporated 866 glargine (64 years), 512 detemir (60 years), and 1794 NPH (64 years) new users. Persistence was defined as proportion of patients remaining on the initial basal insulin (glargine, detemir and NPH insulin) over 2 years. Persistence was evaluated by Kaplan-Meier curves (log-rank tests) and Cox regression adjusting for age, sex, diabetes duration, antidiabetic co-therapy, comorbidities, specialist care, and private health insurance. RESULTS: In BOT, two-year persistence was 65%, 53%, and 59% in glargine, detemir, and NPH users, respectively (p<0.001). In ICT, persistence was higher without differences between groups: 84%, 85%, 86% in glargine, detemir, and NPH, respectively (p=0.536). In BOT, detemir and NPH users were more likely to discontinue basal insulin compared with glargine (detemir vs. glargine: adjusted Hazard Ratio; 95% CI: 1.56; 1.31-1.87; NPH vs. glargine: 1.22; 1.07-1.38). Heart failure (1.39; 1.16-1.67) was another predictor of non-persistence, whereas higher age (per year: 0.99; 0.98-0.99), metformin (0.61; 0.54-0.69), and sulfonylurea co-medication (0.86; 0.77-0.97) were associated with lower discontinuation. CONCLUSIONS: In BOT, treatment persistence among type 2 diabetes patients initiating basal insulin is influenced by type of insulin, antidiabetic co-medication, and patient characteristics.

Factors circulating in the blood of type 2 diabetes mellitus patients affect osteoblast maturation - description of a novel in vitro model.

Type 2 diabetes mellitus (T2DM) is one of the most frequent metabolic disorders in industrialized countries. Among other complications, T2DM patients have an increased fracture risk and delayed fracture healing. We have demonstrated that supraphysiological glucose and insulin levels inhibit primary human osteoblasts׳ maturation. We aimed at developing a more physiologically relevant in vitro model to analyze T2DM-mediated osteoblast changes. Therefore, SCP-1-immortalized pre-osteoblasts were differentiated with T2DM or control (non-obese and obese) sera. Between both control groups, no significant changes were observed. Proliferation was significantly increased (1.69-fold), while AP activity and matrix mineralization was significantly reduced in the T2DM group. Expression levels of osteogenic marker genes and transcription factors were altered, e.g. down-regulation of RUNX2 and SP-7 or up-regulation of STAT1, in the T2DM group. Active TGF-ß levels were significantly increased (1.46-fold) in T2DM patients׳ sera. SCP-1 cells treated with these sera showed significantly increased TGF-ß signaling (2.47-fold). Signaling inhibition effectively restored osteoblast maturation in the T2DM group. Summarizing our data, SCP-1 cells differentiated in the presence of T2DM patients׳ serum exhibit reduced osteoblast function. Thus, this model has a high physiological impact, as it can identify circulating factors in T2DM patients׳ blood that may affect bone function, e.g. TGF-ß.

Increased oxidative stress response in granulocytes from older patients with a hip fracture may account for slow regeneration.

Proximal femur fracture, a typical fracture of the elderly, is often associated with morbidity, reduced quality of life, impaired physical function and increased mortality. There exists evidence that responses of the hematopoietic microenvironment to fractures change with age. Therefore, we investigated oxidative stress markers and oxidative stress-related MAPK activation in granulocytes from the young and the elderly with and without fractured long bones. Lipid peroxidation levels were increased in the elderly controls and patients. Aged granulocytes were more sensitive towards oxidative stress induced damage than young granulocytes. This might be due to the basally increased expression of SOD-1 in the elderly, which was not further induced by fractures, as observed in young patients. This might be caused by an altered MAPK activation. In aged granulocytes basal p38 and JNK activities were increased and basal ERK1/2 activity was decreased. Following fracture, JNK activity decreased, while ERK1/2 and p38 activities increased in both age groups. Control experiments with HL60 cells revealed that the observed p38 activation depends strongly on age. Summarizing, we observed age-dependent changes in the oxidative stress response system of granulocytes after fractures, for example, altered MAPK activation and SOD-1 expression. This makes aged granulocytes vulnerable to the stress stimuli of the fracture and following surgery.

Therapeutic peritoneal lavage with warm saline solution as an option for a critical hypothermic trauma patient.

INTRODUCTION: In this paper, we present the case of a 63-year-old woman, who was found in her flat lying unconscious on the floor for an unknown time. At the time of admission, her core temperature was 24 °C and ventricular fibrillation was detected on the electrocardiogram (ECG). Because of the unstable conditions, the persistent nonperfusing cardiac rhythm and the dramatically inhibited coagulation cascade, a peritoneal lavage connected to a rapid infuser was performed for rewarming, instead of using a transportable heart-lung machine and a haemodialysis device. After a prolonged cardiopulmonary resuscitation (CPR), the patient could be transferred to the intensive care unit (ICU) in a stable condition. After 40 days in the ICU, recovery was fast, and another month of treatment later, she could be discharged back home without any discomfort. CONCLUSION: This report illustrates the successful use of the peritoneal lavage for rewarming a severely hypothermic patient without any extracorporeal rewarming device. Furthermore, it can be used in nearly every hospital if the necessary equipment is affordable. It is demonstrated that this technique is able to provide good outcomes for all victims of accidental hypothermia.

Darbepoetin inhibits proliferation of hepatic cancer cells in the presence of TGF-ß.

Darbepoetin (DPO), an erythropoietin (EPO) derivative, was licensed in 2002 to treat patients with solid tumors suffering from chemotherapy-dependent anemia, although various tumors express EPO to improve vascularization, thus favoring tumor growth and spreading. Therefore, we wanted to investigate direct effects of DPO on the liver tumor cell lines HepG2, SkHep1, Huh-7, AKN1, HCC-T and HCC-M, as well as on primary human hepatocytes (hHeps). DPO (0-40 ng/ml) did not affect viability of hHeps, HepG2, SkHep1, AKN1, HCC-T and HCC-M cells, as determined by Resazurin conversion. However, Huh-7 cells' viability dose-dependently decreased from 5 ng/ml DPO on. Lack of LDH release into culture medium and negative DNA laddering excluded apoptosis or necrosis as the cause for the reduced Resazurin conversion. In Huh-7 cells, DPO increased the expression of p53. Interestingly, Huh-7 cells showed the highest basal TGF-ß1 expression as compared to the other cell lines. Upon inhibition of TGF-ß1 signaling, DPO no longer reduced viability in Huh-7 cells. On the contrary, co-incubation with TGF-ß1 made the other cell lines responsive to DPO. Summarizing our data, we show that DPO reduces the growth of Huh-7 cells by up-regulation of the tumor-suppressor gene p53. This mechanism seems to be dependent on a strong TGF-ß expression and corresponding signaling in these cells, as other cell lines became responsive to DPO with TGF-ß1 supplementation. The knowledge of this mechanism offers great perspectives for the understanding and treatment of solid liver tumors.