A Novel Strategy for the Mechanical Subpulmonary Support in Failing Fontan Patients.

BACKGROUND: The number of single ventricle patients undergoing Fontan palliation and surviving to adulthood worldwide has steadily increased in recent years. Nevertheless, the Fontan circulation is destined to fail. Ultimately, heart transplantation (HTx) remains the definitive treatment option. Due a shortage of organs, mechanical circulatory support in the form of ventricular assist devices (VADs) is widely used to bridge heart failure patients to HTx, but these devices have been mainly developed to address the needs of normal anatomies. A novel venous cannula has been developed as part of the EXCOR® VAD to provide subpulmonary support in these patients. Its clinical application is investigated in the "Registry to Assess the Safety and Feasibility of the Subpulmonary Support with the Novel Venous Cannula in Patients with Failing/Absence of the Right Heart" (RegiVe study, NCT04782232). METHODS: RegiVe is a multicenter, international, observational, prospective, non-randomized registry aiming to collect the routine clinical data of up to 20 patients. The primary endpoints address device performance and safety, while the secondary endpoints target organ status and overall safety (according to the Interagency Registry for Mechanically Assisted Circulatory Support - INTERMACS - definitions). Data analysis will be performed by means of descriptive statistics. RESULTS: RegiVe has received the favorable opinion of an independent ethics committee and enrollment has recently started. CONCLUSION: RegiVe is the first study evaluating the use of a medical device specifically developed for subpulmonary support of failing Fontan patients. The study will provide important insight and further information on this cohort and help to improve a dedicated VAD strategy.

An in vitro system to silence mitochondrial gene expression.

The human mitochondrial genome encodes thirteen core subunits of the oxidative phosphorylation system, and defects in mitochondrial gene expression lead to severe neuromuscular disorders. However, the mechanisms of mitochondrial gene expression remain poorly understood due to a lack of experimental approaches to analyze these processes. Here, we present an in vitro system to silence translation in purified mitochondria. In vitro import of chemically synthesized precursor-morpholino hybrids allows us to target translation of individual mitochondrial mRNAs. By applying this approach, we conclude that the bicistronic, overlapping ATP8/ATP6 transcript is translated through a single ribosome/mRNA engagement. We show that recruitment of COX1 assembly factors to translating ribosomes depends on nascent chain formation. By defining mRNA-specific interactomes for COX1 and COX2, we reveal an unexpected function of the cytosolic oncofetal IGF2BP1, an RNA-binding protein, in mitochondrial translation. Our data provide insight into mitochondrial translation and innovative strategies to investigate mitochondrial gene expression.

MitoRibo-Tag Mice Provide a Tool for In Vivo Studies of Mitoribosome Composition.

Mitochondria harbor specialized ribosomes (mitoribosomes) necessary for the synthesis of key membrane proteins of the oxidative phosphorylation (OXPHOS) machinery located in the mitochondrial inner membrane. To date, no animal model exists to study mitoribosome composition and mitochondrial translation coordination in mammals in vivo. Here, we create MitoRibo-Tag mice as a tool enabling affinity purification and proteomics analyses of mitoribosomes and their interactome in different tissues. We also define the composition of an assembly intermediate formed in the absence of MTERF4, necessary for a late step in mitoribosomal biogenesis. We identify the orphan protein PUSL1, which interacts with a large subunit assembly intermediate, and demonstrate that it is an inner-membrane-associated mitochondrial matrix protein required for efficient mitochondrial translation. This work establishes MitoRibo-Tag mice as a powerful tool to study mitoribosomes in vivo, enabling future studies on the mitoribosome interactome under different physiological states, as well as in disease and aging.

PTCD1 Is Required for 16S rRNA Maturation Complex Stability and Mitochondrial Ribosome Assembly.

The regulation of mitochondrial RNA life cycles and their roles in ribosome biogenesis and energy metabolism are not fully understood. We used CRISPR/Cas9 to generate heart- and skeletal-muscle-specific knockout mice of the pentatricopeptide repeat domain protein 1, PTCD1, and show that its loss leads to severe cardiomyopathy and premature death. Our detailed transcriptome-wide and functional analyses of these mice enabled us to identify the molecular role of PTCD1 as a 16S rRNA-binding protein essential for its stability, pseudouridylation, and correct biogenesis of the mitochondrial large ribosomal subunit. We show that impaired mitoribosome biogenesis can have retrograde signaling effects on nuclear gene expression through the transcriptional activation of the mTOR pathway and upregulation of cytoplasmic protein synthesis and pro-survival factors in the absence of mitochondrial translation. Taken together, our data show that impaired assembly of the mitoribosome exerts its consequences via differential regulation of mitochondrial and cytoplasmic protein synthesis.

Systemic administration of bevacizumab prolongs survival in an in vivo model of platinum pre-treated ovarian cancer.

Ovarian cancer patients often suffer from malignant ascites and pleural effusion. Apart from worsening the outcome, this condition frequently impairs the quality of life in patients who are already distressed by ovarian cancer. This study investigated whether single intraperitoneal administration of the anti-VEGF antibody bevacizumab is capable of reducing the ascites-related body surface and prolonging survival. The study was performed in an orthotopic murine model of peritoneal disseminated platin-resistant ovarian cancer. Mice were treated with bevacizumab and/or paclitaxel or buffer (control). Reduction of body surface and increased survival rates were assessed as therapeutic success. Survival of mice in all treatment groups was significantly enhanced when compared to the non-treatment control group. The combination of paclitaxel plus bevacizumab significantly improved body surface as well as overall survival in comparison to a treatment with only one of the drugs. Treatment of malignant effusion with a single dose of bevacizumab as an intraperitoneal application, with or without cytostatic co-medication, may be a powerful alternative to systemic treatment.

Pilot study for the evaluation of morphological and functional changes in retinal blood flow in patients with insulin resistance and/or type 2 diabetes mellitus.

BACKGROUND: The aim of this study was to investigate early morphological and functional pathology in the retinal micro-circulation in patients with insulin resistance and/or type 2 diabetes mellitus (T2DM). METHODS: Fifty-four subjects, without features of retinopathy under ophthalmological investigation, were recruited for study participation and were classified into three study groups according to their metabolic staging: (1) Group C comprised nondiabetic, insulin-sensitive subjects with a BMI <28 kg/m(2); (2) Group IR comprised nondiabetic, insulin-resistant, obese subjects with a BMI ≥28 kg/m(2); and (3) Group DM comprised patients with manifested T2DM. Retinal microvascular blood flow was assessed using scanning laser doppler flowmetry (Heidelberg Retina Flowmeter) before and after flicker light stimulation (10 Hz; Photo Stimulater 750). RESULTS: No significant difference was observed in retinal blood flow (RBF) among the three groups, neither at baseline nor after stimulating the retina with flicker light. The arterial wall-to-lumen ratio (WLR) tended to be smaller in Group DM compared with Group C, and was significantly lower when comparing Group IR with Group C. When the subjects were grouped according to their insulin resistance, a steady decline in RBF and WLR could be observed with increasing insulin resistance. CONCLUSIONS: In conclusion, laser scanner flowmetry of the retina was found to detect very early changes in microvascular blood flow. Development of insulin resistance seems to be an important component in the deterioration of RBF.

Combination of a MDR1-targeted replicative adenovirus and chemotherapy for the therapy of pretreated ovarian cancer.

PURPOSE: Targeted oncolytic adenoviruses capable of replication selectively in cancer cells are an appealing approach for the treatment of various cancer types refractory to conventional therapies. The aim of this study was to evaluate the effect of Ad5/3MDR1E1, a multidrug resistance gene 1 (MDR1)-targeted fiber-modified replication-competent adenovirus for the therapy of platinum-pretreated ovarian cancer in combination with cytostatic agents. METHODS: MDR1-specific tumor cell killing of Ad5/3MDR1E1 was systematically evaluated in chemotherapy naïve and pretreated ovarian cancer cells in vitro. Combinations of Ad5/3MDR1E1 and cytostatic agents were studied in vivo and in vitro. An in vivo hepatotoxicity model was used to evaluate liver toxicity. RESULTS: We demonstrate efficient oncolysis of Ad5/3MDR1E1 in chemotherapy-resistant ovarian cancer cells as well as therapeutic efficacy in an orthotopic mouse model. Further, combining Ad5/3MDR1E1 with paclitaxel resulted in greater therapeutic benefit than either agent alone. CONCLUSION: These preclinical data suggest that a fiber-modified adenovirus vector under the control of the MDR1 promoter represents a promising treatment strategy for platinum-pretreated ovarian cancer as a single agent or in combination with conventional anticancer drugs.

Hysteroscopic management of residual trophoblastic tissue is superior to ultrasound-guided curettage.

STUDY OBJECTIVE: The aim of this study was to estimate the rate of intrauterine adhesions and subsequent pregnancy outcome in patients with residual trophoblastic tissue treated with hysteroscopic resection versus ultrasound-guided dilation and evacuation (D&E). DESIGN: Cohort study from 2 centers (Canadian Task Force classification II-2). SETTING: Two surgical teams at the University of Duesseldorf Medical Center and the PAN Clinic in Cologne, Germany. PATIENTS: Women with residual trophoblastic tissue after first- or second-trimester miscarriage or term delivery. INTERVENTION: Two techniques were used for the removal of residual trophoblastic tissue: ultrasound-guided evacuation with a curette (D&E) and hysteroscopic resection of trophoblastic tissue (HR). MEASUREMENTS AND MAIN RESULTS: We evaluated 95 patients who underwent secondary intervention for residual trophoblastic disease. A total of 42 patients underwent dilation of the cervix and ultrasound-guided curettage. In a second series of 53 patients, a resectoscope fitted with a 4-mm cutting loop was used for the removal of residual trophoblastic tissue used without application of current. Three months after the intervention, second-look office hysteroscopy was performed. Differences between both treatment groups were statistically significant. After HR, mild intrauterine adhesions were found in 2 patients (4.2%). After D&E, 12 patients (30.8%) presented with intrauterine adhesions (mild intrauterine adhesions: n = 7 [17.9%]; single dense adhesions: n = 3 [7.7%]; and extensive endometrial fibrosis n = 1 [2.6%]). Eighty-two patients wanted to become pregnant. Conception rate of all patients examined was 68.8% (HR) and 59.9% (D&E) (p < .05). In patients younger than 35 years of age who underwent HR, the pregnancy rate was significantly (p < .05) increased compared with patients who underwent D&E (78.1% vs 66.6%). In addition, patients from the HR group demonstrated a significantly (p < .05) shorter time to conception (11.5 month vs 14.5 month). CONCLUSION: The results of this study indicate that selective HR of residual trophoblastic tissue significantly reduces the incidence of intrauterine adhesions and increases pregnancy rates.

PIOfix-study: effects of pioglitazone/metformin fixed combination in comparison with a combination of metformin with glimepiride on diabetic dyslipidemia.

OBJECTIVE: Dyslipidemia in patients with type 2 diabetes is characterized by elevated triglyceride levels, decreased high-density lipoprotein (HDL) cholesterol, and a predominance of small dense low-density lipoprotein (LDL) particles. Also, patients suffer from ß-cell dysfunction, chronic systemic inflammation, increased hormonal visceral adipose tissue activity, and an increased risk of cardiovascular events. The aim of our study was to investigate the effect of a fixed pioglitazone + metformin (PM) combination (vs. glimepiride + metformin [GM]) on diabetic dyslipidemia. RESEARCH DESIGN AND METHODS: A total of 288 type 2 diabetes patients completed this double-blind parallel study (187 men, 101 women; age [mean ± SD], 59 ± 10 years; body mass index, 32.6 ± 5.1 kg/m(2); hemoglobin A1c [HbA1c], 7.3 ± 0.8%). They were randomized to PM or GM for 6 months. Observation parameters at baseline and end point included HDL, LDL, triglycerides, fasting insulin, fasting glucose, total adiponectin, intact proinsulin, and high-sensitivity C-reactive peptide (hsCRP). RESULTS: HDL increased in the PM group by 0.08 ± 0.25 mmol/L (GM, -0.01 ± 0.2.8 mmol/L; P < 0.001 vs. PM), whereas LDL increased in both groups (GM, 0.25 ± 0.90 mmol/L; PM, 0.29 ± 0.66 mmol/L; difference not significant between groups). Improvements were seen for triglycerides (PM, -0.47 ± 1.30; GM, -0.19 ± 1.39 mmol/L), HbA1c (PM, -0.8 ± 0.9%; GM, -1.0 ± 0.9%), and glucose (PM, -1.2 ± 2.1; GM, -1.2 ± 2.2 mmol/L). Decreases in fasting insulin (PM, -5.2 ± 11.9; GM, -0.1 ± 9.8 µU/mL; P < 0.001 between groups), hsCRP (PM, -0.9 ± 1.9; GM, 0.0 ± 1.8 mg/L; P < 0.001), and fasting intact proinsulin (PM, -5.5 ± 11.1; GM, -0.1 ± 10.0 pmol/L; P < 0.001) and an increase in adiponectin (PM, +6.8 ± 6.4 mg/L; GM, +0.7 ± 2.7 mg/L; P < 0.001) were seen in the PM arm, only. CONCLUSIONS: With comparable glycemic control, the fixed PM combination was more efficacious on HDL cholesterol improvement than the GM combination. Additional positive effects were observed for biomarkers of lipid metabolism, ß-cell function, activity of the visceral adipose tissue, and chronic systemic inflammation.

The fixed combination of pioglitazone and metformin improves biomarkers of platelet function and chronic inflammation in type 2 diabetes patients: results from the PIOfix study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by a proinflammatory and procoagulant condition. This study investigates the impact of a pioglitazone plus metformin therapy on biomarkers of inflammation and platelet activation in comparison to a treatment with glimepiride plus metformin. METHODS: The study was designed as a multicenter, randomized, double-blinded two-arm trial. Patients with T2DM and dyslipidemia under metformin monotherapy with hemoglobin A1c value between 6.5% and 9.0% were eligible for trial participation. Blood was drawn at baseline and after 24 weeks of treatment from patients of five centers. Markers of inflammation and thrombocyte function (soluble CD40 ligand, thromboxane, vWillebrand factor, adhesion molecules, clotting reaction) were evaluated subsequently in a central laboratory. RESULTS: A total of 46 patients were included in the final analyses. Mean (± standard deviation) age was 58.5 ± 9.0 years (13 women, 33 men; disease duration 6.3 ± 5.0 years; body mass index 32.0 ± 4.8 kg/m(2)). A total of 25 patients were treated with pioglitazone plus metformin, and 21 patients were in the glimepiride arm. There was a significant decline of E-selectin (-3.7 ± 4.8 ng/ml, p < .001 versus baseline), vWillebrand factor (-19.5 ± 32.0%, p < .05), and high-sensitivity C-reactive protein concentrations (-1.08 ± 0.91 mg/liter, p < .05) in the metformin + pioglitazone arm only (metformin + glimepiride, -0.5 ± 3.4 ng/ml, +1.4 ± 33.2%, + 0.08 ± 0.72 mg/liter, respectively, all not significant). Also, all other surrogate markers for platelet function and inflammation showed slight improvements in the metformin + pioglitazone arm but not in the metformin + glimepiride arm. CONCLUSIONS: The fixed metformin + pioglitazone combination treatment showed an overall improvement of laboratory surrogate markers, indicating improvement of platelet function and of chronic systemic inflammation, which was not seen with metformin + glimepiride.

High-sensitivity C-reactive protein predicts cardiovascular risk in diabetic and nondiabetic patients: effects of insulin-sensitizing treatment with pioglitazone.

Systemic inflammatory activity has turned out to play a key pathogenic role in vascular atherosclerosis, insulin resistance, and type 2 diabetes mellitus. Inflammatory biomarkers may therefore be a valuable tool for risk evaluation. Among them, the best evidence to date supports the use of high-sensitivity C-reactive protein (hs-CRP) to monitor insulin resistance and cardiovascular risk in diabetic and nondiabetic individuals. Data suggest that hs-CRP may also participate directly in the process of atherogenesis. A growing number of clinical trials tested the hypothesis that antidiabetic drugs specifically targeting insulin resistance could benefit individuals by reducing inflammation, atherogenesis, and thus cardiovascular risk. One such class are the thiazolidinediones (pioglitazone and rosiglitazone). These agents act as selective ligands of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma). This article reviewed published data on hs-CRP changes with the thiazolidinedione agent pioglitazone. Here we found pronounced insulin-sensitizing and anti-inflammatory properties in different clinical settings, including diabetic and nondiabetic individuals. Coadministration of pioglitazone to antilipidemic statin therapy resulted in additional effects on low-grade inflammation, and hs-CRP reduction has been demonstrated to occur independently of glucose lowering. The anti-inflammatory effect appeared to be a rapid physiologic reaction on PPARgamma activation and could be observed within a short-term interval after starting pioglitazone therapy. In summary, clinical study results underline the benefit of an early insulin resistance treatment to oppose systemic vascular inflammation and cardiometabolic syndrome in patients with elevated levels of high-sensitivity C-reactive protein.

Increased prevalence of cardiovascular disease and risk biomarkers in patients with unknown type 2 diabetes visiting cardiology specialists: results from the DIASPORA study.

BACKGROUND: Patients with diabetes mellitus and IGT have a high risk for cardiovascular events. It is tempting to speculate that these patients are often first seen by cardiologists. DESIGN: This cross-sectional study investigates the diabetes prevalence in cardiology care units and the correlated metabolic conditions as assessed by several circulating biomarkers. METHODS: Patients aged 55 or older with suspected or overt coronary heart disease were eligible for trial participation. Fasting blood samples were drawn from patients to determine HOMA score, glycaemic and lipid profile, and several risk biomarkers. An OGTT was performed in patients without known diabetes. RESULTS: We enrolled 530 patients (181 male, 349 female, mean age, 68+/-7 years) in this study from 22 German cardiology centres; 156 patients (29.4%) had known diabetes and OGTT revealed that 184 patients (34.7%) had no diabetes, 106 patients (20.0%) had IGT or IFG and 84 patients (15.9%) were newly diagnosed with diabetes. Increased cardiovascular risk as reflected by increased hsCRP, ICAM and MMP-9 values was observed in diabetes patients. A higher cardiovascular biomarkers risk profile was seen in the IGT/IFG cohort. CONCLUSIONS: This study confirms the observation that one third of patients of a cardiologic care unit suffer from impaired glucose regulation. Furthermore, the cardiology patients with previously unknown glucose homeostasis abnormalities had a higher prevalence of macrovacular disease and an impaired biomarker risk profile. This study underlines the importance of joint treatment efforts by cardiologists in concert with diabetologists for treatment of this patient group at high risk for cardiovascular events.

Time-action profile and patient assessment of inhaled insulin via the Exubera device in comparison with subcutaneously injected insulin aspart via the FlexPen device.

BACKGROUND: The goal of our investigation was to compare the pharmacokinetics/pharmacodynamics properties of and patient preference for insulin aspart applied with the FlexPen (Novo Nordisk, Bagsvaerd, Denmark) (IAFP) with pulmonary human insulin applied with the Exubera (Pfizer, New York, NY) device (HIEX). METHODS: Twelve patients with diabetes (six with type 1 and six with type 2; eight men, four women; age, 54.5 +/- 11.0 years; duration of diabetes, 16.5 +/- 10.6 years; hemoglobin A1c, 7.5 +/- 0.7%; body mass index, 29.5 +/- 7.2 kg/m(2); mean +/- SD) participated in an open-label, randomized, euglycemic clamp study. The patients received 11 units of IAFP or a dose-equivalent of (3 + 1 mg) insulin from HIEX in a randomized sequence on two different study days. Insulin plasma levels and the required glucose infusion rate (GIR) were monitored for a time period of 6 h. In addition, the patients' individual ratings from 1 (excellent) to 5 (poor) regarding several different handling items were assessed using a questionnaire. RESULTS: No significant difference in the pharmacokinetics/pharmacodynamics parameters could be observed between IAFP and HIEX within the first 120 min. In the second part of the clamp procedure, plasma insulin levels (area under the curve versus time [AUC]) and the GIR was significantly higher after HIEX compared with IAFP (insulin AUC(120-360), 66,232 +/- 4,521 vs. 48,852 +/- 2,999 pmol/L, P < 0.05; GIR AUC(120-360), 8,928 +/- 1,334 vs. 6,805 +/- 1,655 mg/kg/min). A superior patient judgment was obtained for the FlexPen with regard to trust in insulin delivery (2.3 +/- 1.1 vs. 2.8 +/- 1.0), trust in correct insulin dosing (1.8 +/- 1.1 vs. 2.6 +/- 0.9), size (2.3 +/- 1.1 vs. 3.6 +/- 0.9), and appearance of the device (2.4 +/- 1.0 vs. 3.8 +/- 0.9) (P < 0.05, respectively). CONCLUSIONS: Insulin treatment with HIEX was found to have pharmacokinetics/pharmacodynamics properties comparable to IAFP. Both insulin administration technologies were overall evaluated positive, but most patients preferred IAFP.

Competact, a fixed combination of pioglitazone and metformin, improves metabolic markers in type 2 diabetes patients with insufficient glycemic control by metformin alone--results from a post-marketing surveillance trial under daily routine conditions.

BACKGROUND: In patients with type 2 diabetes, glycemic control to target goals can only be achieved for a while by single-drug treatment. Antidiabetes therapy has to be adapted according to the individual course of the disease. This trial investigates the impact of Competact (Takeda Pharma, Aachen, Germany) (marketed as ActoplusMet in the United States)-a fixed combination of 850 mg of metformin with 15 mg of pioglitazone-for diabetes treatment in patients with insufficient glycemic control by metformin alone. STUDY DESIGN: This observational drug monitoring trial was performed at 1,480 study sites in Germany, and 4,866 complete patient data sets were included into the final analyses. Mean +/- SD age was 60.8 +/- 9.6 years (2,171 women, 2,691 men; disease duration, 6.7 +/- 4.7 years; body mass index [BMI], 31.0 +/- 5.2 kg/m(2)). In total, 43.8% of the patients received lipid-lowering drugs (antihypertensive medication, 74.3%). Main inclusion criteria were type 2 diabetes, metformin monotherapy, and an initial hemoglobin A1c (HbA1c) value between 6.6% and 9.9%. Parameters of glycemic control (HbA1c, fasting blood glucose [FBG]), blood pressure (BP), inflammation (high-sensitivity C-reactive protein [hsCRP]), and lipid metabolism (total cholesterol, high-density lipoprotein [HDL]-cholesterol, non-HDL-cholesterol, and triglycerides) were collected at baseline and after 4 months. RESULTS: All investigated parameters improved significantly (all P < 0.001) after 4 months of therapy with Competact (baseline vs. end point: systolic BP, 139.7 +/- 15.1 vs. 134.4 +/- 12.0 mm Hg; diastolic BP, 83.1 +/- 8.9 vs. 80.5 +/- 7.5 mm Hg; HbA1c, 7.8 +/- 1.0% vs. 7.0 +/- 0.8%; FBG, 9.0 +/- 2.6 vs. 7.0 +/- 1.7 mM; cholesterol, 5.7 +/- 1.1 mM vs. 5.3 +/- 0.9 mM; HDL-cholesterol, 1.2 +/- 0.4 mM vs. 1.3 +/- 0.4 mM; non-HDL-cholesterol, 4.5 +/- 1.2 mM vs. 4.0 +/- 0.9 mM; triglycerides, 2.5 +/- 1.0 mM vs. 2.1 +/- 0.8 mM; hsCRP, 3.2 +/- 2.6 mg/L vs. 2.7 +/- 2.3 mg/L). It is noteworthy that the BMI was not affected by Competact (31.0 +/- 5.2 kg/m(2) vs. 31.1 +/- 6.1 kg/m(2), P = 0.221). CONCLUSIONS: These observational results, obtained from a non-selected patient population under daily routine conditions, show the beneficial effects of a pioglitazone/metformin combination for diabetes patients with insufficient glycemic control under daily routine conditions.

Combined pioglitazone and metformin treatment maintains the beneficial effect of short-term insulin infusion in patients with type 2 diabetes: results from a pilot study.

BACKGROUND: The aim of our study was to examine the efficacy of short-term intravenous insulin intervention followed by oral pioglitazone/metformin therapy to prevent patients from continuous insulin application. METHODS: This prospective, open-label, 4-month pilot study comprised of 14 diabetes patients (5 female, 9 male; age 60 +/- 2 years; body mass index 29 +/- 3.2 kg/m(2); hemoglobin A1c [HbA1c] 7.6 +/- 1.1%) with (1) insufficient glycemic control under a dose of metformin >or=1700 mg/day and/or metformin plus additional oral antidiabetes drugs (OADs) and (2) appropriate residual beta-cell function. Initially, an inpatient 34 h continuous intravenous insulin infusion was performed, and metformin was given (2x 850 mg/day). Insulin was stopped, and pioglitazone 30 mg/day was added at the second inpatient day. Patients were followed for four months. Efficacy parameters [change of HbA1c, fasting blood glucose [FBG], intact proinsulin, adiponectin, and high-sensitivity C-reactive protein (hsCRP)] were assessed after initial normalization of blood glucose values by intravenous insulin and at the study end point. RESULTS: During the acute insulin intervention, FBG levels were stabilized in all study subjects. In the following OAD treatment period, five patients showed an improvement of HbA1c > 0.5% [35.7%; seven patients remained stable (50.0%), two patients were nonresponders (14.3%)]. Fasting glucose values dropped after insulin infusion (-17.7%; p < .001). This effect was maintained during the consecutive OAD treatment period (glucose +0.3%, not significant (NS); HbA1c -6.0%; p < .05). The initial decrease in fasting intact proinsulin levels was also maintained during the study (end value -41%, p < .05). Improvements in hsCRP values (postinsulin value, -15%, NS; end value -37%; p < .05) and adiponectin values (postinsulin value +15%, NS; end value +128%; p < .001) were demonstrated at end point only after continued glitazone intake. CONCLUSIONS: Our pilot study demonstrated that a beneficial effect of a short-term intravenous insulin application on glycemic control was effectively maintained by pioglitazone/metformin treatment for at least 4 months. In addition, the oral therapy significantly improved cardiovascular risk parameters.

The IRIS V study: pioglitazone improves systemic chronic inflammation in patients with type 2 diabetes under daily routine conditions.

BACKGROUND: The peroxisome proliferator-activated receptor-gamma agonist pioglitazone is established as a drug to treat patients with type 2 diabetes mellitus. In addition to lowering blood glucose levels, one of the favorable effects of pioglitazone is improvement of systemic chronic inflammation particularly affecting vessel walls. The effect can be monitored by the measurement of the biomarker C-reactive protein in the range of 0-10 mg/L (high-sensitivity C-reactive protein [hsCRP]). This observational trial was performed to evaluate the effects of pioglitazone on hsCRP values in a large population under daily life conditions. METHODS: A total of 1,170 subjects could be included into the final analysis (633 men, 537 women; age [mean +/- SD], 63.5 +/- 10.4 years, body mass index, 31.0 +/- 5.5 kg/m2; duration of diabetes, 6.9 +/- 8.1 years; glycosylated hemoglobin [HbA1c], 7.5 +/- 1.1%). All patients were glitazone-naive prior to study entry. The patients received pioglitazone alone or in combination with their previous treatment (acarbose, sulfonylurea drugs, and/or metformin). Patients were evaluated at baseline and after 10 +/- 2 weeks and 20 +/- 2 weeks of treatment. Observation parameters were fasting blood glucose, lipids, and blood pressure. The level of hsCRP was determined in a central laboratory at baseline and at end point. RESULTS: All markers showed a significant improvement at trial end point. A decrease of hsCRP (baseline 3.3 +/- 1.0 mg/L vs. end point 2.8 +/- 2.3 mg/L, P < 0.01), HbA1c (7.5 +/- 1.1% vs. 6.8 +/- 0.9%, P < 0.001), fasting blood glucose (8.7 +/- 2.6 mM vs. 7.2 +/- 2.1 mM, P < 0.001), low-density lipoproteins (3.3 +/- 1.0 mM vs. 3.2 +/- 0.9 mM, P < 0.001), and triglycerides (2.4 +/- 2.0 mM vs. 2.2 +/- 2.5 mM, P < 0.001) and an increase in high-density lipoproteins (1.3 +/- 0.4 mM vs. 1.4 +/- 0.4 mM, P < 0.001) was observed. Parallel to the metabolic improvement, both systolic and diastolic blood pressure values were reduced (141 +/- 17 mm Hg vs. 137 +/- 15 mm Hg and 83 +/- 9 mm Hg vs. 80 +/- 9 mm Hg, respectively; P < 0.001 in both cases). CONCLUSIONS: These observational results, obtained from a nonselected patient population under daily routine conditions, confirm the benefits of pioglitazone treatment on blood glucose, lipid metabolism, and blood pressure. The results show that pioglitazone treatment improves chronic vascular inflammation, which may be associated with reduced cardiovascular risk.

Effect of insulin glulisine on microvascular blood flow and endothelial function in the postprandial state.

OBJECTIVE: To investigate the effect of insulin glulisine on postprandial microvascular blood flow in type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 15 patients with type 2 diabetes received insulin glulisine or human insulin before a liquid meal test. Thereafter, skin microvascular blood flow was measured by laser Doppler fluxmetry and blood samples were taken for measurement of plasma levels of glucose, insulin, intact proinsulin, asymmetric dimethylarginine, nitrotyrosine, interleukin-18, matrix metalloproteinase-9, oxidized LDL, and free fatty acids. RESULTS: Insulin glulisine injections resulted in higher postprandial insulin levels (means +/- SEM area under the curve [AUC](0-120) 51.0 +/- 6.8 vs. 38.2 +/- 5.4 mU/l; P = 0.004), while plasma glucose (AUC(0-240) 158 +/- 9 vs. 180 +/- 9 mg/dl; P < 0.05) and intact proinsulin (AUC(0-240) 26.2 +/- 3.5 vs. 31.2 +/- 4.3 pmol/l; P = 0.002) were lower. Microvascular blood flow increased after insulin glulisine injection (27.9 +/- 3.1 to 51.7 +/- 9.9 arbitrary units [AU]; P < 0.05), while only a minor increase was found during human insulin (27.9 +/- 3.1 to 34.4 +/- 7.8 AU; not significant). Asymmetric dimethylarginine and nitrotyrosine levels were reduced after insulin glulisine (P < 0.05). CONCLUSIONS: Insulin glulisine is superior to human insulin in restoring postprandial metabolic and microvascular physiology.

Pioglitazone improves metabolic markers in patients with type 2 diabetes independently from physical activities: results from the IRIS III study.

AIM: Pioglitazone is an established peroxisome proliferator-activated receptor gamma agonist for the treatment of insulin resistance in patients with type 2 diabetes mellitus. This analysis of the observational IRIS III study was performed to evaluate the effects of pioglitazone treatment in relation to the degree of physical exercise activities in a large patient population under daily life conditions. METHODS: A total of 1298 patients out of 2092 enrolled into the IRIS III study who had provided information about their exercise level could be included in the final analysis (622 female, 676 male; age: 63.1 +/- 10.4 years, diabetes duration: 6.6 +/- 5.0 years, mean +/- SD). All patients were glitazone naïve prior to study entry. They received pioglitazone in addition to their previous oral antidiabetic treatment. The patients were stratified according to their physical activity level (never, sometimes, and regularly). Data were evaluated at baseline and after 20 +/- 2 weeks of treatment. Observation parameters were fasting blood glucose, lipids, and blood pressure. Hemoglobin A1c (HbA1c) was determined in a central laboratory, and insulin sensitivity was assessed by the IRIS II score. RESULTS: Glycemic control, blood pressure, and the lipid profile improved independently from the degree of physical activity (e.g., no exercise vs frequent exercise: DeltaHbA1c: -0.89 +/- 1.2% vs -0.72 +/- 1.1%, not significant). A positive impact of exercise on insulin resistance could be observed at baseline, which, however, was further decreased by pioglitazone treatment [IRIS II score (baseline/end point): no exercise vs frequent exercise: 74.0 +/- 15.9/62.5 +/- 20.2 vs 66.7 +/- 19.0/58.0 +/- 21.8, p < 0.001/not significant]. CONCLUSIONS: These observational results, obtained from a nonselected patient population under daily routine conditions, confirm that the benefits of pioglitazone treatment on glycemic control, lipid metabolism, and blood pressure are independent from physical activity. Exercise has a positive influence on insulin sensitivity, but pioglitazone shows additional favorable effects and is, therefore, recommended for use independently from the activity level of the patients.

Relaxin expression correlates significantly with serum fibrinogen variation in response to antidiabetic treatment in women with type 2 diabetes mellitus.

AIM: Diabetes is associated with aberrant coagulation. Relaxin, an insulin-like peptide hormone, is a candidate to be involved in the underlying molecular mechanisms. Therefore, the present study investigated the correlation of relaxin expression with fibrinogen levels in diabetes patients undergoing oral antidiabetic treatment. METHOD: In total, 192 type 2 diabetes patients were enrolled into the study. The patients were randomized to receive either pioglitazone or glimepiride for 26 weeks. Blood was drawn at baseline and at the end of the study to measure the concentrations of relaxin and fibrinogen with an enzyme-linked immunosorbent assay and a turbimetric method, respectively. In addition, platelets were counted at both time points. RESULTS: Total datasets were available from 161 patients (age 62.5 +/- 8.1 years, mean +/- standard deviation; 58 women, 103 men). The median initial parameter concentrations were: relaxin, 27.4 pg/ml (range 0.4 - 380 pg/ml); fibrinogen, 3.0 g/l (range 1.1 - 7.9 g/l); platelets, 217,000/microl (range 51,000 - 547 000/microl). The data were analyzed according to the increase or decrease of each parameter after therapy compared with baseline. There was a significant correlation of relaxin variation with fibrinogen variation, seen particularly in the female subgroup (p < 0.05). The correlation was independent of the antidiabetic medication. CONCLUSION: The data suggest that there is a correlation between fibrinogen levels and relaxin expression. Relaxin may exert its cardioprotective properties after pathologic fibrinogen increase. This regulation may be affected by diabetes. As a consequence, cardiovascular risk may increase in women with aberrant relaxin functionality.

Relaxin expression correlates significantly with serum changes in VEGF in response to antidiabetic treatment in male patients with type 2 diabetes mellitus.

Recent studies indicate that relaxin as well as VEGF possess cardioprotective properties. This study aimed to determine the association of relaxin with VEGF in patients with type 2 diabetes. We therefore analyzed samples from a recent study showing the benefits of anti-diabetic treatment on cardiovascular risk markers independently from glycemic control. VEGF, relaxin and markers of endothelial dysfunction, s-ICAM-1 and s-VCAM-1, were compared after 26 +/- 2 weeks of antidiabetic treatment with pioglitazone or glimepiride with their base line values. A total of 151 data sets (patients age, 62.7 +/- 8.1 years, diabetes duration, 6.8 +/- 6.6 years, 57 women, 94 men) were available for the analysis. Baseline values were in median, relaxin: 27.4 pg/mL 125% quartile 15.8; 75% quartile: 45.21, s-ICAM-1: 294 ng/mL [25% quartile: 260; 75% quartile: 331], s-VCAM-1: 677 ng/mL [25% quartile: 589; 75% quartile 871], VEGF: 350 pg/mL [25% quartile: 251; 75% quartile: 514]. Parameter variation after therapy showed a significant correlation of relaxin expression with VEGF expression (p = 0.02) in the entire study group. The correlation was seen in the subgroup of male patients (p < 0.01) but did not reach significance in the female patients (p = 0.71). No further correlation was observed analyzing the other investigated parameters. Our data suggest that relaxin may exert its cardioprotective action possibly via VEGF increase, particularly in men. In women, other pathways may superimpose this effect. In conclusion, our study supports the hypothesis of different regulating pathways and effects of relaxin in men and women also in patients with type 2 diabetes.