Cloth Hohberg

Pilot Study for Assessment of Optimal Frequency for Changing Catheters in Insulin Pump Therapy—Trouble Starts on Day 3

Background: Continuous subcutaneous insulin infusion (CSII) by means of insulin pump devices is considered to be one of the most optimal therapies to achieve treatment targets in patients with diabetes mellitus. In CSII, the insulin is delivered through Teflon catheters or steel needle infusion sets, which need to be renewed on a regular basis. This pilot study was performed to investigate the optimal change frequency in daily practice and to explore potential problems that may occur when the sets are used for a more prolonged time than the recommended up to 72 hours of usage (Teflon catheters). Method: Twelve patients with type 1 diabetes participated in the trial [age (mean ± STD): 40.3 ± 12.6 years, body mass index: 26.2 ± 3.3 kg/m2, hemoglobin A1c: 6.7 ± 0.6%]. They were asked to wear their infusion set (Comfort™ or Silhouette®) for increasing periods of 1, 2, 3, 4, and 5 days. After each use, patients completed standardized questionnaires regarding technical and medical issues associated with infusion set use. A health care professional investigated the infusion sites and infusion sets and completed an “infusion set inspection” questionnaire. Blood glucose was measured and recorded to assess a potential Influence of duration of catheter use on glycemic control. Results: Infusion set and injection site problems (itching, bruising, swelling, and pain) started to occur in measurable amounts on the 3rd day of catheter use, and about 40% of patients reported significant issues when using a catheter for 5 days. In parallel, there was a consistent increase in mean daily blood glucose levels that correlated with the number of days of catheter use (e.g., day 1: 7. 5 ± 3.8 mmol/liter, day 3: 8.4 ± 4.2 mmol/liter, day 5: 9.0 ± 4.0 mmol/liter, day 7: 11.6 ± 2.2 mmol/liter, p < 0.05 vs day 1). Conclusions: Using the catheters for 2 days resulted in a safe and well-tolerated therapy. Clinically relevant adverse events started to occur during the 3rd day and their incidence increased constantly with longer use. This was associated with undesired changes in mean glycemic control. Data support the recommendation by the drug and device manufacturers that insulin pump catheters should only be used for 48–72 hours to avoid adverse events and potential metabolic deterioration.

Reliability of lightguide spectrophotometry (O2C) for the investigation of skin tissue microvascular blood flow and tissue oxygen supply in diabetic and nondiabetic subjects.

Background and Aims: Skin microvascular assessment has progressed to an important evaluation in patients with diabetes mellitus. This study was done to evaluate a new device using micro-lightguide spectrophotometry in the assessment of skin microvascular function. Material and Methods: Twenty nondiabetic subjects (age 46.6 ± 14.8 years; mean ± SD) and 20 diabetic patients (age 59.4 ± 8.4 years) participated in repeated microvascular measurements using micro-lightguide spectrophotometry. This technique allows simultaneous, noninvasive measurement of microvascular blood flow and hemoglobin oxygenation (SO2) at the same anatomical area in different tissue layers. A skin probe was placed on nonhairy skin at the thenar eminence of the left hand for the measurement of SO2, and the postischemic reactive hyperemia response (PRH) was measured in skin and underlying muscle tissue. Results: Repeated measurements in PRH revealed a good correlation at the superficial skin layer (r = 0.97, p < 0.0001) with a coefficient of variation at 9.2 ± 1.7% and at the superficial muscle layer (r = 0.80, p < 0.0002) with a coefficient of variation at 9.7 ± 1.5%. A slightly weaker correlation was observed for the SO2 measurement at the skin layer (r = 0.69 ± p < 0.0001) with a coefficient of variation at 17.5 ± 3.8% and at the muscle layer (r = 0.48; p = 0.0016) with a coefficient of variation at 18.1 ± 10.5%. Conclusions: Lightguide spectrophotometry is an easy, noninvasive, and reliable method for simultaneous measurement of superficial microvascular blood flow by laser Doppler fluxmetry and skin oxygenation by spectrophotometry. Further studies are required to clarify the validity of these measures in special patient populations such as diabetes mellitus with specified microvascular complications.

Postprandial Vascular Effects of VIAject Compared With Insulin Lispro and Regular Human Insulin in Patients With Type 2 Diabetes

OBJECTIVE Recent studies suggested an impact of prandial insulin delivery on postprandial regulation of tissue blood flow. This study compared the effect of VIAject with human regular insulin and insulin lispro on postprandial oxidative stress and endothelial function in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Fourteen patients (seven men; aged 61.5 ± 1.8 years; duration of diabetes 6.6 ± 4.6 years; A1C 7.2 ± 0.5% [mean ± SEM]) received a prandial injection of VIAject, human regular insulin, and insulin lispro. At baseline and after a standardized liquid meal test (Ensure Plus), the postprandial increases in asymmetric dimethylarginine (ADMA) and nitrotyrosine levels were investigated. In addition, the postprandial effects on microvascular blood flow, skin oxygenation, and vascular elasticity were measured. RESULTS Treatment with VIAject resulted in a significant reduction in the peak postprandial generation of ADMA compared with human insulin and insulin lispro (VIAject −27.3 ± 22.6, human insulin 97.7 ± 24.4, and insulin lispro 66.9 ± 33.9 nmol/l; P < 0.05, respectively). The postprandial increases in nitrotyrosine levels were significantly less after VIAject than after human regular insulin (VIAject −0.22 ± 0.17 vs. human insulin 0.25 ± 0.15 μg/ml; P < 0.05), whereas nitrotyrosine after insulin lispro was in between (insulin lispro 0.09 ± 0.07 μg/ml; NS). In parallel, earlier and more pronounced increases in microvascular blood flow and skin oxygenation were obtained after VIAject compared with those after human insulin or insulin lispro (P < 0.05, respectively). All insulin formulations resulted in comparable improvements in central arterial elasticity. CONCLUSIONS Treatment with VIAject reduced postprandial oxidative stress and improved endothelial function compared with human regular insulin or insulin lispro.

Intuitiveness, instruction time, and patient acceptance of a prefilled insulin delivery device and a reusable insulin delivery device in a randomized, open-label, crossover handling Study in patients with type 2 diabetes

BACKGROUNDnBecause the use of insulin therapy can place a substantial burden on patients with diabetes, insulin administration should be as simple as possible.nnnOBJECTIVESnThe primary aim of this trial was to compare the use of 2 insulin delivery devices-one prefilled (NovoMix 30 FlexPen [FP]; Novo Nordisk, Copenhagen, Denmark) and the other reusable (HumaPen Luxura [HL]; Eli Lilly and Company, Indianapolis, Indiana)-in patients with type 2 diabetes in terms of intuitiveness and training time. A secondary aim was to evaluate the ease of use and overall acceptance of the 2 devices.nnnMETHODSnThis was a randomized, open-label, comparative, crossover handling study in adult patients with type 2 diabetes who had been treated with oral antidiabetic drugs for >or=2 years and had no previous experience with insulin injection devices. Patients were randomly allocated to the intuitiveness group (no instruction in the use of the devices provided) or the instruction group (instruction provided). The time taken to deliver an injection into a cushion was measured for each device in both groups. Patients answered questionnaires concerning the intuitiveness and ease of use of the 2 devices, their trust and confidence in the devices to deliver the insulin dose, and their overall pen preference.nnnRESULTSnSixty-one patients were enrolled in the study (70.5% male; mean [SD] age, 61.80 [7.60] years), 30 in the intuitiveness group and 31 in the instruction group. When all handling steps for the HL device were included, the mean (SD) injection time was significantly shorter for the FP device compared with the HL device in the intuitiveness group (1.21 [1.04] vs 1.74 [0.79] minutes, respectively; P = 0.035). The outcome was similar in the instruction group (0.71 [0.29] vs 1.09 [0.49] minutes; P < 0.001). When the time for cartridge insertion in the HL device was excluded, there was no significant difference in injection time for the respective devices in either group (intuitiveness group: 1.21 [1.04] and 1.07 [0.91] minutes; instruction group: 0.63 [0.35] and 0.71 [0.29] minutes). Twenty-two patients preferred the FP device in terms of ease of learning, compared with 8 patients preferring the HL device (P = 0.007).nnnCONCLUSIONSnIn this study, when all handling steps were included, the FP device was associated with significantly greater intuitiveness and a shorter injection time compared with the HL device. Further research is needed to determine whether these differences between devices are clinically meaningful.

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/m2). 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.

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/μl (range 51 000 – 547 000/μl). 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.

Limitations of the HOMA-B Score for Assessment of β-Cell Functionality in Interventional Trials—Results from the PIOglim study

BACKGROUNDnDrugs with unspecific stimulating effects on beta-cell secretion increase the homeostasis model assessment (HOMA)-B score, indicating improved beta-cell function. We investigated whether the beta-cell protection provided by adding pioglitazone (PIO) to glimepiride (GLIM) in comparison to up-titrating the GLIM dose alone is reflected by appropriate changes in several measures of beta-cell function, including HOMA-B score.nnnMETHODSnThis double-blind, parallel prospective 6-month study was performed with 82 patients (47 men, 35 women; age, 61 +/- 9 years; duration of disease, 5.3 +/- 4.4 years; body mass index, 32.6 +/- 6.0 kg/m(2); hemoglobin A1c [HbA1c], 7.3 +/- 0.7%) with GLIM monotherapy (1-3 mg). They were randomized to receive a GLIM + PIO combination with up-titration (2 mg + 30 mg/4 mg + 30 mg/4 mg + 4 mg) or to remain on GLIM (up-titration 4/5/6 mg). Observation parameters determined at baseline and end point included HOMA-B, HOMA-IR, HbA1c, glucose, insulin, and intact proinsulin.nnnRESULTSnThere was a slight increase in the HOMA-B score in the GLIM group but not in the GLIM + PIO arm (baseline/end point: for GLIM, 71 +/- 48/88 +/- 64; for PIO + GLIM, 74 +/- 56/69 +/- 52). Improvements in the other observation parameters were predominantly detected in the PIO + GLIM group (HbA1c, 7.20 +/- 0.61%/6.36 +/- 0.90%; HOMA-IR, 7.0 +/- 4.5/4.1 +/- 2.1; intact proinsulin, 12.4 +/- 10.3/7.6 +/- 4.8 pmol/L [all P < 0.05 vs. baseline]) compared with the GLIM group (HbA1c, 7.45 +/- 0.69%/7.15 +/- 0.97% [P < 0.05]; HOMA-IR, 7.4 +/- 4.5/7.5 +/- 4.3 [not significant]; intact proinsulin, 17.3 +/- 21.6/16.3 +/- 15.5 pmol/L [not significant]).nnnCONCLUSIONSnThe PIO + GLIM combination led to overall improvement of laboratory biomarkers for beta-cell function, except for HOMA-B. Glimepiride up-titration had no such effects but increased the HOMA-B score. HOMA-B seems to provide misleading results when used as a diagnostic tool in patients treated with sulfonylurea drugs. A corrective term for consideration of proinsulin in the HOMA-B equation may address this limitation.

Time–Action Profile and Patient Assessment of Inhaled Insulin via the Exubera Device in Comparison with Subcutaneously Injected Insulin Aspart via the FlexPen Device

BACKGROUNDnThe 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).nnnMETHODSnTwelve 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.nnnRESULTSnNo 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).nnnCONCLUSIONSnInsulin 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.

Pioglitazone in addition to metformin improves erythrocyte deformability in patients with Type 2 diabetes mellitus

The aim of the present study was to compare the effect of PIO (pioglitazone) or GLIM (glimepiride) on erythrocyte deformability in T2DM (Type 2 diabetes mellitus). The study covered 23 metformin-treated T2DM patients with an HbA1c (glycated haemoglobin) >6.5%. Patients were randomized to receive either PIO (15 mg, twice a day) or GLIM (1 mg, twice a day) in combination with metformin (850 mg, twice a day) for 6 months. Blood samples were taken for the measurement of fasting glucose, HbA1c, fasting insulin, intact proinsulin, adiponectin and Hct (haematocrit). In addition, the erythrocyte EI (elongation index) was measured using laser diffractoscopy. Both treatments significantly improved HbA1c levels (PIO, -0.9+/-1.1%; GLIM, -0.6+/-0.4%; both P<0.05) and resulted in comparable HbA1c levels after 6 months (PIO, 6.5+/-1.2%; GLIM, 6.2+/-0.4%) Treatment with PIO reduced fasting insulin levels (-8.7+/-15.8 milli-units/l; P=0.098), intact proinsulin levels (-11.8+/-9.5 pmol/l; P<0.05) and Hct (-1.3+/-2.3%; P=0.09), whereas adiponectin levels increased (8.2+/-4.9 microg/ml; P<0.05). No significant change in these parameters was observed during GLIM treatment. PIO improved the EI, resulting in a significant increase in EI at all physiological shear stress ranges (0.6-6.0 Pa; P<0.05). The improvement in EI correlated with the increase in adiponectin levels (r=0.74; P<0.001), and inversely with intact proinsulin levels (r=-0.47; P<0.05). This is the first study showing an improvement in EI during treatment with PIO, which was associated with an increase in adiponectin and a decrease in intact proinsulin levels, but independent of glycaemic control.

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/m2; hemoglobin A1c [HbAlc] 7.6 ± 1.1%) with (1) insufficient glycemic control under a dose of metformin >1700 mg/day and/or metformin plus additional oral antidiabetes drugs (OADs) and (2) appropriate residual β-cell function. Initially, an inpatient 34 h continuous intravenous insulin infusion was performed, and metformin was given (2× 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.