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Heise T.,Profil Institute For Stoffwechselforschung | Tack C.J.,Radboud University Nijmegen | Cuddihy R.,International Diabetes Center | Davidson J.,University of Texas at Dallas | And 6 more authors.
Diabetes Care | Year: 2011

OBJECTIVE - Insulin degludec/insulin aspart (IDegAsp) is a soluble coformulation of the novel basal analog insulin degludec (IDeg: 70%) and insulin aspart (IAsp: 30%). We compared the safety and efficacy of IDegAsp, an alternative formulation (AF) (55%IDeg and 45% IAsp), and insulin glargine (IGlar) in insulin-naïve subjects with type 2 diabetes inadequately controlled with oral antidiabetic drugs. RESEARCH DESIGN AND METHODS - In this 16-week, open-label trial, subjects (mean age 59.1 years, A1C 8.5%, BMI 30.3 kg/m 2) were randomized to once-daily IDegAsp (n = 59), AF (n = 59), or IGlar (n = 60), all in combination with metformin. Insulin was administered before the evening meal and dose-titrated to a fasting plasma glucose (FPG) target of 4.0-6.0 mmol/L. RESULTS - After 16 weeks, mean A1C decreased in all groups to comparable levels (IDegAsp: 7.0%; AF: 7.2%; IGlar: 7.1%). A similar proportion of subjects achieved A1C <7.0% without confirmed hypoglycemia in the last 4 weeks of treatment (IDegAsp: 51%; AF: 47%; IGlar: 50%). Mean 2-h postdinner plasma glucose increase was lower for IDegAsp (0.13 mmol/L) and AF (0.24mmol/L) than IGlar (1.63 mmol/L), whereasmean FPG was similar (IDegAsp: 6.8mmol/L; AF: 7.4 mmol/L; IGlar: 7.0 mmol/L). Hypoglycemia rates were lower for IDegAsp and IGlar than AF (1.2, 0.7, and 2.4 events/patient year). Nocturnal hypoglycemic events occurred rarely for IDegAsp (1 event) and IGlar (3 events) compared with AF (27 events). CONCLUSIONS - In this proof-of-concept trial, once-daily IDegAsp was safe, well tolerated, and provided comparable overall glycemic control to IGlar at similar low rates of hypoglycemia, but better postdinner plasma glucose control. © 2011 by the American Diabetes Association.


Kruczek C.,University Clinic of Dusseldorf | Gorg B.,University Clinic of Dusseldorf | Keitel V.,University Clinic of Dusseldorf | Bidmon H.J.,Heinrich Heine University Düsseldorf | And 3 more authors.
Biological Chemistry | Year: 2011

Ammonia is a major player in the pathogenesis of hepatic encephalopathy (HE) and affects astrocyte function by triggering a self-amplifying cycle between osmotic and oxidative stress. We recently demonstrated that hypoosmotic astrocyte swelling rapidly stimulates nitric oxide (NO) production and increases intracellular free Zn 2+ concentration ([Zn 2+] i). Here we report effects of ammonia on [Zn 2+] i homeostasis and NO synthesis. In cultured rat astrocytes, NH 4Cl (5 mm) increased within 6 h both cytosolic and mitochondrial [Zn 2+]. The [Zn 2+] i increase was transient and was mimicked by the nonmetabolizable CH 3NH 3Cl, and it was dependent on NO formation, as evidenced by the sensitivity toward the nitric oxide synthase inhibitor N G-monomethyl-l-arginine. The NH 4Cl-induced NO formation was sensitive to the Ca 2+ chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl) ester and increases in both NO and [Zn 2+] i were blocked by the N-methyl-d-aspartate receptor antagonist MK-801. The NH 4Cl-triggered increase in [Zn 2+] i was followed by a Zn 2+-dependent nuclear appearance of the metal response element-binding transcription factor and metallothionein messenger RNA (mRNA) induction. Metallothionein mRNA was also increased in vivo in rat cerebral cortex 6 h after an NH 4Ac challenge. NH 4Cl increased peripheral-type benzodiazepine receptor (PBR) protein expression, whereas PBR mRNA levels were decreased in a Zn 2+-independent manner. The Zn 2+-dependent upregulation of metallothionein following ammonia intoxication may reflect a cytoprotective response, whereas the increase in PBR expression may augment HE development. © 2011 by Walter de Gruyter Berlin Boston 2011.


Arnolds S.,Profil Institute For Stoffwechselforschung | Dellweg S.,Profil Institute For Stoffwechselforschung | Clair J.,Profil Institute For Stoffwechselforschung | Dain M.-P.,Sanofi S.A. | And 3 more authors.
Diabetes Care | Year: 2010

OBJECTIVE - To assess the effect of a 4-week adjunctive therapy of exenatide (EXE) (5-10 μg b.i.d.) or sitagliptin (SITA) (100mgonce daily) in response to a standardized breakfast meal challenge in 48 men or women with type 2 diabetes receiving insulin glargine (GLAR) + metformin (MET). RESEARCH DESIGN AND METHODS - This was a single-center, randomized, open-label, active comparator-controlled study with a three-arm parallel group design, consisting of: screening, 4- to 8-week run-in period, 4-week treatment period, and follow-up. In all three groups, the GLAR dose was titrated according to an algorithm (fasting blood glucose ≤100 mg/dl). RESULTS - The unadjusted 6-h postprandial blood glucose excursion of both GLAR + MET + EXE and GLAR + MET + SITA was statistically significantly smaller than that of GLAR + MET (606 ± 104 vs. 612 ± 133 vs. 728 ± 132 mg/dl/h; P = 0.0036 and 0.0008). A1C significantly decreased in all three groups (P < 0.0001), with the greatest reduction of -1.9 ± 0.7 under GLAR + MET + EXE (GLAR + MET + SITA -1.5 + 0.7; GLAR + MET -1.2 ± 0.5%-points; GLAR + MET + EXE vs. GLAR + MET P = 0.0154). The American Diabetes Association A1C target of <7.0% was reached by 80.0, 87.5, and 62.5% of subjects, respectively. GLAR + MET + EXE had the highest number (47) of adverse events, mostly gastrointestinal (56%) with one dropout. GLAR + MET or GLAR + MET + SITA only had 10 and 12 adverse events, respectively, and no dropouts. Hypoglycemia (blood glucose 50 mg/dl) rates were low and comparable among groups. Weight decreased with GLAR + MET + EXE (-0.9 ± 1.7 kg; P = 0.0396) and increased slightly with GLAR + MET (0.4 ± 1.5 kg; NS; GLAR + MET + EXE vs. GLAR + MET P = 0.0377). CONCLUSIONS - EXE or SITA added to GLAR + MET further substantially reduced postprandial blood glucose excursions. Longer-term studies in a larger population are warranted to confirm these findings. © 2010 by the American Diabetes Association.


Heinemann L.,Profil Institute For Stoffwechselforschung | Nosek L.,Profil Institute For Stoffwechselforschung | Flacke F.,Biodel Inc. | Albus K.,Biodel Inc. | And 4 more authors.
Diabetes, Obesity and Metabolism | Year: 2012

Aims: VIAject® is a formulation of human insulin with a very fast onset of action. Previous studies used VIAject in a concentration of 25 U/ml and a pH of 4 [VIAject 25 (VJ25)]. Objective of this double blind, three-way crossover study was to compare the pharmacodynamic/pharmacokinetic properties of a novel formulation of VIAject with a concentration of 100 U/ml and a neutral pH [VIAject 7 (VJ7)] with VJ25 and insulin lispro (LIS). Methods: Forty-three patients with type 1 diabetes [aged 43 (21-65) years, BMI 24.1 (20-28) kg/m2 and HbA1c 7.5 (5.7-9.5) %] participated in this study. They received subcutaneous injections of 12 U of each insulin formulation under euglycaemic glucose clamp conditions. Results: VJ7 was bioequivalent to VJ25 [90% confidence interval (CI) of the ratios for total insulin AUCs and maximum insulin concentration (CINS max) was within 0.80-1.25]. VJ7 showed a faster absorption compared to LIS [time to CINS max 23 vs. 60 min; difference (CI) -30 (-35 to -23)] and faster onset of action [time to early half-maximal glucose infusion rate (GIR) 25 vs. 44 min; -18 (-26 to -10)], and a higher AUC of glucose infusion rate (AUCGIR) in the first 60 min after injection [176 vs. 107 mg/kg; ratio 1.65 (1.27 to 2.14)], contributing to a slightly higher value for AUCGIR 0-480[1263 vs. 1095 mg/kg; 1.15 (1.06 to 1.26)]. Maximum GIR was similar between VJ7 and LIS [6.1 vs.6.6 mg/kg/min; ratio 0.93 (0.86 to 1.01)], whereas the duration of action (tGIR50%-late) was longer with VJ7 [274 vs. 228 min; 50 (25 to 73)]. Conclusions: This formulation of VIAject is bioequivalent to the previously used formulation and has a faster absorption/onset of action than LIS. © 2011 Blackwell Publishing Ltd.


Bolli G.B.,University of Perugia | Dahmen R.,Sanofi S.A. | Hahn A.D.,Sanofi S.A. | Heise T.,Profil Institute For Stoffwechselforschung | And 3 more authors.
Diabetes Care | Year: 2012

OBJECTIVE - In vivo, after subcutaneous injection, insulin glargine (21A-Gly-31B-Arg-32B-Arg-human insulin) is enzymatically processed into 21A-Gly-human insulin (metabolite 1 [M1]). 21A-Gly-des-30B-Thr-human insulin (metabolite 2 [M2]) is also found. In vitro, glargine exhibits slightly higher affinity, whereas M1 and M2 exhibit lower affinity for IGF-1 receptor, as well as mitogenic properties, versus human insulin. The aim of the study was to quantitate plasma concentrations of glargine, M1, and M2 after subcutaneous injection of glargine in male type 1 diabetic subjects. RESEARCH DESIGN AND METHODS - Glargine, M1, and M2 were determined in blood samples obtained from 12, 11, and 11 type 1 diabetic subjects who received single subcutaneous doses of 0.3, 0.6, or 1.2 units · kg-1 glargine in a euglycemic clamp study. Glargine, M1, and M2 were extracted using immunoaffinity columns and quantified by a specific liquid chromatography-tandem mass spectrometry assay. Lower limit of quantification was 0.2 ng · mL-1(33 pmol · L-1) per analyte. RESULTS - Plasma M1 concentration increased with increasing dose; geometric mean (percent coefficient of variation) M1-area under the curve between time of dosing and 30 h after dosing (AUC0-30h)was 1,261 (66), 2,867 (35), and 4,693 (22) pmol · h · L-1 at doses of 0.3, 0.6, and 1.2 units · kg -1, respectively, and correlated with metabolic effect assessed as pharmacodynamics-AUC0-30h of the glucose infusion rate following glargine administration (r = 0.74; P < 0.01). Glargine and M2 were detectable in only one-third of subjects and at a few time points. CONCLUSIONS - After subcutaneous injection of glargine in male subjects with type 1 diabetes, exposure to glargine ismarginal, if any, even at supratherapeutic doses. Glargine is rapidly and nearly completely processed to M1 (21 A-Gly-human insulin), which mediates the metabolic effect of injected glargine. © 2012 by the American Diabetes Association.


Vora J.,University of Liverpool | Heise T.,Profil Institute For Stoffwechselforschung
Diabetes, Obesity and Metabolism | Year: 2013

Lowering blood glucose with insulin therapy towards beneficial target levels while also avoiding hypoglycaemia is a challenging task. An important confounding factor, which might be under-appreciated in this scenario, is that of variable glucose readings causing difficulties with dose adjustment. Furthermore, this glucose variability is, to some extent, a reflection of variability in the glucose-lowering action of the insulin therapy itself. Not only is glucose variability a major confounding factor in disease management but it is possibly also of direct prognostic consequence and is increasingly recognized as an informative measurement in diabetes management. The scope for insulin-induced glucose variability is particularly great with basal insulins because of their prolonged absorption from high-dose depots. Pharmacodynamic (PD) variability manifests as both fluctuations in the level of glucose-lowering effect over time, and as inconsistencies in the response from one injection to another. Well-controlled pharmacokinetic (PK)/PD studies using repeated isoglycaemic clamp methodology clearly how that many injected basal insulin products have high variable absorption with correspondingly variable action. Incomplete resuspension and precipitation appear to be important issues with regard to unpredictability in this action, while an inadequate duration of action relative to the dosing interval results in a fluctuating action profile. There are some ultra-long-acting basal insulins with novel protraction mechanisms currently in clinical development for which clamp studies show markedly improved PK/PD profiles. © 2013 Blackwell Publishing Ltd.


Heise T.,Profil Institute For Stoffwechselforschung | Mathieu C.,Catholic University of Leuven | Hey-Hadavi J.,Pfizer | Strack T.,Pfizer | Lawrence D.,Pfizer
Diabetes Technology and Therapeutics | Year: 2010

Objective: This study was designed to compare glycemic control (glycated hemoglobin [A1C] level) with either once-daily basal insulin (BI) (insulin glargine) or preprandial insulin (PPI) (Exubera® [insulin human (recombinant DNA origin)] inhalation powder, Pfizer Inc., New York, NY) in patients with type 2 diabetes mellitus (T2DM) poorly controlled on at least two oral antidiabetes agents (OADs). Methods: This was a 26-week, open-label, parallel-group, randomized study where 257 patients (mean A1C 8.6%) on OAD treatment for ≥3 months were treated with either BI (n = 122) or PPI (n = 135). Based on self-monitored blood glucose levels, PPI dose was adjusted before each major meal, whereas BI dose was titrated in the morning or before bedtime. Prestudy OADs were continued, but doses could be modified. Results: At 26 weeks, change from baseline in A1C was greater with PPI (-1.7 vs. -1.4%, P = 0.0389). Numerically, more patients achieved A1C <6.5% (28% vs. 19%) and A1C <7.0% (63% vs. 55%) with PPI compared with BI. PPI had lower postmeal glucose increments, but higher prebreakfast glucose and weight gain (1.1kg), than BI. Mild or moderate hypoglycemic events were more frequent with PPI (6.2 vs. 2.9 events/months), but nocturnal hypoglycemic events were less frequent (22% vs. 30%). Conclusions: PPI improved postprandial glucose and A1C levels significantly more than BI. More patients achieved A1C targets with PPI, at the expense of more hypoglycemia and body weight gain. These results illustrate the potential benefits and detriments of prandial insulin supplementation in patients with T2DM poorly controlled on OADs alone. Copyright 2010, Mary Ann Liebert, Inc.


Heinemann L.,Profil Institute For Stoffwechselforschung
IFAC Proceedings Volumes (IFAC-PapersOnline) | Year: 2012

The development of an artificial pancreas (AP) has made huge steps forward in the last 3 to 5 years and a large number of activities are going on in this area of research. Until now most AP systems under development were tested under highly controlled conditions only. The aim of our project, funded by the European Union, is to develop an AP system to such a level, that it can be studied under daily life conditions at the home of patients with diabetes (hence AP@home). Based on a Sc-Sc Closed-Loop strategy (= glucose sensing and insulin infusion in the subcutaneous tissue), two different approaches will be taken to achieve this aim: a "two-port AP system" and a "single-port AP system". The first clinical trials with the two-port AP system under controlled clinical conditions have been performed and good progress was made with the development of the single-port AP systems. We believe that our consortium of 12 European partners, which builds on existing achievements and on a close cooperation between academic centers and industry, can contribute substantially to the development of an AP system, which can be used by patients in daily life. © 2012 IFAC.


PubMed | MODEL Clinical Research, Diabetes Lipid Management & Research Center, Profil Institute For Stoffwechselforschung and Sanofi S.A.
Type: Journal Article | Journal: BMJ open diabetes research & care | Year: 2016

Uncomplicated, acute upper respiratory tract infections (URTIs) occur in patients with diabetes at a similar frequency to the general population. This study (NCT00642681) investigated the effect of URTIs on the pharmacokinetic (PK) and pharmacodynamic (PD) properties of Technosphere inhaled insulin (TI) in patients with type 1 or type 2 diabetes.This was a phase 2 study conducted in patients who developed a URTI while being treated with TI in a phase 3 study (N=20, mean age 50years, 60% men). Patients underwent two 4-hour meal challenges, during which blood samples were drawn to measure serum fumaryl diketopiperazine (FDKP; the excipient representing an essential part of TI), serum insulin, serum C-peptide, and plasma glucose. The primary outcome was the ratio of serum FDKP area under the concentration-time curve from 0 to 240min (AUC0-240min) during URTI and after clinical resolution of URTI symptoms (15 to 45days).No significant differences in PK parameters were seen during URTI versus post-URTI for FDKP. The ratio of serum FDKP AUC0-240min during URTI and post-URTI was 1.1 (SD 0.6), p=0.4462. Plasma glucose concentrations during each 4-hour meal challenge were similar, showing small non-significant differences. No adverse events, including hypoglycemia, occurred during meal challenge visits.Development of an active, symptomatic URTI during treatment with TI had no significant impact on the PK/PD properties of TI, suggesting that no adjustment in prandial insulin dosing is needed. However, if patients are unable to conduct proper inhalation, they should administer their prandial insulin subcutaneously.NCT00642681; Results.


PubMed | Profil Mainz GmbH & Co. KG, Profil Institute For Stoffwechselforschung and Johannes Gutenberg University Mainz
Type: | Journal: Der Internist | Year: 2017

Cardiovascular disease significantly determines morbidity and mortality in patients with diabetes mellitus type2. Large clinical trials in the past left controversial evidence about the effect of blood glucose-lowering treatments on cardiovascular outcomes. In 2008, the regulatory authorities defined new requirements on cardiovascular safety data for the approval of new drugs for the treatment of type2 diabetes mellitus. Since then, numerous large safety studies have been initiated to prove cardiovascular noninferiority of new antidiabetic drugs. Preliminary data from these safety studies have become available and provided promising results. While treatment with DPP-4 inhibitors and the short acting GLP-1 receptor agonist lixisenatide were shown to be safe, treatment with the SGLT-2 inhibitor empagliflozin and the long-acting GLP-1 receptor agonist liraglutide even significantly improved cardiovascular outcomes in patients with type2 diabetes mellitus. With the evidence of cardiovascular benefits of the new drugs, new treatment strategies for patients with diabetes mellitus type2 are expected.

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